The Quest to Beat Aging

Home , Centenarian, Gary Taubes, Jeanne Calment, Leonard Hayflick, Roy Walford

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SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT

AGIQUARTERLY $5.95 NGwww.sciam.com THE QUEST TO BEAT AGING

BIONIC ORGANS WILL YOU LIVE TO 120? urel Volume 11, Number 2 Quarterly MOLECULAR FOUNTAINS OF YOUTH Display until September 6, 2000 52>

0974851 08716 LIFE EXTENSION DIET • LONGEVITY GENES Copyright 2000 Scientific American, Inc. OTHER EDITIONS OF SCIENTIFIC AMERICAN ® PRESENTS Sandra Ourusoff Spektrum der Wissenschaft PUBLISHER Verlagsgesellschaft mbH [email protected] Vangerowstrasse 20 69115 Heidelberg, GERMANY The Quest to Beat Aging is published NEW YORK ADVERTISING OFFICES by the staff of SCIENTIFIC AMERICAN, 415 MADISON AVENUE tel: +49-6221-50460 NEW YORK, NY 10017 [email protected] with project management by: 212-451-8523 fax 212-754-1138 John Rennie, EDITOR IN CHIEF Gary Stix, ISSUE EDITOR Denise Anderman Pour la Science Michelle Press, MANAGING EDITOR ASSOCIATE PUBLISHER Éditions Belin [email protected] 8, rue Férou Steve Mirsky, STAFF WRITER 75006 Paris, FRANCE MARKETING Contributors Laura Salant tel: +33-1-55-42-84-00 John B. De Santis, DESIGN DIRECTOR MARKETING DIRECTOR LE SCIENZE Mark Fischetti, ISSUE EDITOR [email protected] Le Scienze Lisa Burnett, PRODUCTION EDITOR Diane Schube Piazza della Repubblica, 8 Peter G. Cotton, Eugene Raikhel, RESEARCHERS PROMOTION MANAGER 20121 Milano, ITALY Art [email protected] tel: +39-2-29001753 [email protected] Johnny Johnson, ART DIRECTOR Susan Spirakis Bridget Gerety, PHOTOGRAPHY EDITOR RESEARCH MANAGER [email protected] Copy Maria-Christina Keller, COPY CHIEF Investigacion y Ciencia Nancy Mongelli Molly K. Frances; Daniel C. Schlenoff; PROMOTION DESIGN MANAGER Prensa Científica, S.A. a [email protected] Muntaner, 339 pral. 1. Katherine A. Wong; Myles McDonnell; 08021 Barcelona, SPAIN Rina Bander; Sherri Liberman DALLAS tel: +34-93-4143344 Administration THE GRIFFITH GROUP [email protected] 972-931-9001 Rob Gaines, EDITORIAL ADMINISTRATOR fax 972-931-9074 Eli Balough [email protected] Production EUROPE Majallat Al-Oloom William Sherman, ASSOCIATE PUBLISHER, PRODUCTION Roy Edwards Kuwait Foundation for INTERNATIONAL ADVERTISING DIRECTOR the Advancement of Sciences Janet Cermak, MANUFACTURING MANAGER Julie Swaysland P.O. Box 20856 Carl Cherebin, ADVERTISING PRODUCTION MANAGER Chester House Safat 13069, KUWAIT Silvia Di Placido, PREPRESS AND QUALITY MANAGER 25 Ecclestone Place tel: +965-2428186 Georgina Franco, PRINT PRODUCTION MANAGER London SW1W 9NF Christina Hippeli, PRODUCTION MANAGER England Norma Jones, ASSISTANT PROJECT MANAGER +44 207 881-8434/35 Madelyn Keyes, CUSTOM PUBLISHING MANAGER fax +44 207 881-8503 Swiat Nauki [email protected] Proszynski i Ska S.A. Circulation [email protected] ul. Garazowa 7 Lorraine Leib Terlecki, ASSOCIATE PUBLISHER/ 02-651 Warszawa, POLAND VICE PRESIDENT, CIRCULATION FRANCE tel: +48-022-607-76-40 Katherine Robold, CIRCULATION MANAGER Christine Paillet [email protected] AMECOM Joanne Guralnick, CIRCULATION 115, rue St. Dominique PROMOTION MANAGER 75007 Paris, France Rosa Davis, FULFILLMENT AND DISTRIBUTION MANAGER +33 1 45 56 92 42 Nikkei Science, Inc. fax +33 1 45 56 93 20 1-9-5 Otemachi, Chiyoda-ku Subscription Inquiries U.S. and Canada 800-333-1199; GERMANY Tokyo 100-8066, JAPAN Maren Scupin Günther tel: +813-5255-2821 Other 515-247-7631 Am Wingertsberg 9 Business Administration D-61348 Bad Homburg Marie M. Beaumonte, GENERAL MANAGER Germany Constance Holmes, MANAGER, ADVERTISING +49 6172-66-5930 fax +49 6172-66-5931 Svit Nauky ACCOUNTING AND COORDINATION Lviv State Medical University Electronic Publishing MIDDLE EAST AND INDIA 69 Pekarska Street PETER SMITH MEDIA & MARKETING 290010, Lviv, UKRAINE Martin O. K. Paul, DIRECTOR +44 140 484-1321 tel: +380-322-755856 Ancillary Products fax +44 140 484-1320 [email protected] Diane McGarvey, DIRECTOR JAPAN ΕΛΛΗΝΙΚΗ ΕΚ∆ΟΣΗ PACIFIC BUSINESS, INC. Chairman Emeritus Scientific American Hellas SA John J. Hanley Yoshinori Ikeda 35–37 Sp. Mercouri St. MT Bldg., 1-7-8 Gr 116 34 Athens GREECE Chairman Nihonbashi Kayabacho, Chou-ku tel: +301-72-94-354 Rolf Grisebach Tokyo 103-0025 [email protected] +81 3-3661-6138 President and Chief Executive Officer fax +81 3-3661-6139 Joachim P. Rosler [email protected] KOREA Ke Xue BISCOM, INC. Institute of Scientific and Vice President +82 2 739-7840 Frances Newburg fax +82 2 732-3662 Technical Information of China P.O. Box 2104 HONG KONG Chongqing, Sichuan Scientific American, Inc. HUTTON MEDIA LIMITED PEOPLE’S REPUBLIC OF CHINA 415 Madison Avenue +85 2 2528 9135 tel: +86-236-3863170 New York, NY 10017-1111 fax +85 2 2528 9281 212-754-0550

Summer 2000 Volume 11 Number 2 THE QUEST TO BEAT AGI NG introduction 8 When Life Knows No Bounds 6 Mark Fischetti and Gary Stix, issue editors Postponing death changes the meaning of life.

getting ever older

How Long Have You Got? Kathryn Brown 8 To 120 years old and beyond. Plus: World’s Oldest Creatures 68 Design for Living Polly Shulman 18 Centenarians can teach us how to age gracefully. From Baby Boom to Geezer Glut 22 J. R. Brandstrader By 2030 one in five Americans will be a senior.

Social Insecurity The Editors 26 Don’t count on retiring at age 65.

the battle against aging Living Longer: What Really Works? 30 Robin Marantz Henig Science has yet to do much better than snake oil. Plus: Fountains of Youth

A Radical Proposal Kathryn Brown 38 At the molecular level, we all rust like the Tin Man of Oz. 44 The Famine of Youth Gary Taubes 44 Would a starvation diet give you a few more years? Plus: Four Square Snacks a Day

Counting the Lives of a Cell Evelyn Strauss 50 The attempt to turn back the clock for cells in decline.

Copyright4 2000 Scientific American, Inc. 80

Mother Nature’s Menders Mike May 56 Stem cells might build new hearts, livers—even brains. Spare Parts for Vital Organs David Pescovitz 62 Melding advanced materials with cell cultures may do away with transplants. Plus: The Cryonics Gamble

Of Hyperaging and Methuselah Genes Evelyn Strauss 92 68 The search is on for genes that lengthen life span—or cut it short.

thwarting major killers Preventing Good Brains 72 from Going Bad Mia Schmiedeskamp New hope in the fight against Alzheimer’s and Parkinson’s. Plus: Coping with Alzheimer’s

Stopping Cancer Before It Starts Ken Howard 80 Finding it early may prevent this scourge of the elderly. 56 Plus: Reduce Your Risk of Cancer and Early Cancer Detection Saving Hearts That Grow Old Delia K. Cabe 87 Studying everything from baldness to bacteria is helping to unlock the mysteries of atherosclerosis. Plus: Ticked Off: Anger Can Knock You Dead

meditations on quality of life 62 Promised Land or Purgatory? Catherine Johnson 92 Whether old age is worth living depends on mental health. Plus: The Dangers of Overmedication and A Right to Die?

Cults of the Undying Compiled by Eugene Raikhel 98 Visions of endless life from Gulliver to cyberpunk. It Smells of Immortality Steve Mirsky 104 Socially speaking, long life might stink.

ong Scientiﬁc American Presents (ISSN 1048-0943), Volume 11, Number 2, Summer 2000, published quarterly by Sci-

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nce you see the pictures, you never forget. They cline, extending longevity well beyond the century mark. At elicit horror, pain and, yes, a gawking fascination. a minimum, the findings could lead to therapies that counter An eight-year-old boy, bald with withering limbs. the major killers in old age, such as heart disease and cancer. A nine-year-old girl stooped like a 99-year-old Gerontologists have a long way to go. First they have to woman. They suffer from progeria—premature settle on a good definition of aging. Is senescence a genetic aging—and usually meet their death by the time program that kicks in once we pass our childbearing years they reach their early teens. and evolution no longer needs us? Or is it a gradual degrad- OWhat’s remarkable, however, is that many of these kids are ing of the body from daily wear and tear? We may be closing happy to be alive. Some have an uncanny emotional maturi- in on an answer. But even if we find the mechanisms that ty; they are cognizant of their genetic death sentence and em- cause aging, that doesn’t mean we will have figured out how brace the short time they have left. Their example suggests to stop it. We know something about how cancer and AIDS that knowledge of one’s own mortality, even at an age when work, but we haven’t knocked them out. With that in mind, the concept is normally unfathomable, can en- a “cure” for death from old age may be nothing dow life with essential meaning. more than mere fantasy. The possibility of slowing the processes that Still, researchers have rounded up at least one cause us to age, and thereby extending the hu- or two likely suspects in the war on decrepitude. man life span, has been raised by recent scien- Oxidizing agents in our bodies, created as we tific findings that have simultaneously provoked metabolize food, cause our cells to degrade in blistering polemics among ethicists, clergy and the same way that rust eats away at a car. New gerontologists. What becomes of childhood, drugs, some of which may be cousins of the vi- youth, the middle years and old age if people tamins we now gobble down like jelly beans, routinely live to 150? “Don’t worry, Dad, I’ll go may combat the effects of these potent chemi- to college when I’m 30 maybe, 40 for sure. Until cals. A harshly restrictive diet might also slow then, I want to drink beer with my friends. Who our inevitable decline. wants to be a wage slave for 80 years?” If any of these ideas have merit, the ethicists may find long- The philosophers maintain that if there is no end to our ex- term job security. What would happen to society if we could istence, there is no motivation to fill it, to accomplish, to do all live to 100, much less 120 and up? Could it accommodate good “before we go.” They might have an argument if life a massive population of old people? What would a “family” were to become infinite, but it won’t. Research targeted to in- mean? Could we ever afford to retire? It’s possible that we creasing average life span isn’t focused on immortality but on could manage the enormity of the upheavals if longevity crept stretching it from 76 (in the U.S.) to 100 or even 120. If it up over time. After all, the average life span in the U.S. alone

succeeds, we’ll still be inspired to live full lives. has risen from 47 to 76 since 1900. That’s a 62 percent in- Disabilities in Developmental Institute for Basic Research A spate of laboratory experiments has provided clues, at crease, and we’ve dealt with it. the cellular level, to the processes of aging. The implications But what if we suddenly found, say, a wonder antioxidant

have fueled hopes that medical advances will slow our de- or some other metabolic miracle that would immediately al- TED BROWN W.

low the world to live much longer? Mil- lions in the developed world might be able to pay for the therapy. Could the billions of poor also do so? Society could rocket toward social and ﬁnancial convulsions. That’s why some pragmatic philosophers take aim at the funding of longevity research, which they say steals money that would be better spent on improving the quality of life in old age, instead of the quantity of years. But research to extend life is exactly where cures may be found for some of the most debilitating ills the elderly face: Alzheimer’s, Parkinson’s, heart disease, liver and kidney disease, and cancer, not to mention depression and social isolation. The ethical arguments are important, but they may be overridden, at least in the short run, by our instincts for survival. Just ask yourself, Do you want to die next year? Probably not. Do you want to die when you’re 80? “Well,” you might reason, “perhaps, if I had lived a full life and was no longer in good health.” But ask a 79-year- old—even a very sick one—if he wants to die “next year,” and studies have shown that his answer will almost surely be the same as yours: “No thank you.” Whether extra decades of life are a thrill or a bore, cheating death is a fundamental human quest. Just as certain, though, is that if the science fulﬁlls its promise, the emerging centenarian society will transform work, family and social institutions in ways we ASHI

cannot even begin to imagine. ED K

orget growing old gracefully. For centuries, Given the rate at which America is aging, that’s a graying adults have tried all kinds of things timely question. A century ago only 4 percent of the to live longer: prayers, yogurt, mystical hot American population was above age 65. Now 13 springs—even injections of goat-testicle ex- percent is [see “From Baby Boom to Geezer Glut,” tracts. Despite it all, the maximum human on page 22]. One crowd stands out. According to life span hasn’t budged. At best, the statis- the U.S. Census Bureau, the number of centenarians tics say, you can hope to reach about 120 doubled over the past decade and may increase Fyears of age—and precious few actually do. more than 11-fold by the year 2050. So far our se- But don’t throw out those birthday candles just niority is mostly attributable to improved public yet. Some scientists now say they’re about to trump health and modern medicine. But antiaging thera- Father Time. Working in the lab, biologists have al- pies may soon add even more candles to the cake, ready reared worms, fruit flies, mice and yeast that says zoologist Steven N. Austad of the University of live twice as long as normal, thanks to mutations in Idaho. “The first 150-year-old person is probably a mere handful of genes. Other researchers are peer- alive right now,” Austad predicts. Will it be you? ing into the increasing molecular disorder that char- acterizes aging in humans, Why We Age RACONTEUR: from damaged DNA to mis- Comedian George behaving cells. And physiol- ncient civilizations blamed the gods for old age. Burns lived to 100. ogists are finding out why Today many scientists blame evolution, which When asked if his some people do get to cele- A holds that the swift hand of natural selection doctor knew he still brate their 100th birthdays. weeds out genes that hinder reproduction. So genet- smoked, Burns said, The oldest-known human, ic traits that cause disease early in life, before our “No ...he’s dead.” Jeanne Calment of France, childbearing years, are fairly rare. While we’re young, recently died at 122, leaving we’re usually healthy and strong. “Our bodies are researchers to marvel at the possibilities of long life. like rented cars,” says demographer S. Jay Olshan- “Who’s to say we couldn’t go 10 or 20 years long- sky of the University of Chicago. “We use them up, er?” asks Caleb E. Finch, director of neurogerontol- and before things start to go dramatically wrong, ogy at the University of Southern California. we pass on our genes to the next generation.”

After our baby-bearing time has best chance to succeed. After 10 gener- passed, however, our job is done. Evo- ations, Rose’s flies lived twice as long as centenarians who lution needs us no more. There are two their original ancestors. “It’s possible for made prevailing theories about what happens evolution to reshape patterns of mortal- next. According to the first, developed ity,” Rose concluded. in the 1950s by British immunologist But demographer Olshansky says we Peter Medawar of the University of Lon- shouldn’t expect to see a similar phe- don, harmful mutations of the human nomenon at work in humans. It would genome kick into gear during midlife. take huge numbers of older mothers Because natural selection is no longer who delayed childbirth—and then doz- looking out for us, he reasoned, our ens of generations of women who did bodies fall prey to decline and disease. the same—for evolution to even corre- Putting a slightly different spin on life, late the trend with longer and healthier University of Manchester scientist Thom- lives, if indeed that resulted. as B. L. Kirkwood offered the “dispos- able soma” hypothesis in the 1970s. It Altered Genes Alter Aging suggests that the more energy you spend bearing babies, the less you have for ome molecular biologists contend other metabolic feats, such as defending that these evolutionary theories are against mutations that cause the battles S wrong altogether. They say we are of aging. If you live fast—having a lot of bombarded with damage from daily Charles Greeley Abbot (1872–1973) babies when young—you tend to die life and genetic malfunctions across our Determined that the sun’s radiation varies. younger. Natural selection will gladly entire genome, including the reproduc- make that swap, says evolutionary biol- tive portion. That means that stopping ogist Linda Partridge of University Col- aging lies in changing our genes. Over lege, London. In recent years scientists the past few years an increasing number have fleshed out this theory, proposing of researchers have altered animal life that some genes act beneficially early in spans by tweaking certain genes. “Evo- life yet negatively later on. lutionary biologists would have never At first glance, both evolutionary im- thought you could change a single gene ages of aging seem impossible to counter. and double an organism’s life span, es- If our golden years really are determined pecially without decreasing fertility,” by mutations or subtle life trade-offs, says Cynthia J. Kenyon of the Universi- ) how can scientists hope to understand ty of California at San Francisco. “But ai-shek

aging—much less ﬁght it? The process of that’s precisely what we’ve done.” hiang K aging could be dominated by perhaps In Kenyon’s laboratory the longevity adame C

36 genes, although there may be anoth- gene at hand is called daf-2. Worms M ( er 200 that ﬁne-tune it, concedes with a mutated daf-2 live for a month, os hot Edward E. Kleinschmidt (1876–1977) Michael R. Rose, an evolutionary biol- twice the norm. Moreover, by tinkering e P

chiv Teletype inventor. ogist at the University of California at with related genes—daf-12, daf-16 and r Irvine. “But that doesn’t mean it’s im- daf-23—researchers have reared worms ers/A eut possibly complicated,” he says. that live up to four times longer than R In fact, Rose has already managed to the normal span. Kenyon thinks the daf assemble generations of long-lived fruit genes direct hormones that ratchet up

ﬂies. In a classic experiment published or down a worm’s rate of aging in re- ); CHENG HUI HSU in 1991, he collected and hatched eggs sponse to environmental challenges such

laid by middle-aged fruit ﬂies. He then as food supply or temperature. And leinschmidt . K

collected the eggs of these offspring, but worms aren’t the only ones lingering on d E ar w d

only those laid late in life. On he went, the lab bench. Yeast, fruit ﬂies and mice E

repeating the process, saving only the have all eked out far longer lives than and ot eggs laid by older and older ﬂies. By do- normal with the aid of a little genetic bb ing so, Rose was acting as an evolution- manipulation [see “Of Hyperaging and y A eele r

ary force: selecting for ﬂies that repro- Methuselah Genes,” on page 68]. les G har C

duced late and lived long. If a species Researchers still debate whether ag- ( consistently delays reproduction until ing is the cumulative result of life’s tiny later in life, over many generations, then assaults or a more programmed series ORBIS Madame Chiang Kai-shek (1897–present)

evolution will select for traits that allow of events determined at birth. They MANN/C Anti-Communist crusader. T

for longer life, so reproduction has the don’t know how all these genes work. BET

10 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. And even if they someday understand humans is utter nonsense. There are an the genetic mechanisms, that doesn’t incredible number of genes related to a difference mean they’ll ﬁnd a “cure” for aging. We aging in humans that don’t even exist in know how cancer works, for example, those organisms.” but we haven’t stopped it from com- Researchers do agree that oxidative mencing in people. damage is only one possible cause of At present, we must be content with aging. According to a recent tally, some the few pieces of the puzzle that are 300 theories of aging have been pro- starting to come together. For instance, posed—and at the very least, several at least four of the newfound genes af- key processes are involved. In addition fecting the longevity of lab creatures en- to free radicals, for instance, aimless code antioxidant enzymes. These chem- glucose (sugar) molecules attach to pro- icals disarm harmful oxygen molecules, teins, causing those proteins to link up called free radicals, that emerge when- unnaturally and change function, possi- ever cells turn food and oxygen into en- bly leading to hardened arteries, tough- ergy. Like dancers looking for partners, er skin tissue, cataracts and other evils free radicals careen within and between of the silver years. cells, binding to nearby molecules and Furthermore, some cells start misbe- disrupting normal activity. Over time, having all on their own. After many scientists suggest, this free-radical dam- years, somatic (body) cells stop dividing, Irving Berlin (1888–1989) age adds up, causing tissues and organs but some don’t simply die. Many ap- Composer of American song standards. to deteriorate with age. This oxidizing parently switch functions—often for the of our bodies is often compared to the worse. Biologist Judith Campisi of Law- Healthy habits now can add years later.

oxidizing—rusting—of metal [see “A rence Berkeley National Laboratory has Radical Proposal,” on page 38]. found that cells that give youthful skin Lab organisms endowed with certain its smooth elasticity stop dividing and extra longevity genes seem to fend off then go awry late in life, breaking down damage from free radicals and similar the very same elasticity. “As we start to )

y stresses, such as UV radiation, says sci- understand how this works, we have the Grandma Moses (1860–1961) entist Thomas E. Johnson of the Uni- hope of stopping these altered func- Folk artist, began painting at 78. enned versity of Colorado at Boulder. That tions,” Campisi says. This work goes ose K R ( molecular trick results in longer life. If hand in hand with studies of cancerous

agnum researchers can reduce free radicals or cells that won’t stop dividing, as well as M A boost antioxidant defenses in these ani- studies of multipurpose stem cells that AP mals, he adds, they may be able to de- could replace mature cells lost to heart

ORNELL C sign drugs to do the same for humans. disease, Parkinson’s disease and other ills. ); C “I’m conﬁdent we’ll ﬁnd drugs that [Studies on cell senescence are detailed in stimulate resistance to environmental “Counting the Lives of a Cell,” on page stresses and so increase longevity,” says 50; “Mother Nature’s Menders,” on andma Moses r G ( Johnson, who works with GenoPlex, a page 56, describes stem cell research.] orbis

C Denver company he helped to found. Not everyone is so conﬁdent. Genes Your Number Is Up THSTEIN

O that contribute to the lengthier lives of certain lab animals may not explain ag- he biochemical bits of aging may be THUR R ing in people at all, argues anatomist the same for everyone, but they cer- ); AR lin er Leonard Hayﬂick of the University of T tainly add up differently. Your neigh-

Rose Kennedy (1890–1995) ving B California at San Francisco. “Humans bor may have run a marathon at 70, Ir America’s best-known matriarch. ( are not big ﬂies,” Hayﬂick says. “To ex- while your landlord was busy having ORBIS

C trapolate from ﬂies, mice and yeast to heart surgery. Your great-aunt was a

how we age BRAIN: Memory and reaction time may begin to decline around age 70.

EARS: Ability to hear high- EYES: Difficulty focusing on close objects frequency tones may decrease begins in 40s; ability to see fine detail in 20s, low frequencies in 60s; decreases in 70s; from age 50, between ages 30 and 80, men susceptibility to glare increases, and lose hearing more than twice ability to see in dim light and to as quickly as women. detect moving targets decreases.

HEART: Heart rate during maximal exercise falls by 25 percent between BLOOD VESSELS: Arterial ages 20 and 75. walls thicken; systolic blood pressure rises 20 to 25 percent between ages LUNGS: Maximum 20 and 75. breathing capacity diminishes by 40 percent between ages 20 and 80.

PANCREAS: Glucose metabolism declines progressively.

BONES: Bone mineral loss begins to outstrip replacement around age 35; loss speeds up in women at menopause.

MUSCLES: Muscle mass AGE GAUGE: Each person’s body declines; oxygen consumption ages in unique ways, but a during exercise decreases hypothetical average person can 5 to 10 percent per decade; expect these changes over time. hand grip strength falls by 45 percent by age 75. W O

SOURCE: Baltimore Longitudinal Study of Aging TERESE WINSL

12 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. chess champion, but your grandfather couldn’t remember his address. Aging is centenarian boom incredibly variable. “Researchers used to believe that the older you get, the sicker 1,000 RAPID RISE: you get,” says Harvard Medical School By midcentury 800 physician Thomas T. Perls. “That’s the Census Bureau completely wrong.” 600 predicts the U.S. To ﬁnd out what “normal” aging is, could be home to researchers with the National Institute 400 nearly 835,000 on Aging’s Baltimore Longitudinal Study (thousands) centenarians, more of Aging (BLSA) examine the bodies and 200 than 11 times the Projected Centenarians Projected number today. brains of volunteers every two years. 0 CE The longest-running scientiﬁc study of 2000 2010 2020 2030 2040 2050 A human aging in the U.S., the BLSA be- Year URIE GR A gan in 1958 and now has more than L 1,100 active participants. The study is a snapshot of healthy aging, and yes, it Limit red meat? The answers to such That’s pretty good—already almost does portray a gradual physical decline. questions may affect your likely expira- twice as long as our recent relatives. Since As a senior, you probably won’t see, tion date. And if you’d like to calculate 1900 the average life span in the U.S. hear or breathe quite as easily as you that fateful moment yourself, try the Life has jumped from about 47 to about 76 once did. But the study also suggests Expectancy Calculator (www.beeson. years, according to the National Institute that life’s slings and arrows aren’t all org/Livingto100/). The tool, presented on Aging. It’s not that we’re aging more outside your control. Without exercise, in Perls’s 1999 book, co-authored with slowly. We’re living longer simply be- for example, a 30-year-old woman will Margery H. Silver, Living to 100: Les- cause we escape many of the illnesses lose a quarter of her muscle mass by the sons in Living to Your Maximum Po- and events that plagued our ancestors, age of 70. But a few jaunts around the tential at Any Age, will put a number on from death during childbirth to tubercu- park or trips to the gym every week can your mortality by analyzing your an- losis, largely because of better sanitation, fend off this by-product of aging. swers to 23 behavior and background cleaner water supplies and basic medical Indeed, Perls says, starting healthy questions. Perls says those of us with advances such as immunizations. There habits now can add years later on. Do average genes and healthy habits can is new light at the end of the tunnel, you smoke? Keep a positive attitude? expect to live until about 85. too: once you creep far enough along, it

taking it to the limit n the good old days, aging wasn’t viewed as complex. kind of vital substance. As time passes, our tanks drain ISome scientists reasoned that, like a car with a full tank and our bodies age. Here are a few of the notorious theo- of gas, our bodies arrive on earth topped off with some ries about life’s limits that have emerged in modern times.

Vital humors 19th century Energy 1920s–1930s Heartbeats 1950s

As you use energy, your cells steadily break down. The faster you live, the faster you burn energy and the sooner your demise, Vital humors control all your maintains Mammals get about one billion bodily functions. When these this rate-of- heartbeats. As you near that limit, humors run dry, your time is up. living theory. your heart breaks down. DUSAN PETRICIC

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 13 Copyright 2000 Scientific American, Inc. world’s Bristlecone pine oldest creatures iding inside rocky crevices 1,800 feet below the Pacific Ocean, rockfish stubbornly persist well past 100 years, Hfar surpassing their peers. Giant 10-foot-long tube worms sway in the dark depths of the Gulf of Mexico for up to 250 years. Blanding’s turtles can slosh through Midwest- ern U.S. wetlands for at least 70 years, and certain giant tortoises push 300. Defying even greater odds, some bristlecone pines high in the California and Nevada moun- tains have lived almost 5,000 years! How do these remarkable creatures do it? Scientists are trying to find out, hoping to learn more about how nature’s organisms age and thus how we might lengthen human life. “The natural world offers hundreds of lessons in longevity,” says University of Southern California gerontologist Caleb E. Finch. One lesson: find an environment free of predators. Re- Galápagos giant tortoise searchers have identified yelloweye and rougheye rockfish as old as 118 and 149 years, respectively, at great ocean depths. They endure partly because many of their predators prefer shallower waters, says Allen H. Andrews, a research associate at California State University. Blanding’s

) turtles may outlive soft-shelled varieties because their

ckfish rough, hard exterior deﬂects the bite of hungry critters, ex- o e r y

e plains ecologist Justin D. Congdon of the Savannah River w

ello Ecology Laboratory in Aiken, S.C. y ( The record-breaking bristlecone pines have also found a nimals safe haven; they prevail at around 11,500 feet above sea level, too high for the comfort of many insects or competing nimals A A trees. One pine at Nevada’s Wheeler Peak was estimated to be 4,900 years old, based on its annual growth rings, before it was cut down in 1964. Amazingly, Finch says, the trees seem DOUG WECHSLER

; to reproduce just as well in their 4,000th year as in earlier days. ) oise

t For a long time, scientists didn’t bother to study the or longevity of animals and plants. They assumed that most creatures would die before their time because of predators, Yelloweye rockfish competition, natural disasters, insects or disease. But that alápagos giant t G ( idea is changing. To measure more precisely the effect of environment on aging and longevity, University of Idaho nimals biologist Steven N. Austad turned to an animal that nor- nimals A

A mally lives fast, breeds madly and dies young: the opos- CZ

A sum. Austad reasoned that opossums living without the

ALD L evolutionary pressure of many predators—such as owls, GER ;

) coyotes and wolves—would age and breed more slowly, ultimately living longer. About a decade ago he found that one pine very situation on Sapelo Island, a scrap of land off the Geor- istlec br

( gia coast. There opossums live up to 50 percent longer .

, Inc than on the mainland—and actually age more slowly

rnold along the way, according to Austad’s measurements of er A

et their tissues over time. Austad is now looking for similar P longevity in island mice, considerably easier creatures to WELL O study in the lab. GALEN R

seems, your chances of dying actually begin to ease. Demog- raphers have found that death rates steadily climb until about 85—and then begin to slowly edge back down again. The same phenomenon holds true for some fruit flies, wasps, worms and yeast in studies led by researcher James W. Vaupel of Duke University and the Max Planck Institute for Demographic Re- Austad’s research underscores the flexibility—or “plas- search in Rostock, Germany. It’s as though we all decline to a ticity”—of aging, suggesting that the right environment certain point, rest, get our second wind and rally back. can increase life span. The question now at hand is: Once And some people really rally. As the number of centenari- predators and competition are removed, do biological ans in the U.S. climbs, scientists hope to learn the secrets of processes take over and cause aging in animals, even their success. Already Perls has a few hints, gathered as head those that live a squeaky-clean lifestyle? of the New England Centenarian Study, which tracks more For clues, Austad and University of Idaho ecologist than 450,000 older adults in Massachusetts to see who Donna J. Holmes are looking skyward. Five years ago reaches 100 and why. they proposed birds as the ideal animal to use in aging So far 169 centenarians have participated in the study; there studies. After all, birds are closer to humans, biologically is data on 250 others. They are a motley crew: Some exercise. speaking, than are worms or fruit flies, the favorite sub- Some smoke. Some brazenly defy the notion of a healthy jects of aging-study labs. They are warm-blooded, like us, lifestyle. Nevertheless, almost all have lived free of cancer, so they don’t lapse into periods of dormancy or hiberna- and up to a fourth have escaped any form of dementia. tion, as do fish and turtles. Moreover, some birds live for How do they do it? With luck—and a few “genetic booster decades against all odds. rockets,” Perls says. Studying half a dozen families that in- This is even more remarkable because, to rev up for clude 10 or more centenarians, he is closing in on chromo- flight, birds generate extremely high levels of blood sug- some regions with genes linked to long life. Isolating the genes ar. The 150 parakeets twittering around a basement lab won’t be easy, but drugs to mimic their effects could one day at the University of Idaho have blood sugar levels so high prevent some deadly diseases of old age. “In the future, we they should be diabetic. They have elevated tempera- may be able to look at your genetic profile, determine your tures and burn energy at feverish rates. Yet they live to risk for various diseases, and give you vitaminlike pills to de- 20, old for parakeets. These bird traits defy a primary the- lay or prevent those diseases,” Perls forecasts. Blessed with ory of aging—that increased metabolism creates higher centenarian-style health, you too may live to well over 100. levels of oxygen molecules, called free radicals, that oxi- [“Design for Living,” on page 18, relates more about what dize cells, damaging tissue in ways normally associated scientists have learned from studying centenarians.] with aging. Rather than rapidly growing weak and dying, Whether you will live many years beyond 100, though, re- birds carry on in good health, year after year. mains to be seen. No one knows when or how scientists might In 1998 Holmes, Austad and their colleagues reported extend our life spans. It’s been more than 60 years since re- that the cells of three bird species—canaries, European searchers first discovered that lab animals that consume fewer starlings and budgerigars (a.k.a. parakeets)—can endure a calories than normal—a regimen known as caloric restriction— battery of oxidative stresses with surprisingly little dam- tend to live unusually long. But scientists still don’t know how age. The scientists exposed these bird cells, along with the caloric restriction works or if it can slow aging in humans [see cells of mice, to baths of hydrogen peroxide, bolts of radi- “The Famine of Youth,” on page 44]. There are other dilem- ation, chambers of oxygen and doses of pesticide. Under mas as well. Could the U.S. afford legions of elderly people? these assaults, the DNA inside the mouse cells often un- Would you be alive but ridden with ailments at age 130? At raveled, broke or stopped replicating, typical signs of free- 150? “This research raises all kinds of ferocious social and radical damage. The bird cells, on the other hand, divided economic questions,” University College’s Partridge observes. normally and repaired much of the induced DNA damage We just might find ourselves answering these questions. right away. “We don’t have any idea yet how the bird cells “People tend to underestimate how fast the aging field is are doing it,” Holmes says. “But it appears that birds have moving,” claims biologist Leonard P. Guarente of the Mas- special enzymes that dispose of free radicals. If free radi- sachusetts Institute of Technology. “We’re uncovering the cals are a primary mechanism of aging, then this may ex- molecular basis of aging. No, we’re not at a point where we plain why these birds live so long.” can intervene in humans yet. But we have every reason to be If the scientists find the genes responsible for birds’ re- hopeful that day will come.” sistance to free-radical damage, they might someday apply them to humans. “Ultimately,” Holmes continues, “it’s possible that gene therapy could transfer a gene from the Kathryn Brown is a writer at Science News. bird genome to the mammalian genome.” As U.S.C.’s Finch puts it, “We’re in a major discovery phase now.” If re- Further Information searchers can understand the endings of other species, Life Expectancy Calculator can be found at www.beeson. we just might learn how to rewrite our own. —K.B. org/Livingto100/ on the World Wide Web. Why We Age. Steven N. Austad. John Wiley & Sons, 1997.

lBY POLLiY SHULMANving

eanne Calment had the longest memory in human more important, says Richard M. Suzman, associate director memory. As recently as 10 years ago, she recalled a for behavioral and social research at the National Institute trip she took to Paris where she saw an impressive on Aging, the rate of disability in all populations, including new structure going up—the Eiffel Tower. Vincent the oldest old, has been dropping since 1982. Demographers, van Gogh used to buy paint at her family’s shop in geneticists and medical researchers hope that studying Arles, and the artist made a bad impression on young healthy people in their 80s, 90s, 100s and beyond—“the super- Jeanne: he was ugly, bad-tempered and reeked of al- stars of longevity,” as Perls refers to them—will yield vital clues cohol,J she told reporters years later. At 85 she took up fenc- to how all of us can live longer, healthier lives. ing and at 120 gave up smoking—“It was becoming a habit,” To Leonard W. Poon, principal investigator of the Georgia she explained. She outlived all her descendants, including her Centenarian Study, the secret to longevity is that there is no grandson, a doctor, who died in 1963. Asked at 115 how she secret. Poon and his colleagues followed 144 cognitively in- saw her future, she quipped, “Short. Very short.” But she tact, independently living centenarians, whom he calls “the was wrong: she lived seven more years, dying on August 4, cream of the crop.” Some were compared with groups of 1997, at 122 years, five months and 14 days, the longest veri- people in their 60s and 80s from similar backgrounds; others fiable life span of any human being. She attributed her long were interviewed and tested every six months for what re- life variously to olive oil, wine and a sense of humor. “I have mained of their lives. He believes the most important lesson of only one wrinkle,” she said, “and I’m sitting on it.” the study is the qualities that stood out among the oldest old. Most of us, of course, can never hope for longevity (or hu- For example, few of the centenarians in the study smoked, mor) to match Calment’s—she’s one in six billion, points out were obese or drank heavily. They remained active through- Thomas T. Perls, acting chief of gerontology at Beth Israel out life, ate breakfast regularly, and consumed plenty of vita- Deaconess Medical Center in Bos- min A and carotenoids by eating fruits and vegetables. “In FOR THE RECORD BOOKS: ton. But the number of centenar- terms of psychology and attitudes, they’ve resolved whatever Jeanne Calment, whose life ians is rising every year. Accord- issues they have, they’re sure of themselves, and they want to was the longest ever docu- ing to a July 1999 census report, have their way,” Poon says. “They would not take your word mented, here contemplates there are about 72,000 people for anything—they want to find out for themselves. And the world from the vantage older than 100 in the U.S., a num- they’re very protective of themselves.” Learning about the di- point of 121 years, a year be- ber expected to reach 834,000 versity of characteristics that centenarians share, he thinks, fore her death in 1997. within the next 50 years. Even “isn’t a bad result, because anyone can find one factor rele-

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 19 Copyright 2000 Scientific American, Inc. getting ever older vant to their lives, one thing that’s pos- treme old age, such as a group of seven The fact that members of such groups sible to change. The diversity gives all siblings, five of whom passed the 100- share large amounts of genetic material of us hope to be able to live longer.” year mark. (Calment’s family is another makes it easier to find relevant genes. Poon, a psychologist by training, con- good example: her father died at 93, The geneticists compare the genes of siders motivation and attitude as impor- her mother at 86.) People in the past long-lived group members with those of tant as genes. But Perls, director of the thought there were tens of thousands of members with short or normal-length New England Centenarian Study and a genes that had a weak effect on longev- lives. Because these people have so much co-author of Living to 100, believes there ity, but Perls and his colleagues believe genetic material in common, any genes are genes that can guarantee their lucky there are probably just a few genes with found in the long-lived group but not in recipients a better chance to live a long, very strong effects: “When you see the the short- or normal-lived group have a good chance of being the ones the scientists are looking for. But once they find them, what good will it do the rest of us? If we’re not blessed with lucky genes, should we throw up our hands and write our wills? Of course not, Barzilai says. The whole point is to find out what functions those genes perform, then develop medicines to mimic them. “If they have to do with oxidation, we’ll try to manipulate oxidation. If they increase levels of HDL—that’s the beneficial kind of cholesterol—maybe we can increase HDL. Here’s another example: I had a 102-year- old who had a very high grade cancer, with a prognosis of two months, but she lived with it for VEN five or six years. Maybe some-

MARK HA thing in her genes protected her from this cancer,” Barzilai notes. WHAT’S HIS SECRET? Artist Harry kind of clustering [of people] we’re see- If so, understanding how that protec- Shapiro, who is 100 years old, is an ing, mathematically it’s got to be only a tion worked could help doctors develop Ashkenazi Jew, a group being studied few genes—maybe just 10 or so. In one cancer-fighting drugs. The genes will also in a search for longevity genes. family, you may find one or two.” His shed light on healthy behavior. If cente- team is very close to finding regions of narians have genes that keep them slim, chromosomes, he says, that contain such the rest of us could try to mimic that by healthy life, and he means to find them. genes. Right now they’re checking their cutting down on the excess calories, as Siblings of centenarians in his study, he results. “It’s such a big-deal finding, we Perls does (his work with the very old points out, have a five times greater want to make sure we’re correct. Once has inspired him to shed 15 pounds). chance than average of living to their you find a region, you know everyone Although it’s too soon for genetic re- early 90s and a 15 times greater chance and his grandmother is going to be fall- sults in their study, Barzilai and his team of living to 100. Of course, siblings share ing all over themselves to find the genes have been quizzing their centenarians environmental factors as well as genes. on that region.” for shared characteristics. Like Poon, Could some of these be responsible? “Is Nir Barzilai, a gerontologist at the Al- they’ve found a lot of diversity. “No one it the chicken soup their mom makes?” bert Einstein College of Medicine who of the centenarians is telling me that he Perls asks. “No, because their parents collaborates with Perls’s group, is look- did anything special to reach that age,” also live unusually long.” ing for longevity genes as well. He and Barzilai says. “Many of them ate what Along with medical and population his colleagues study “founder popula- they shouldn’t have eaten, or they studies, the New England Centenarian tions”—small, genetically isolated groups smoked. But one thing they seemed to Study does genetic work with centenar- that gradually expanded to large num- have in common was some form of ians in collaboration with molecular bers, all the while marrying within the flexibility. Many of them had very hard geneticists. The scientists look for lon- community. One collaborator hunts lives. They rolled with punches, got up gevity genes in families with a high pro- through the genes of the Amish; Barzi- and continued with a good attitude.” portion of members who live to ex- lai does the same with Ashkenazi Jews. One tough problem is to separate

20 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. cause from effect. Did Barzilai’s and fact, for most of the el- Poon’s centenarians live longer because derly population, Suz- they rolled with the punches, or did 10 man argues, mortality decades of experience give them the wis- goes up, and the preva- dom to accept experiences that would lence of disability and have thrown them for a loop in their chronic diseases also youth? Centenarian researchers would increases with each ad- like to go back in time and interview ditional year of age, al- their subjects at 20, 50, 80—but of though the rate of in- course, they can’t. crease does seem to slow down sometime Butterfat for Couch Potatoes past 90. One factor that sheds oon’s centenarians got plenty of vi- both light and confu- tamin A and ate breakfast regularly. sion on the question of PWell and good; Mom, your doctor what the oldest Ameri- and your cereal box would approve. cans will be like in up- But they also drank more whole milk coming decades is the and were less likely to avoid cholesterol cohort effect. Groups than the 60- and 80-year-olds in the born in different de- THE SENTINEL study. Is butterfat good for you? Or did cades have very differ- they have genes that protected them ent patterns of mor- AND THE WINNER IS ...114-year-old Eva Morris of Eng- from its deleterious effects, as Perls be- tality and survival, Suz- land, who is currently the oldest person alive, accord- lieves? “The centenarians in our study man says, which can ing to the Guinness Book of Records. don’t have a history of exercise, but the be difﬁcult to tease out. rest of us can’t get away with this,” he For example, levels of education that Internet. “Life expectancy is the least of says. And what about Calment’s ciga- Americans attain have been rising with it,” Suzman says. “More important is rette habit? Do genes make smoking safe every generation. Increased education health expectancy.” for some of us but deadly for others? improves their life and health expectan- Calment notwithstanding, most of us Such questions are important not only cy—although why is a big mystery. Part have genes that will take us to 85 or so, on an individual level but also demo- of the explanation is that education af- barring physical catastrophe. But our graphically. Understanding and predict- fects income level, which affects health. behavior can help reduce or eliminate ing changes in the general population Education may also encourage people chronic diseases that make the last years and the health statistics of older people to adopt healthier lifestyles. More high- painful for many. And geneticists are will be increasingly important to poli- ly educated people may end up in jobs planning to search the genes of cente- cymakers and health care providers as that are less stressful, or education may narians for clues not only to killer dis- well as to aspiring centenarians. allow people to deal better with the rig- eases but also to diseases you can live The demographics of the oldest pop- ors of stress. “It may have an impact on with but may not want to—things like ulations may yield some surprises. A the brain, and the brain may turn out macular degeneration, Barzilai says, or study conducted at Odense University to be the major arbiter of survival, rath- hearing loss. “Sans teeth, sans eyes, sans in Denmark, analyzing mortality data er than the coronary artery,” Suzman taste, sans every thing,” moaned Shake- from 13 European countries and Japan, observes. And education is only one of speare, describing the last years of life. showed that after age 97 a person’s dozens of factors that vary dramatically Thanks to centenarians, the future may chance of dying at a given age slowed from one decade to another, including not need to be like that. from the expected exponential growth nutrition, smoking, sun exposure and trend. Indeed, many diseases strike pre- exercise. Polly Shulman is a freelance writer in ferentially at earlier ages. Rates of many How much, for example, does medi- New York City as well as the great-grand- cancers decline after 85, as does the cal care affect mortality? “Oddly, that’s daughter of a centenarian. chance of developing Alzheimer’s dis- never been effectively measured,” Suz- ease, particularly for the 25 percent of man says. Medical intervention will Americans who have at least one copy have an increasing impact, he believes, Further Information of a gene type predisposing them to it. sometimes through information pro- 100 over 100. Jim Heynin and Paul On the other hand, the incidence of duced by medical research, rather than Boyer. Fulcrum Publishing, 1990. other major diseases increases with age. medical treatments. Convincing Ameri- Living to 100: Lessons in Living And the very old, whose immune sys- cans to get off the couch and shed ex- to Your Maximum Potential at Any tems have weakened with age, are more cess pounds, for instance, could have a Age. Thomas T. Perls and Margery susceptible to some common infectious huge impact. So could new methods of Hutter Silver, with John F. Lauerman. diseases, such as pneumonia and ﬂu. In disseminating information, such as the Basic Books, 1999.

GOING GRAY: The elderly will morph from 13 percent of the U.S. population to 20 percent by 2030. SLIM FILMS

ant to put a face on the demographics of U.S. Census Bureau’s International Programs Center, the life aging? Meet Mary Kikukawa Fichter, who’s expectancy of a U.S. citizen born in 1996 is 76, a few years 93. Age has largely silenced this educated behind most European countries, Canada, Israel and Singa- mother of seven, but she still manages a pore. Japan is the champ at 80. “Our infant mortality rates smile when her son, Joe, presides over a are somewhat higher than those in northern Europe and rousing game of Trivial Pursuit for her and Japan,” says Bob Anderson, a senior statistician at the Na- her friends. Mary, who was born in the U.S. tional Center for Health Statistics. “And that makes a big inW 1906 of Japanese and Irish parents, lives in a nursing difference.” home in northern New Jersey. Her roommate is a friend of Vagaries lie behind some of the numbers. For instance, 40 years, but Mary can no longer remember her name. Joe children in Japan who are born alive but die within a few calls the place “a bus stop for people waiting to die.” Re- hours are counted as fetal deaths, not infant deaths, reducing membering his mother’s voice from an earlier time, he talks the country’s infant mortality figures and thus raising the av- about the inevitability of her passing: “I know she’d welcome erage life expectancy. Other differences have clear causes; it.” Whether Mary’s age is a result of healthful habits, rela- northern Europe’s health care system “doesn’t do quite as tive wealth or just plain luck, she shares ancestry with the de- well as our system at the oldest ages,” Anderson explains, mographic group with the longest life expectancy in the “but it does much better at the youngest ages,” improving country—Asian-American women. overall life expectancy. Today Mary’s age is exceptional, but her present may be- Life expectancy has climbed significantly in the past centu- come the normal future for baby boomers. The millions of ry. Census Bureau analyses show that in 1900, the average people born between 1946 and 1964 now create a bulge in life expectancy across the planet was less than 30 years. By the U.S. population between ages 36 and 54. In another de- 1950 it had climbed to 46. By the late 1990s it was 66. By cade the first men and women who hoped they died before 2050, projections indicate it could be 76. A large part of the they got old (to quote rocker Pete Townshend) will turn 65. increase has been attributable to safer childbirth for babies From that watershed forward, the number of U.S. elderly and mothers and declining fertility rates, lowering the inci- will swell from 13 percent of the population to 20 percent by dence of infant deaths, which tends to drag down the average 2030. The baby boom will become a geezer glut. life expectancy in a population. Simple public health measures The sheer numbers mean many more people will live to a such as cleaner water, sanitation, antibiotics and basic immu- very old age. But American life expectancy is far from the nizations account for much of the rest, eradicating widespread highest in the world, ranking 21st globally. According to the killers such as diphtheria and polio in the developed world

ELDER EARTH: The ranks of the oldest old (age 75 and up) vary widely among nations but will have increased significantly in many countries by 2025.

and holding them in check elsewhere. Only in recent times Mary are outliving even Japanese women. But Native Amer- has modern medicine significantly lengthened the years peo- ican men in Bennett County, South Dakota, have the life ex- ple can expect to live once they reach middle age. pectancy of a copper miner in AIDS-ravaged Botswana, which has one of the lowest life expectancies on earth. Closing the Gender Gap Don’t let averages raise your hopes or fears too much, though. Plenty of people diverge from the odds. A life ex- iving in a prosperous country is no guarantee you will pectancy of 76 applies to no real group, not even actual U.S. reach Mary’s age, however. A study called the U.S. Bur- babies born in 1996. Average life expectancy is a statistical L den of Disease and Injury, by the Harvard School of Pub- concept, not a predictor of how long a particular person will lic Health, found a staggering 40-year gap between the live. “Life expectancy figures can speak to some general cul- longest-lived Americans—Asian-American women—and the tural trends,” says James Walsh, an expert in actuarial and shortest, Native American men. Asian-American women like risk management and author of True Odds: How Risk Af- fects Your Everyday Life. “They do not speak to whether you, who drink half a fifth of gin a day and smoke a pack of cigarettes, are going to live to 80.” leading causes of death in the U.S. Nevertheless, mortality statistics tell us that in general, boomer women, unlike their great-great-grandmothers, have 1900 1997 a better chance than their guy pals of getting that 100th 1. Pneumonia and flu 1. Heart disease birthday party. At the beginning of this century, men outlived 2. Tuberculosis 2. Cancer women in many countries. As a result of better childbirth 3. Diarrhea and 3. Stroke and methods, women have caught up, adding more than 30 years intestinal ills brain lesions to their life expectancy during the 20th century. Men have 4. Heart disease 4. Lung disease added years, too, but the higher rates of smoking and occu- 5. Stroke and 5. Accidents pational hazards among men during most of the 1900s brain lesions slowed their progress as compared with women. Today VENTION 6. Pneumonia and flu women in developed countries outlive men by about six 6. Kidney inflammation 7. Diabetes years. Men still live longer in a few areas where women’s so-

OL AND PRE 7. Accidents 8. Suicide cial status is low and maternal mortality is high.

ONTR 8. Cancer 9. Kidney Interestingly, the gender gap is now closing in the U.S. 9. Senility inflammation Men’s life expectancy is rising faster than women’s because 10. Diphtheria 10. Liver disease heart disease has been declining at a faster rate for males than females. At the same time, the incidence of lung cancer NEW THREATS: Clean water and immunizations have in females is rising faster than in males. “Women didn’t real-

CE: CENTERS FOR DISEASE C reduced basic killers, leaving room for others to rise. ly start smoking until the 1950s or 1960s,” Anderson says.

SOUR “They are feeling the effects now, whereas men have already

Less than 2 percent 2–5.9 percent 6–10 percent

More than 10 percent CE A

SOURCE: U.S. Census Bureau’s International Programs Center URIE GR A L had that effect and are beginning to quit.” As women behave All these comparisons and predictions must be taken with more like men, they die more like men. a grain of salt, however. The United Nations, which gathers Improving life expectancy among U.S. males is also driving international statistics, is the first to point out that global the nation’s overall life expectancy gains. Life expectancy of a data collection can be pretty spotty, especially in regions 65-year-old male in 1995 was 15.5 years, but it promises to wracked by disease, war and illiteracy. In the U.S., there are climb to 20 years in the first half of this century, according to gaps in Census Bureau data, the fount of most national aging median Census Bureau projections. The bureau’s rosiest cal- numbers. But these glitches won’t stop demographers from culations indicate that the life expectancy of some of the later using the figures. “The Census’s numbers are statistically boomers could hit 25 years by the time they reach 65. valid and well within the range of methodology used in most demographic surveys,” Walsh says. Poverty Hurts Even if the count were perfect, projections derived from it might not be. Every prediction includes an assumption that verything from income and diet to occupation and bad may or may not come to pass. What if a new bug appears habits can move people off the average curve. Poor, unin- and makes short work of us? After all, the AIDS epidemic E sured people have only minimal health care and succumb threatens to slash life expectancy 10 to 30 years in southern to disease sooner than average. Drug overdoses, alcoholism Africa in the next decade. On the other hand, maybe scien- and suicide are all factors in the early demise of many rock tists will figure out a way to keep us going until age 150. If musicians. Nationwide, the Bureau of Labor Statistics says, they do, perhaps it would be a good move to buy shares of highway crashes are the leading cause of on-the-job fatalities. Hasbro; there will be a lot of boomers playing Trivial Pursuit And left-handed people appear to be more prone to prema- while they pass the time at Mary Kikukawa Fichter’s “bus ture deaths than righties are. stop”—providing a latter-day Joe comes to visit and orga- Although such factors may sound haphazard, they can co- nizes the game. alesce within certain demographic groups. “The classic case is among black males in the United States,” Walsh says. “They have a lot of really bad life expectancy stressors at the begin- J. R. BRANDSTRADER contributes to Barron’s magazine and ning of life,” including high child mortality, tuberculosis and the Wall Street Journal Radio Network from New York City. homicide, which are exacerbated by poor medical care, over- crowding and poverty. Young black men die at a rate dispro- Further Information portionate to other demographic groups. Ironically, Walsh True Odds: How Risk Affects Your Everyday Life. James says, “if a black man lives to 40, his life expectancy can in- Walsh. Silver Lake Publishing, 1996. crease because he has kind of made it through the early hur- The U.S. Census Bureau (www.census.gov) is the source of dles.” Anderson notes that one of the reasons people in Swe- U.S. life expectancy data and collects information from den live so long is because the country is economically homo- countries worldwide. Also useful are www.overpopulation. geneous and has socialized medicine. At 18 percent, Sweden’s com and the Population Reference Bureau at www.prb.org proportion of population over 65 is the highest in the world. on the World Wide Web.

PAYDAY: Ida Mae Fuller of Ludlow, Vt., received the first Social Security check in 1940, for $22.54. She had paid only $22 into the infant system. She lived to 100 and collected more than $20,000 before her death in 1975. SOCIAL SECURITY ADMINISTRATION

or three generations, working Americans percent in 1998. In that year (the latest with com- have thought that Social Security would plete numbers), Social Security paid out $327 bil- allow them to retire at age 65 and enjoy lion to 38 million retirees and survivors. More than the good life. That dream is now a fantasy. 60 percent of seniors today receive most of their If you want to retire with financial securi- retirement income from the system. ty, you’d better start saving and investing Virtually no one quarrels with Social Security’s heavily—now. Because although our cur- achievements—or with the values they reflect. The Frent Social Security system has done a great job re- debate is over how to sustain them as the aging of ducing elderly poverty and is currently running a America places a wrenching strain on the system’s $53-billion surplus, it faces a long-term funding finances. shortfall of trillions of dollars. Social Security was initiated by the Social Secu- Unless the system is overhauled, closing that gap rity Act of 1935 as a “pay as you go” system: cur- means pushing the 12.4 percent payroll tax way rent workers lay money on the table, and retirees up to 20 percent or more. Or cutting benefits by get benefits from it. When the system is running 30 percent. So while you’re upping your savings, surpluses, as it is today, funds not paid out are remember to exercise more and eat right; you may “lent” by the Social Security Administration to the need to work longer than you’ve planned. government to cover the cost of other programs— everything from aircraft carriers to park rangers. Pay as You Go In exchange, the Social Security trust funds are credited with special, nontradable debt obliga- ebate over how to reform Social Security rose tions from the Treasury Department. These book- to fever pitch in the late 1990s and is figuring keeping debts of one government unit to another D prominently in the 2000 presidential election are the only trust fund “investments” allowable campaign. As the number of Americans over age by law. The funds cannot be invested, for example, 65 climbs from 37 million in 1998 to 64 million in stocks or bonds. “Pay as you go” made sense in by 2025, the nation will have to grapple with an 1935, because the U.S. economy was in dire straits, imbalanced Social Security system, rising medical and the first priority of the system’s designers was costs, health care rationing and age discrimina- to bring immediate relief to many people who had tion. The very nature of retirement will change. paid in little or nothing. But as more people retired The debate is highly emotional because Social over the years, the payroll taxes (or FICA, estab- Security is a pillar of most Americans’ retirement lished by the Federal Insurance Contributions Act) planning. It has helped reduce elderly poverty that support Social Security’s payouts had to be from 35 percent of seniors in 1959 to roughly 10 raised dozens of times. FICA was originally set at

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 27 Copyright 2000 Scientific American, Inc. the U.S. gets age-heavy The advancing baby-boom bulge is dramatically altering the U.S. age profile, placing a burden on 1 percent of all income up to $3,000. ed to get $1,000 a month in 2037, plan the Social Security system. The most recent major reform, in 1983, on getting only about $710. The short- set FICA taxes on course to this year’s fall is nasty, especially for the poor. Age level of 12.4 percent. The maximum 85+ amount of a worker’s wages that can be Search for a Solution 80–84 1960 75–79 taxed—“the cap”—has also risen, to 70–74 $76,200 in 2000. Given an estimated roposals for closing Social Securi- 65–69 payroll of some $3.7 trillion this year, ty’s long-term funding gap come 60–64 Baby Boom FICA taxes should produce revenues of mainly from two camps. The “tin- 55–59 P 50–54 $479 billion, more than enough to meet kerers” want to raise payroll taxes, trim 45–49 the needed payout of $409 billion. benefits or adopt some combination of 40–44 The trouble is that Social Security’s the two. A host of policy tweaks have 35–39 surpluses will evaporate. Even the $887 been floated in recent years, including 30–34 25–29 billion in the trust fund will not be lowering the inflation adjustments now 20–24 enough to meet promised future bene- made to benefits; requiring several mil- 15–19 fits once the huge baby-boomer genera- lion state and local workers now ex- 10–14 tion retires. The basic cause of the empt from Social Security to join the 5–9 0–4 shortfall resides in the awesome, glacial system and begin paying FICA taxes; pressures of demographics. The pay-as- and delaying the age at which full 01234567891011 12 you-go concept was adopted in an era benefits can be drawn, from 65 now to Percentage of Population of large families, rising populations and 67 or even 70, and then indexing this Age moderate life spans. When the retire- number up as longevity continues to 85+ ment age was set at 65 in the 1930s, rise. Another proposal is to “pop the 80–84 1990 American life expectancy was just over cap”—that is, eliminate the ceiling on 75–79 70–74 61, ensuring that there would be many wages for which the 12.4 percent FICA 65–69 active workers paying in the funds that tax must be paid. Or just raise the tax 2 60–64 went out to retirees. percent starting right now. 55–59 The “support ratio” of workers to re- All these proposals would require 50–54 45–49 tirees has been declining steadily as peo- some pain. Not surprisingly, each one 40–44 ple live longer, retire earlier and have provokes furious resistance from well- 35–39 fewer children. It has fallen from 42 to funded interest groups. 30–34 1 in 1940 to 3 to 1 in 2000 and will The other camp, the “privatizers,” 25–29 20–24 drop to 2.5 to 1 in 2025, when millions wants to raise returns by investing some 15–19 of boomers will have retired and the of Social Security’s holdings in stocks 10–14 nation’s age profile will resemble Flo- and bonds, not just the nonmarketable 5–9 rida’s today. Treasury Department obligations to 0–4 By 2014, according to the system’s which Social Security’s trust fund is 0123456 7891011 12 own trustees, Social Security will be now limited by law. Percentage of Population taking in less money from FICA taxes Most of the privatizers support the Age than it is obliged to pay out—a short- creation of a national system of individ- 85+ fall of $21 billion a year by 2015, rising ual retirement accounts—like 401(k)s— 80–84 2020 to $252 billion by 2030, in inflation- that would receive some, most or all of 75–79 adjusted dollars. a person’s incoming FICA taxes. Each 70–74 65–69 That doesn’t mean Social Security citizen would be given some degree of 60–64 will go bankrupt. A pay-as-you-go sys- choice over how the money is invested. 55–59 tem literally can’t do that. Even with no Although stock markets fluctuate, pri- 50–54 reform, the Social Security Administra- vatizers argue that over the long haul 45–49 40–44 tion has a claim on 12.4 percent of fu- they produce significantly higher returns 35–39 ture U.S. payroll. But from the time it than government bonds do. A variant U 30–34 goes cash-flow negative and begins put forward by the Clinton administra-

UREA 25–29 drawing down its trust-fund holdings, tion would allow Social Security’s trust 20–24 15–19 the system’s FICA income will cover a fund to be invested in “index funds” 10–14 dwindling part of its obligations to re- like the Wilshire 5000, which hold 5–9 CE: U.S. CENSUS B tirees. By 2037 the last trust-fund assets stocks in thousands of U.S. companies, 0–4 will be exhausted, according to the lat- so that the government, not individuals,

CE; SOUR 0123456 7891011 12 A est estimates. bears the risks of market ﬂuctuations. Percentage of Population Without reform, this means less mon- Whichever way the U.S. heads, it will URIE GR A

L ey for you. If, for example, you are slat- be playing catch-up. Britain, Canada,

Sweden, Chile, Mexico, China and doz- SHORT SUPPORT: The ratio ens of other countries have either adopted of workers to retirees will fewer people to bear the load or are debating national pension plans drop sharply in many that rely heavily on investments in private countries, forcing reform in 1990 vs. 2020 capital markets. No nation—anywhere— public pension systems AUSTRALIA is establishing from scratch a public pen- worldwide. CANADA sion system based on the pay-as-you-go FINLAND principle, and every nation that has such FRANCE a structure is facing great fiscal pressure to ly as an underutilized re- GERMANY IRELAND raise taxes, cut benefits or invest in capital source, and many boomers ITALY markets to raise returns. will want to keep a hand in JAPAN Although the financial considerations the work of society, maybe NETHERLANDS in reforming Social Security are com- well into their 80s. NEW ZEALAND plex, the political challenge is even more Perhaps legislation to re- NORWAY daunting. Social Security is ground zero move the “earnings penal- PORTUGAL ANK for bitter ideological and political clashes ty” on benefits, which Pres- SPAIN ORLD B over values. Bridging these deep emo- ident Bill Clinton signed in SWEDEN U.K. CE: W tional divides won’t be easy but will be early April, will help en- U.S.

necessary to secure retirement for boom- courage more people to CE; SOUR 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 A ers, Gen-Xers and future generations. stay in the workforce long- Workers per Retiree URIE GR

Indeed, the debate over how to “fix” er. Under the Senior Citi- A Social Security is a harbinger of a chang- zen’s Freedom to Work Act, L ing attitude toward retirement. With people between 65 and 70 will no long- projected monthly benefit you can look America’s over-65 population projected er lose $1 of their Social Security bene- forward to (adjusted for inflation). to rise to more than 20 percent of the fits for every $3 they earn above $17,000 These data will give you a sense of total by 2025 and with birth rates de- a year. your worst-case shortfall. As in the ear- clining, an early, lengthy retirement—it- The rising percentage of seniors and lier example, if your inflation-adjusted self a relatively recent social construct— their high voting rate virtually assure monthly payout will be $1,000 a month, will soon become lore. that politicians will be offering both the you live past the year 2037, and noth- The percentage of 62-year-old men elderly and their employers new incen- ing is done to improve Social Security’s still working in America fell from 81 tives to work longer. That’s something return, you can expect to receive only percent in 1950 to just 51 percent by of a rosy scenario for well-heeled, well- 71 percent of your benefits. So at a min- 1985, but it has since begun to tick back educated seniors. But further down the imum, you should plan now to invest up, past 54 percent in 1998. Similarly, financial food chain, millions of seniors enough to provide you with an ad- half of American men aged 70 held jobs who lack private pension coverage or ditional, inflation-adjusted $290 per in 1950; this fell to just 16 percent by personal savings—roughly half the el- month—indefinitely. 1985 but is back up to 21 percent. With derly population—may have to bid for Note, however, that this amount of Social Security declining in power, se- less lucrative “second careers” as check- savings and investment will just cover niors may have to work longer. And giv- out clerks or night guards. your Social Security shortfall. Your en the improvements in elderly health, monthly check will not be enough to they just may be more able—and more What You Can Do live on comfortably. You’ll need to cre- willing—to work than those a genera- ate further income streams with every tion ago were. he best thing you can do to shield form of personal and pension savings What’s more, with younger workers yourself against possible future you can muster. Social Security benefits in short supply, sustaining the American T shortfalls in Social Security is to were never intended to cover all the economy’s extended “boom” will de- step up all forms of savings to cover a financial needs of all retirees. The money pend on more seniors in the workforce. “worst case” gap in what the system was, and is, meant to be only a base. Conveniently, the shift to a service econ- will be able to pay you. omy means that there are more highly A first step is to visit the Social Secu- skilled and less physically demanding rity Web site. There you can request a jobs for seniors to compete for—or just form for getting a statement of all of Further Information hang on to. Longer-term, it’s not hard your past Social Security payments and Opposing views of how to manage So- to envision millions of seniors planning your projected monthly benefits, adjust- cial Security can be found at The Heri- to use their mid-60s—following their ed for inflation (see www.ssa.gov/top10. tage Foundation (pro-privatization) “first retirement”—to go back to school html). Once you have returned the com- at www. heritage.org; and at The Eco- and retool before pursuing a second or pleted form, the administration will send nomic Policy Institute (anti-privatiza- third career, whether full- or part-time. you a free report that details every pen- tion) at http://epinet.org on the World Society may well come to see the elder- ny you’ve paid in FICA taxes and the Wide Web.

TONIC DREAMS: We have always sought fountains of youth and life- giving nostrums. GASLIGHT ADVERTISING ARCHIVES

CONDITIONING—HAVE YET TO PROVE THAT THEY DO MUCH BETTER THAN THE POTIONS AND PATENT MEDICINES OF YESTERYEAR living longer: what really works? BY ROBIN MARANTZ HENIG

New Yorker cartoon shows two old geez- than line the pockets of the people hawking them. ers creaking in their rocking chairs on Today more temperate sages offer the same ad- the front porch. “I don’t want to live for- vice our mothers did: eat and drink in moderation, ever,” says the male geezer to the female exercise regularly, get enough sleep. All boring, and geezer. “But I damn sure don’t want to only marginally effective. Good health habits can be dead forever, either.” We may not make you leaner, more aerobically ﬁt and less liable want to live forever, but how about for to suffer some of the worst ravages that aging aA long, long time? How about for 200 years or 300— brings—but they won’t keep you young, and they two or three times the age that is now considered won’t make you live much longer than you were ge- the outer limit of the human life span? A longer spin netically programmed to live. on this earth is apparently something that appeals The advice that is really getting people excited to many of us, but as the checkered history of aging these days sounds much more scientiﬁc, derived as “cures” makes clear, it remains an elusive goal. it is from what we are learning about how cells age, Advice abounds about how to beat aging, by how that relates to organisms’ aging and how the which we usually mean either living to the age of process can be forestalled. But even these tech- 150 or more or staying youthful while living out a niques—hormones, antioxidants, gene therapy, calo- life span closer to the biblical threescore and 10. rie restriction—have not been proved conclusively Some of the methods promoted over the years to make any difference in how long you will live or have sounded like sorcery: sleep with virgins, drink how well you will age. the blood of virile youth, get injections of a concoc- It’s true that some laboratory animals who have tion derived from the testes of dogs and guinea been exposed to a few of the latest rejuvenating pigs. These techniques have done nothing more compounds have indeed lived longer—on average,

from 40 to 100 percent longer when healthy ones. Today nearly half of all sion of decline within however many treated with melatonin or calorie-re- Americans over age 85 require some sort years we have. Sometimes the same in- stricted diets. But this does not necessar- of help to get through their daily chores. tervention seems to do both things; cal- ily translate into a human life span that Unless we make great strides in antiag- orie restriction, for instance, not only is 40 to 100 percent longer. As far as ger- ing research, the oldest Americans of signiﬁcantly increases the life span of ontologists are concerned, people cannot the new century may spend their last 30 laboratory animals but also makes them live beyond the limit of about 120 years, years in a state of dreadful and debili- measurably more youthful than their with the occasional exception, such as tating dependency. contemporaries at every stage along the Jeanne Calment, who was 122 years Such a spectacle struck horror in the way. But one intervention doesn’t nec- old—and had the birth records to prove hearts of the ancient Greeks—even essarily have to do with the other. The it—when she died in 1997. You and though in their day, the average life ex- techniques that stave off age-related de- your grandchildren, and probably your pectancy was only 18 years. They told clines are much further along the road to great-grandchildren, will almost surely the story of Tithonus, a handsome young real-world usefulness than are any meth- die before you reach that limit. But you, prince with whom Eos, the goddess of ods of helping humans live to be 200. and certainly they, are more likely than the dawn, had fallen in love. Unable to These methods might not extend the any previous generation to achieve a marry a mortal, Eos asked Zeus to grant maximum life span, but they do tend to life span of close to 120 years. In other Tithonus eternal life. He did so, and increase the average life expectancy— words, scientiﬁc progress will enable a Eos and Tithonus lived happily togeth- that is, the number of years within that greater proportion of the population er for many years. But Eos had forgot- maximum life span that the average than ever before to live out the human ten to ask Zeus to grant her lover eter- person can hope to attain. When life life span to its fullest. nal youth as well. So it was Tithonus’s expectancy increases, it is because med- fate to age forever. He grew weaker and ical science has concocted a way to pre- Centenarian Tsunami smaller; he shriveled and shrank; he vent some of the catastrophes responsi- lost strength in his limbs and power in ble for most premature deaths: infec- ccording to the U.S. Census Bureau, his voice. As he became more and more tions and accidents in the younger age more than 800,000 baby boomers wizened, his voice reduced to a mere groups, heart disease and cancer after A will have celebrated their 100th squeak, Eos hid him in a basket. Titho- midlife. With the exception of infec- year by the middle of this century. The nus could get no relief from his cease- tions, which require medical interven- nearly one million boomers joining the less aging. Eventually, he turned into a tion, most of the biggest killers of adults ranks of the oldest old will constitute a grasshopper, ignored in the basket, can be staved off by healthy living. swell of centenarians so substantial that chirping away for all eternity. We’ve all heard the advice, if not from the tradition of congratulating them Longevity research must go hand in our mothers then from our doctors, our during the morning weather report will hand with research on the effects of ag- partners or our television newscasters: go by the wayside. Millions more will ing if the result is to be of any use. These don’t smoke; keep your weight within a reach their 80s and 90s. studies focus on adding years to our normal range; eat plenty of grains, fruits But there is no guarantee that the last 120-year life span, whereas other anti- and vegetables; go easy on the red meat decades of those 100 or so years will be aging research tries to slow the progres- and animal fat; drink alcohol only in

32 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. the battle against aging moderation; get some kind of exercise theory. They promote “antioxidant” out full of promise for their antiaging for at least half an hour a day; put on compounds because of the “free radical powers, but they still have not proved sunscreen when you go outdoors; and theory of aging,” which states that ag- themselves in careful clinical trials. The wear your seatbelt. ing is a matter of cellular oxidation and most familiar antioxidants are vitamins By the same logic, a vigorous exercise can be slowed if you can prevent that A, C and E —especially vitamin C, which program would be good, too. But it can oxidation. Or they look to hormonal the brilliant chemist Linus Pauling cele- have some real drawbacks for those replacement in anticipation that getting brated in the ﬁnal decades of his life. who revel in their laziness. Let’s say, as certain hormones back to youthful lev- (Pauling lived to the ripe old age of 93, some gerontologists believe, that a per- els will lead to youthful functioning. But attributing his relatively good health to son who starts a program of vigorous it remains to be seen whether any of the megadoses of vitamin C he ingested aerobic exercise at the age of 40—three these supplements or hormones really every day.) Their action is thought to times a week for half an hour at a make any difference, either in prolong- relate to what may be a basic underly- time—will live two years longer than ing life or in delaying the disabilities of ing mechanism of aging: the buildup in she might have if she had remained age. So far whenever a “Methuselah the cell of molecules known as free rad- sedentary. Those extra two years are factor” pill has sounded too good to be icals. Free radicals, the inevitable by- just about the exact amount of time she true, it turned out that it was. product of cell metabolism, are highly spent exercising—not worth it, ulti- Antioxidants, for instance, started reactive molecules that attach to and re- mately, for someone who hates jogging so much that she’d rather die a little sooner so that she can live a little happier.

Methuselah and Beta-carotene

hat if there were some easier way toward a longer life, W something that did not involve prolonged sacriﬁce? What if longevity could be packed into a pill? That is the Holy Grail that has driven hucksters and con men for centuries [see box on page 36], and it is the goal of many reputable researchers today. We have always looked for the easy way out; when studies showed that the healthiest people were those who ate the most fruits and vegetables, American in- dustry promptly packaged the active ingredients into a more palat- able form, the beta-carotene pill. This proved to be of little health ben- eﬁt, though; whatever it was about fruits and vegetables that was keeping people healthy was probably not beta-carotene at all, or at least not beta-carotene without the other components of the plant itself. As distinct from the snake-oil sales- men of old, today’s life extensionists base their efforts on solid-sounding

MEGADOSE OF HYPE: Nobelist orbis C

Linus Pauling linked high levels of YER vitamin C to prevention of cancer and heart disease, a claim that has OGER RESSME never been substantiated. R

THE JOYS OF DEEP FAT: Woody Allen as Miles Monroe in the 1973 movie oxidant effect—and for its role as one Sleeper is revived in the 22nd century into a world that has discovered that of the body’s most powerful internal “life-preserving foods” include steak, cream pies and deep fat, not the wheat clocks—is melatonin. The main func- germ and organic honey sold in his health food store 200 years earlier. tion of this hormone, which is secreted by the pineal gland located in the center act with structures in the cell and dam- longevity but can even be bad for your of the brain, is to help us differentiate age them. As more and more of these health. One study designed to examine night from day. radicals accumulate, cell functioning beta-carotene’s protective effect against For this reason, it is not surprising that gradually slows down [see “A Radical lung cancer actually uncovered a higher melatonin has proved to be useful for Proposal,” on page 38]. rate of lung cancer among male smok- treating insomnia and jet lag. But claims Antioxidants reduce the chances that ers who took beta-carotene than among have gone far beyond its effects on bio- a free radical will turn into an oxidizing comparable smokers who took a place- rhythms. Melatonin is being promoted menace. The theory is provocative, but bo. Another found that vitamin E pro- these days to prevent diabetes, cataracts, it has yet to be converted into any kind vided no more protection against heart cancer, Alzheimer’s disease, schizophre- of substantive antiaging regime. In fact, attack or stroke in high-risk patients nia and epilepsy. It has also been said to studies involving beta-carotene have than did either a placebo or a popular extend life span (up to 20 percent, based shown that this powerful antioxidant medication for blood pressure. on studies on laboratory rodents), treat not only fails to slow aging or increase One new drug promoted for its anti- depression, prevent sunburn and, of

34 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. the battle against aging course, revivify an uninspired sex life. in the film, which takes place in the lat- preliminary results indicate that with Any single compound that is sup- ter part of the 22nd century, talks of the a 30 percent caloric restriction—once posed to do all these things should raise health foods of the day—steak and again, in a diet that emphasizes under- a few eyebrows. It may turn out that cream pies—while expressing astonish- nutrition without malnutrition—mon- melatonin does have some beneﬁcial ment that denizens of the late 20th cen- keys age more slowly and possibly live age-retarding and possibly even life-ex- tury consumed such unwholesome fare longer. The calorie-restricted monkeys tending effect, but no one has proved as wheat germ and organic honey. have measurements of lean body mass, this yet. We would be well advised to The only intervention ever shown to fat, blood pressure, triglycerides and in- wait for some rigorously conducted studies before putting too much faith in this hor- CHIVES mone, now sold over the counter in grocery and health TISING AR VER food stores as a “natural” dietary supplement.

Other chemicals in the body GASLIGHT AD are, like melatonin, present at signiﬁcantly lower levels in

Enter your health food store sulin that are typically associated with their younger brethren. And their levels of the hormone DHEA decrease more with caution. slowly than expected. extreme But even if these monkeys live way beyond their normal life spans—and we old people than in young ones. Apply- extend maximum life span reliably, at will not know if they do for another ing the logic that putting back what has least in laboratory animals, is calorie decade or so—it is unclear that this can been lost must be rejuvenating, people restriction—a strict dietary regimen also be translated into a benefit for humans. have been pushing supplements of “an- known as “undernutrition without And without such assurance, who tiaging hormones” like DHEA, human malnutrition.” Scientists have used this would willingly put himself on a diet of growth hormone, estrogen and testos- method to extend significantly the life 1,500 calories a day? One of the few terone as the newest and most scien- spans of experimental rodents, insects who has done so is Roy L. Walford, a tific-sounding form of youth-restoring and fish. In mice, for instance, limiting respected gerontologist at the Universi- nostrums. food intake to one-third fewer calories ty of California at Los Angeles, who for But any one of these in too large a dose than normal increased a mouse’s maxi- the past 13 years has been limiting his can be dangerous. DHEA, for instance, mum expected life span of 39 months food intake to about one third less than has been associated with increased risks by more than 40 percent. This would the rest of us. of breast and prostate cancers, liver translate in humans to a maximum life In 1991 Walford signed on to the problems, and masculinizing effects in span of nearly 170 years [see “The highly publicized “experiment” known women (acne, facial hair, voice changes Famine of Youth,” on page 44]. as Biosphere 2. As the official team and a more dangerous profile of blood Not only do calorie-restricted ani- doctor, he expected that he would be lipids). For now, the jury is still out as to mals tend to live longer, but they tend called on to take care of injuries and in- whether restoring hormones to a more to look and act younger every step of fections for the other seven “biospheri- youthful level bears any relation at all the way. They are leaner and more ac- ans” who lived together for two years to making an older body look, feel or tive than their fully fed agemates; their in a self-sustaining greenhouse in the act like a younger one. fur loses its pigment more slowly; they Arizona desert. But he ended up doing are less likely to develop cancer and something quite different. Because of Perils of Wheat Germ other diseases of old age. Even at the problems in the climate and agricultur- age of two and a half—advanced old al parts of the experiment, food was he message here is that you should age for lab rodents—calorie-restricted scarce in Biosphere 2, and team mem- enter your local health food store mice tend to look young. bers were restricted to about 1,500 cal- T with extreme caution. From vita- The question now is whether this ap- ories a day, made up primarily of veg- min E to DHEA, the fickle wisdom of proach will work in primates, including etables, beans, grains and fruit (mostly nutrition lore seems to mutate cease- humans. Early results in monkeys ap- bananas). This was, in essence, the same lessly. In his 1973 movie Sleeper, Woody pear promising. In the late 1980s ger- calorie-restricted diet Walford had been Allen spoofed the absurdity of the eter- ontologists began calorie-restriction stud- following for four years. And here he nal quest for dietary elixirs. A scientist ies on 200 rhesus and squirrel monkeys; was able to measure the effect of such a

n the summer of 1889 the highly respected Parisian Soon special potions were developed that also prom- neurologist Charles-Édouard Brown-Séquard made a ised a longer and more fruitful life. During the Tang dy- Istunning announcement to the Societé de Biologie. At nasty in seventh-century China, for instance, a “golden the age of 72, he had concocted an emulsion drawn elixir” that took nine months to prepare was said to from the testicles of dogs and guinea pigs and had in- guarantee immortality. It was made mostly of cinnabar, jected himself with it. He said he felt great—and he lived combined with the red sulfate of mercury, a red salt of on, still feeling great, for another five years. arsenic, potassium and mother-of-pearl. When you drank With Brown-Séquard’s self-experiment, claims for it, the story went, you turned into a crane, took up resi- “organotherapy” took off, and the testes of all kinds of dence with the gods and lived forever. animals—as well as their prostates, ovaries, pancreases, In our own century, there have been dozens of treatments that were supposed to make you live forever. Yogurt was one. Remember the vil- lage of centenarians in the Caucasus Moun- tains of Georgia, the ones who appeared on the Dannon commercials with their ancient craggy faces, faded babushkas and cartons of supermarket yogurt? It turned out that not only was the theory of yogurt as an antiaging food—propounded by Nobel Prize–winner Elie Metchnikoff in the early 1900s—based on the mistaken assumption that aging was caused by intestinal toxins, but the villagers weren’t nearly as old as they claimed. They just looked it. Then there were restorative sea algae; the dried cells of fetal pigs, sheep or rabbits; and Gerovital. This last concoction was promoted in the 1970s by Romanian physician Ana As- lan. Aslan herself always looked younger than her age, and when she died in 1988 she had reached the respectable age of 91. Her spas and research institute had made her into one OMPRES

O/R of the richest women in Romania, all from the T sales of Gerovital—which turned out to be nothing more than simple Novocain, the pain- EAST PHO killer you get in the dentist’s office. RICH, RED QUACK: Ana Aslan became one of the richest women in And how about amino guanidine? The drug Communist Romania during the 1970s by selling Gerovital, a tonic attracted some attention in the mid-1990s for that turned out to be nothing more than ordinary Novocain. its ability to clear out the bulky sugar-protein molecules called AGEs, which were thought thyroids and spleens—were cut out and ground up for to age cells in the same way that oxidized free radicals the sake of rejuvenating a gullible public. do—by clogging cells and preventing them from doing But that 19th-century craze was only the most scientif- their work. ic-sounding approach in the quest for long life that Amino guanidine seems to have fallen off the antiag- dates back to ancient Greece and Rome, when the prac- ing radar, much the way that deprenyl, bioflavinoids tice of “gerokomy”—the injunction for old men to sleep and centrophenoxene have done. But never fear. New beside young virgins to regain their youthful vigor—was variations on old-fashioned snake oil—most of them widely and quite enthusiastically entertained. Proof of dressed up in long scientific names ending in “ine” and the value of such a remedy was said to be long-lived “oid”—continue to gush through the pipeline. And, of Hermippus, headmaster of a Roman school for girls who course, they will keep on coming as long as people con- supposedly lived to the age of 150. The reason? A life- tinue to look for the latest shortcut to the ever elusive time spent breathing in the air around all those maidens. fountain of youth. —R.M.H.

viding again, in some cases continuing to multiply indeﬁ- nitely. Scientists still have no idea whether any of these cellular changes will ultimately translate into a longer life span for humans, but some researchers are optimistic that manipulating telomeres may serve as a treatment for reviv- ing tired tissue. It might sound like a dream come true—a world where no- body ages and where people live for 200 years or more—but such a world is still a long way away. This is a good thing, basically, because it gives us time to think about whether this is y really a world we want to live genc in or whether there’s something

Liaison A useful, in terms of maintaining OS the social balance to which

OPOUL we’ve become accustomed, in

GAR replacing the older generation OUL V at least every 100 years or so. In the meantime, each of us DIETARY GUINEA PIG: Gerontologist Roy L. Walford was both participant and observer can do a tiny bit of “life exten- in an informal experiment in calorie restriction—the most promising antiaging sion” for ourselves if we so de- approach—during the two years he spent in the self-sustaining Biosphere 2 sire. If you set your alarm greenhouse located in the Arizona desert (seen in background). clock half an hour earlier every morning, you’ll be awake for diet on the physiological changes of sev- chromosomes that seems to resemble that much longer each day. At the end en young people over the course of two an internal hourglass, counting off the of 60 years, you’ll have gained a year years in their confined home. number of times a cell divides until it and a quarter of extra conscious mo- “It happened just by a freak of chance reaches a kind of molecular old age and ments during which you would other- that I should be positioned inside, tak- the relentless divisions halt. The telo- wise have been asleep—about as many ing care of these people, when the same mere is a region at each end of the chro- months as would be added to the aver- kind of diet was forced on them,” Wal- mosome that acts like an aglet, the little age life span if we eliminated stroke as ford has said. “So this, then, was an ex- hard tip at the end of a shoelace. Just as a cause of death. That is one way, only periment of nature.” His ﬁndings were the aglet keeps the shoelace from fray- partly facetious, to obtain the grail of that many of the physiological mea- ing, the telomere keeps the chromosome all these other longevity quests: to surements that get worse with age— intact. But it gets progressively shorter make you feel as if you’ve lived each such as cholesterol, blood pressure and with each cell division, until it ultimate- day allotted you, however many that glucose metabolism—improved among ly all but disappears. When that hap- might be, to its absolute maximum. the calorie-restricted biospherians. pens, the cell stops dividing—unless it is Even if a calorie-restricted diet does a cancer cell, which divides and grows ultimately add years to your life, is it in a way that becomes completely out Robin Marantz Henig is author most worth sticking to, given the fact that it of control [see “Counting the Lives of a recently of The Monk in the Garden: doubtless subtracts life from your years? Cell,” on page 50]. The Lost and Found Genius of Gregor Is it worth it to you to spend most of Recently scientists have rejuvenated Mendel, the Father of Genetics. your life being vaguely hungry to gain old cells by inserting the gene for telo- another 10, 20 or 30 years? merase, an enzyme that maintains the Further Information Eating less to live longer may not be length of telomeres, and thus prevent- How and Why We Age. the only strategy to deal with the perils ing the aglets from wearing away. In Leonard Hayflick. Ballantine Books, 1996. of aging. A significant stride toward re- the laboratory, cells approaching the A Means to an End: The Biological newal of fading flesh and organs may end of their natural lifetimes, a mile- Basis of Aging and Death. William R. come from a small section at the end of stone called the Hayﬂick limit, begin di- Clark. Oxford University Press, 1999.

38 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. THERE MAY BE A WAY TO PREVENT OURSELVES FROM RUSTING FROM THE INSIDE OUT pa rradicoalposal BY KATHRYN BROWN

ou can drop cigarettes. Avoid alcohol. But get through. “The house is always getting dirty, and there’s one toxin you just can’t dodge: oxy- we’re always trying to clean it up,” remarks John Car- gen. With every gulp of air, oxygen gives ney, chief technical officer at Centaur Pharmaceuticals you life. Some of it, however, gets converted in Sunnyvale, Calif., which is developing drugs to fight inside your cells into a radical molecule that various diseases of aging. But eventually, the theory can wreak havoc, degrading those same goes, our tired cells get less efficient at repelling free rad- cells and others. A growing number of sci- icals and mopping up oxidative messes, and the dam- Yentists say this damage is what causes aging. They also age accumulates. We begin to rust from the inside out. think they may one day be able to fend off oxygen’s ill If oxidants do send us crumbling into old age, then effects and help us live a lot longer. ramping up our biochemical defenses should extend Scientists have long known that oxygen is capri- life. That’s what scientists are finding, at least in the flies, cious. As molecules go, it gets around, reacting with all rats, worms and other animals they have under scruti- kinds of things. Mostly, that’s good. Oxygen combines ny in the laboratory. Whether the techniques they are with fats and carbohydrates, in a part of cells known pursuing will ever lengthen life in humans remains an as the mitochondrion, to churn out the energy that open question. But some researchers think they’re get- gets you through the day. But the conversion isn’t per- ting close to an answer. “The key is to really understand fect. A small amount of oxygen is regenerated in a how oxidative damage works, and we’re learning that,” nasty form called a free radical, or oxidant—the very says biochemist Bruce N. Ames of the University of critter that causes metal to rust. The oxidants careen California at Berkeley. “I’m convinced life expectancy about, binding to and disrupting the membranes, pro- will get longer a lot faster than anybody thinks.” teins, DNA and other cell structures that make your body work. Over time, this damage adds up, and the The Original Pollutant result just might be an older, frailer you. According to one estimate, oxidants bombard the xygen’s checkered past goes way back—about two DNA inside every one of our cells roughly 10,000 times billion years. Around that time, scientists believe, a day. Thankfully, most of the assailants are intercept- O cyanobacteria began releasing more and more ed by a small army of antioxidant chemicals. Proteins oxygen into the earth’s atmosphere, until many organ- also patch up the damage caused by the radicals that do isms were forced to either accommodate the gas or risk being degraded by its corrosive nature. Over time, some particularly oxygen-adept bacteria evolved into mito- WIZARD OF O2: Water killed the wicked witch in Oz, chondria, the tiny powerhouses in all human cells that but oxygen may kill us, oxidizing our cells the way it use oxygen to help turn food into energy. rusted Dorothy’s pal the Tin Man. The “free radical theory of aging” was first laid out

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 39 Copyright 2000 Scientific American, Inc. the battle against aging about 45 years ago by Denham Har- man of the University of Nebraska. The idea won credibility in 1969, when sci- cellular entists identified a key antioxidant, superoxide dismutase (SOD), an enzyme damage and defense that breaks down the harmful superoxide, a leader among the various free radicals that can form inside the human In cell metabolism, the mitochondria body. Soon researchers began to realize convert glucose and oxygen into en- CELL MEMBRANE that mitochondria created oxidants in ergy. Oxygen radicals also form as a high amounts. And by now dozens of normal by-product. experiments have linked oxidative damage and aging. Until recently, however, that link had been a matter of indirect correlation. In the lab, for instance, some young human cells do far better than older cells at resisting or repairing oxidative damage, whether the cells are being doused with hydrogen peroxide or stuck inside a chamber filled with pure oxygen. Also, lab flies, worms and mice carrying genetic mutations that proffer long life tend The highly reactive oxygen radical can bind with to withstand oxidative assaults better other molecules, damaging cell proteins and than their peers. “All these studies sug- membranes. The DNA molecules in the mitochondria gest oxidative damage may be an im- themselves are especially susceptible. portant part of aging, but they lack the kind of direct experiments to nail that link down,” notes John Tower, a molecular biologist at the University of DNA DAMAGE IN Southern California. “The question is, MITOCHONDRION if we actually alter oxidative stress, will it extend life?” To find out, Tower and his U.S.C. colleague Jingtao Sun recently reared fruit flies with an engineered protein that could—when exposed to heat—turn up the activity of SOD and another antioxidant, catalase. The flies started life in the lab normally, along with a control group of flies. Then, on the fifth day, the experimental flies got pulses of heat, ratcheting up their antioxidant defenses. The results were striking. Most of the everyday flies keeled over long before CELL MEMBRANE DAMAGE six weeks—but those with supercharged SOD, in particular, survived an average of 48 percent longer. “That’s pretty convincing evidence that overexpression of SOD extends life,” Tower says. DNA DAMAGE That’s not the only evidence. Five years IN NUCLEUS ago William Orr and Rajindar Sohal of Southern Methodist University in Dal- las equipped their own flies with extra copies of genes for SOD and catalase. OU APEL

Those ﬂies lingered up to a third longer AR than their normal maximum life span— . K

and seemed to age more slowly along JOHN W

the way, exhibiting higher energy, faster movements and less oxidative damage. Eventually, Sohal says, similar studies will be done with mammals and then, if deemed safe and efﬁcient, with humans.

MITOCHONDRION Intercepting the Interloper n the meantime, scientists hope to pinpoint exactly where oxidants do NUCLEUS Itheir dirtiest work—and ways to intervene. The idea, says molecular biologist John Phillips of the University of Guelph in Ontario, is to tailor therapies to the most important injured cells, rather than trying to fight oxidative damage throughout the body. Phillips CHROMOSOME has one candidate cell in mind: the motor neuron, which directs muscles from the brain and spinal cord. People with a paralyzing disease called familial amyotrophic lateral sclerosis die early, with heavily damaged motor neurons as well as mutations in SOD. Maybe motor ENERGY neurons are a critical target of oxidants, kick-starting or dominating the process OXYGEN RADICAL of aging. (SUPEROXIDE) WITH To test that idea, Phillips and his co- UNPAIRED ELECTRON workers bred fruit flies with a jolt of (dark spot) one of the human superoxide dismutase compounds, SOD1, to be expressed only in the flies’ motor neurons. Sure enough, the bugs lived 40 percent longer than SOD DEFENSE normal. And those extra days were live- ly ones. “We didn’t just delay dying, so that we had geriatric flies living longer,” Phillips says. “The extended time of life was youth.” In contrast, boosting SOD1 levels in unrelated muscle cells seems to HYDROGEN PEROXIDE have had no effect on the flies’ life span, he adds. Still, questions remain. “We don’t really know why these animals are living longer,” Phillips concedes. To The body‘s antioxidant pin down SOD’s relevance, the team is defenses limit damage now spiking different types of neurons by neutralizing most but with the antioxidant to see how the not all free radicals. For various cells react. example, superoxide CATALASE Another target for protection is the dismutase (SOD) helps mitochondria inside all cells. Because convert the oxygen radi- these tiny powerhouses are the very cal superoxide into source of harmful oxidants, they’re the hydrogen peroxide (also first cell structures to be clobbered by harmful), which is then the chemicals. In a 1998 study Sohal and converted with the help his co-worker Liang-Jun Yan exposed of catalase into molecular flies to high doses of pure oxygen and oxygen and water. OXYGEN then went looking for signs of oxidants WATER at work in the flies’ mitochondrial membranes. Rather than far-flung havoc, they

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 41 Copyright 2000 Scientific American, Inc. the battle against aging found that oxidants targeted several spirit and a sleeker look. “I don’t want Even if antioxidant supplements do vulnerable proteins, attaching to their to say we’ve gone so far as turning old boost your defenses against free radi- strings of DNA, forcing them out of rats back into young rats,” Ames says, cals, it’s tricky to know which ones—or work and upsetting the entire cell’s abil- “but that sure looks like what’s going how much—to take. As with any ingre- ity to act normally. “Free radical dam- on in the mitochondria.” The team has dient, too much can be a bad thing. In age during aging is not random, caus- just begun a study to see whether the 1996, for instance, two large studies ing decline all around our cells,” Sohal antioxidant-endowed rats actually out- made news when researchers discov- says. “We’re talking about damage that’s live their lab mates. ered that beta-carotene supplements— very selective, and that may mean aging thought to help ward off some types of comes from specific biochemical losses.” Supermarket Solutions cancer—actually increased rates of lung Proof of this notion would be good cancer among smokers who were taking news, Ames says. “The key thing is to f antioxidants work for flies and rats, the pills. Some antioxidants hawked in understand how aging really works. If what about us? Can you down a dai- health food stores will never do any it’s the decay of mitochondrial DNA, I ly supplement that will extend your good; walk right past those bottles of well, we can do things to beef up these years? Don’t count on it. “Everybody is SOD, catalase and glutathione peroxi- old mitochondria.” talking about popping antioxidant vita- dase, because these compounds must Ames, Tory Hagen of Oregon State mins,” Phillips groans. “The evidence is be created inside the body. When swal- University and their colleagues have done strong that taking moderate amounts lowed, they are simply broken down in just that. In preliminary work, they of vitamin C and E is not harmful, but digestion and rendered useless, research- found that the liver cells of older rats do the evidence that it’s actually useful for ers state. not fend off free radicals as well as the delaying aging is very thin.” For one Still, there are some antioxidants that liver cells of younger rats do. So last year, thing, researchers say, your body can hold promise, Ames says, such as lipoic over a two-week period, they fed a group absorb only so much of these vitamins; acid, which directly protects the mito- of older rats food laced with lipoic acid, the rest goes the way of other wastes. chondria. Perhaps, he adds, some of the a chemical that the mitochondria can Also, in the industrial world, most of us more obscure antioxidants dry up in the convert into a potent antioxidant. After get enough of the basic antioxidants in body as we age, leaving us more vulner- this high-powered diet, the older rats’ our daily diets. In contrast, lab animals able to oxidative damage. If that’s the liver cells deflected oxidant intruders that live unusually long with extra anti- case, downing extra amounts of these with greater resilience. What’s more, the oxidants may be deficient in those chem- conditional nutrients might slow aging’s senior rats scrambled around with new icals to begin with. cellular effects. “We just don’t know yet,” Ames says. Indeed, there are a lot of unknowns. rust inhibition: What proportion of aging changes in cells are the result of oxidative damage? an enzyme extends life Is there a way to reduce the rate of oxidants the body churns out, rather than 100 simply boosting antioxidants? And what 90 do all these long-lived lab mutants really explain about oxidative stress in peo- 80 ple? Sohal worries that some of the most 70 touted studies are misleading. For in- SOD1 FLIES stance, biologists have won lots of at- 60 NORMAL FLIES tention by reporting that in worms, sin- 50 gle mutations in a gene called daf-2 can 40 double life span, partly by resisting oxidative stress. But this is a “bogus kind Survivorship (percent) 30 of life extension,” charges Sohal, because

uelph 20 the worms’ metabolism (energy level)

y of G plummets during their extra time on

ersit 10 earth. “It’s just like going to sleep for Univ 0 0 10 20 30 40 50 60 70 80 90 three years and calling those three extra Life Span (days) years of life,” he says. The extra time is akin to hibernation, Sohal adds, so any

CE: JOHN PHILLIPS LONGER YOUTH: Fruit flies bred with a dose of SOD1, an antioxidant en- therapy based on it would rob people zyme that breaks down free radicals, lived 40 percent longer than normal of the energy they normally have. CE; SOUR

A fruit flies did in a University of Guelph laboratory. Notably, the phase of The most basic challenge is under- life extended was youth, not old age. standing aging itself. Growing old is a URIE GR A

L slow, subtle process that’s hard to de-

42 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. fine with blood tests or cellular studies. Oxidants can muddy the picture, observes Carney of Centaur Pharmaceuti- the cals. After all, these omnipresent molecules can strike a cell’s proteins, fats or antioxidant diet DNA, all very different beasts. “Under- standing oxidative damage and the bi- our best bet for fending off cellular damage from free radicals, ology of aging is a massive undertak- scientists say, is to maintain a healthy supply of antioxidant ing,” he points out. Ycompounds by eating fruits and vegetables—not by taking a In the short run, Carney says, re- pill. Here are some foods rich in antioxidants. searchers may first unravel the role of Fruits: blueberries, cherries, kiwis, pink grapefruit, oranges, oxidants in specific diseases of aging. plums, prunes, raisins, raspberries, red grapes, strawberries Centaur, for instance, is working on Vegetables: alfalfa sprouts, beets, broccoli flowers, Brussels drugs to fight Alzheimer’s and Parkin- son’s diseases. People who suffer from sprouts, corn, eggplant, kale, onions, red bell peppers, spinach these conditions show telltale signs of oxidative damage in the brain. Eventu- ally these studies may inch scientists closer to understanding basic brain changes during aging. Carney has reason to be optimistic. Some 10 years ago, while at VICE the University of Kentucky, he and his CH SER colleagues were the first to report that high levels of a synthetic antioxidant, AL RESEAR PBN, can decrease harmful oxidative TUR

proteins in the brains of old gerbils. “Ag- GRICUL ing may indeed be a treatable process,”

Carney maintains. CE: U.S. A ; SOUR orbis

Self-Imposed Treatment C

ome individuals are prescribing

their own treatments. According to VIN R. MORRIS Sone idea, you can starve yourself, KE cutting back on calories until your increased antioxidants. Instead he found even identify all the compounds, much metabolism drops so low that fewer free a host of cell changes, from better anti- less explain how they might work to- radicals are formed in the first place. A inflammatory activity to more pliable gether to fight free radicals. The an- more pleasant alternative, perhaps, is membranes—all of which could act to- swers could be years in coming. In the munching on fruits and vegetables that gether to combat aging changes. meantime, he asks, why not stroll down are high in antioxidants. Last year neu- “If you take a supplement, you never the produce aisle? A few berries might roscientist James A. Joseph of Tufts get the benefit of a fruit or vegetable just offset a little oxidation—or at least University and his colleagues reported that contains hundreds of compounds,” make the wait for answers to aging that that middle-aged rats fed extracts of Joseph says. Right now researchers can’t much sweeter. spinach, blueberries or strawberries for eight weeks showed marked declines in oxidative stress in their brain cells, as Kathryn Brown is a writer at Science News in Washington, D.C. well as improved memory and coordination. The most successful rats noshed Further Information on blueberries—the equivalent of a cup The Free Radical Theory of Aging Matures. Kenneth B. Beckman and Bruce a day for humans. N. Ames in Physiological Reviews, Vol. 78, pages 547–581; April 1998. The research also highlights how much scientists have to learn about the Extension of Drosophila Lifespan by Overexpression of Human SOD1 in processes that contribute to aging. Ap- Motor Neurons. Tony L. Parkes et al. in Nature Genetics, Vol. 19, No. 2, pages parently, it’s the blend of ingredients in- 171–174; June 1998. side blueberries—not just isolated an- Reversals of Age-Related Declines in Neuronal Signal Transduction, tioxidants—that benefited the racy rats. Cognitive, and Motor Behavioral Deficits with Blueberry, Spinach or Studying the rats’ brain cells, Joseph was Strawberry Dietary Supplementation. James A. Joseph et al. in Journal of surprised to find relatively few signs of Neuroscience, Vol. 19, No. 18, pages 8114–8121; September 15, 1999.

FIGHTING WEIGHT: Michael Cooper has cut his calorie intake nearly in half in his bid to SABA beat aging. GREG SMITH

44 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. SEVERELY RESTRICTING DIET MAY INCREASE LIFE SPAN, BUT FEW WILL BE ABLE TO FOLLOW SUCH A HARSH REGIMEN the famine of

yoBY GARY TAUBES uth

espite the national propensity for fad di- thusiasm. Their reasons are clear—the list of the ets and miracle health cures, despite the beneficial effects of calorie restriction in laboratory ubiquitous talk of “eating healthy”—a animals reads like the packaging on a miracle cure. concept so mercurial that every decade Calorie restriction will, for instance, increase both brings a new definition—only a single di- average and maximum life spans, and the fewer cal- etary regime has ever been conclusively ories consumed, the greater the increase; it will re- demonstrated to extend the life span and duce the occurrence of virtually all age-related dis- Dimprove the health of laboratory animals, let alone eases, including heart disease, diabetes and cancer. humans. It is known in the scientific lingo as “calo- It will prevent kidney disease and cataracts as well ric restriction” or “calorie restriction” and less tech- as the development of Parkinson’s and Alzheimer’s nically as “eating considerably less than you might diseases. It will lower blood cholesterol and forestall normally prefer”—perhaps 30 to even 50 percent the age-related deterioration of the immune system. less. In other words, an average-size human on a In mice, calorie restriction from an early age raises calorie-restricted diet might consume 1,500 calories the maximum life span from 39 months to 56 months a day, compared with the 2,100 calories of the typi- and at the same time preserves what passes for intel- cal American. It’s four or five small meals a day, pre- lectual function: a three-year-old calorie-restricted dominantly vegetables and fruits, and a life in which mouse, for example, can negotiate a maze with the you are perpetually cold, painfully thin and constant- quickness and ease of a normally fed mouse of six ly hungry. Calorie restriction, quite simply, is a Dra- months, which is the mouse version of salad days. conian diet and a lifelong one at that. “It requires a This harsh regime has been shown to work its life- psychological profile only one person in 1,000 has,” extending magic on almost every species that’s ever says Richard Miller, associate director for research been tested—from paramecium and worms to spi- at the University of Michigan Geriatrics Center. ders, insects, rodents and (although the data are still Nevertheless, the study of calorie-restricted diets preliminary) primates. The two caveats are that the has lately become a hot-ticket item among longevity later in life the animals start on caloric restriction, and nutrition researchers, who have taken to ex- the less the benefit, and that the diets must include tolling its virtues with remarkably unrestrained en- plentiful amounts of vitamins and minerals. The an-

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 45 Copyright 2000 Scientific American, Inc. organisms alive long enough to ﬁnd food, and at that point they could go typical meal back to reproducing and to a normal aging process, which is exactly what salad with lettuce happens in the laboratory. 1 /5 head apple strudel The question of how this might work 1 piece is still open. The leading hypothesis is that calorie restriction reduces the sparkling amount of oxidative damage to the water body. Oxidative damage is the foremost 8 ounces baked potato 7 ounces theory as to what causes the deteriora- carrots sour cream 1 tablespoon tion that comes with age. The concept is 1 cup known in the business as the “oxygen french bread paradox”: we require oxygen to turn 2 slices the food we eat into cellular fuel, but peas butter 1 1/2 tablespoons 1 /2 cup the side effects of this oxygen metabolism are detrimental to our health. The calories: 1,268 process takes place in cellular factories beef sirloin called mitochondria, where electrons 6 ounces From fat: 33% are stripped from energy-rich substanc- (before broiling) From protein: 22% es—in particular, glucose—while con- From carbohydrates: 45% verting them to the kind of fuel that cells can use. The electrons are then captured by restricted meal oat bran muffin oxygen atoms, which join with hydro- dates 1 piece gen to form water. But the process is 5 pieces inefﬁcient, and the electrons often go skim milk astray, resulting in the formation of 1 cup highly reactive molecules known as free radicals. Roy L. Walford, a gerontologist at the University of California at Los steamed baked Angeles and a pioneer of calorie-restric- spinach potato calories: 750 1 cup 7 ounces tion research, refers to free radicals as From fat: 10% “great white sharks in the biochemical From protein: 25% sea—short-lived but voracious agents From carbohydrates: 65% chicken [that] oxidize and damage tissues.” breast The oxidation that occurs in the hu- 3 ounces man body is identical to the way in

SLIM FILMS which rust is formed in metals, so it is not unreasonable to say that we will all imals must be undernourished without In the 65 years since Clive M. McKay eventually rust to death if given the op- being malnourished, as calorie-restric- of Cornell University first noticed that portunity. The free radicals damage the tion researchers say. the regimen doubled the life span of his tissues but also seem to damage the ge- All of this, though, leaves researchers lab rats, and in the decade or so since netic material, the DNA, that codes for struggling to answer three key questions: calorie restriction moved from the fring- the proteins required for the body’s What exactly does calorie restriction do es of longevity research to the main- physiological functions. The primary physiologically to extend longevity and stream, much of the laboratory work candidate for most of this damage is fight off disease? Will it have the same has been aimed at discerning the funda- the mitochondria themselves, which are effect in humans? And, if so, is there a mental biology underlying the benefi- not spared by the free radicals they pro- way to get the benefits without the ac- cial effects. What researchers generally duce. And once damaged, they produce tual diet? “The purpose of studying cal- agree on is that the response to calorie even more free radicals. orie restriction,” Miller says, “is not to restriction in organisms seems to be an Calorie restriction, by this theory, re- develop yet another diet that people evolutionary adaptation to periods of duces the amount of fuel available for won’t follow.” Rather researchers would scarcity. As food becomes hard to find, cells and the amount of oxygen needed ideally like to concoct a pill or potion organisms evolve ways to “up-regulate” by the mitochondria to convert the ex- that will mimic the effects of calorie re- those defense mechanisms that increase isting fuel into energy, and it makes the striction and produce the benefits while life span and down-regulate reproduc- existing metabolic process more effic- allowing us to eat to our heart’s content. tive mechanisms. That would keep the ient. Not only do the mitochondria gen-

46 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. the battle against aging erate fewer damaging free radicals, but come about because the less food eaten, “And many of the changes that occur in the lack of food also seems to up-regu- the lower the metabolism and, hence, calorie-restricted rodents are hard to late the production of enzymes that the lower the oxidative damage. “It’s explain by the idea that fuel and oxy- neutralize the free radicals. known that rodents can decrease their gen consumption go down.” In one of the more fascinating experi- body temperature, their metabolic rate, ments in the field, Richard Weindruch and that [that] is how they survive fam- A Shot of Hormones and Tomas A. Prolla of the University ine periods,” says Rajindar S. Sohal, a of Wisconsin–Madison recently com- biologist at Southern Methodist Uni- hat there is more going on is sug- pared the expression of genes in young versity. “But mice and rats are not hu- gested by the work of James F. Nel- mice, normally fed aging mice and calo- mans. We don’t have that mechanism.” T son, a physiologist at the University rie-restricted aging mice. Weindruch, Other researchers, however, disagree of Texas Health Science Center at San who has been studying calorie restric- with this interpretation of the evidence, Antonio. Nelson and his colleagues have tion since he was a U.C.L.A. graduate and the argument often comes down to shown that calorie restriction subtly student in the mid-1970s with Walford, a dispute about how best to measure raises the levels of hormones called glu- believes that the process lowers oxida- metabolism in normally fed versus cocorticoids. These hormones do “prob- tive stress and damage to the mitochon- calorie-restricted animals. “It’s a dis- ably a zillion different things” in an or- dria while having its effect predomi- tinct oversimplification to say that the ganism, Nelson says, of which research- nantly in “critical target tissues” such calorie-restriction phe- ers have nailed down only a few. Their as the brain and nerve cells and nomena are merely primary function is to mobilize glucose heart and skeletal muscle. “All due to a decline from the liver to provide fuel to the mus- these tissues depend heavily on in metabolic cles during periods of stress or during a mitochondrial energy metab- rate,” Miller flight-or-fight response. “They also mo- olism to generate cellular comments. bilize glucose to help you get through a energy, and all these tissues have fairly limited repair capabilities,” he says. Weindruch and Prolla examined tissues from the calf muscles of mice and found that normally fed aging mice were putting most of their genetic effort into repairing genes and proteins damaged by stress, of which a good part is oxidative damage. The active genes of calorie- restricted mice, on the other hand, were much less involved in genetic repair and much more involved in biosynthesis—building new proteins and other cellular components—just like the mice in the prime of their lives. Most researchers buy the oxidative- damage theory of calorie restriction, but they disagree on two controversial aspects. One is whether calorie restric- LIGHTENING THE LOAD: A restricted tion actually lowers metabolism to diet may reduce wear and tear on achieve its goal, in which case the rele- the body and may delay the slow vance to humans might be lessened—do descent toward death from free radi- we have to go into something akin to cals and other aggressors that weigh hibernation to get the benefits of calorie down the eater of a normal diet. restriction? The second question is whether lowering metabolism is the primary route that allows calorie restric- Compromised Glucose (Sugar) tion to achieve its effect on longevity. Immune System Damage to Tissue The fact that calorie-restricted rodents have body temperatures that are con- Disordered Gene Biological Increase in siderably lower than normal implies Expression Stress Free Radicals that the benefits of calorie restriction SLIM FILMS

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 47 Copyright 2000 Scientific American, Inc. fasting stage, to keep blood sugar high four square enough so you can keep going to your next meal,” he says. These hormones, snacks a day too, serve to fight inflammation, hint- ing that they play a direct role in the survival of the organism. And glucocor- ichael Cooper, suffice it to say, wear year-round in Texas, and I can’t ticoids are only one of a host of hor- is obsessed with the problem generate any body heat. If I sit still, I mones in laboratory animals that seem Mof aging and has been since get cold even in a warm room. I to be affected by calorie restriction. he was a boy. He recalls looking at have a little bit of digestive trouble, his seventh-grade teacher, a bald- probably related to consuming too The Human Question ing man in his 50s, and thinking, “I few calories. And my bones are don’t want to be like him,” and, he quite vulnerable. They’re more sen- elson and his colleagues are cur- says, “Those thoughts never left my sitive to sitting. I have to sit on a pil- rently testing lab animals to find mind.” Now Cooper is 51, a former low. And my feet don’t have any N out if the hormonal changes in electrical engineer who recently pad on the bottom. So I have to ex- calorie-restricted animals are a side ef- went back to school to study biolo- tra-pad my shoes. It’s not a big deal; fect of calorie restriction or a mecha- gy at Southern Methodist Universi- I get along just fine.” nism that directly leads to longevity. In ty. Since the mid-1970s he has been As for his daily diet, he explains, one experiment, for instance, Nelson’s reading voraciously about longevi- it’s basically the equivalent of a laboratory is spiking the drinking water ty, nutrition and health. And in handful of snacks a day: “Most of lab mice with glucocorticoids to de- February 1986 he began practicing wouldn’t consider it very tasteful, termine if the mice live longer. “The calorie restriction, hoping to extend but I like it a lot. In the morning, for next thing would be to see if any of his life well beyond the biblical instance, I mix up wheat bran and these effects are translatable to hu- solid protein, and I put mans,” he asserts. some canned pumpkin in The human question is the big one. it, a little bit of spices and The existing data on humans are very occasionally half a cup of thin. Most human populations that are yogurt. For lunch I have forced to survive on low-calorie diets vegetables. For supper I are also malnourished and are as like- have two meals, one at ly as not to die prematurely from vita- about 5:00, which is just min and mineral deficiencies. The only vegetables, maybe three known exception is on the Japanese is- different kinds. And around land of Okinawa, Walford notes: “The 7:30 I have what I call Okinawans have about 70 percent of dessert, which might be the calorie intake of the rest of Japan. berries mixed up with They eat mainly fish and vegetables.

A whey protein.” They have as much as 40 times the inci- SAB So far Cooper sees little dence of people over 100. They have evidence that his severe less diabetes, tumors and so forth than

GREG SMITH diet has slowed the aging the rest of Japan.” THE SKINNY ON AGING: Michael Cooper process, and it certainly On the other hand, he adds, there consumes a 350-calorie lunch that includes hasn’t diminished the un- could be numerous other factors that whey protein, brewer’s yeast and broccoli. aesthetic side effects, al- contribute to the Okinawans’ longevity. though he remains relent- Doing a controlled trial of calorie-re- three score and 10 years. The 6’2” lessly optimistic. “My hair is thin- stricted humans is impractical for what Cooper has reduced his daily calorie ner,” he notes, “and when you’re David B. Allison, an obesity researcher intake from 2,800 to 1,500, and his thinner you look older. Wrinkles at St. Luke’s-Roosevelt Hospital Center weight has dropped over a seven- show up more. On the other hand, if in New York City, calls “the obvious year period from 160 pounds to a I weren’t doing this I might already reasons”: researchers would have to con- feather-light 120. be in decrepit condition. I have no vince hundreds or thousands of humans Cooper would have gone lower, way of knowing. And even if I come to spend the better part of their lifetime but he found plenty of reasons to down with a disease like cancer or living on an extreme diet, without be- convince him otherwise. “For one heart disease and I know I’m ing able to promise them beneﬁts. And thing,” he points out, “if I was any going to die, I figure I’ve probably the trial would, by deﬁnition, take the thinner I would probably freeze to gained a few years by doing what better part of a century to complete. death. I wear long thermal under- I’ve done.” —G.T. Instead the National Institute on Ag- ing (NIA), in collaboration with Wein-

They’re using a compound called 2- deoxy-D-glucose, which is virtually identical to glucose but lacks two oxygen atoms. Once inside the body, it goes where glucose would normally go, but it can’t be metabolized by the cells. The compound is synthetic, relatively inex- pensive and has been used in research laboratories for years. It’s also mildly toxic in high enough doses, however, which makes it a debatable intervention for humans even if UNCONTROLLED it works. EXPERIMENT: Oki- The researchers nawans, with 70 gave moderate dos- percent of the es to rats for six calorie intake of months—not long other Japanese, enough to establish count among whether the com- their number up pound increased to 40 times as longevity but long many centenari- enough to see if it ans as their coun- might. With the 2- trymen do. deoxy-D-glucose added to their diet, the rats continued to eat the same amount of calories, and yet they lost weight and their body temperature dropped, as it would have had they been dieting. Their insulin levels also dropped, another hallmark of calorie restriction. This convinced the NIA researchers that 2-deoxy-D-glucose was worth testing for the lifetime of the rats, a study that’s ongoing. If the rats do indeed live longer, orbis C the NIA researchers will at least have UFF

TR proved that the mimetic phenomenon, AR as they call this calorie-restriction mim- VE B

DA icry, has promise. “Then we’ll look for other kinds of compounds that exert the druch and his colleagues, is testing the most anyone willing to try it. One possi- same effects without any toxicity,” Roth calorie-restriction proposition on rhe- bility, Allison says, is to give all people, says. That would mark a big step to- sus and squirrel monkeys, assuming that not just the excessively overweight, anti- ward the ultimate goal of letting people if it works for any primates, it’s a good obesity drugs. This would suppress ap- have their cake and live longer, too. bet it would work for humans. They petite, but a healthy unsatisfied appetite now have some 200 monkeys in the trial, may be a necessary factor in convincing half on a calorie-restricted diet and half an organism that famine has arrived Gary Taubes is a California-based sci- eating normally. Even these monkeys are and thus stimulate the beneficial effects. ence writer. likely to live 30 or 40 years, so the study “That this might lengthen life is real is a long-term endeavor. But the calorie- speculation, and it goes far beyond any Further Information restricted monkeys are already showing data,” Allison observes. “We’ve never Caloric Restriction and Aging. Rich- signs of unnaturally robust health. demonstrated in humans that antiobesi- ard Weindruch in Scientific American, With so little information on whether ty drugs even make the obese live long- Vol. 274, No. 1, pages 32–38; January calorie restriction will benefit humans, er, let alone the average-weight person.” 1996. researchers have barely touched on how At the NIA, George S. Roth, Donald K. Roy Walford, the gerontologist who is to mimic its effect without going on a Ingram and Mark P. Mattson are trying observing a calorically restricted diet, diet that could take the fun out of liv- another tack—fooling cells into think- maintains a site at www.walford.com ing, and certainly out of eating, for al- ing they’ve been fed when they haven’t. on the World Wide Web.

MOLECULAR GLOWWORMS: Telomeres light up University of Center; Southwestern Medical Texas the tips of chromosomes. JERRY W. SHAY SHAY W. JERRY

50 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. STUDIES OF CLOCKLIKE ELEMENTS IN THE NUCLEUS OF CELLS COULD LEAD TO A RANGE OF THERAPIES THAT MIGHT BOLSTER THE IMMUNE SYSTEM, REVERSE HEART DISEASE, EVEN COMBAT CANCER counting the lives of

BYa EVELYN STRAUSS cell

iologists have always warmed to the no- When some human cells are examined in the lab- tion of a cellular alarm clock that would oratory, their telomeres shorten each time a cell di- mark off the moments of a cell’s life and vides. As a cell divides more than a set number of ring when its time to die had arrived. The times, its telomere fuses become too short. At that existence of such a molecular timepiece point, the cell may die, or else a kind of alarm may go might suggest ways to slow the ticking or off within it that causes the cell to go into a senes- even rewind the clock and thus give people cent state, in which it Blengthened, healthier lives. CAPPING ceases multiplying. CHROMOSOMES: Biologists have the- Telomeres—stretches of orized that cell senes- DNA and the proteins cence might have a that bind to them— good side. It could be protect the ends of a defense against can- chromosomes. cer, which is marked by uncontrolled cell Would that biology were division. Cells that are unable to regrow their telo- so manifestly simple. Mother Nature doesn’t wear a meres should stop dividing before they can cause Rolex, and scientists have yet to hear a ticking sound too much mischief. Yet telomere shrinkage could inside a cell’s walls. The closest thing that anyone conceivably disrupt the repair and replenishment of has found to a cellular clock resides at the tips of tissues, making them age. “It’s absolutely clear that chromosomes in the nucleus of cells. Chromosome the aging of many human cells in culture is a telo- ends, stretches of DNA called telomeres, do not mere-dependent process,” states Titia de Lange of the contain genes that program hereditary traits. But Rockefeller University. “The question is how sig- they do bear some resemblance to a kind of clock or niﬁcant it is for aging of the whole organism.” Does a fuse that sets off a time bomb. the behavior of cells that reside in the test tube have

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 51 Copyright 2000 Scientific American, Inc. the long and the short LIKE A CLOCK: Telomeres, the tips of telomeres of chromosomes, shorten every time a cell divides, but the enzyme telomerase restores them so that a germ cell their length stays the same in germ cells, such as sperm or eggs (a). In mature adult cells, such as the fi- broblasts of the skin, the telomere resembles a timer that marks off telomerase cell divisions. Telomerase is absent telomere chromosome in these cells, so the telomeres continue to contract (b). They do so up to the point when the cell dies or enters a senescent state (c). When b adult cell telomerase is reactivated in the laboratory, some normal cells have their life extended indefinitely. Such reactivation occurs naturally in most cancer cells (d).

c cell senescence d cell immortality and cancer telomerase SLIM FILMS anything at all to do with how we age? in brains, you can get new neurons,” and they die young. Furthermore, they’re Scientists have now begun to explore says Calvin B. Harley of the biotechnol- infertile, presumably because the cells de Lange’s question. In animal studies, ogy firm Geron Corporation. “In every destined to become eggs or sperm can’t they are examining whether the wear- tissue except possibly the heart, cells di- reproduce or survive optimally. Some ing down of the telomere fuse can illu- vide. Some divide slowly, but we live a cells have “walked the telomere plank,” minate the process of growing old or at long time.” says Ronald A. DePinho of Harvard least explain why some organs start to Age-related deterioration in these and Medical School. The mice have short deteriorate. “No one’s ever proved that other tissue types could result from cells telomeres, he says, and their stem cells short telomeres cause aging,” acknowl- running out of steam because of telo- can’t multiply as many times as they usu- edges Jerry W. Shay of the University of mere loss, Harley asserts. At sharp turns ally do. Stem cells give rise to many cell Texas Southwestern Medical Center. in blood vessels, where turbulent blood types, such as the various components “The only way to do that is to prevent flow wears out tissue and thus requires of skin. it from happening, and that’s what needs restoration, the telomeres are shorter But the physiology of these mice to be done—but there’s already some than in long, straight stretches. doesn’t mimic all aspects of aging, De- pretty suggestive evidence.” Pinho cautions. “We don’t see an in- Some hallmarks of aging in humans, Walking the Telomere Plank crease in cataracts or osteoporosis” or such as hair loss or skin wrinkling, are other pathology typical of old animals. easy to understand as consequences of o explore methodically what telo- “Telomere attrition does not precipitate cells’ inability to multiply, says de Lange, meres mean to an intact animal, sci- a classical premature aging syndrome. because the cells that replace hair and T entists genetically engineered mice But we do believe it influences an abso- rejuvenate skin divide throughout a per- so that they have unusually short telo- lutely critical aspect of getting old—the son’s lifetime. Similarly, the immune sys- meres. At first glance, you might think ability of organisms to counteract acute tem gradually loses its ability to bounce the animals in these experiments belong and chronic stress.” back. Even “nonrenewing” tissue might in a murine nursing home. They go gray, As individuals age, their organs can replenish itself. “We know now that even their hair thins, their skin turns papery, still function adequately, but they re-

52 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. the battle against aging spond poorly when confronted by chemical or physical insults. “The difference between a young person and an old person is a diminished capacity to respond to major environmental stresses,” De- Pinho notes. The mice in his experiments healed poorly after enduring various shocks—minor surgery and chemother- ) om apy, for example. “Wound healing re- ott b

quires robust proliferative responses, and op t and so does replenishing the blood sup- ( ply after chemo wipes out white blood edicine cells,” he explains. How relevant these results are to hu- ol of M mans remains to be seen, however. “Mice are not little people,” DePinho ollege Scho ial C points out. Unlike human cells, for in- er mp stance, mouse cells’ telomeres do not grow shorter, so it is implausible that mice normally age as a result of the ospital and I gradual shriveling of the ends of their chromosomes. ammersmith H H

Although no one has directly tested AL the relation between telomeres and human aging or disease, nature may have

inadvertently conducted a relevant ex- INDERJEET DOK

TELOMERE DEFECTS: in the laboratory has increased the A patient suffering healthy life span of human cells from from dyskeratosis the skin, blood vessels, eyes, muscles congenita, which is and immune system, and Geron is cur- characterized by rently targeting these and other cell aberrant telomeres, types to develop new therapies. shows signs of pre- Telomerase therapy might one day mature aging. help generate a new supply of skin and blood cells to treat lesions that don’t heal or to enhance the waning immuni- ty of aging blood cells, both common mere-restoring en- problems of old age. Although some zyme called telomer- stem cells produce telomerase, there’s ase. This enzyme re- not enough to maintain telomere length sides in the stem cells when demand for reproduction is par- periment. Telomere defects might under- that eventually become sperm and eggs ticularly high, according to some re- lie a rare inherited disorder called dys- (which need to multiply throughout a searchers. Adding telomerase to stem keratosis congenita (DKC). Patients with large part of a person’s life). It is also cells that generate new blood and skin the disorder carry abnormally short telo- present in certain other cells—those used cells could permit them to survive long- meres. They have discolored-looking to revitalize the blood and skin, for ex- er and continue dividing to produce skin that doesn’t renew itself well.They ample—but not in most other types. new cells virtually indefinitely. become anemic in their teens, and many “What the disease tells us,” Collins says, Earlier this year researchers reported die from infections. “We can see what “is that there are some cell types that that a telomerase-based treatment al- happens in a telomere-deficient person,” need to turn on telomerase in a normal lowed cells to stay alive in culture and says Kathleen Collins of the University human life span.” that they functioned properly when of California at Berkeley, warning that Using telomerase to maintain the ends transplanted back into a different ani- the results need to be confirmed in more of chromosomes—and so heal damaged mal. Someday a similar therapy that ex- than the two families studied so far. or tired organs in people of any age— tracts cells from a patient, adds telo- The cell types that are most compro- has become a focus of research at Geron merase and then reimplants them into mised in this disease, Collins says, are and a number of academic research the donor’s body might avert the risk of ones that in humans produce a telo- laboratories. So far adding telomerase immune rejection. The telomerase could

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 53 Copyright 2000 Scientific American, Inc. the battle against aging also spur cells lining veins and arteries however, alleviate age-related diseases. think of as aging takes place in nonre- to make new blood vessels when plaque Questions remain about whether telo- producing cells,” de Lange observes. buildup blocks arteries, according to mere shortening actually makes cells de- “Alzheimer’s is generally viewed as an scientists at Geron. teriorate except in a laboratory dish. important aspect of human aging. I One approach may eventually in- Even where scientists have established a don’t think there’s any reason to believe volve gene therapy—in which the gene causal link between telomere biology that those plaques [damage to the brain that gives rise to telomerase is delivered produced by the disease] to the desired site in the body. Because have anything to do with telomeres are shorter in cirrhotic livers SAFEGUARD: Damage loss of the proliferative than in healthy ones—possibly a result to a mouse liver at abilities of nerve cells.” of too many cycles of cell damage and the onset of cirrhosis Not all human cells are subsequent regeneration—this method (arrows in top image) likely to snap awake with might increase the replicative capacity was not as dire in the addition of telomer- of surviving liver cells and thus could another mouse liver ase; freeing some types renew livers damaged by alcohol or dis- that received the from the chains of mor- ease. DePinho recently inserted the gene gene for telomerase tality (at least in the test for telomerase into mice with artificial- (bottom). tube) requires additional ly induced liver damage. Production of the enzyme reduced injury in Telomerase therapy may one day the animals from cirrhosis of the liver. Of course, gene therapy of any type confronts prevent liver cirrhosis. the same safety concerns that arose after the death and cellular life span, they genetic alterations. Furthermore, some last year of a patient re- have done it in cells re- cell types senesce within a small num- ceiving treatment for a moved from the body. ber of generations—long before their rare metabolic disease The strongest proof that telomeres have decayed significantly— unrelated to telomeres. telomerase reinvigorates indicating that other mechanisms can As an alternative to gene tissues in an animal arrest growth. Even if you could make therapy, researchers are would be to produce the a cell immortal, you might not want to. seeking drugs that might enzyme in cells that nor- Adding telomerase to a cell can have control the gene when mally shut it off and then dire consequences. “You have to con- it is already present in determine that it can ex- front the reality that you’re creating a cells so it can be turned tend life in those cells. cell that is one step closer to cancer,” on and off at will. Such experiments are under way in mice, Weinberg says. “Cell mortality is an Human trials of telomerase therapy but the results have yet to be reported. important impediment to cancer.” have yet to begin, and it’s not clear “To connect telomere shortening what the first treatment will be. Telo- with aging may be a brilliant stroke of The Cancer Connection mere shortening, Harley posits, is prob- insight, or it may represent a distrac- ably “a fundamental underlying path- tion, having little to do with human ag- umor cells, after all, can live forever. way that contributes to many diseas- ing,” remarks Robert A. Weinberg of According to several studies, telo- es.” And he adds: “The technology isn’t the Massachusetts Institute of Technol- T merase plays a critical role in main- decades away—it’s on the horizon. We ogy’s Whitehead Institute. “To show a taining, if not triggering, this disease hope to be in clinical trials within a connection, you’d want to see that or- that affects the elderly in disproportion- handful of years.” gans are giving out because they’ve lost ate numbers. Telomerase by itself does Harley’s views have yet to achieve a telomeres. It would be wonderful if not cause cancer: healthy cells err in consensus among molecular biologists there was such a simple molecular ex- multiple ways in their slide toward ma- and gerontologists. But even Harley de- planation of the aging process, but biol- lignancy. But cancer cells do seem to rides the popular misconception that ogy doesn’t necessarily oblige.” have figured out how to use telomerase telomere research will increase longevi- Even if it does help rejuvenate certain to sustain the abnormal cell division that ty. “We’re not saying that we have a tissue, telomerase will not likely serve as is the hallmark of the malady. Accord- maximum life span of 120 because of an all-purpose antiaging preparation. ing to some researchers, they achieve telomere loss and that if you were to The enzyme should not have an effect this unchecked multiplication by acti- activate telomerase in a controlled way, on cells that do not divide in the mature vating telomerase or restoring telomere you’d live to be 200,” Harley clarifies, body, many of which are involved in length by other mechanisms. In contrast SCIENCE adding that halting telomere loss may, processes of aging. “A lot of what we to most normal cells, about 85 to 90 ©

54 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. TUMOR INHIBITOR: Cancer cells thrive when the enzyme telomerase is present (left). When it is inhibited, the cells change shape and die (right). percent of tumor cells produce telomerase. And treatments that inactivate telomerase kill cancer cells growing in the lab. “That is formal proof that the ongoing activities of telomerase are essential for proliferation in cancer cells,” Weinberg concludes. A drug or genetic therapy that blocked telomerase might quash the unbridled growth of malignant cells. “It’s too early to tell, but based on the available evidence, we think the prospects mgen look good for antitelomer- A ase therapy,” asserts Murray OBINSON

O. Robinson of Amgen, a . R Y O biotechnology ﬁrm. “It’s in- A credibly exciting that telo- MURR merase is a property that crosses virtually all tumor types, be- about 10 to 15 percent of human tu- cancers. Only clinical trials will ulti- cause such drugs might be universal mors apparently do not produce the en- mately resolve the many lingering ques- chemotherapeutic agents.” The idea of zyme, suggesting that not all cancer cells tions about which, if any, types of telo- developing them is “not just a pie-in-the- need it. “There’s clearly some kind of mere therapies might succeed for aging sky hope,” he continues. “We know if bypass pathway in mammalian cells,” or cancer. The original hope that we we inhibit this enzyme we can kill tumor warns Carol W. Greider of the Johns could trick Father Time into giving us cells, and we know we can make inhib- Hopkins University School of Medicine. immortality by manipulating telomeres itors against other enzymes of this type.” Other researchers argue that resistance will probably prove naive, however. We Some scientists expect that telomere- of this type is unlikely to pose a serious cannot simply rewind telomeres like an based anticancer strategies will trigger problem, because none of the investiga- old-fashioned Swiss watch. But study- fewer severe side effects than other che- tions have discovered it in the types of ing the tips of chromosomes as they motherapies. Most healthy cells do not cells from which most cancers arise. fritter away may still yield insights into carry telomerase, and they would thus Telomere research has created a para- how the cell, the basic biological unit, be expected to remain unaffected if a dox that must still be resolved: the en- grows old. That accomplishment alone drug were to inhibit the enzyme. Nor- zyme telomerase might revive an aging would mark a fundamental contribu- mal cells that do produce telomerase— liver. Alternatively, it might promote tion to the science of human aging. sperm, egg and stem cells—start out with much longer telomeres than about Evelyn Strauss, a molecular biologist turned science writer, freelances from Santa 50 percent of cancers, so cancer cells Cruz, Calif., and is a correspondent for Science magazine. should stop dividing before they do. This aspect of telomere biology might Further Information provide a means to attack malignant Endgames. John Travis in Science News, Vol. 148, No. 22, page 362; November cells without interfering with the nor- 25, 1995. mal renewing activities of other cells. Still, some researchers worry that tu- Telomeres, Telomerase and Cancer. Carol W. Greider and Elizabeth H. Black- mors might develop resistance to an- burn in Scientific American, Vol. 274, No. 2, pages 92–97; February 1996. titelomerase therapies. Mice that lack Descriptions of research at the biotechnology company Geron on telomerase for telomerase can still form tumors, and age-related disorders can be found at www.geron.com on the World Wide Web.

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 55 Copyright 2000 Scientific American, Inc. the battle against aging ) inset and main photograph main photograph ( California Institute of Technology Institute of Technology California COURTESY OF DAVID ANDERSON OF DAVID COURTESY

mendersmendersBY MIKE MAY

n the 1970s The Six Million Dollar Man television program opened each week by showing a terrible accident that turned astronaut Steve Austin into “a man barely alive.” Then we heard: “Gentlemen, we can rebuild him. We have the technology.” The idea intrigued us but seemed centuries away. It’s not. An explosion of work surrounding stem cells, which can differentiate into many other Icell types, raises hope for medical repairs beyond our imagi- nation—mending a damaged heart, fixing a failing liver, improving a forgetful brain and, most exciting, significantly extending life. Instead of using bionic parts, like the ones that made Steve Austin stronger and faster, this technology could provide us with longer and healthier lives by en- abling us to control our natural repair mechanisms. This emerging field takes advantage of a cell that may

TWO FROM ONE: Neural stem cells (inset) can give rise to differing cell types: neurons (yellow), which are wired to their neighbors, and glia (red), nucleated structures in the background.

BLOOD SPERM BLASTOCYST

NEURON

EGG INNER CELL MASS MUSCLE

SPECIALIZATION: Some scientists consider a stem cell to low sphere that emerges after several cell divisions (cen- arise when a sperm fertilizes an egg (left). Others think it ter). Either way, stem cells can differentiate into unique ASHIMA originates in the inner cell mass of the blastocyst, a hol- cell types, such as muscle, blood and nerve tissue (right). OMO NAR T emerge from the moment of concep- stantly all over the body. Stem cells also an electronic retina. But why rely on so tion. When a sperm cell works its way seem to make new cells continuously many different parts—essentially a new into an egg during fertilization, some for bone, liver, heart, muscle and even fix for every problem—when you could scientists consider the result to be a the brain, where scientists long thought use stem cells instead? Stem cells might stem cell. Other researchers consider that we were incapable of generating be a cure-all of sorts, basically one-stop stem cells to appear after several cell di- new cells. shopping for repairing anything that visions that turn a fertilized egg into a ails you. hollow sphere of cells called a blasto- Bodily Tune-ups Despite the recent interest in stem cyst. That sphere includes a region cells, they are not entirely new in medi- called the inner cell mass, consisting of tem cells serve as a natural defense cal therapies. Physicians have been ex- a group of stem cells. Wherever stem against aging. As things wear out, tending human lives for years by includ- cells first arise, they can branch out in S these cells can repair some damage. ing stem cells in some treatments. For many directions. A stem cell holds all As we get older, though, the failures in example, some forms of cancer, such as the information it needs to make bone, our bodies apparently overrun the stem childhood leukemia, require such a dev- blood, brain—any part of a human cells. Consequently, we decline—getting astating dose of chemotherapy that it body. It can also copy itself to maintain slower, weaker, more forgetful. Never- destroys a patient’s bone marrow. A a stock of stem cells. theless, many scientists believe that they bone marrow transplant can restore a Many of us imagine that a human could slow these processes with a stem patient’s blood-making capability, pre- body builds up most of its cells and tis- cell tune-up. Moreover, a regular dose sumably because it provides a new sup- sues early in life, and then everything of jazzed-up stem cells might fight off ply of blood-making stem cells. When begins to fall apart, cell by cell. New degeneration and keep us living a long- physicians started using bone marrow findings prove otherwise. Stem cells er and healthier life. transplants, though, no one had seen a busily work away throughout our lives, The inherent qualities of stem cells human stem cell. They just assumed that acting like an army of housekeepers, have drawn tremendous attention to such cells existed. cleaning up a little mess here and re- them. To be sure, some scientists take In late 1998 all that changed. Two sets pairing some damage there. In some the Six Million Dollar Man approach of researchers in the U.S.—John Gear- cases, a group of these cells work to- and try to fabricate new parts from ex- hart’s group at Johns Hopkins Univer- gether to perform gargantuan tasks. otic metals and space-age polymers. You sity and James Thomson’s team at the For example, the stem cells located in can already get an artificial hip joint, an University of Wisconsin–Madison—iso- bone marrow must replace more than implantable device to help with hearing lated human stem cells. These results one billion red blood cells every day. loss, and replacement valves for your shook up science and society, raising Such rebuilding might be going on con- heart. Some groups are even pursuing hope for therapeutic uses of stem cells

58 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. the battle against aging as well as a range of ethical questions. and turns into what looks exactly like a searchers receiving federal funding for After the first reports, investigators neuron doesn’t mean that it works prop- their studies, as all powerful laborato- launched a parade of promising animal erly. Still, McKay and his colleagues did ries do. A ban put in place by the U.S. experiments. Evan Snyder of Harvard show at least one case in which new Congress on the use of federal money Medical School has shown that neural neurons did work. First, they caused a means that research is confined to the stem cells seek out damaged areas of a Parkinson’s-like disease in rats by killing narrow universe of just a few private mouse’s cortex—the highest centers of neurons that communicate through a biotechnology companies—Geron Cor- the brain—and make new neurons there. neurotransmitter called dopamine. Then poration and Advanced Cell Technolo- He has very preliminary evidence that they obtained neural stem cells from rat gy being the leaders. Progress in the neural stem cells can do this in pri- embryos and injected the cells into the field is slower than it might be without mates, too. “We’re starting to move our Parkinsonian adult rats. In less than three the prohibition. But the funding envi- way up the evolutionary ladder,” Sny- months the normal movement in most ronment may change. der says, “suggesting that this really of the treated rats improved by about In November 1998 President Bill Clin- may be a kind of intervention or kind 75 percent. ton asked the National Bioethics Advi- of application that we could use.” He Over this incredibly promising work sory Commission to investigate the med- also mentions evidence that neural stem looms a controversy that threatens some ical and ethical issues behind embryonic cells could generate new neurons in stem cell research. It all revolves around stem cells. Its report concluded: “[T]he other areas of the brain and even in the one word: embryo. In essence, scientists Commission believes that federal fund- spinal cord. If human neural stem cells talk about two general classes of stem ing for the use and derivation of [em- can go to damaged areas in the nervous cells, ones that come from embryos and bryonic stem] cells should be limited to system and create neurons there, such a ones from adults. Some people would two sources of such material: cadaveric technique might fend off Parkinson’s never condone using embryos in any fetal tissue [from naturally aborted fe- disease, amyotrophic lateral sclerosis way because of ethical beliefs. If you tuses] and embryos remaining after in- (better known as Lou Gehrig’s disease) can get stem cells from adults, though, fertility treatments.” The report thus or old-age dementia. surely this entire problem can be re- encouraged federal funding for certain solved by forgoing the use of embryon- approaches to stem cell research. Then, Tissue Flipping ic stem cells. But, as Thomson explains, in December 1999, the National Insti- “the embryonic stem cells have the po- tutes of Health, the primary source of hese findings seem to be cropping tential to form any- up in one organ after another. For thing. It’s not clear T instance, Bryon Petersen of the Uni- what the develop- versity of Florida says his work in rats mental potential is of showed that a cell that originated in the some of these other bone marrow could travel to the liver, stem cells.” In other incorporate into that organ and be- words, an embryon- come a functioning liver cell. Pre- sumably, that bone marrow cell A NEW IDENTITY: Stem was a blood-making stem cell. As cells in bone marrow Ronald McKay of the National transplanted from one rat Institute of Neurological Disor- to another developed into ders and Strokes explains, “One cells that produced a really exciting thing that’s going functional enzyme (red- on in the field at the moment is, in orange areas) in the liver fact, we’re sort of discovering that of the recipient animal. ida lor the stem cells that have been de- F y of

fined in different tissues are actually ca- ic stem cell can do it ersit niv pable of flipping from one tissue to an- all—make any cell U other.” McKay notes that researchers needed—and adult are not absolutely sure that the flipping stem cells might be ETERSEN ON P really goes on in stem cells but adds limited to making a Y that “there are cells that are capable of few kinds of cells. BR giving rise to the cells of another tissue: Furthermore, adult stem cells could be U.S. biomedical funding, published a brain into blood, brain into muscle, partially worn out, so that they would draft for guidelines on stem cell re- pancreas into liver, muscle into blood.” not offer the full rejuvenating benefits search, which went out for public com- Still, scientists must answer a crucial of embryonic ones. ment. These documents suggest that the question: Do the new cells really work? Despite all the potential benefits of outlook for at least limited federal sup- In most cases, it’s hard to tell. Just be- using embryonic stem cells, working port has become less bleak. cause a stem cell ends up in the brain with them remains off-limits for re- But the National Bioethics Advisory

Commission did not endorse an ap- there is when you drink cow’s milk.” ly forever. About his human embryonic proach called nuclear transfer, which In any case, you need West’s approach cells, for instance, Thomson says, “We’ve Michael West of Advanced Cell Tech- only if your body really is likely to re- kept them growing for well over a year. nology champions. In his technique, reject foreign stem cells. West says your By any measure that we have, they ap- searchers remove the nucleus from a immune system would search out for- pear to be immortal.” And once re- cow’s egg, implant a human cell—say, a eign cells with the efficiency of a hawk searchers know how to culture whatev- skin cell—inside it and allow it to grow hunting a mouse. Thomson, one of the er kind of cells they have, they can embryonic stem cells. With this system, first to isolate human embryonic stem make incredibly large numbers of them. West and his colleagues might be able cells, agrees that the body would reject For example, a single human skin cell to use skin cells—obtained by merely stem cells as it does some organ trans- can spawn 170 trillion trillion trillion scraping a toothpick across the inside plants: “Absolutely. Once they differen- cells. Moreover, farming these cells in of your cheek—to make embryonic tiate, they’ll become adult cells like any culture could reduce the concerns about stem cells just for you. That could be other cell in the body,” which would using embryonic tissue. “One of the important because your immune sys- cause them to be rejected. But Thom- things I think people don’t like about tem might fight off stem cells from any- son’s opinion is not universal. One com- this is the idea of constantly going back one else, seeing them as foreign in- pany, Osiris Therapeutics, has found to human embryos and doing the stuff vaders, like a virus. In addition, cow’s through its studies that foreign stem over and over and over again,” McKay eggs come cheaply and in large num- cells are not cast out by the immune sys- says. “But technically, we can grow the bers. Still, combining human and cow tem. “It really doesn’t seem to be the cells, we can really grow them. I think cells started more than a little disgrun- case. We don’t quite know why that is,” this is going to be very efficient, so you tled mooing, because some people see it says Osiris scientist Mark Pittenger. needn’t be concerned that this is going as a dangerous mixing of species. West Luckily, investigators do agree on to be a big [embryo] harvesting indus- defends his approach, saying, “We take some topics. For example, most every- try. It’s not going to be like that.” The the [cow] egg and remove its DNA, so one thinks they could grow these cells recently created WiCell Research Insti- there’s no more mixing of species than in culture and keep them alive essential- tute—with Thomson as its scientific di-

tissue rejuvenation b BIOENGINEERING: Companies have already begun to contemplate medical techniques that would use stem cells to reverse the effects of aging on flesh, blood and numerous or- a gans. A sample of bone marrow containing stem cells could be ex- CULTURING tracted from the pelvis (a). The cells could then be grown in a culture (b) before being removed, inserted into a blood bag and reinjected into the body (c). (The solution would contain both stem cells and progenitor cells, products of stem cells primed to make certain tissue.) In the body, this mixture would home in on locations where they could help revive, say, a damaged liver or kidney. One company, Aastrom Biosciences, is developing a machine that will cul- OM BIOSCIENCES ture enough stem cells over a 12- day period to make medical uses AASTR practical (photograph). ASHIMA EXTRACTION OMO NAR T

60 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. rector—plans to grow and sell human further in the future. In theory, physi- Thomson speculates that a newly dis- embryonic stem cells for research. cians could get so good at fixing organs covered technique that cures diabetes in Although physicians already rely with stem cell treatments that such or- mice might not help human diabetics but somewhat on stem cells—at least for gan fabrication might never be needed. instead leave them with a worse disease— bone marrow transplants—many more pancreatic cancer, for example. In other clinical applications might lie just over Just Hit “Play” words, a treatment for a serious but the horizon. Stem cells might be used to survivable disease could give patients a repopulate or replace cells devastated ome companies are already count- certain death sentence. by disease. It might even be possible to ing on a market in stem cell med- “So you want to make really sure take a stem cell, nudge it chemically to- S icine. For instance, Douglas Arm- what you’re doing isn’t worse than the ward making the kind of tissue desired strong of Aastrom Biosciences describes disease you’re trying to cure and that and then control its environment in a a machine developed by his company there’s a lot of safety involved,” Thom- way that causes it to build an entire or- that is primed with a sample of bone son continues. “Because the therapies gan. The organ could then be used in marrow or even blood from an umbili- are so new, going straight into humans someone who needs a transplant, the cal cord, both of which contain stem would be a problem.” Much more re- pinnacle of so-called tissue engineering. cells. According to Armstrong, “The search on primates and then extensive When could some of these stem cell equipment operates much like a VCR clinical testing must be completed be- techniques be available? “I think we’re with a videocassette. The user takes the fore new stem cell techniques become going to be moving into clinical trials cassette, pops it into the machine and available as a routine form of treatment. with human neural stem cells of some the machine takes over. Twelve days Scientists do know that stem cells type for some disease within two years,” later the cassette comes back out, goes promise entirely new views of how the Snyder says. That means that stem cell– on another machine and transfers the human body works. “For me, the abso- boosting treatments could be available cell product to a blood bag that’s ready lute true potential of these is more in in five to 10 years. Making entire or- for therapy.” how it’s going to give us a clue to under- gans from scratch, however, lies much The resulting blood bag would con- stand the human body,” Thomson says. tain stem cells as well as so-called pro- “So even if [stem cells] were never to be genitor cells, which are products of stem used for transplantation purposes, they cells that are primed to make specific give you this brand-new scientific mod- tissues. A physician could simply inject el to study. If you’re interested in heart stem and progenitor cells into the blood- disease, you can study populations of stream, and many of them would home human heart cells in tissue culture for in on locations where they were needed. the first time on a regular basis. Armstrong adds, “It’s practical to “I think the transplantation stuff will think we may be entering a future period be important,” he goes on, “but some- where all of us put aside a small amount day we’ll understand enough about the of bone marrow or even our umbilical human body that these transplantation cord blood when we are born, and then therapies won’t be necessary, because it c samples of that are grown out into pop- will be possible to cause specific cells to ulations and we get infusions of those regenerate themselves in ways they don’t cells later in life that might, indeed, help naturally do, because we will understand us live much longer, healthier lives.” how that development normally occurs.” Many hurdles lie between ongoing re- We might never see science rebuild a search and turning stem cell techniques man with Steve Austin–like techniques. into therapies for humans. “These ther- Instead researchers may rebuild us by apies are brand-new,” Thomson says. tweaking systems that our bodies pos- “There are no precedents for them.” sessed all along—stem cells, the ulti- Consequently, a researcher can’t simply mate medical weapons. Now we must see what stem cell treatments do in rats wait to see if science and society can and mice and then try the same thing in agree on ways to use these seemingly humans. In a hypothetical example, magical wonders of biology.

Mike May lives and works as a freelance writer in Clinton, Conn.

Further Information Stem Cells: A New Lease on Life. Elaine Fuchs and Julia A. Segre in Cell, Vol. 100, REINJECTION No. 1, pages 143–155; January 7, 2000. Stem Cells: A Primer. Available at www.nih.gov/news/stemcell/primer. htm

HOPE: A bioartificial kidney could someday end the exhausting regimen of dialysis. One prototype (right) has been developed

The Image Works by the University of Michigan. MULVEHILL MULVEHILL

62 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. ENGINEERS ARE CREATING ARTIFICIAL REPLACEMENTS FOR FAILING HEARTS, KIDNEYS, PANCREASES AND LIVERS parts for vital

rgaBY DAnVID PESCOVITZ s

therosclerosis, diabetes, cirrhosis, hepatitis and other af- ﬂictions kill or disable millions of people every year by ravaging their organs over time. The elderly suffer the greatest toll. Bioartiﬁcial organs—a merger of mechanical parts with cells grown in laboratory cultures—could reduce premature death, improve quality of life and serve as vital bridges for seniors waiting for natural- Aorgan transplants. In the U.S., thousands of people die annually waiting for a transplant, and many thousands more never even make it onto a waiting list, according to the United Network for Organ Sharing in Rich- mond, Va., which manages the nationwide transplant network.

Engineering whole organs from scratch using pristine stem cells that can differentiate into any kind of body tissue would, of course,

be the ultimate solution. But that is a longer-term prospect. For STEM now, bioartiﬁcial organs offer the greatest hope for spare parts that ARE SY

can perform the complex tasks of a kidney, pancreas or liver. “We THC call these the smart organs,” says Bartley P. Grifﬁth, director of the McGowan Center for Artiﬁcial Organ Development at the Univer- sity of Pittsburgh. A heart simply pumps blood through one-way A ANN ARBOR HEAL

valves. Kidneys, pancreases and livers face the arduous task of V

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 63 Copyright 2000 Scientific American, Inc. creas and liver, experts must combine electrical, mechanical and tissue engineering. The strategy thus far is to take organ cells from humans or pigs,

GH grow them in a culture medium, then UR

SB load them into a bioreactor—a box or T tube in which they are kept alive with

Y OF PIT oxygen and nutrients. The bioreactor is AN CENTER, W inserted into a larger machine outside GO C M UNIVERSIT the body. A patient’s blood is diverted via tubes through the bioreactor, where NEW PUSH: The McGowan Center’s ble that passes through the patient’s it is cleansed—similar to the setup of to- prototype artificial heart propels skin, but it buys crucial time. day’s kidney dialysis machines. blood with a tiny impeller, rather than LVAD progress has renewed interest “Of course, the trick would be to un- the power-hungry pumps used in in a new generation of artificial hearts. derstand the cell culture science and en- past attempts to replace the organ. They are smaller and more efficient be- gineer the bioreactor well enough to cause they move blood in a fundamen- implant one of these organs,” Griffith tally different manner. Instead of pump- notes. “I think we’re 10 years away from chemically removing waste from incoming with flexing diaphragms as did the that at least.” Closer to fruition, he being fluids and producing key compounds previous generation, they have a tiny lieves, is a “get out of trouble” bioar- for the body. “If a heart is thought of as spinning impeller that propels the blood tificial kidney, worn like a fanny pack, a first-grader,” Griffith says, “a kidney is like a boat propeller moves water. The that could keep a patient alive during a senior in high school, and a liver is a McGowan Center uses this approach in the wait for a donated human organ. postdoc.” its Streamliner artificial heart, designed Despite its “simplicity,” building an to be placed in the abdomen and to push Beyond the Dialysis Machine artificial heart has proved difficult. The blood through the natural heart and ar- image of Barney Clark, recipient of the teries using a pair of tubes. Inductive iabetes and hypertension—the lead- first Jarvik-7 artificial heart in 1982, coupling could transfer energy from a ing causes of kidney disease— was telling; his mechanical heart, which coil attached to a battery worn on a belt D plague the elderly. Today there are replaced his failed natural heart, was to a secondary coil and battery implant- more than 40,000 Americans waiting connected by hoses to a large, thumping ed under the skin. The subcutaneous for a kidney transplant. They must un- pneumatic bellows outside his body that battery would then send power to the dergo dialysis or hemofiltration for hours did the actual pumping. The unit had to artificial organ over a thin wire. at a stretch, multiple times each week. be plugged into the wall, limiting Clark’s The Streamliner may be the Cadillac The regimen is exhausting. Just as vex- movement. When Clark and a second of artificial hearts. The oblong device, ing is that the machines can do only artificial heart patient, William Schroe- made of titanium, is about four inches half the task at hand. While the kidney der, died within two years as a result of long, two inches across and weighs sev- filters urea waste products from the infections and strokes caused by blood eral ounces. It features an impeller sus- blood, its tubules must also reclaim 98 clots, the public’s hope in the technolo- pended internally with magnets. “This percent of the filtrate, returning impor- gy died with them. eliminates the risk of failure because of tant sugars, salts and other substances It took years for researchers to rethink bearings wearing out,” says Griffith, to the body. Dialysis machines just can’t their approach and miniaturize compo- who adds that the Streamliner faces at pull off the second step. nents. Instead of a full-blown replace- least 18 more months of well-funded By combining mechanical devices with ment, recent devices have attempted to development before it is ready for testing. engineered tissue, a bioartificial kidney assist a failing heart until a transplant Other leading research teams are us- could perform the entire function. Neph- can be found. The left ventricular assist ing the turbine approach in experimen- rologist David Humes and his colleagues device (LVAD), the foremost example, tal LVADs. Thermo Cardiosystems is at the University of Michigan have cul- is now in clinical use. A surgeon im- working with the McGowan Center, and tured proximal tubule cells, which plants it into the abdomen, where it Micromed Technology has partnered handle the bulk of filtrate reclamation, pumps blood that has been diverted with the Baylor Medical Center. from pig kidneys. The cells are en- from the left ventricle, one of the heart’s Developing a “dumb” organ like the meshed along hair-thin plastic fibers four main chambers that pump blood. heart is a major engineering challenge, that line the inside of a polycarbonate The device is powered by a small console yet it pales in comparison with the com- filtration cartridge about 10.5 inches or portable battery pack outside the plexity of building organs that have bio- long and 1.4 inches in diameter. The body. The LVAD solves only some heart chemical brains. To craft “smart” bio- cartridge is housed in a larger machine. problems and still requires a power ca- artificial organs like the kidney, pan- As the patient’s blood is pumped through

64 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. the battle against aging the bioartificial kidney, the engineered there is no effective feedback mecha- produce insulin but also can sense and cells filter out urea while returning the nism” for the level of insulin required, regulate that production in response to useful compounds. injection “is done as a best guess,” says glucose levels, we’re essentially repro- Trials of the new system conducted Barry Solomon, president and chief sci- ducing what the natural pancreas on dogs last year were successful, and entific officer of Circe Biomedical in does,” Solomon explains. Humes is hoping for approval from the Lexington, Mass. The resulting large An early version of the PancreAssist Food and Drug Administration to be- swings in glucose levels are thought to proved effective in animals several years gin human trials later this year. “At this lead to the major complications of dia- ago, but a reengineering of the vascular point, this is a temporary device for betes—vascular disease, retinal disease graft was required before human stud- acute kidney failure,” he explains. “But and heart disease. ies could begin. Solomon hopes the we’re working on devices that have The goal is to automate the system. slimmed-down system will be proved both filtration and a tubule element Existing implantable insulin pumps on animals and ready for human clini- that could be wearable. We’re in a pro- tend to leak, and electronic glucose sen- cal trials within two years. totype stage.” sors are notorious for failing after little According to Humes, the first-gen- more than a month inside the body. But Letting the Liver Regenerate eration wearable renal assist device the real shortfall is that today’s systems could diminish a patient’s dialysis time cannot supply the feedback informa- he challenge is greater for a bioar- by 30 to 50 percent and someday possi- tion needed to administer precise and tificial liver to replace a natural one bly eliminate it entirely. “The first dialy- properly timed dosages. T damaged by diseases and insults sis machine was a huge 10-by-4-foot Circe’s PancreAssist system is designed such as hepatitis C and alcoholism. A cylinder,” Humes says. “Our cartridges to solve the problem. It is an insulin-on- healthy liver metabolizes toxins, pro- demand system based on the body’s duces bile, regulates the balance of many SWEET: Now in development, Circe own chemistry. Now in preclinical de- hormones and manufactures blood-clot- Biomedical’s PancreAssist would auto- velopment, PancreAssist is an implant- ting proteins. Designing an organ to ac- matically monitor blood sugar levels able tubular membrane surrounded by complish all these complex tasks is and dispense insulin for diabetics. insulin-producing islets, all contained in daunting. But a device may be needed to replace these functions only for a

AL short time, says Achilles Demetriou, a bioartiﬁcial liver pioneer who is chairman of the surgery department at CE BIOMEDIC

CIR the Cedars-Sinai Medical Cen- ter in Los Angeles. “The liver has such a remarkable capacity to regenerate that temporary support could result in complete recovery of the injured organ,” Demetri- ou points out. If a damaged liver could be re- lieved of all its duties for just one week, it would have a good chance of repairing itself. There is currently no machine do the same thing, but you can hold a plastic housing. As the patient’s blood that can take over the organ’s function, them in your hand.” If fabrication ad- flows through the center of the tube, however. vances make possible even more minia- the islets, harvested from pigs, detect The goal, therefore, is a bioartificial turization, he adds, he and his team changes in the patient’s glucose levels organ that can bridge the repair time. might be able to “devise one of these and respond by producing insulin when Several companies are pursuing state- for implantation.” needed. The insulin diffuses across the of-the-art work, including Organogene- An implantable bioartificial device to membrane into the person’s blood. The sis in Canton, Mass., developers of FDA- assist a malfunctioning pancreas would membrane prevents white blood cells approved lab-grown skin, and Circe create a similar revolution in the treat- and antibodies from attacking the Biomedical, whose HepatAssist system ment of insulin-dependent diabetics. At porcine cells, so immunosuppressant was developed in collaboration with present, diabetics must follow a strict drugs are not needed. The unit, half the Demetriou. daily regimen of self-administered tests size of a hockey puck and weighing HepatAssist is undergoing phase II to check blood sugar levels and one or only a few ounces, will be implanted and III clinical trials in liver transplant more insulin injections to pick up the near the kidney. “Because we’re using centers around the U.S. It uses pig liver slack of a weak pancreas. But “because cells that not only have the ability to cells in a bioreactor to remove toxins

o “corpses” reside at the Alcor Life Extension Founda- tion. Just three dozen “patients” entombed at a rock- Nhard 320 degrees Fahrenheit below zero who have bet that future physicians will have the technology to “reani- mate” them. When each one was at death’s door, a friend or family member had phoned Alcor’s CryoTransport team. The outfit rushed to the scene. Once a doctor had pronounced the subject clinically dead, the team put the deceased on ice, pumped the body full of medications and solutions and transported it to Alcor headquarters in Scottsdale, Ariz. The team then circulated glycerol, used as antifreeze, into the major arteries to prevent damaging ice crystals from forming among cells. The patient was then placed in a “dew- ar”—a tall metal thermos that is filled with liquid nitrogen. The patients stand there today in wait. But don’t dare compare them to mummies. Cryonics, Alcor insists, has nothing to do with “bringing people back from

ALD the dead.”

CHIB Freeze now, revive later is certainly one way to attempt to extend your THY AR longevity. The first Alcor “member” TIMO has been frozen since 1976. “If you’re YOU BET YOUR LIFE: feeling good and you enjoy life, it’s At her death, Chris- not a matter of figuring out why you tine Peterson will be should do this,” says Christine Peter- frozen in a tank by son, a 42-year-old writer and Alcor Alcor, run by Linda subscriber. “It’s more a question of Chamberlain (right), why you would want to check out.” in hopes she can be Nice theory—but there’s a catch. revived and repaired. Someone someday will have to figure out how to reconstruct your body, mind and soul. And at present neither Alcor nor anyone else knows how to do it. Therein lies the gamble. But no one has crafted a single nanobot. And although Peterson’s not worried. She believes a cure for aging will nanotechnology is all the rage in the popular press, many come along before she needs to be frozen. “For people scientists ridicule molecular robots as little more than the ru- around my age and younger, cryonics is more like backup minations of science-fiction aficionados. insurance,” she says. If a fix doesn’t materialize, then she’s Peterson has such faith in nanotechnology that she has betting that nanotechnology will bring her back from the signed up for Alcor’s neuropreservation service—freezing just deep freeze. Nanotechnology is one of her life’s passions. She her head. It’ll simply be attached to a more youthful body has penned a book about it and is married to scientist K. Eric when it’s thawed. Nanotechnology will fix any complications Drexler, a maverick nanotechnology evangelist. The believ- from her recapitation and will subsequently keep her new ers say that one day thousands of nanobots—microscopic body youthful forever. Her mother, husband, friends and col- robots one billionth of a meter long—will be able to travel leagues such as artificial-intelligence researcher Marvin Min- through your body Fantastic Voyage–style, repairing cells to sky will be glad to see it; all of them are signed up with Alcor. fix whatever ails you. The army of dutiful nanobots would re- Putting your frozen corpse—er, body—in Alcor’s care pair widespread cellular damage caused by the freezing, re- doesn’t come cheap. The flat fee is $120,000. Whether that’s juvenate your brain cells and rebuild your tired old body, cell enough for the needed half-century of minding isn’t clear. by cell, into something new. Charles Platt, a writer of science fact and fiction and director

from the blood of patients, in a technique similar to Humes’s bioartificial kidney. A cylindrical plastic cartridge 14 inches long and 2.5 inches in diameter, lined with engineered cells, fits into a larger machine. A patient’s blood passes through it for cleansing. Patients undergo six-hour sessions for seven consecutive days. “By then,” Demetri- ou says, the hope is that either “their liver recovers and takes over or they receive a transplant.” HepatAssist is intended to serve solely as a bridge. An implantable liver replacement, Demetriou believes, will probably have to be engineered from stem cells, a venture he asserts will be “orders of magnitude more complex” than those for other organs. In the meantime, whichever bioartificial organs emerge may face competition from other organ-replacement approaches that are also advancing, notes Peter Stock, associate professor of transplant surgery at the University of Cali- fornia at San Francisco. Most anticipat- ed, perhaps, is xenotransplantation, in which organs harvested from transgen- ic pigs or primates could be transplanted into humans. The organs would be endowed with certain human genes and engineered to not induce immune rejection. Various attempts to fix faulty or- ibune r gans by altering genes directly are un-

o/Mesa T der way, too.

hot Whether tomorrow’s spare organs are AP P Y

T built around bioartiﬁcial cartridges, pig innards or stem cells will in the end be UGHER determined by lab work and by safety

WIN DA and effectiveness questions that get IR hashed out during the FDA approval of the CryoCare Foundation, which subcontracts freezing, isn’t expecting a cryon- process. But no matter which technolo- ics patient to be successfully resuscitated for at least 60 years. gy beats the organ shortage, the ultimate If we all could be frozen and defrosted, the earth might become a crowded prize will go to the individual who gets place. Peterson has an otherworldly solution for that, too: colonize outer space. a new lease on life after a visit to the Her vision of a space-faring society, common among her future-minded peers, is human body shop of the future. reminiscent of the late LSD guru Timothy Leary’s prescription for the human race: SMI2LE, an acronym for “space migration, intelligence increase and life extension.” Indeed, Leary was arguably the most famous advocate of cryonics. (Contrary to David Pescovitz writes frequently for rumors, Walt Disney was cremated after his death in 1966, and Michael Jackson Scientific American and is a contribut- has never publicly announced plans to take a liquid-nitrogen bath.) But if, as En- ing editor at Wired magazine. glish scholar Samuel Johnson noted, the prospect of one’s imminent demise tends to concentrate the mind wonderfully, then eternity on ice may lose some of Further Information its allure. During his final hours of life, Leary abruptly changed his plans for cold American Heart Association storage. His stated reason, according to friends who were at his bedside: “Waking (www. americanheart.org). up in the future surrounded by a bunch of men in white lab coats holding clip- McGowan Center for Artificial boards didn’t sound like so much fun.” —D.P. Organ Development (www.upmc.edu/mcgowan).

OLD YOUNG PEOPLE: Hutchinson-Gilford syndrome patients often die by their early teens from

heart disease or Disabilities Institute for Basic Research in Developmental stroke. W. TED BROWN W.

68 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. CHILDREN WITH DISEASES OF THE ELDERLY AND STUDIES OF GENES THAT EXTEND LIFE SPAN IN ANIMALS ARE OPENING A WINDOW ON HOW WE AGE of hyperaging and methuselah genes BY EVELYN STRAUSS

hree-year-old Sam likes to feel starfish in his hands, cells or at some point after fertilization. Because researchers and you can just forget about changing the subject can’t track the gene through relatives, this disorder doesn’t when he’s discussing planets. But Sam is not quite lend itself to traditional gene-hunting approaches. your average toddler. He’s almost bald, his seven So Gordon, a research associate in the department of anat- teeth don’t align properly, and he is smaller than omy and cell biology at Tufts University School of Medicine, his peers. So far these are the only clues that he has is taking a different tack. She’s focusing on the one consistent Hutchinson-Gilford syndrome, a rare genetic disor- difference between Hutchinson-Gilford patients and healthy Tder that mimics some aspects of aging. children: sick kids have much higher levels of a particular No one can predict what course Sam’s disease will take, compound—hyaluronic acid (HA)—in their urine. HA is nec- but children with Hutchinson-Gilford syndrome typically de- essary for life because it helps hold tissue together, but too velop arthritis and grow slowly. Their skin becomes thin, and much of it might be a bad thing, Gordon says. People with age spots and prominent veins emerge. Most acquire severe another form of progeria, called Werner syndrome, also have atherosclerosis that can thwart blood flow to the brain and high levels of HA, and its concentrations creep up in elderly other organs. About 50 percent of afflicted children die of people, too. heart disease or stroke by their early teens. When Sam’s mother isn’t talking to him about Neil Arm- A Trickle of Evidence strong and Buzz Aldrin, she’s in the laboratory, looking for the biochemical basis of her son’s disease. Leslie B. Gordon’s laques that build up in the blood vessels of people who die work on Hutchinson-Gilford syndrome—and research on of heart disease are steeped in HA. “Whether it’s cause or other related disorders—may have implications far beyond Peffect, no one really knows,” Gordon says. “These kids finding a cure for a rare disease. It might also provide clues have these same plaques throughout their bodies, and that’s about the normal human aging process and yield insight into what plays a major role in causing heart attacks and strokes.” diseases common to old age, such as atherosclerosis, which The idea that HA contributes to heart disease is not new, could lead to new avenues of research for treatments that but work in this area has been fostered recently by new ana- prolong life. lytical tools. In this relatively unexplored area of research, Hutchinson-Gilford syndrome is one of several human Gordon is trying to follow the trickle of evidence to its source. progerias; “progeria” means premature aging. Very little is She wants to find out whether the disease grows more severe known about the disease, and the condition is extremely as HA levels rise and to establish whether the chemical does rare—only about 100 cases have been documented since it indeed promote plaque formation. If such a connection were was first described in 1886. Although the disease appears to confirmed, it could lead to therapies that fight both Hutch- be caused by a genetic defect, it doesn’t run in families, sug- inson-Gilford syndrome and cardiovascular disease by low- gesting that the mutation occurs randomly in egg or sperm ering HA levels. “Any treatments that help these children will

very likely help millions of people with In test-tube experiments, WS cells are sible for Hutchinson-Gilford and Wern- cardiovascular disease and potentially much more susceptible than normal to er syndromes. It’s even possible that other problems associated with aging,” harm from a compound that is toxic to klotho is the yet to be revealed gene she says. DNA. These results suggest that the ab- that underlies Hutchinson-Gilford. “It In another classical premature aging normal WS protein might fail to repair would be interesting to see if Hutchin- disease, Werner syndrome (WS), symp- damaged DNA. son-Gilford patients have a mutation in toms don’t begin until adolescence or And that’s just one thought. Studies the klotho gene,” says Makoto Kuro-o early adulthood. In this syndrome, hair on a yeast protein that resembles the of the University of Texas Southwestern thins and goes gray, skin wrinkles, and WS protein have suggested that it un- Medical Center at Dallas. muscles atrophy. Individuals with this dermines DNA integrity in other ways. condition suffer from cataracts, diabe- A mutation in a yeast gene that encodes Antiaging Hormone tes, heart disease and other afﬂictions this protein shortens life span. In cells that don’t typically strike until old age. carrying the altered gene, DNA is cut ased on an analysis of klotho’s Although people with Hutchinson- after it loops into circles, and the ends DNA and the symptoms exhibited Gilford and WS look old and share stick together. The resulting DNA cir- B by the mice, Kuro-o hypothesizes many ailments with geriatric patients, cles contribute to the cell’s eventual that the mutated gene encodes an aber- the physiological changes overlap only demise. No one has detected similar rant protein that circulates in the blood partially with how people usually age. DNA rings in cells of people with WS and triggers age-related processes in or from old individuals. different tissues—perhaps a buildup of Some researchers have con- plaque in blood vessels. If so, the nor- jectured, however, that the mal version of the protein might do the normal WS protein quash- opposite—serving as what Kuro-o calls xas allas e es formation of aberrant an “antiaging hormone.” The idea of y of T er at D DNA structures in humans, such a blood-borne factor that might ent ersit

niv a process that might go keep at least some tissues healthy is a al C U

edic awry when the gene suffers new concept for mammalian aging, O-O n M

er a mutation. Kuro-o says. He is trying to identify the est O KUR T

O Already studies on WS molecules with which the klotho pro- outhw S MAK have spurred investigators tein interacts in tissues and to figure out DODDERING RODENT: A klotho mutant mouse to think about new ways how cells with defective klotho behave (right) has a small, bent back, unlike a normal of looking at common dis- differently from normal cells. mouse (left), and a range of age-related disorders, orders of human aging. Per- When healthy versions of genes such such as atherosclerosis and osteoporosis. haps DNA damage from as klotho or the one underlying WS go subtle but common varia- haywire, they expedite an organism’s de- WS sufferers experience a high incidence tions in the WS gene may predispose mise. Studying these mutations and dis- of cancer, for example, but “they in- people to vascular disease, cataracts orders may well yield insight into partic- clude rare, weird cancers that you don’t and diabetes, even if they don’t suffer ular illnesses and conditions of old age. see too often,” says George M. Martin from a full-blown form of the disease. But they will probably not shed much of the University of Washington. The big limitation of studying hu- light on one of the most important ques- Still, these disorders can provide some mans, of course, is that you can’t ma- tions surrounding aging research—that intriguing insights, says W. Ted Brown nipulate people as you can laboratory is, how scientists might move beyond of the Institute for Basic Research in animals. Enter a mutant mouse strain simply fighting diseases of old age to Developmental Disabilities in Staten Is- that is afflicted at a young age with finding ways of extending life span be- land, N.Y. “Mutations in one gene can many of the diseases common to older yond the current maximum limit of produce a set of effects that dramatical- humans. The defect in the responsible about 120 years. ly resemble aging. That implies that rel- mouse gene—called klotho, after the To go further, investigators have be- atively few genes could be controlling goddess in Greek mythology who spins gun to examine how overproducing aging.” the thread of life—accelerates the onset some proteins prolongs the lives of mi- Several years ago scientists tracked of disorders such as atherosclerosis and crobes, flies and mammals. In yeast, ex- down the gene responsible for WS. In its osteoporosis. tra servings of a protein called Sir2 healthy form the gene encodes a protein Researchers have isolated the klotho lengthen lifetime, increasing the num- that unwinds DNA, presumably so other gene from both mice and humans. The ber of times the organism can duplicate. proteins that manipulate DNA can wrig- human klotho lies in a region of the In contrast, yeast harboring a defect in gle between the strands to do their work. chromosome with no known genetic Sir2 has a curtailed life span. No one yet knows exactly how a defec- disorders. Because mice with defective Yeast Sir2 keeps large stretches of tive version of this gene, which would klotho exhibit some aspects of prema- genes turned off. Perhaps, as organisms give rise to a faulty protein, could lead to ture aging, the gene may be analogous age, they lose their ability to silence genes WS. But many ideas are floating around. to progeria genes, such as those respon- effectively, suggests Leonard P. Guarente

70 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. codes a protein that receives messages long live from hormones such as insulin and growth factors. Researchers believe genetic alterations in the worms that ren- the worms der this protein insensitive to such hormones increase their life span. No one NORMAL WORM MOUTH ALTERED WORM knows exactly how this works, but the mutant worms—known as daf-2 mu- SENSORY tants—increase production of enzymes NERVE FIBER (a) DAMAGED SIGNAL SENSORY that protect cells from oxidants [see il- SENSORY NERVE lustration at left]. NERVE CELL Studying worms suggests a general strategy for antiaging therapies. “If ag- HORMONE (b) ALTERED ing is regulated by a hormone, it can RECEPTOR probably be slowed by a hormone,” says Gary B. Ruvkun of Harvard Med- DAF-2 RECEPTOR ical School. A drug that regulates such a hormone, however, may be a mixed BODY CELL blessing. Some but not all mutations predicted to decrease hormone signal- SIGNAL ing in worms also slow metabolism. As for possible antiaging treatments, what’s REPRODUCTIVE (c) INJURY TO the point of being alive if your metab- CELLS REPRODUCTIVE olism is so slow that you’re essentially CELLS asleep? Still, it’s possible that scientists could ﬁnd a hormone that affects longevity but not metabolism. Drugs that target such a hormone might prolong life without making people sluggish. Fur- thermore, many daf-2 mutants remain healthy and vigorous for much longer than their normal counterparts do, suggesting that extending life without slow- TAIL ing anyone down might be relatively easy, says Cynthia J. Kenyon of the Uni- CELL TWEAKING: The reproductive and sensory systems of the worm Cae- versity of California at San Francisco. norhabditis elegans send signals affecting activity of hormones that stimu- Every organism has its idiosyncrasies, late the daf-2 receptor on certain cells (left). Experiments suggest that those but many basic truths of nature apply OU

EL hormones influence longevity. Manipulated worms (right) live longer than across the boundaries of species. The AP

AR normal when their sensory nerves are cut (a), the hormone receptor is ge- discovery of hormones that apparently . K netically inactivated (b) or particular reproductive cells are injured (c). control life span, or some aspect of age-

JOHN W related diseases in worms and mice, hints at a general biological mechanism of the Massachusetts Institute of Tech- If natural aging results from general for health and longevity that extends be- nology. In this scenario, activation of deterioration of various bodily functions, yond any single organism. In the future, particular genes would spur changes in it might seem surprising that single mu- we may be able to apply lessons learned physiology that lead to aging. Mam- tations could dramatically lengthen life. from our simpler cohabitants to stay mals, too, carry a Sir2-like protein, and it Last year, though, researchers reported younger and healthier ourselves. may function in a manner similar to that a strain of mouse that can live almost a of the one in yeast. Adding to the evi- third longer than normal because of a Evelyn Strauss is a science writer based dence, results in mice suggest that loss of mutation in one gene. in Santa Cruz, Calif. silencing may promote mouse aging, says It’s now known that single gene mu- Bruce M. Howard of the National Insti- tations in other organisms can lengthen tutes of Health. Other genes increase life life span. Several long-lived worms carry Further Information span when overproduced as well. In ﬂies, mutations in a gene involved in a pro- Basic information about progeria can be extra copies of enzymes that neutralize cess that appears to use chemical signals found at the Progeria Research Foun- oxidants, harmful oxygen-containing to trigger activities inside cells. The dation site at http://progeriaresearch. molecules, extend the insects’ lifetimes. gene resembles one in humans that en- org on the World Wide Web.

TWO CLUES: Studies of identical twins—including Sonja Buth and Wilma Bruno (right)—in which only one sibling (Buth) has Alzheimer’s

Zuma Press Zuma Press may determine to what extent genes and the environment contribute to the disease. JAMES ARONOVSKY

72 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. THE FIGHT AGAINST TWO LIFE-ROBBING DISEASES, ALZHEIMER’S AND good PARKINSON’S, HAS JUST BEGUN brains from going bad BY MIA SCHMIEDESKAMP

t’s hard to believe now, but 30 years ago the average layman and the average doctor thought that “senility” was the result of either normal aging or hardening of the arteries. “What do you expect from an old person?” people would say. Mercifully, science has enlightened this rather Dickensian view. Today we may be close Ito understanding what causes the major neurological diseases of old age, which ravage mental and physical function—the very stuff of life—and in their extreme form can kill. But that does not mean we’ve found cures for the four million Americans suffering from Alzheimer’s disease and the one million with Parkinson’s. The numbers could swell fourfold by 2040 as baby boomers reach old age. Legions of us worship at the temples of Physical Fitness and Cooking Light, in an attempt to ensure strong bodies at retirement. But what can we do when it’s our brains that be- tray us? The silent siege of Alzheimer’s causes a relentless deterioration of memory and bodily control. The disease is a formidable foe. Most Alzheimer’s patients are in their 70s and beyond, and those who survive into its ﬁnal stages lose the ability to speak, walk, even lift their head as their brain slowly shuts

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 73 Copyright 2000 Scientific American, Inc. BRAIN SCAN: Reds and yellows indicate a brain’s glucose metabolism. There is a progressive decrease from a normal older person (left) to mild Alzheimer’s (below) to advanced disease (right), which resembles activity in an infant’s brain (far right). edicine ol of M U.C.L.A. Scho HELPS Y SMALL AND MICHAEL P GAR down. Given how debilitating the phys- a structure closely ical throes are, it is confounding that tied to memory —at- the disease first appears years earlier as rophies and shrinks mental troubles such as chronic forget- in Alzheimer’s pa- fulness and difficulty handling routine tients. The decline is chores. Indeed, the onset is so elusive evident even during that doctors are only now determining MCI. Someday a combination of memo- can’t figure out what you would do to where normal aging of the brain stops ry tests and magnetic resonance imaging get them back.” and Alzheimer’s begins. may offer early warnings to those des- Mohs points out that everybody gets The borderland is a state called mild tined for Alzheimer’s —valuable informa- more forgetful with age. “The rate at cognitive impairment (MCI). Individu- tion if drugs are developed that can pre- which people can put new information als with MCI aren’t demented, but they vent the disease or stop its progression. into memory does slow down. When do perform worse than their peers on Elderly people who feel forgetful but they say, ‘I forget more,’ it’s usually that memory tests. They sense they are for- perform well in cognitive tests—Pe- they just didn’t learn it quite as well.” getful, and somebody close to them has tersen refers to them affectionately as Elderly people can boost memory by probably noticed it, too. Otherwise, “the worried well”—develop Alzheim- taking extra time and care to learn new they do quite well, although demanding er’s at much lower rates, about 12 per- information. tasks such as mastering new technology cent over four years in Reisberg’s study. may prove challenging. All that’s necessary, Reisberg says, is Rays of Hope People who meet the criteria for MCI “to reassure them.” will evolve to clinical Alzheimer’s dis- Older people these days do seem quick nce Alzheimer’s is diagnosed, fami- ease at a rate of 10 to 15 percent a year, to diagnose themselves or loved ones as lies can brace for the future, but according to Ronald Petersen, director having Alzheimer’s when they are just O the medical profession finds itself of the Mayo Alzheimer’s Disease Cen- experiencing simple forgetfulness. The at something of a loss. Neurotransmit- ter. “That’s in contrast to normal elder- knee-jerk response is in part the result ter-boosting drugs such as Aricept help ly people,”—without MCI—“who do of stepped-up media coverage. about 50 to 70 percent of patients, ac- so at a rate of 1 to 2 percent a year,” he So what should set off alarms? Fail- cording to Peter Rabins of the Johns says. Barry Reisberg, clinical director of ure to remember important items with Hopkins School of Medicine, but their the Silverstein Aging and Dementia Re- increasing frequency, Petersen says — efforts are modest. Rabins says, “I ask search Center at New York University, “things that you would have remem- families to think back to what the per- finds similar trends. When he tracked bered without question six months son was able to do seven or eight months people with MCI in their early 70s, ago”—especially if other people also ago; that’s an average improvement.” about two thirds progressed to Alzheim- say they see a change in you. “It’s not Although this reprieve is precious, it’s er’s within four years. that you misplaced your keys,” adds unclear if any improvement can last Images of the brain can help pinpoint Richard Mohs of the Mount Sinai longer than a few months. For now, those most at risk. The hippocampus — School of Medicine. “It’s that you managing Alzheimer’s consists mainly of

74 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. thwarting major killers emotional and practical support, plus compared with their cage-potato coun- 1,100 New York City women for up to strategies to help patients retain skills terparts. Others have found that pro- five years for the appearance of Alz- and live a full life [see box on next page]. longed stress actually leads to hippo- heimer’s. The women who had taken An ounce of prevention may be worth campal atrophy. estrogen for longer than a year showed a pound of cure. Various studies, includ- The search for ways to slow or pre- the greatest benefit. ing a landmark University of Kentucky vent Alzheimer’s is widening. The nuns, Studies in Minnesota, Baltimore and study of elderly nuns belonging to the as well as identical twins and a group Italy have yielded similar results, and order of the School Sisters of Notre of women in upper Manhattan, are the researchers hope that estrogen can also Dame, suggest that the brain’s ability to primary test subjects. Many of the help prevent dementia in those with resist dementia is greater if it has been School Sisters nuns donate their brains Parkinson’s disease. But estrogen is a mentally stimulated throughout life. “If to the University of you don’t use it, you lose it,” exhorts Kentucky’s Sanders- the University of Kentucky’s William Brown Center on Ag- Markesbery, part neuropathologist, part ing; Markesbery, the personal trainer. center’s director, has Richard Mayeux, director of the Taub examined them and Institute on Alzheimer’s Disease and the others. One remark- Aging Brain at Columbia University, able thing he sees are also finds that people with complex jobs organs rife with the edicine ol of M U.C.L.A. Scho HELPS Y SMALL AND MICHAEL P GAR

lesions characteristic powerful hormone; although many of Alzheimer’s—from women take it to mitigate the effects of individuals who were menopause, it is implicated in promot- not demented. ing certain cancers of the reproductive Perhaps these brains system. Until clinical trials better estab- had something extra lish the ratio of risk to reward, Mayeux in reserve, or maybe doesn’t recommend taking estrogen they avoided stroke. solely to protect against Alzheimer’s. Dementia from vascular disease alone Scientists are eager to devise drugs have reduced risk of Alzheimer’s no mat- is fairly uncommon in the U.S. But that imitate estrogen’s positive role in ter their education—suggesting again among nuns with the brain lesions of cognition without subjecting women to that intellectual challenge throughout Alzheimer’s, those who also had tiny an increased risk of cancer. Estrogen life is important. Mohs of Mount Sinai strokes were more likely to be dement- may stave off Alzheimer’s disease by di- suggests exercising the brain by read- ed. To lessen the risk of stroke, Markes- rectly influencing nerve cells in the ing, taking classes and joining intellec- bery advises people to eat right, exercise, brain. Researchers hope to find chemi- tually engaging clubs. not smoke, and keep blood pressure cal substitutes that affect only these cells. Caring for the body is a good idea, and diabetes under control—good ad- Such drugs might benefit men, too: males too. People who are aerobically fit tend vice in any case. produce estrogen from testosterone, and to suffer less cognitive decline with nor- Aging women in upper Manhattan testosterone levels wane with age. The mal aging. Intriguingly, when Fred H. point the way to another possible pro- right estrogen might delay Alzheimer’s Gage of the Salk Institute for Biological tection: estrogen. “For women who took in men without subjecting them to the Studies in La Jolla, Calif., allowed mice estrogen in the postmenopausal period, feminizing effects of traditional hor- to run at will—about five kilometers a the risk of developing Alzheimer’s dis- mone therapy. day on average—they generated many ease subsequently was reduced by half,” Other promising leads come from more new neurons in their hippocampi explains Mayeux, who monitored about studies of identical twins. In the early

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 75 Copyright 2000 Scientific American, Inc. coping with About two thirds of Alzheimer’s patients are cared for at home by family, according to Peter Rabins of the alzheimer’s Johns Hopkins University School of Medicine. This can be tough. The founding of the Alzheimer’s Association in alk of an eventual cure for Alzheimer’s generates a 1979 focused resources to help those family members, lot of excitement, but millions of people must deal he says. What the families need is practical assistance: an Twith the devastation of the disease right now. Much aide to help with bathing, day care so the breadwinner depends on creative coping. can work, and emotional support. Barry Reisberg of New York University has studied the Teaching families specific coping strategies can allevi- course of Alzheimer’s for more than two decades. He ar- ate depression—among patients and caregivers alike. gues that the characteristic decline can be understood “Oftentimes it’s just become this stressful, difficult situa- best as a reversal of childhood development. The sufferer tion,” says Linda Teri of the University of Washington. incrementally loses the ability to handle finances, then “The patients can’t do things they used to enjoy, they to dress, then to be continent, speak, walk and sit up. get frustrated, and the caregivers may not understand This view must be handled with what they still like to do.” caution, so that the adults are not NEW DAY: Patients with advanced dis- One important focus is identify- infantilized. But it may be useful in ease relearn basic skills at the Maria ing appropriate pastimes. The fam- guiding caregivers. “A [late-stage] Wolff Alzheimer’s center in Madrid. ily members of one former profes- Alzheimer’s patient requires the sor with Alzheimer’s discovered a same amount of care as an infant,” pleasant, stimulating activity after Reisberg says, and he doesn’t mean recalling how he loved doing the just feeding and bathing. “You would New York Times crossword puzzle. read to an infant; you should be They found a variety of children’s reading to the [late-stage] Alzheim- word puzzles he could still handle.

er’s patient, too.” What the Alzheim- “You give caregivers strategies, ’S CENTER er’s sufferer needs most is attention ideas,” Teri says, “and they come and activity. Simple exercise reduces back and say, ‘We had a nice day agitation. Visiting them when they yesterday. We haven’t had that in a get restless at night calms them. long time.’” —M.S. OLFF ALZHEIMER MARIA W

1980s John Breitner, now at the Johns persons with a family history of Alz- competing theories. One of the strong- Hopkins School of Public Health, helped heimer’s-like dementia for a random- est—and the one most drug companies to show that Alzheimer’s disease aggre- ized prevention trial that could nail are pursuing—is that the primary villain gates in families: “If you could follow down the role of anti-inflammatories. is a protein fragment called Aß (A-beta) hypothetical relatives of somebody with Markesbery advocates a regimen in- that clumps into plaques in Alzheimer’s- the disease, let’s say siblings, out to age cluding high doses of vitamin E, C and affected brains. Aß results when a ubiq- 90 or 95, then almost half those siblings folic acid, plus nonsteroidal anti-inflam- uitous protein called amyloid is snipped would themselves get the disease—a matories for those at highest risk of Alz- to pieces by two enzymes called proteas- much higher rate than in the general heimer’s—people whose close relatives es. Aß is present in everyone, although population.” To tease out how much of have the disease, for example. But physi- no one is sure what it does. But when this aggregation is a result of genetic in- heritance, rather than shared family environment, several groups studied the Anti-inflammatory drugs may occurrence of Alzheimer’s in identical and fraternal twins. The studies suggest that one half to three fourths of a person’s disposition to Alzheimer’s is in- reduce risk of the disease. herited. But that leaves plenty of room for outside influences. At Duke University, Breitner and his cian supervision is required; some of disposal of Aß can’t keep up with its colleague Brenda Plassman focused on these compounds thin the blood and can production, trouble may loom. Various twin pairs in which only one twin had cause gastrointestinal bleeding. “Right genetic mutations that cause rare early- Alzheimer’s. The disease often develops now we’re not recommending it for onset Alzheimer’s increase the produc- in the initially unaffected twin after a those who don’t have the risk factors,” tion of Aß, whereas two other genes al- lag, but in some identical pairs the sec- Markesbery notes. Eric B. Larson, a tered in late-onset disease may be im- ond twin remains free of disease for 20 longtime Alzheimer’s researcher at the portant for clearing Aß. years after it appears in the first, in one University of Washington Medical Cen- Protease-inhibiting drugs are in the case almost two decades. The research- ter, says, “In my own practice, I don’t works at several pharmaceutical com- ers studied the histories, lifestyles, infirm- recommend taking any drug for the panies, in hopes that simply cutting back ities and medications of many pairs. principal purpose of preventing cogni- Aß production will prevent Alzheim- “What surprised us,” Breitner says, “was tive decline. There’s nothing out there er’s. “Drugs are about to enter clinical an unexpected association between use that’s convincing enough.” trials. They really exist, and they reverse of anti-inflammatory drugs and the ab- Greater insight may come from un- plaque lesions in mice,” reports Dennis sence of disease in the unaffected twin.” derstanding the mechanisms underlying Selkoe of Harvard Medical School, who Many studies have since suggested that Alzheimer’s disease. There are many has been hunting down Aß for years. nonsteroidal anti-inflamma- Similar medicines have met tory drugs, such as ibupro- with great success in the past, fen, are associated with a delaying alzheimer’s including the protease inhib- reduced risk of Alzheimer’s, itors that have recently revo- but other results have been with estrogen lutionized HIV treatment. But contradictory. The jury is 100 even if the new drugs block also out on other substances 90 Aß overload and plaque for- proposed as neuroprotective, 80 mation, it remains to be including very high doses of 70 proved whether that’s enough vitamin E, until more studies 60 to beat Alzheimer’s. And there are completed. The wait for are always worries about side 50 Estrogen Use definitive answers shouldn’t effects. 40 More Than a Year be long. Several trials spon- Less Than a Year Another promising ap- 30 sored by the National Insti- Never proach is vaccination to spur tutes of Health or pharma- 20 the body’s own immune sys- ceutical companies are al- 10 tem to clear Aß. Mice that Subjects Free of Alzheimer’s (percent) of Alzheimer’s Subjects Free ready under way, testing 65 70 75 80 85 90 95 overproduce Aß develop Alz- anti-inflammatories and vi- Age at Onset heimer’s-like plaques as they tamin E in hundreds of sub- age; immunization with Aß jects with mild cognitive im- AFTEREFFECT: In a Columbia University study, women not only prevents the appear- CE pairment. A group led by who had taken estrogen for postmenopausal treat- A ance of such plaques in young Breitner at Johns Hopkins ment also postponed the onset of Alzheimer’s. mice but reduces the extent of URIE GR A is seeking over 2,600 older L existing plaques in older ani-

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 77 Copyright 2000 Scientific American, Inc. thwarting major killers mals. Human clinical trials are now un- ical dopamine. Without dopamine, neu- tek of Emory University. “One patient der way at Elan Pharmaceuticals, a firm rons that control motor activities go told me about being bent over his couch in South San Francisco that Selkoe haywire, leading to shaking, slowness to pick something up, and he froze like helped to start in the 1980s. “Drug com- and rigidity. As more and more dopa- that for two hours.” Many people also panies are working 24 hours a day, and mine-producing neurons die, sufferers develop involuntary motions in response so am I,” he explains. “My wife says, can develop balance problems, crip- to the drug. ‘Why don’t you get going—you’re going pling distortions of the hands and feet, The new challenge of Parkinson’s to get the disease before you cure it.’ I and episodes of freezing in midstep. treatment is to smooth out levodopa’s don’t want that to happen.” Late-stage Parkinson’s often means con- effect or retire the chemical altogether. finement to bed and wheelchair. One long-standing strategy is pairing Calming the Parkinson’s Storm Levodopa can’t halt the progress of levodopa with other drugs. Some com- the disease, but it can replace missing pounds ensure a richer stream of lev- tronger signs of hope for fighting dopamine, with miraculous effect. Many odopa to the brain. Others act to delay neurodegenerative disorders may be of those afflicted with Parkinson’s are temporarily the onset of levodopa ther- S found in the history of treatment for symptom-free after their first dose. Doc- apy as long as possible. Then there is Parkinson’s disease, which strikes at tors started relying on the drug in the brain surgery. It turns out that certain age 60 on average. With no reliable late 1960s, and today it is almost uni- neurons that go awry in Parkinson’s are treatment decades ago, its onset often versally prescribed. “Levodopa was re- actually hyperactive; by burning a tiny meant a quick decline to years hole in specific brain regions, surgeons of crippling tremors and ri- can quell tremor and alleviate rigidity gidity. There has since been to various degrees. some success with a drug But the burning may not solve all called levodopa. The first problems, and it destroys brain cells, whisper of tremor or a slight- perhaps healthy ones needed for other ly odd gait means that a Par- functions. More and more, surgeons kinson’s sufferer has already are switching to deep brain stimulation lost 70 or 80 percent of a tiny (DBS). In this technique, an electrode segment of the brain that inserted deep into the brain and pow- churns out the signaling chem- ered by a battery implanted near the collarbone silences neurons that would otherwise misfire. SILENT SHOCK: Electrodes DBS can turn some patients’ lives inserted deep into the brain around. Before the new surgery in 1998, deliver current from a bat- Vern Setterholm’s Parkinson’s disease tery implanted near the col- had advanced to such a degree that he larbone to quiet misfiring had trouble handling silverware, dress- neurons that cause severe ing himself, even shaping his face into a Parkinson’s disease. smile. Now the tremor in the 81-year- old retired executive’s right hand is gone, ally one of the great biologi- he can grin, and he enjoys exercise class cal successes of the century,” a few times a week. Asked whether he’d says C. Warren Olanow of have this new kind of brain surgery Mount Sinai. again, Setterholm shoots back, “If they Like most classic heroes, wanted me tomorrow, I’d be there.” though, levodopa has a dark Olanow says he has patients who are side. At first, its benefits last “totally unable to be controlled with hours on end, but after five or medicine. They are frozen, cannot move. 10 years many patients take We turn on the stimulator, and they get

er levodopa much more fre- up and start walking. It’s absolutely ent quently and still can’t get a amazing.” al C

edic consistent effect. “You could The use of DBS to control Parkinson’s be in a grocery store, reach- symptoms was pioneered in France. Al- inai M ing into your purse to pay, though still experimental, using DBS in edars-S

C and all of a sudden you go the thalamus and other brain structures UE ‘off’—you can’t move, and to ameliorate crippling rigidity is be- you don’t know when you’re coming more popular. One great pay- . LÉVESQ going to come ‘on’ again,” off: DBS often reduces the side effects

MICHEL F says neurologist Jerrold Vi- of levodopa, which can then continue

78 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. to be used to manage the disease. Ste- ven Gaede of St. John Medical Center in Tulsa, one of the first Americans to perform the procedure, figures that about 1,000 DBS operations were done in the U.S. last year. Currently DBS is used for advanced Parkinson’s patients, those “at the end of the rope,” Vitek says. There’s talk of starting much earlier, to slow Parkin- son’s before its effects become extreme. Ethical questions abound, though; the risk of major complications is 3 to 5 percent, and the benefits of early use are still highly speculative. The next dream is replacing the dopamine-producing neurons that die in Par- kinson’s. In one experimental approach o tried at several research centers, surgeons hot transplanted human fetal neurons that AP P produce dopamine into the brains of AJIC Parkinson’s patients, hoping to restore O P AMENK some normal dopamine manufacture. K They’ve achieved modest success so far. VISIBILITY: Awareness of Parkinson’s has been raised by public figures, such as Ideally, the transplanted cells would U.S. Attorney General Janet Reno, who have disclosed they are battling the disease. come from the patients themselves. This notion was outlandish just a few years ago, before scientists proved that even exciting than giving people a shiny new kills the neurons. The most promising adult human brains generate new neu- set of dopamine-producing neurons clinical trial began in the late 1980s and rons from precursors known as stem would be helping them keep the origi- involved 800 early-stage Parkinson’s cells. Gage of the Salk Institute says of nals. But no one knows what causes patients at 28 research centers. The pa- his experimental work with animals, Parkinson’s disease. The idea of a toxin tients given a drug called selegiline de- “We and others have shown that if you is intriguing. In the 1980s drug addicts layed levodopa therapy about nine take primitive cells from a lab culture, who shot up with a relative of morphine months longer than those on a placebo. you can actually put them into parts of resembling a pesticide came down with It’s not clear how much of the effect the brain that are damaged, and they the classic symptoms of Parkinson’s. was a result of preventing the disease’s can turn into cells that are appropriate Vitek says that although some patients spread, rather than relieving its symp- for whatever is happening in that part seem to be genetically predisposed to toms. (The brains weren’t dissected be- of the brain.” acquire the disease, it’s also possible that cause the patients still needed them.) Physicians are eager to harness this “exposure to an environmental insult “But there is no question that selegiline astonishing potential. Already neuro- gets the ball rolling.” The details re- slowed the appearance of disability in surgeon Michel F. Lévesque of the main a mystery. Parkinson’s patients,” says Olanow, who Cedars-Sinai Medical Center in Los An- Researchers are busy testing hundreds sat on the study’s steering committee. geles has launched the first clinical trial of drugs, hoping to toss a molecular Whether for treatment or prevention, using patients’ own cells for transplant. monkey wrench into whatever process that’s good news. From a snippet of brain taken during surgery, he says, “we are able to identi- Mia Schmiedeskamp holds a Ph.D. in biochemistry and contributes regularly to fy about 10 to 15 neural stem cells on Scientific American Presents. average.” Properly fed, these cells multiply into the millions over four to six Further Information months and are coaxed into becoming Alzheimer’s Disease: A Guide for Families. Lenore S. Powell and Katie Courtice. dopamine-producing neurons that can Perseus Press, 1993. be placed back in the patient’s own brain. Levesque has performed one such The Alzheimer’s Association outlines strategies for coping and has details of treat- transplant so far and expects to do 12 ment at www.alz.org on the World Wide Web. By telephone, call 800-272-3900. more, but it’s far too early to judge the The American Parkinson’s Disease Association offers information on treatment results. and helping patients at www.apdaparkinson.com on the World Wide Web. By Perhaps the only breakthrough more telephone, call 800-223-2732.

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 79 Copyright 2000 Scientific American, Inc. thwarting major killers stoppingc EARLY INTERVENTION MAY PREVENT CANCER FROM BECOMING INEVITABLE WITH AGE

HERCULEAN TASK: Fighting cancer can be like trying to kill the Hydra, which grew back two heads when one was severed. GIOVANNI CASELLI, REPRINTED BY PERMISSION OF EUROBOOK LTD. GIOVANNI

BY KEN HOWARD

o a degree, we are all ticking time bombs. As we eat, sleep, think and work, our cells divide again and again. Randomly over time, occasional bad copies are created. Meanwhile external insults such as tobacco smoke trigger other mutations. Most of the sin- ister cells are too crippled to survive, but some do. And sometimes they undergo further aberrations. When enough mutations have occurred, the result can be cancer. T“We are all walking around with millions of premalignant cells,” explains Robert A. Weinberg, professor of biology at the Massachusetts In- stitute of Technology’s Whitehead Institute. “If we live long enough, we’ll all come down with one form of cancer or another.” After decades of research, scientists are getting a more complete picture of cancer. Most cancers do not suddenly spring up and run wild. They develop over many years, as a result of biochemical and genetic changes that push healthy cells into a precancerous state and later into cancer. This greater understanding is now prompting researchers to find drugs that can intervene early in the process, rather than be resigned to battling cells that have already become malignant. In the short term, this “chemoprevention” strategy will probably involve chemical compounds that retard the proliferation of cancer cells in patients who have had cancer surgery, chemotherapy or radiation, buying them more years of life. In the longer term, it is hoped that these agents can slow, stop or even reverse precancerous cells from developing into the full-blown disease. Ultimately, drugs would prevent normal cells from even starting down the path to malignancy. At the same time, researchers are trying to develop cellular imaging tests that would indicate mutations early in the precancer stage, giving far more advance notice of potential trouble than do current screening tests such as PSAs, which indicate the likelihood of prostate cancer. If such early indica- tors proved reliable, they could be used throughout life, and at the first signs of trouble a chemoprevention strategy could be set in motion. Because the road to cancer often takes place over 20 years or more, it is a disease skewed toward old age. Cancer is rare among children. The median age of a U.S. cancer patient is 70, according to the National Cancer Institute. The odds of getting cancer after age 60 are 16 times greater than before age 40, according to the National Cancer Institute. Although we all carry around mutated cells, it fortunately takes a number of mutations acting in concert to create problems. Michael B. Sporn, professor of pharmacology and medicine at Dartmouth Medical School,

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 81 Copyright 2000 Scientific American, Inc. the progression toward Cells don’t “switch” from normal to cancerous. Over time, biochemical and genetic changes may cause cells to ad- cancerous cells vance gradually in a process of carcinogenesis from normal normal precancer cancer

ASHIMA Normal epithelium Hyperproliferation Low-grade dysplasia High-grade dysplasia Carcinoma in situ OMO NAR T suggests we think of our body “as a women at increased risk for breast can- mone’s effect in others. Animal studies knit sweater with 100 fibers going cer showed a 49 percent reduction in have shown that the use of two SERM along the x axis and 100 fibers along breast cancer risk for women taking ta- agents with different mechanisms of ac- the y axis. If you have one tear, you still moxifen versus a placebo. The result tion—in these cases, fenretinide and ta- have a functional sweater. But if you get was so dramatic that researchers identi- moxifen—can suppress cells’ advance- enough tears, it’s no longer a functional fied those subjects taking the placebo ment from precancer to cancer. unit. The nature of carcinogenesis is before the trial ended, so they could be- one of increasing disorganization.” gin taking the drug. Developing a Preventive Arsenal The number of tears any individual “The study proves for the first time sustains in a lifetime depends on an that you can decrease women’s chances iscovering a prevention pill for any overwhelming number of variables, of getting breast cancer by taking a pill,” one cancer will nonetheless prove from inherited genes to diet, environ- says Therese B. Bevers, medical director D difficult. In breast cancer, for in- ment and lifestyle. But the time lag be- of the M. D. Anderson Cancer Preven- stance, a variety of mechanisms are im- tween the early stages of the process tion Center in Houston. Soon after the plicated, and there are various types of that leads to cancer, called carcinogene- results were announced, the Food and breast cancer that respond differently sis, and full-blown cancer gives scien- Drug Administration approved tamox- to hormones such as estrogen. “Cancer tists a window of opportunity to stop ifen as the first drug that can be pre- is not one disease but hundreds of dis- or at least slow the process before can- scribed to reduce the risk of a cancer. eases,” emphasizes Steven K. Clinton, cer emerges. Recent trials indicate that Tamoxifen is far from perfect, how- program leader for cancer prevention certain chemicals can indeed interrupt ever. The trial linked it with an in- and control at the Ohio State Universi- the steady progression from normal to creased risk for endometrial cancer and ty Comprehensive Cancer Center. carcinogenic cells. pulmonary embolisms. Over the next Many cancers, however, harm similar 10 years, tamoxifen will be compared tissues in the body, such as the epithelial Don’t Wait with another drug, raloxifene, which is tissue that lines all internal organs. used for treating osteoporosis. During “Over half of cancer deaths in adults ancer chemoprevention research is an osteoporosis trial, it was observed are epithelial, including cancers of the 10 to 15 years behind cancer treat- that women on raloxifene had a 76 per- lung, breast, prostate and colon,” says C ment research, but the field is cent decrease in risk for invasive breast Dartmouth’s Sporn. “From what we evolving, says David S. Alberts, director cancer, but there was no corresponding know, you have to have a lot of muta- for cancer prevention at the Arizona increase in risk for endometrial cancer. tions—a series of multiple hits—to lead Cancer Center in Tucson. “We have a The Study of Tamoxifen and Raloxi- to cancer.” Because the hits accumulate lot of work to do, but it makes more fene (STAR) has already begun to enroll with age, intervening early could pre- sense to treat precancerous lesions than 22,000 postmenopausal women and will vent our cellular sweater from sustaining to wait for people to develop cancer.” follow their progress over five years. too many tears as we get older and older. The idea of prevention was demon- The trial may offer clinical corrobo- The approach, then, in designing drugs strated in practice in 1998, when a his- ration in humans of cancer prevention to thwart carcinogenesis is to take aim at toric study with a drug called tamox- seen in animal studies. Tamoxifen and various points in the process where mu- ifen demonstrated that agents could be raloxifene are known as selective es- tations may occur. One target is drugs introduced into patients to prevent can- trogen receptor modulators (SERMs)— that limit the damage from substances cer from occurring. The Breast Cancer chemicals that block estrogen reception that can cause cell mutations, such as to- Prevention Trial (BCPT) of 13,388 in some tissues while mimicking the hor- bacco smoke, environmental pollutants

Some unusual cases of cancer Clinical trial data on sulindac indicate to precancerous to cancerous. Today’s treat- may provide opportunities to that polyps regress while such drugs are ments attack only the last stages. The goal is to test the chemoprevention strate- administered but may recur afterward, detect this growth earlier and intervene. gy. For example, people with the according to Robert J. Mayer, director inherited disease familial adeno- of the center for gastrointestinal oncolo- matous polyposis (FAP)—about gy at the Dana-Farber Cancer Institute 1 percent of colon cancer pain Boston. tients—are at very high risk for It is still unknown whether Celebrex colon cancer. They are born with would reduce cancer in the general a mutation in their Apc gene, a population, and even if it did, the drug tumor-suppressant gene whose may have potentially adverse side ef- main job is to prevent cancer fects, perhaps on other organs. Investi- cells from multiplying uncontrol- gators have already begun to look at a lably. It leads to “lots of polyps broader group of patients, those with Invasive carcinoma Metastasis in the colon, and 100 percent of sporadic adenoma polyps, of whom 30 the patients then develop colo- percent will have additional polyps af- rectal cancer at a young age,” ter three years. If the drug is deemed and anything toxic we may eat—from ni- explains Waun Ki Hong, professor of beneficial and safe after a three-year tri- trosamines in bacon to pesticide residue medicine at the M. D. Anderson Cancer al, researchers might move to larger in fruits and vegetables. Another target is Center. The current standard of care is populations at less of a risk. to stop random genetic miscopies from prophylactic removal of the colon. But going further down the road toward recent understanding of the carcinogene- Future Prevention Trials cancer. A third target is to intercept “free sis of colon cancer indicates possible ad- radicals”—errant oxygen molecules re- ditional forms of treatment. Preliminary he design of trials for larger popula- leased during normal cellular metabo- data suggest that two anti-inflammatory tions will be aided by better under- lism that can damage cells and possibly drugs, sulindac and celecoxib (Cele- T standing of specific carcinogenesis trigger genetic mutations. Antioxidants brex), may reduce the number of polyps pathways. Work on the Human Gen- currently under study include selenium, in FAP patients enrolled in clinical trials. ome Project may contribute through beta-carotene and vitamin E. But the long-term efficacy is uncertain. the identification of genes that may fos-

reduce your prevention and control at the Ohio State University Comprehen- sive Cancer Center. “These people are entrepreneurs and not sci- risk of cancer entists. They are selling $50 bags of garbage.” For those of us who’d like to do something reputable to per- ost cancers stem from an accumulation of genetic faults haps increase our odds of escaping cancer, here is the accepted and exposure to environmental hazards and carcinogens medical wisdom, according to “7 Ways to Prevent Cancer,” by Mover time. Preventive strategies, such as not smoking and the Harvard Center for Cancer Prevention at the Harvard School good diet, can reduce cancer risk, but don’t be lured by fads or of Public Health. pills that can purportedly “prevent” or “cure” cancer. “There are a You can further improve your cancer defenses by knowing your lot of people who promote substances in health food stores and family’s history of cancer and getting recommended screening supermarkets,” says Steven K. Clinton, program leader for cancer tests at appropriate ages [see box on next page].

1. Eat a healthy diet. Make fruits and vegetables part of every 4. Maintain a healthy weight. Lowers risk of cancers of the meal. Opt for chicken, fish or beans instead of red meat. colon, rectum, uterus and breast. Choose foods like pasta, brown rice and whole wheat bread. Lowers risk of cancers of the prostate, breast, lung, colon, rectum, 5. Don’t smoke. This includes cigarettes, pipes, cigars and stomach and pancreas. chewing tobacco. Lowers risk of cancers of the lung, throat, pancreas, kidney, bladder, cervix, prostate, colon and rectum. 2. Get at least 30 minutes of physical activity every day. Many activities count: walking, jogging, dancing. Any activity is better 6. Protect yourself from sunburn. Stay out of direct sunlight than none. Lowers risk of colon cancer and may lower risk of breast between 10 A.M. and 4 P.M., the peak burning hours. Use hats, cancer. long-sleeved shirts, and sunscreens rated SPF 15 or higher. Do not use sunlamps or tanning booths. Lowers risk of skin cancer. 3. Drink no more than one alcoholic drink a day. One drink is a glass of wine, a bottle of beer or a shot of liquor. Lowers risk of 7. Follow safe sex practices. Some sexually transmitted infections cancers of the breast, colon, rectum, mouth, throat and esophagus. are linked to cancers of the cervix, vagina, anus and liver. —K.H.

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 83 Copyright 2000 Scientific American, Inc. early markers would also provide a basis for cancer detection evaluation of the general population for risk factors, helping doctors decide who The American Cancer Society recommends the following tests to maximize early might be a candidate for a particular detection of cancer, thereby improving the chances for effective treatment. chemopreventive agent. Other technologies to evaluate risk GENERAL factors are also being developed. Cur- A cancer-related checkup is recommended every three years for people aged 20 rently there are only a few screening tests to 40, every year for ages 40 and older. Depending on age, the exam might check (such as the Pap smear for uterine can- for cancers of the thyroid, oral cavity, skin, lymph nodes, testes and ovaries. cer) that are able to detect precancerous cells, allowing intervention before pro- BREAST gression to fully expressed cancer. If Women aged 20 to 39 should have a clinical breast exam (CBE) every three years. more tests were developed, it would Women aged 40 and older should have an annual mammogram and an annual still be difficult to access organs such as CBE. All women should perform monthly breast self-examination. the prostate, liver or breast as easily as the cervix to get cell samples. And doc- COLON AND RECTUM tors can’t biopsy the entire population. Beginning at age 50, men and women should follow one of the schedules below: Even if they could, the results wouldn’t • Fecal occult blood test every year and a flexible sigmoidoscopy every five years. support the effort: the likelihood of ac- • Colonoscopy every 10 years. tually hitting the speciﬁc spot in an or- • Double-contrast barium enema every five to 10 years. gan where cancer may be developing A digital rectal exam should be done at the same time as sigmoidoscopy, would be too small. colonoscopy or barium enema. The grand solution would be the equivalent of x-rays on the gene level, PROSTATE so that an entire organ could be evalu- Beginning at age 50, men with a life expectancy of at least 10 years should have an ated noninvasively. Unlike traditional annual prostate-specific antigen (PSA) blood test and a digital rectal exam. medical imaging, which is based on Men in high-risk groups (two or more affected first-degree relatives) and black macroscopic information such as bone men should begin at a younger age, such as 45. mass and blood flow, this “molecular imaging” could peer into cells at the UTERUS microscopic gene level, explains Ralph Cervix: All women aged 18 and older (or younger if sexually active) should have an Weissleder, director of the Center for annual Pap test and pelvic exam. After three or more consecutive successful results, Molecular Imaging Research at Mas- the Pap test can be performed less frequently, after discussion with a doctor. sachusetts General Hospital. Research- Endometrium: Women at high risk of uterine cancer should have a sample of ers must understand more about molec- endometrial tissue examined when menopause begins. ular changes in precancerous cells, how- SOURCE: “Cancer Facts & Figures 2000,” American Cancer Society ever, before imaging schemes can be devised. Weissleder estimates that practical use of this tool “is decades away.” ter initiation of tumors. Epidemiologi- validated. “We have nothing like LDL What should people do until better cal studies may also uncover precancer- [the bad cholesterol] levels that are linked imaging technology, biomarkers and ous associations. One example is the Al- to heart disease,” says Peter Greenwald, preventive drugs arrive? Wait for more pha-Tocopherol, Beta-Carotene Cancer director of the division of cancer pre- data from the dozens of chemopreven- Prevention Study (ATBC), begun in vention at the National Cancer Institute. tion trials being supported by the Na- 1985 by the National Cancer Institute. Finding a marker would improve re- tional Cancer Institute. And keep eating The trial failed to demonstrate that beta- search efficiency and save money. The your fruits and vegetables. carotene prevented lung cancer for the Finnish smokers enrolled, but analysis did show that the men in the vitamin E KEN HOWARD, a journalist based in New York City, is making sure that he eats plen- (alpha-tocopherol) arm of the study ex- ty of grapefruit and carrots. perienced 34 percent fewer cases of prostate cancer and 16 percent fewer cases Further Information of colorectal cancer. Prevention of Cancer in the Next Millennium. Report of the Chemoprevention Discovery of biomarkers that are asso- Working Group to the American Association for Cancer Research in Cancer Re- ciated with precancerous lesions could search, Vol. 59, pages 4743–4758; October 1, 1999. (For reprints, call 215-440-9300.) also become an important tool in prevention studies. Myriad markers have Harvard Center for Cancer Prevention (www.hsph.harvard.edu/cancer). been proposed, but none have yet been National Cancer Institute’s CancerNet (http://cancernet.nci.nih.gov/).

BETTER UNDERSTANDING OF ATHEROSCLEROSIS—THE INFLAMMATION AND BUILDUP

OF FATTY DEPOSITS IN BLOOD VESSELS—HAS TRIGGERED NEW APPROACHES TO TREATING THE NATION’S LEADING CAUSE OF DEATH saving hearts that BY DELIA K. CABE grow old

BAD BUGS: Common bacteria—Chlamydia pneumoniae (left), Helicobacter pylori

(right) and other ) right microorganisms—may ( cause infections that lead to heart disease. SPL/Photo Researchers, Inc. SPL/Photo Researchers, ); KARI LOUNATMAA ); KARI LOUNATMAA left ( SPL/Photo Researchers, Inc. SPL/Photo Researchers, A. B. DOWSETTA. B.

lood vessels are built to last. Up to about 100 years, can control. We get heart disease—some 14 million Ameri- some experts say, under normal wear and tear. For cans have it, and 500,000 die from heart attacks annually. that to happen, you not only have to abide by a The older we get, the more likely it is we’ll end up with it. heart-healthy lifestyle—low-fat diet, weight in The proof is in the numbers: heart disease affects an estimat- check, exercise, stress management, blood pressure ed 15 percent of adults in their late 30s to early 40s, about 50 control, good cholesterol numbers, moderate alco- percent of 55- to 64-year-olds, and 65 percent of those in the hol use, no smoking—but you also should be a next decade. Obviously, many of us slept through Heart Dis- Bwoman, have the right genes and age slowly. ease Prevention 101. Cut to reality: we’re not perfect. Our blood vessels endure Yet the heart cognoscenti say only half to three fourths of various assaults because of factors only some of which we heart disease cases result from the established risk factors. The

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 87 Copyright 2000 Scientific American, Inc. thwarting major killers rest come about from infection and other maker cholesterol as well as bacteria Such a marker as baldness may seem factors that may promote atherosclerosis, and baldness. Yes, baldness. an unlikely place to look for risk fac- the buildup of fatty deposits in blood ves- Manson and her colleagues at Har- tors. But in 1988 Manson’s group also sels. Indeed, current research indicates vard Medical School, which is affiliated found a correlation between height and that all of us are in jeopardy from the with Brigham and Women’s Hospital, heart disease. Let’s just say that taller leading cause of death in the U.S. “Every- published a study this year that found people are better off—perhaps because one needs to maintain a healthy life- that hair loss, specifically on the crown they have wider blood vessels. Such in- style,” says endocrinologist Joanne Man- of the head rather than at the front, is formation may help identify people who son, chief of the division of preventive linked to a threefold greater risk of are more prone to heart disease and may medicine at Brigham and Women’s Hos- heart disease in men. Blame it on male lead to better means for prevention and pital in Boston. “Everyone’s at risk.” hormones. The connection may be ele- interruption of disease progression tai- Efforts to find additional means of vated androgen levels, which are associ- lored to an individual’s physiology. The preventing heart disease have led to the ated with baldness and have been discovery of many of these markers unearthing of about 300 predictors, in- linked to atherosclerosis and a higher arose from a closer examination of the cluding bad relatives of the trouble- risk of blood clotting. cycle of inflammation, plaque formation and injury that causes atherosclerosis, the forerunner to angina and to heart attack and stroke, the major a primer on causes of death and disability as we move into later life. vascular disease The broadened understanding of a the underlying causes of heart dis- MONOCYTE ease has paved the way to potential SIGNAL therapies, including antibiotics and BLOOD ACE (angiotensin converting enzyme) inhibitors. ACE inhibitors were developed to control high blood pressure, but they have recent- PLATELET ly been found to have therapeutic ef- ENDOTHELIUM RUPTURED fects in preventing heart disease. b ENDOTHELIUM SMOOTH Read My Lipids MUSCLE CELLS therosclerosis, which begins in PLAQUE THROMBUS our teenage years and builds (CHOLESTEROL A up as we age, starts when the AND OTHER smooth muscle cells underneath SUBSTANCES) the endothelium, or inner lining, of blood vessels release a signal in response to high cholesterol levels. This signal attracts monocytes— white blood cells that fight infection BLOCKED and amass cholesterol, calcium and ARTERY c other substances. The resulting cheesy d mass, or plaque, bulges like a pim- TISSUE DAMAGED ple. Over time, the endothelium IN A HEART ATTACK loses its elasticity and may rupture. (MYOCARDIAL INFARCTION) This injury to the lining summons clot-forming platelets, which fur- OBSTRUCTIONS: The events that precipitate plaque-clogged blood vessels— ther restrict blood flow through the the disease called atherosclerosis—begin when smooth muscle cells under- already narrowed artery. An inade- neath the inner cell lining, the endothelium, release a signal that attracts mono- quate supply of oxygen-rich blood cytes (a). These white blood cells migrate into and under the endothelium, to heart muscle may cause tempo- where they amass cholesterol and other substances. The swollen endothelium rary chest pain, or angina, and if OU may rupture, drawing clot-forming platelets (b). The platelets may aggregate blood flow is completely cut off, a APEL red blood cells and form a blood clot, or thrombus (c). The narrowed artery AR heart attack—in clinical terminolo- . K may cause chest pain (angina) or, if completely obstructed, a heart attack (d). gy, a myocardial infarction. All this

JOHN W from the best-known harbinger of

88 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. heart trouble, the lipid cholesterol. But only to a degree. Cholesterol has been the cause célèbre in heart disease prevention. Fifty percent of Americans have elevated cholesterol levels. And the increase occurs naturally as we age—mostly after about age 45 for men and age 55 for women. Women in their reproductive years tend to have lower levels than men of the same age. After menopause, their cholesterol levels rise. But we also should fault our lifestyles. Without a doubt, lowering dietary intake of cholesterol and saturated fats does wonders for the heart. The goal is to keep down blood levels of the bad cholesterol (low-density lipoprotein, or LDL), behavior that can produce a 25 to 35 percent reduction in what the pros term “cardiovascular events”—that is, heart attacks, strokes and the like. At the same time, don’t forget about raising your levels of good DUSAN PETRICIC cholesterol (high-density lipoprotein, or HDL), which mops up LDL. studies suggest that reduction in LDLs chairman of the department of medi- But the picture’s more complex. Some may help. cine at the University of California at people develop heart disease in spite of But it now seems that some LDL par- Los Angeles School of Medicine. attaining ideal lipoprotein levels. For ticles are worse than others. In the few Normally, HDL prevents LDL oxida- them, an approach that goes beyond studies done to date, people with pre- tion. But he and other researchers have controlling cholesterol and other lipids dominantly small LDL particles have a observed HDL in its other guise. After may be in their future. risk of heart disease between three and surgery or during infections, atheroscle- Six years ago researchers with the four and a half times greater than those rotic plaques burst more easily. These Framingham Heart Study (the decades- with large LDL particles. Why does size ruptures may occur because the immune long study that brought us the term matter? Small particles are more prone system has geared up to fight infection. “risk factor”) identified a relative of to oxidizing, damaging blood vessel In this environment, HDL changes into LDL called lipoprotein(a) as an inde- walls and invading them 50 percent a molecule that promotes LDL oxida- pendent risk factor for heart disease. faster than larger particles to initiate tion. If studies bear out this model, re- Lp(a) fosters the deposition of choles- cholesterol accumulation. searchers could develop medications to terol on artery walls and interferes with thwart HDL’s metamorphosis. the body’s means of dissolving clots. Looking for Little Stuff The possibility that the inflammation Lp(a) also enhances oxidation of LDL. within the blood vessel walls and the im- Oxidation is nature’s way of spoiling blood test to measure LDL particles mune system’s response might be trig- things like food. But old food gets is useful in determining which drugs gered by an infection led investigators to thrown out, whereas oxidized LDL stays A would be most effective in individ- two bacteria—Chlamydia pneumoniae in the bloodstream and penetrates the uals with heart disease or in those who and Helicobacter pylori (the latter was endothelium. Elevated levels of Lp(a), have a strong family history of it. For- recently deemed the culprit in stomach which are most likely genetic, place peo- tunately, current heart disease interven- ulcers)—and herpesvirus. Of these three, ple in the “high risk” category, as would tions cut down small-particle LDL levels. C. pneumoniae, which causes respirato- a total cholesterol level greater than 240 These include exercising, taking niacin ry infections, has received the most at- milligrams per deciliter of blood (mg/dl) (but only under a doctor’s supervision) tention. The burning question is whether or an HDL level less than 35 mg/dl. or some cholesterol-lowering drugs. Diet this bacterium, which has been found Blood tests to measure Lp(a) have be- can also help lower triglycerides (an- in 70 to 80 percent of plaques taken come available, but Lp(a) is difficult to other type of fat in the blood). from heart disease patients, is an inno- lower. Two therapies that show promise Even the good cholesterol, HDL, turns cent bystander or an accomplice. include the vitamin niacin at prescrip- into a traitor in certain environments, Cardiologists Jeffrey L. Anderson and tion doses that are 100 times higher than much like a chameleon changes its col- J. Brent Muhlestein of the University of the recommended daily allowance and ors in different surroundings, says car- Utah are among several researchers look- the hormone estrogen. In addition, a few diologist Alan M. Fogelman, executive ing for the answer. But these two col-

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 89 Copyright 2000 Scientific American, Inc. ticked off: scores of developing heart disease by the time they were 50. Williams and others have since sifted through Type A char- anger can knock you dead acteristics and found that some of the traits are worse for your health. Overt anger has dire consequences, as Williams Barnes and Noble or Borders bookstore carries many of writes. One study found that an episode of anger doubles the 1,000 or so stress management guides, primers and heart attack risk up to two hours later. But no increased risk oc- A tomes all intent on revitalizing, detoxing and stream- curred in people who took aspirin, which prevents the blood lining the lives of road ragers and drivers in the fast lane, id- clots that could cause a heart attack. Such research hinted at a iots and dummies, managers and underlings, and a host of connection between clotting tendencies and anger. others based on the principles of Zen or the habits of zebras. Now stress researchers are focusing on blood flow to the The promise is inner peace and healing, emotional wellness heart to try to uncover a direct relation between stress and and self-renewal in six seconds, one minute, 16 minutes or a heart disease. Ischemia, a lack of blood flow to the heart day. Or you could avoid sweat- caused by narrowed or blocked ing the small stuff altogether. arteries, may produce transient Why the fervor to calm down? chest pain called angina and The most important reason can may lead to a heart attack. In the be found in the title of a book, 1990s several studies showed Anger Kills, written by psychia- that ischemia can be induced by trist Redford B. Williams, one of mental stress in the laboratory the pioneers in the research and by negative emotions in linking heart disease to Type A daily life. Hostility and anger were behavior. Type A people are usually the culprits. those who are driven, tense, Results of the largest study to competitive and hostile, and his date to measure the heart’s physi- work showed that these folks ological response to stress—which are on the road to cardiac ruin. combined blood tests and pres- Stress may age their hearts fast- sure measurements along with er than a New York minute— radionuclide angiography to view and it only gets worse as they blood flow through the heart— get older. A study conducted by reached publication in the Jour- psychologist James A. Blumen- nal of Health Psychology early thal of Duke University Medical this year. Headed by psycholo- Center, where Williams is direc- gist Mark Ketterer of Henry Ford tor of behavioral research, found Hospital in Detroit, the study that a group of physicians from showed that laboratory-induced the University of North Carolina stress—especially anger and irri- at Chapel Hill who scored in the tability—in heart disease pa- upper half of a hostility ques- HOT UNDER THE BREAST POCKET: James A. Blumen- tients caused ischemia more than tionnaire administered at age 25 thal of Duke University Medical Center uses medita- half the time. Women, who had a four to five times greater tion and other techniques to teach students strate- more readily acknowledge their chance than those with lower gies to quell anger and hostility. anger, fared better. Williams’s ODD LES T leagues were not about to take their cue researchers set their sights on humans 50 percent reduction among those treat- from the scientist who gave himself an with heart disease who had evidence of ed with the antibiotic in the frequency ulcer by ingesting H. pylori. Instead of past infection with C. pneumoniae. Af- of heart attacks, angina, stroke, and pro- hardening their arteries in the name of ter six months on the antibiotic azithro- cedures such as angioplasty and bypass medicine, Anderson and Muhlestein opt- mycin, the human subjects had a modest surgery. ed for studies on other animals. They set but significant reduction in key markers Anderson is among the investigators about infecting rabbits, which normally of blood vessel inflammation: C-reac- taking part in long-term trials now un- do not develop atherosclerosis, with C. tive protein, tumor necrosis factor, and der way at several medical institutions pneumoniae. Plaques did indeed appear, the interleukins IL-1 and IL-6, all of with large numbers of human subjects. and antibiotics reduced the number of which are released by the immune sys- If antibiotics do significantly reduce the these thickenings. tem. At the end of two years, Anderson incidence, physicians say this would be Having shown cause and effect, the and his colleagues hope to see at least a a major advance in heart disease treat-

Heart Study and others seems to point ple medical institutions was stopped six to a direct relationship. And homocys- months early and its results released last book is required reading in Ketterer’s stress teine levels in blood could be the smok- November, before publication, so that management classes, in hopes that the ing gun. Homocysteine, an amino acid study participants receiving a placebo students recognize these tendencies in that results from the body’s metabolism could also reap the drug’s benefits. themselves. of food, may contribute to atheroscle- “We got stunning results—more than Blumenthal has also published several rosis and increase clotting because it we expected,” says study chairman and studies showing that stress serves as a makes platelets stickier. In addition, ho- cardiologist Salim Yusuf of McMaster trigger for ischemia. He has found that mocysteine may lessen the flexibility of University in Ontario. “It is like the dis- stress management graduates experi- blood vessels, slowing blood flow. In covery that cholesterol drugs lower risks enced fewer ischemic episodes. But get- people such as older adults and post- of heart attacks.” The data showed a 22 ting in touch with one’s angry side is a menopausal women, who typically have percent overall reduction of heart attacks, gradual process among heart disease pa- high levels of homocysteine in their stroke or death from other cardiovascular tients in his classes. “It’s not as if a light- blood, the risk of heart attack and stroke causes. The benefit was independent of bulb goes off in their heads,” Blumenthal increases. Folate and other B vitamins ramipril’s small reduction in blood pres- says. In addition to observing other peo- may bring about a decrease in heart sure. In fact, most of the participants did ple, his relaxation wannabes learn to rec- disease risk because they break down not have hypertension when they enrolled ognize the physiological reactions to stress homocysteine. in the study. Ramipril, Yusuf adds, may and anger, such as increased heart rate have an important effect within blood and muscle tension. Folate in Your Diet vessel walls, but it is unknown if other Once enlightened, the students learn ACE inhibitors work in a similar fashion. strategies to deal with their anger and andomized, controlled trials are Now physicians can offer one more pre- hostility. Altering one’s thought patterns needed to determine if managing ventive approach to their patients. is vital. Easily angered people engage in Rhomocysteine levels, as is done with But these pills and other advances are all-or-nothing thinking, producing exag- cholesterol, could join the list of heart meant for those of us who have flaunt- gerated reactions to ordinary life events safeguards. Nevertheless, the American ed time-tested heart-saving advice or and taking everything personally. Blu- Heart Association currently advocates the few who have only their genes to menthal teaches them these ABCs in that people who are at high risk for blame for abnormal lipid levels and anger management and illustrates with a heart disease include more folate and such. As for waiting for that quick fix, familiar situation: other B vitamins in their diet—at least researchers promise none. You can hope 400 micrograms’ worth. That deed is and pray. Take it from the grand pooh- Recognize Antecedents: You are driving, accomplished simply by eating a bal- bah of heart health, American Heart As- and a car cuts you off. anced diet that includes the already rec- sociation president Lynn A. Smaha: New Assess Your Beliefs: He’s out to get me. ommended five daily servings of fruits research findings hold promise but no Know the Consequences: I feel angry. and vegetables. certainty of licking heart disease, so “in Dispute the Thoughts: The person was High blood pressure, or hypertension, the meantime, take care of yourself.” rude, but it wasn’t directed at me. was long ago shown to predispose people to atherosclerosis, heart attack and Delia K. Cabe is a freelance writer based Notice that there’s no E for yelling Epi- stroke. Hypertension is indeed an afflic- in Boston who frequently covers health- thets. Maybe if those ABCs appear on tion of aging. The number of men and related issues. bumper stickers, road rage will diminish. women with high blood pressure rapid- And those bad drivers won’t give you a ly escalates in older age groups. More heart attack. —D.K.C. than 50 percent of Americans over age Further Information 65 have high blood pressure. First-line Saving the Heart: The Battle to Con- treatment to control hypertension in- quer Coronary Disease. Stephen Klaid- volves a healthy diet, exercise and man. Oxford University Press, 2000. ment. Heart patients who show these weight loss. If that fails, physicians pre- The Michigan Electronic Library, a proj- inflammatory markers might be pre- scribe antihypertensives such as ACE in- ect of the University of Michigan and scribed medication to combat the bac- hibitors. Until the 1980s, the presumed the Library of Michigan, maintains a teria. “Until that time, though, I think and only benefit of ACE inhibitors was Heart and Cardiovascular System site: we shouldn’t be giving antibiotics to the foiling of the body’s production of http://mel.org/health/health-disease- our patients,” Anderson says, because angiotensin, a chemical that constricts heart.html studies are still ongoing. arteries, so that blood can flow through Meanwhile cardiologists are assess- vessels easier. But new research indicates Research projects on heart disease can ing whether taking folate and other B that ACE inhibitors do more. So much be surveyed at the Web site of the Na- vitamins might lower heart disease rates. more that the HOPE study evaluating tional Heart, Lung and Blood Insti- Accumulating evidence from the Physi- the effects of the ACE inhibitor ramipril tute of the National Institutes of Health: cians Health Study, the Framingham in 9,541 heart disease patients at multi- www.nhlbi.nih.gov/

WHETHER OLD AGE IS WORTH LIVING DEPENDS LARGELY ON MENTAL HEALTH BY CATHERINE JOHNSON promisedpromised landland or or purgatory

sn’t it great that we’re all going to live to 100? Sure ... if we can stay healthy that long. Will greater longevity mean 30 years of quality old age or a 30-year purgatory of pain, disability and isolation? Most of Ithe scientiﬁc work on aging concerns the physical body—genes, cells, organs, and plaques in the arteries and brain. As our bodies last longer, however, we face an increasingly daunting challenge to psychological well-being. Even if we live through bone loss, hearing decline, arthritis, heart trouble, cancer and a weakened immune system, the daily battles threat- en to wear down our spirit. ASHI ED K

Indeed, with a growing arsenal of people are asked whether they would ment the large majority of people think, countermeasures to the physical ail- rather live one year in their current con- ‘Oh, I’m going to have so much time to ments of aging, quality old age will de- dition or die sooner in good health, they do stuff,’ and then they end up watch- pend more and more on good mental choose quantity over quality. ing TV. Nonaction begets nonaction— health. And that’s a tough nut to crack, Still, choosing to live instead of die is these older people don’t move enough because age weakens our minds as much a far cry from enjoying a life that is and slide into lethargy.” as our bodies, severely challenging our happy or even marginally satisfactory. A global state of mental and physical ability to remain mentally acute and The truth is, the elderly suffer very high torpor is not much of a life. But snap- emotionally positive. There is hope, rates of depression compared with the ping out of depression by means of self- though: science is beginning to provide rest of the population. Old age can be generated positive illusions gets harder, clues about how to overcome the major a mental grind. because with advanced age, positive il- mental challenges of old age. Boston psychiatrist John J. Ratey, au- lusions become difficult to sustain. thor of the forthcoming book A User’s No one knows precisely why this is Battling Depression Guide to the Brain, sees a number of el- so, but researchers believe that age- derly patients in his practice. “Loneli- related changes in the serotonin system eople are notorious minimizers of ness is a huge issue for them. They play a key role. Serotonin is the neuro- unpleasant realities. As University don’t interact as much. They get a little transmitter most closely linked to feel- P of California at Los Angeles psy- depressed because they’re losing peo- ings of happiness, conﬁdence and calm, chologist Shelley E. Taylor and others ple, structure, function and purpose.” and it declines with age. Although the have shown, “positive illusions” are a Add the physical challenges, and a neg- neurological basis of emotion is far standard feature of the psychologically ative feedback loop begins to spiral. more complicated than the relative lev- healthy person. On the face of it, there’s They don’t feel like doing anything el of one neurotransmitter, researchers no reason why people shouldn’t simply productive, physically or mentally. As nonetheless ﬁnd that people with low continue deluding themselves into old Ratey observes, “They’re losing energy, levels of serotonin are more likely to age. Many do. When very old and sick arousal and vigilance. Going into retire- feel depressed, anxious or angry. Car-

the dangers of overmedication

y the time the average American has turned 70, the seven-day pill organizer may be overflowing with col- Bored capsules. As medicine finds more fixes for the maladies of old age, the elderly are in danger of becoming increasingly dependent on scores of pills, reducing their quality of life and potentially killing themselves via overdose or unintended drug interactions. The Golden Years are exactly the wrong time to face a panoply of pills. Neither our memories nor our kidneys are up to processing half a dozen different prescriptions half a dozen times a day. It’s just too easy to mess up (as this author—a long way from “elderly”—discovered one morn- ORBIS

ing when she took her aging dog’s medication instead of C her own). CONTRAINDICATION: Too many pills can confuse or harm. One major cause of the problem is polypharmacy—the prescribing of numerous drugs by different doctors for the Brian White, a registered nurse at the Community Hospi- same person, often for the same disorder. The marketplace tal in Dobbs Ferry, says senior citizens are routinely admit- is also implicated. “The elderly obtain drugs from many dif- ted to the emergency room who are in grave danger from ferent sources—over the counter, their local pharmacies, overdoses of necessary medication. And it doesn’t even and mail-order sources their insurance companies man- take an overdose to cause serious complications. “As you date,” notes Joseph J. Bova, owner of Cary’s Pharmacy in get older, you don’t metabolize drugs as efficiently,” White Dobbs Ferry, N.Y. “They can end up receiving the same explains, “so medications can build to toxic levels in the medication with different names and not realize they are blood. Just being dehydrated can cause a dangerously taking it twice.” high level.”

94 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. olyn Meltzer, associate professor of ra- ever. In fact, old people may show more after study has shown that social sup- diology and psychiatry at the Positron sustained cortisol production when sub- port and active engagement with other Emission Tomography (PET) Center in jected to stress tests. Apparently, we people combat depression. Pittsburgh, has found a 55 percent re- simply cannot exhaust the body’s abil- duction in serotonin receptors in older ity to flood itself with cortisol when Taking Charge subjects. (Aging women suffer the fur- life gets hairy. ther complication of a sharp decline in This sounds like some malevolent orcing yourself to fight depression estrogen after menopause. Estrogen is a Greek god’s idea of a joke. If so, it gets and stress requires initiative and precursor to serotonin in the brain.) funnier: the body’s ability to recover F planning. But the single most funda- Battling depression becomes harder from stress diminishes with age. The mental change gerontologists see in the still because the elderly find themselves stress from a virus, an argument with a normal aging brain is a 5 to 10 percent in the constant company of death. Old friend or a dip in a cold swimming pool loss of tissue in the frontal lobes, which people lose friends and loved ones at stays with you longer when you’re old are largely responsible for these very rates far higher than the rest of us. And than when you’re young. As we age, we skills, notes Mony J. de Leon, professor when you’re 90, you know that your get better at becoming stressed and of psychiatry at the New York Univer- own death is likely to be close. worse at letting stress go. sity School of Medicine. Although the Lower levels of serotonin combined brain declines slightly in size overall, no Reducing Stress with higher levels of cortisol make for a other part undergoes a change of this harsh cocktail. This is the very hormon- magnitude. aybe the most ironic fact concern- al makeup found in clinically depressed The frontal lobes are the seat of what ing the neurology of aging is that young people. Yet researchers are not neuropsychologists call “executive func- M while practically every other sig- sure how meaningful this resemblance tion” (EF), a cognitive capacity defined nificant hormone in the body declines might be. Owen M. Wolkowitz, profes- in the 1990s. Executive function is a per- precipitously with age, cortisol, the stress sor of psychiatry at the University of son’s ability to plan, organize time, stay hormone, shows no drop-off whatso- California at San Francisco, points out focused and motivate oneself. Any de- that although the elderly have higher gree of impairment to EF is going to cortisol levels, they are still within nor- hamper an elderly person’s ability to mal limits. The real villain might be a ward off depression by creating an ac- drop in DHEA, a hormone that regu- tive, purposeful and structured exis- Better drug management strategies lates cortisol. “DHEA goes down dra- tence—or even to want to do so. Ratey are the key to safety. Bova cites the Brown matically with age,” Wolkowitz says. observes that for all people, a sense of Bag program sponsored by New York “The important thing may be the ratio purpose in life—a mission—is essential State’s Pharmacists Society, available at between DHEA and cortisol.” The to happiness as well as to good brain most pharmacies, as one approach. “Pa- “grumpy old man” view of the aged function. tients are asked to bring in the contents takes on new meaning considering the An impaired EF can also interfere of their medicine chests for their phar- hormonal state elderly men (and wom- with an individual’s ability to establish macist’s review,” Bova explains. “We can en) often endure. If your balance of cor- and maintain social support. Motiva- pick up problems such as duplication of tisol is off, those crying children in the tion to see friends and family may wane. drug therapy and help avoid mistakes.” supermarket can be really irritating. Unattractive personality traits may arise, Midwesterners can find local Brown Bag Here again, negatives beget negatives. making others less inclined to spend help through the Meijer Online Pharmacy A person whose stress response system time with that individual, because an- (www.meijer.com/pharmacy/ askpharm_ is permanently stuck on high will devel- other EF function is impulse control. frameset.html). op strategies designed to limit his expo- The “grump” was there all along, but it Ultimately, though, advances in medi- sure to stress—strategies that are likely was controlled. Now the older person cine itself will provide the best solution. to result in even less involvement with can no longer manage this behavior. Researchers anticipate that when the Hu- the social world than his fading energy Stimulants may help counteract brain man Genome Project is completed we’ll has already decreed. deficits such as frontal lobe loss. Ratey discover hidden links among disorders Stanford University neuroscientist and his colleagues have begun to treat we have traditionally viewed as distinct. If, Robert M. Sapolsky observes that when the loss of energy associated with ad- say, we find an underlying genetic link old people are faced with a difficult situ- vanced age with the new medication among heart disease, Type II diabetes ation, they are more likely than younger Provigil, a novel compound that is the and high blood pressure, it’s possible people to distance themselves from it. It first to be approved for narcolepsy in 40 we’ll need only one highly refined medi- may be that the intense stress reaction, years. No one has pinned down exactly cation to treat them all. accompanied by slow recovery time, how Provigil affects brain cells, but it Until then, if you’re elderly, keep the or- makes the cost of a direct approach to has been shown to promote alertness. ganizer organized, and if you’re not, offer life’s stressors too great. Withdrawing Ratey describes one patient as “an 86- to help someone who is. —C.J. from society, however, is one of the worst year-old woman who would have to re- things an elderly person can do; study turn to bed for hours each day because

of tiredness. Now she is ‘thrilled’ with a plastic into one’s 80s and beyond. The cular systems seems to keep the brain restored energy level and sense of well- brain is not a preset, unalterable net- more pliable. One study shows that aer- being. Instead of being slumped over in work of cells. Aging connections can obic walking improves executive func- bed, she is reading, catching up on her remain flexible, and new ones can even tion in people between the ages of 60 correspondence and exercising.” Ratey be formed, regardless of how old that and 75, and there is no reason to believe has also found that Provigil can coun- gray matter becomes. This is extremely that this would not hold true for 80- teract the sedation that often accom- important because it indicates that the and 90-year-olds. The subjects’ ability panies the many medications taken by brain can reroute connections around to switch rapidly from one task to an- seniors. Soon the elderly may routinely areas that may be growing rigid with other improved, their distractibility de- be given medications like this to treat age or even bring those areas back to creased, and their ability to stop doing frontal-lobe deficits. greater functionality. whatever they were doing (like taking “The brain remains plastic until their foot off the accelerator while driv- Mental Exercise Pays Off death,” says Arnold B. Scheibel, a robust ing) increased. 78-year-old professor of neurobiology All three of these skills, by the way, f by now you’re becoming depressed and psychiatry at U.C.L.A. and former are the ones affected in childhood dis- and stressed about the prospects for a director of the Brain Research Institute. orders such as attention-deficit hyper- I mentally healthy old age, cheer up. “With plasticity we can short-circuit activity disorder. It is easy to see how Help may come from sustaining simple evolution. We can force ourselves to the notion of old age as a second child- daily habits in our lives. The key tactic evolve within our own lifetimes.” hood developed—and how age-related is to keep challenging the brain. Scientists are only beginning to un- brain deficits may one day be treated in Although some decline in hormones derstand how we can maintain our much the same way. is inevitable, mental decline is not. One brain’s plasticity, but a few promising There are reams of evidence that old of the most fundamental research find- avenues have been found. Physical ex- people who stay in touch with family, ings of the 1990s—“the decade of the ercise is one. Although the mechanism friends, church and society stay in better brain”—is that neurons and their inter- has not been pinned down, the physical shape physically and mentally. Data connections can remain remarkably exertion of the cardiovascular and mus- even show that an active social life bene-

a right to die?

dvocates of the right to die—as well as journalists may be social contact. Researchers have found that a sick covering the issue—routinely raise the horrors of or disabled senior who is surrounded by friends and fam- A old age as an argument in favor of assisted suicide, ily will tend to characterize his or her life as satisfactory. championed by Jack Kevorkian. But oldness, like beauty, Studies by Joel Tsevat of the University of Cincinnati is in the eye of the beholder. Although an 80-year-old Medical Center found that 43 percent of his subjects in might look miserable to a the worst physical condi- middle-ager, she is most tion and 51 percent with likely to compare herself severe pain described their to a 90-year-old—and to quality of life as good. In conclude that she is doing short, no one can divine an reasonably well. old person’s state of mind This positive outlook is by looking at the state of a standard feature of hu- his or her body. man psychology. Even ma- It is a slippery slope from jor illness and loss cannot believing in assisted sui- put a dent in an ordinary cide to simply assuming person’s sense of well-be- that a sick old friend or ing for more than a few relative wants someone years. In study after study, to help him or her die. Old- victims describe them- er Americans, who have a o selves as being as happy strong collective voice in hot

AP P overall as they were be- politics and culture, should fore their trauma. be allowed to speak for The trick to happiness ASSISTED SUICIDE CRUSADER: Jack Kevorkian. themselves. —C.J. WILFREDO LEE

96 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. fits brain function as much tele until 25 years ago,” as physical fitness does. Scheibel says. “And re- Staying socially active also search interest in aging goes helps maintain a positive back only another 15 years attitude, by improving before that.” feelings of self-worth. One At the social level, retire- study showed that older ment will change substan- adults who attended reli- tially or be done away with gious services at least once altogether. Scheibel him- a week had a survival ad- self exemplifies the trend: vantage over those who forced retirement has been did not attend. Whether it abolished in the University was the activity or a spiri- of California system, and tual boost, the message is he has continued to teach clear: you’ve got to stay and conduct research at engaged. U.C.L.A. Scheibel believes Elderly people who sim- the social custom of retire- ply cannot get around may ment may itself be respon- find help from the Inter- sible for the loss of frontal- net. An aged person who lobe function that we now can no longer walk or accept as normal. He notes drive can find great cheer that research work at the in keeping up with friends University of California at and family via exchanging Berkeley by his wife, Mari- e-mail, electronic photos an Diamond, “has shown and on-line chats. that if you stimulate [brain Perhaps the most critical function] you keep it; if you act in maintaining plasti- don’t, you lose it. One of city is mental exercise. As the worst things we did for Scheibel points out, mental high-achieving people was exercise keeps the brain to make them retire. Now alive. “We now realize, we’re developing legislative through some very exhaus- acts to reject this.” tive work, that the so- At 78 years old, Scheibel called aging brain is just is a committed optimist. as powerful in learning as “In most cases,” he says, younger brains. The old “aging brings about wis- phrase ‘You can’t teach an USE IT OR LOSE IT: Physical exertion helps to keep the dom.” The growing ranks brain supple; mental exercise keeps it sharp. old dog new tricks’ is sim- ASHI of elderly, he feels, will be

ply not true.” Indeed, men- ED K “like having a vastly ex- tal challenges, from cross- panded senate in our civi- word puzzles to political debates with as an entitlement, not the minor mira- lization.” We humans will not go gently friends, keep neuronal connections cle it is today. As a result, a significant into a 30-year state of disability and de- strong, just as physical exercise keeps segment of medicine will change. “Ger- spair. Once we know what the prob- muscle fibers strong. The “workout” iatrics as a specialty is only 15 or 20 lems are going to be, we will do our lesson is the same: use it or lose it. years old—there was such a small clien- best to figure out how to thrive. Undertaking completely new hob- bies, vocations, or intellectual pursuits Catherine Johnson of Irvington, N.Y., is co-author with John Ratey of Shadow can help even further. Learning in old Syndromes (Pantheon, 1997). age may take a little longer, Scheibel says, but we remain potential learners Further Information our entire lives. Why Zebras Don’t Get Ulcers. Robert Sapolsky. W. H. Freeman, 1998. More exact advice on how to preserve mental health will surely expand Time of Our Lives: The Science of Human Aging. Tom Kirkwood. Oxford as millions of baby boomers gray. The University Press, 1999. sheer numbers will change everyone’s Treatment of Depression with Antiglucocorticoid Drugs. Owen M. Wolkowitz view of what old age can and should and Victor I. Reus in Psychosomatic Medicine , Vol. 61, pages 698–711; Septem- be. Robust mental health will be seen ber/October 1999.

he prospect of living forever, or at least a millennium, has served as a T theme for storytellers throughout history. Although writers disagree over whether freedom from death would lead to an enchanted existence, an eternity of boredom and decrepitude—or more likely, some amalgam of the two— few doubt its power to fascinate people. The three excerpts from stories we have chosen (two contemporary, one from the 18th century) imagine how the achievement of a deathless existence, or the attempt to achieve it at all costs, might affect human society as well as the tenor of people’s everyday lives. The Immortal in the Mirror How would the option of eternal life extend human lives indeﬁnitely, parent- her by surprise. It had been immediate change the way we view ourselves and hood comes with certain trade-offs that and deep, eclipsing the previous loves the people close to us? In the epilogue to protect society from the perils of a world of her long life. Make no mistake, Mi- his 1999 book Time of Our Lives: The in which death is a rarity. randa’s earlier loves had lacked neither Science of Human Aging, Tom Kirk- warmth nor joy. One of them even re- wood explores these issues through an regor had entered Miranda’s life a sulted in the birth of her cherished son, imagined future in which people are reg- short time after her ninth fraitch, Nico, now one of her closest friends. ularly rejuvenated by a technique called Gwhich, she reﬂected, would put her But the problem, if problem it had been, fraitching. This technology harnesses the in her late 220s. Gregor himself was was that Miranda had always held some- mutability of stem cells, inducing them then nearing his third fraitch, which thing important in reserve. to migrate to particular parts of the made him about 150 years her junior. Holding back from full commitment body and brain to replace older cells. Not that it mattered. was a habit conditioned by the bound- Although fraitching has the potential to Miranda’s love for Gregor had taken less possibilities of an unlimited future.

NANTES TRIPTYCH (1992), BY BILL VIOLA

The only known strategy to cope with intensity and passion that went way be- choice to share bounded periods of time. this awesome prospect, short of mind- yond all of her previous experience. Fifteen full and happy years passed numbing drugs and escapist diversions, Not short of passion herself, Miranda quickly in Miranda’s and Gregor’s lives, was to cultivate and preserve an exag- found her reserve and self-absorption their time occupied with creative work gerated love of oneself. In the early cen- melting away. She delighted in Gregor’s and play. During these years, Miranda’s turies after fraitch technology was de- presence and he in hers. When Miran- love for Gregor had grown ever strong- veloped, the emotional burden of long da gave up her farmland home to live er and deeper, until the day finally came life was poorly understood and the sui- permanently in the limestone caves that Miranda made the decision that cide rate grew alarmingly high. Psycho- where Gregor had carved his beautiful would alter their lives for ever. Miranda fraitching of the mind quickly became dwelling, her friends were jolted with decided that she wanted to share with as important as the regeneration of the the shock. With the quaint exception Gregor the making of a child. cells and tissues of the body. of the Snuggees, a near-invisible sect In a world freed from the necessity of After their first meeting by the river, that inhabited the far north-east and aging, the making of children had very and during the heady weeks that fol- practiced, so it was said, the bizarre great significance. Children were still lowed, Miranda had been startled to habit of “family living,” most individu- needed to replace those who died from discover that Gregor loved her with an als preferred to live alone, meeting by accidents or suicides, but the accidental

THE QUEST TO BEAT AGING SCIENTIFIC AMERICAN PRESENTS 99 Copyright 2000 Scientific American, Inc. meditations on quality of life death rate was so small that their pro- For a person with a quota of two, responsibility for the welfare and educa- duction had to be strictly controlled. like Miranda, the making of a first tion of the child rested with the com- The method was simple and stark. child was without major consequence. munity of which the child would, in due Each individual at birth was genetically The parents might choose to participate course, become a long-term participant. screened and assigned the right to share closely in the rearing of the infant, or However, the making of the final in the making of a certain number of they might spend only occasional time child of a person’s quota was an entire- children. The usual number was two, with their child, as they preferred. They ly different matter. The birth of this last but sometimes a smaller number was might do so jointly or, more usually, as child signaled the parent’s forfeiture of awarded to limit the spread of harmful individuals. A greater preoccupation the right to any further fraitches beyond genotypes. Exceptionally, a person might with self had weakened the traditional an immediate and final one, at the com- be allowed three children if, for exam- bonding of parents with each other and pletion of which a Capsule was im- ple, the recent toll of accidents had been with their child. planted. This terminal fraitch delivered unusually great. The bonus of a third In the interests of all, it had become the same rejuvenatory effects of the ear- child was awarded by random selection. both custom and law that the primary lier fraitches, but the implanted Cap- To guard against abuse of sule imposed a delayed sen- the quota system and to pro- tence of death. At a random tect against possible genetic point in time, between 40 and damage to the reproductive 50 years from the date of im- cells, which might have a very plantation, the Capsule would long wait before use, all fer- detonate, causing the release of tilizations were carried out a sequence of neurotoxins that in vitro from stored germ would bring painless death in 5 cells. Once sufficient germ days. Any attempt at surgical cells had been removed to removal of the Capsule would cold storage, the gonads were trigger immediate detonation. rendered sterile. The bearer of such a Capsule To share in the making of a became a Timed One. child, a couple would declare It was this fate that Miranda their request in a civil cere- elected for herself when she de- mony of great solemnity, and cided to make a child with following rigorous checks on Gregor. quota status and genetic com-

patibility, the fertilization From Time of Our Lives: ck would be performed. The re- o

The Science of Human Aging, erst up sulting embryo would then by Tom Kirkwood, copyright S be raised to term either with- ©1999 by Thomas Kirkwood. in the womb of the mother Used by permission of Oxford or, as was increasingly the University Press, Inc., and Ori- custom, in fetal incubators. THIS MORTAL COIL (1992), BY CHRISTINA HOPE on Publishing Group Ltd. CHRISTINA HOPE Upgrade or Die The current obsession with aging might here were a hundred clever ways to medical vaporware, leaving their sur- pale in comparison with that of a soci- judge a life-extension upgrade. Stay vivors internally scarred and psychical- ety constructed entirely around the quest T with the blue chips and you were ly wrecked. for youth, suggests cyberpunk author practically guaranteed a steady rate of Medical upgrades were always im- Bruce Sterling. His 1996 novel Holy Fire survival. Volunteer early for some bril- proving, never steadily, but with con- depicts a time one century from the pres- liant new start-up, however, and you’d vulsive organic jumps. Any blue-chip ent, where political power is held by probably outlive the rest of your gener- upgrade licensed in the 2090s would be “gerontocrats” and the economy fueled ation. Keep in mind, though, that nov- (very roughly speaking) about twice as by the “medical-industrial complex.” In elty and technical sweetness were no effective as the best available in the this world, living longer means taking guarantees of genuine long-term suc- 2080s.... a gamble on an “upgrade” that might cess. Many lines of medical advance- Given these circumstances, it was wise leave you with obsolete hardware. ment folded in a spindling crash of to postpone your upgrade for as long as

100 SCIENTIFIC AMERICAN PRESENTS THE QUEST TO BEAT AGING Copyright 2000 Scientific American, Inc. possible. The longer you waited, the bet- If you were responsible in your own almost guaranteed good health, or at ter your choices would become. Unfor- daily health-care practices, the polity least good health care. Nowadays mere tunately, the natural aging process never appreciated the way in which you eased wealth guaranteed very little. People who stopped in the meantime, so waiting the general strain on medical resources. publicly destroyed their own health had too long made you subject to serious cu- You had objectively demonstrated your a rather hard time staying wealthy—not mulative damage from natural metabolic firm will to live. Your serious-minded, because it took good health to become decline. Sooner or later you had to hold meticulous approach to longevity was wealthy, but because it took other peo- your nose and make your choice. Since easily verified by anyone, through your ple’s confidence to make and keep mon- the outcome of leading-edge research public medical records. You had disci- ey. If you were on a conspicuously pub- was unknown by definition, the author- pline and forethought. You could be lic metabolic bender, then you weren’t ities could make no guarantees. There- fore, the pursuit of longevity was de- clared a fundamental freedom left to eit GmbH tz the choice of the individual. The polity offered its best advice, consensually de- © ech rived in endless open meetings through vast thriving packs of experts, but advice was nothing better than advice. If you were smart or lucky, you chose an upgrade path with excellent long- term potential. Your odds were good. You would be around for quite a while. Your choice would become and remain popular. The installed base of users would expand, and that would help you quite a lot. If anything went wrong with your upgrade, there’d be plenty of expertise in dealing with it. If you were unlucky or foolish, your short-term gains would reveal serious long-term flaws. As the years ground on, you’d become isolated, freakish, obsolescent. The truly bad techniques were the ones that complicated your transitions to another and better upgrade. Once your quality of life was ir- reparably degraded, you’d have no VIRTUAL HEAD (1999) choice but to turn your attention to the quality of your death. kept alive fairly cheaply, because you the kind of person that people trusted There were various methods of hedg- had been well maintained. You deserved nowadays. You were a credit risk and a ing your bets. You could, for instance, to live. bad business partner. You had points be conspicuously and repeatedly good. Some people destroyed their health, demerits and got cheap medical care. You always voted, you committed no yet they rarely did this through deliber- Even the cheap medical treatments crimes, you worked for charities, you ate intention. They did it because they were improving radically, so you were looked after your fellow citizens with a lacked foresight, because they were care- almost sure to do very well by historical smile on your face and a song in your less, impatient, and irresponsible. There standards. But those who destroyed heart. You joined civil support and were enormous numbers of medically their health still died young, by com- served on net committees. You took a careless people in the world. There had parison with the elite. If you wanted to tangible wholehearted interest in the once been titanic, earth-shattering num- destroy your health, that was your indi- basic well-being of civilization. The bers of such people, but hygienically vidual prerogative. Once you were community officially wanted you kept careless people had died in their billions thoroughly wrecked, the polity would alive. You were probably old, probably during the plagues of the 2030s and encourage you to die. well behaved, and probably a woman. 2040s. The survivors were a permanent- You were awarded certain special con- ly cautious and foresightful lot. Care- From Holy Fire, by Bruce Sterling, siderations by a polity that appreciated less people had become a declining in- copyright ©1996 by Bruce Sterling. your valuable public spirit. You were terest group with a shrinking demo- Used by permission of Bantam Books, a the exact sort of person who had basi- graphic share. division of Random House, Inc., and cally seized power in modern society. Once upon a time, having money had Orion Publishing Group Ltd.

Gerontology, the science of aging, fo- which was an infallible mark that it country, not without some laughter at cuses more on improving mental and should never die.... my expense. At last, the same gentleman physical health during the time we’ve I freely own myself to have been who had been my interpreter said he got than on extending our natural life struck with inexpressible delight upon was desired by the rest to set me right span. And for good reason. To live for- hearing this account…. I cried out as in in a few mistakes, which I had fallen ever may not be to attain the exalted a rapture, “Happy nation, where every into through the common imbecility of status of the Greek gods. Long before child hath at least a chance for being human nature, and upon that allowance the advent of the scientiﬁc study of the immortal! Happy people, who enjoy so was less answerable for them.... old, Jonathan Swift documented, in his many living examples of ancient virtue, After this preface, he gave me a partic- classic account of the Struldbrugs from and have masters ready to instruct ular account of the Struldbrugs among Gulliver’s Travels, why an eternity of them in the wisdom of all former ages! them. He said they commonly acted like aging—absent the things that make liv- But happiest beyond all comparison are mortals till about thirty years old, after ing worthwhile—may not be something those excellent Struldbrugs, who, being which, by degrees, they grew melancholy to wish for. born exempt from that universal calami- and dejected, increasing in both till they ty of human nature, have their minds came to fourscore. This he learned from ne day, in much good company, I free and disengaged, without the weight their own confession: for otherwise, was asked by a person of quality, and depression of spirits caused by the there not being above two or three of O whether I had seen any of their continual apprehension of death!” … that species born in an age, they were Struldbrugs, or immortals. I said I had I enlarged upon many other topics, too few to form a general observation not; and desired he would explain to which the natural desire of endless life by. When they came to fourscore years, me what he meant by such an appella- and sublunary happiness could easily which is reckoned the extremity of liv- tion, applied to a mortal creature. He furnish me with. When I had ended, ing in this country, they had not only all told me that sometimes, though very and the sum of my discourse had been the follies and inﬁrmities of other old rarely, a child happened to be born in a interpreted as before to the rest of the men, but many more which arose from family with a red circular spot in the company, there was a good deal of talk the dreadful prospect of never dying. forehead, directly over the left eyebrow, among them in the language of the They were not only opinionative, pee- vish, covetous, morose,

) vain, talkative, but inca- / er pable of friendship, and dead to all natural af- fection, which never de- om/lee/gulliv

.c scended below their os grandchildren. Envy and ebr impotent desires are .jaff their prevailing passions. But those objects against which their envy seems principally directed, are the vices of the younger

TESY OF LEE JAFFE (www sort and the deaths of the OUR

C old. By reﬂecting on the former, they ﬁnd themselves cut off from all possibility of pleasure; and whenever they see a funeral, they lament and repine that others have gone to a harbor of rest to which they themselves never can hope to arrive. They have no remem- brance of anything but STRULDBRUGS (1912), BY MILO WINTER what they learned and

middle age, and even that is W Y very imperfect; and for the truth , NE or particulars of any fact, it is CE safer to depend on common traditions than upon their best T RESOUR recollections. The least miser- A/AR AL

able among them appear to be SC those who turn to dotage, and entirely lose their memories; these meet with more pity and assistance, because they want many bad qualities which abound in others. If a Struldbrug happen to marry one of his own kind, the marriage is dissolved of course by the courtesy of the kingdom, as soon as the younger of the two comes to be fourscore. For the law thinks it a reason- able indulgence, that those who are condemned, without any fault of their own, to a perpetual continuance in the world, should not have their misery doubled by the load of a wife. As soon as they have completed the term of eighty years, they are looked on as dead in law; their heirs immediately succeed to their estates; only a small pittance is reserved for their support; and the poor ones are maintained at the public charge. After that period, they are held incapable of any employment of trust or proﬁt; they cannot purchase lands, or take leases; neither are they allowed to be witness- es in any cause, either civil or criminal, not even for the decision of meers and bounds. At ninety, they lose their teeth TWO HEADS, BY LEONARDO DA VINCI (1452–1519) and hair; they have at that age no distinction of taste, but eat and drink sentence to the end; and by this defect, vantage of living like foreigners in their whatever they can get, without relish or they are deprived of the only entertain- own country. This was the account giv- appetite. The diseases they were subject ment whereof they might otherwise be en me of the Struldbrugs, as near as I to still continue, without increasing or capable. can remember. diminishing. In talking, they forget the The language of this country being common appellation of things, and the always upon the ﬂux, the Struldbrugs The full electronic text of Gulliver’s names of persons, even of those who of one age do not understand those of Travels, which includes the account of are their nearest friends and relations. another; neither are they able, after two the Struldbrugs in chapter 10, can be For the same reason, they never can hundred years, to hold any conversa- downloaded without charge from Proj- amuse themselves with reading, be- tion (farther than by a few general ect Gutenberg at ftp://metalab.unc.edu/ cause their memory will not serve to words) with their neighbors the mor- pub/docs/books/gutenberg/etext97/ carry them from the beginning of a tals; and thus they lie under the disad- gltrv10.txt on the World Wide Web.

y mother, who turns 39 next year (for the cal natural foods store to pick up some supplies. (Apparently, second time), says of her septuagenarian sta- I’m a health-food enabler.) While my friend wandered, pre- tus, “I always wanted to look like Elizabeth sumably examining the latest in garlic presses and garlic sup-

Taylor. And now I do.” Not everyone is so plements, I perused the soy goods. Years ago I wrote a story DUSAN PETRICIC sanguine about getting older. Some of us about the possible benefits of soy and convinced myself that fight it tooth and nail, both of which looked there was enough basic research on its anticancer and choles- whiter and shinier years ago. A friend of terol-lowering powers to make a few of the bean’s products a mineM (really, it’s a friend, not me) has embarked on a life-ex- small part of my diet. I spotted and bought some soy-based tension regimen that he expects will lead to birthday cakes vegetarian pepperoni. A few hours later I adulterated a per- visible from space. My buddy gets regular aerobic exercise, fectly respectable slice of Bronx-made Sicilian-style pizza avoids stress and eats a remarkably healthful diet consisting with thin slices of same soy. Though not terrible, it wasn’t in great part of steamed vegetables. And garlic. real pepperoni. And it probably won’t happen again. Garlic does indeed appear to impart a bounty of health After stopping at my house for a while, we prepared to get benefits. According to published reports, garlic has proved to back in the car. I then noticed that he had never taken off a be good for you in more than 1,000 studies. It seems to cut pair of thin glove liners while in my home. Now, I admit to the risk of various cancers; it lowers blood pressure; it wards being a lousy housekeeper—like nature, I abhor a vacuum— off vampires; it lowers cholesterol; it has antifungal proper- but I don’t think the place is actually dangerous. “You don’t ties. It also richly deserves its nom de fume: the stinking rose. want to touch anything here, do you?” I asked. He said, My friend, on learning of garlic’s health-enhancing powers, “No, I’m just chilly,” which may be true now that his body- replaced the apple with a clove of garlic in the old proverb re- fat levels are down to the point where even his nerve cells are garding methods to keep the doctor away. He then extrapo- probably losing their insulation. But the sheepish grin on his lated that if one clove per day was good, two or three might face convinced me that at least part of the issue might be my- be even better. I saw him recently for the first time in weeks. sophobia (which sounds like fear of soy soup but is actually As soon as I entered his apartment, the fragrance slammed dread of germs). “Listen,” I said, “I have one question. How me. As I got close to him, my eyes began to water. I instinc- you gonna keep those gloves on when your fingernails are tively (emphasis on the “stinct”) covered my nose with the two inches long, Howard Hughes?” back of my hand. “How many today?” I asked. “Seven!” he My friend could have the last laugh. I may be long dead replied proudly. I struggled for oxygen and muttered during when he is still steaming broccoli, distilling water and, of an exhalation, “Well, you’ll never get an infection, that’s for course, gobbling garlic. But I figure, based on genes and my sure. No one’s ever going to get close enough.” Sitting in his more moderate but still relatively healthy lifestyle, that I have apartment, I slowly got somewhat used to the rich bouquet a solid 85 years in store, maybe more. And I swear to you, a that was making me a bit queasy and light-headed. I took a good slice of Bronx-made Sicilian pizza really is to die for. few sips of what I would have taken to be ordinary tap water but was in fact distilled, from his new home water distiller. We soon left for a drive, during which we stopped at a lo- STEVE MIRSKY is an editor and columnist at Scientific American.