A Biological Quest

National Institutes of Health National Institute on Aging Office of Communications and Public Liaison Building 31, Room 5C27 Bethesda, MD 20892-2292 Phone: 1-301-496-1752 Website: www.nia.nih.gov

NIH Publication No. 02-2756 NATIONAL INSTITUTE ON AGING NATIONAL INSTITUTES OF HEALTH “ row old along with me! The best is yet to be, Theg last of life, for which the first was made.”

—Robert Browning, (1812-1889) TABLE OF CONTENTS

Introduction i

Posing Questions, Biochemistry Physiologic 1Finding Answers 1 3and Aging 17 4Clues 29 What is Aging? What is Senescence? 3 Oxygen Radicals 18 Normal Aging 30 What is the Difference Between Life Antioxidants and Aging Nematodes 19 The Immune System 31 Expectancy and Lifespan? 4 Protein Crosslinking 20 What Is Normal Aging? 32-33 Why Do We Age? 5 Research on Sunlight May Help Explain Caloric Restriction 34 Theories of Aging 6 What Happens to Skin as We Age 21 The Next Step: Caloric Restriction DNA Repair and Synthesis 22 in Primates 36 Heat Shock Proteins 24 Behavioral Factors 38 Hormones 25 Exercise: It Works at Any Age 37 The Genetic Hormone Replacement 25 7 2Connection Hormones and Research on Aging 26-27 Longevity Genes 8 Growth Factors 28 Tracking Down A Longevity Gene 9 The Future Age-related Traits Are All in the Family 11 5of Aging 39 Microarrays in Action 12 Stem Cells: Great Expectations, In the Lab of the Long-Lived Fruit Flies 13 but Many Barriers Remain 41-42 Cellular Senescence 13 Proliferative Genes 15 Telomeres 15 Glossary/ 6 Bibliography 43 Glossary 44-45 Bibliography 46-48 “ ne of two things happens after sixty, when old age takes a fellow by the hand. EOither the rascal takes charge as general factotum, and you are in his grip body and soul; or you take him by the neck at the first encounter and after a good shaking make him go your way.”

—William Osler, 1913

Life is short, so enjoy every minute. Hang gliding, for me, lifts the spirit and recharges the old batteries. It is the greatest sport going, and lots of exercise too. — Robert Byrd hang glider, age 74 Introduction

The study of aging is not what it used to be. Gerontology was a young science when Congress created the National Institute on Aging (NIA) in 1974 as part of the National Institutes of Health (NIH). At that time, theories of aging abounded, but data was scant. Gerontology lacked, or was just in the early stages of developing, ways to explore the fundamentals of the aging process. Knowledge of aging clustered around specific dis- eases associated with advancing age; indeed the notion that aging equated with decline and illness was widespread. Now, nearly 30 years later, the science base has grown in depth, breadth, and detail. And, with this growth have come new insights into the processes and experience of aging. Where gerontologists once looked for a single, all-encompassing theory to explain aging—a single gene, for instance, or the decline of the immune system—they are now finding multiple processes, combining and interacting on many levels. Cells, proteins, tissues, and organ systems are all involved, and gerontologists are now able to discern many more of the mechanisms by which these components cause or react to aging. Much of this research has been supported or conducted by the NIA. In addition to research in its laboratories in Baltimore and Bethesda, Maryland, the Institute sponsors basic, clinical, epidemiological, and social research on aging at universities, medical centers, and other sites worldwide. As this work evolves and new knowledge accumulates, gerontologists hope to move closer to their ultimate goal of promoting health and independence throughout the lifespan.

i Aging Under the Microscope Posing Questions, FindingAnswers

In 1965, a lawyer made an unusual deal with one of his older clients, Jeanne Calment of Arles, France. In exchange for ownership of her apartment, he agreed to pay her a monthly pension for the rest of her life. Because Mme. Calment was 90 years old at the time, it seemed likely that the lawyer would only have to make a few payments before her demise. As it turned out, however, it was a much better bargain for Mme. Calment. During the next 32 years of her extraordinary life, she was paid three times the worth of the apartment. “We all make bad deals in her lawyer who died—at lives. Is it where people live? life,” Mme. Calment once age 77—soon after Mme. As of 2001, ten of the world’s joked to the astounded Calment’s 120th birthday. oldest people were Japanese, attorney. When her well- Long lives like Mme. six were American, three documented life ended on Calment’s are a wonder. were French, and two were August 4, 1997 at age 122 Of the planet’s current 6 Italian. Is there something years 5 months and 14 days, billion inhabitants, perhaps special about how these she is believed to have lived no more than 25 people are people live? Mme. Calment longer than any other person more than 110 years old. So took up fencing lessons at 85, in recorded history. She out- these super centenarians, as still rode a bicycle at age 100, lived Shigechiyo Izumi of they are known, are clearly smoked until she was 117, Japan, who had held the humanity’s ultimate mara- and ate a diet rich in olive unverified longevity record of thoners. But why? What fac- oil all of her life. In truth, 120 years, 237 days. She out- tors allowed Jeanne Calment, there probably is no single lived her husband, who died who was 14 when the Eiffel “secret” of aging. More than in 1942, four years before their Tower was completed and likely, all of these elements— 50th wedding anniversary. She who once sold painting heredity, environment, and outlived her daughter, who supplies to Vincent Van lifestyle—have complex roles died in 1936. She outlived her Gogh, to live such a long in determining whether an only grandson, who died in life that she herself became individual will have a long 1963. And yes, she outlived part of history? and healthy life, according to Is genetics the key factor? scientists who study aging. Mme. Calment’s ancestors were legendary for their long

t her 120th birthday party, a journalist hesitantly Atold Mme. Calment, “Well, I guess I’ll see you next year.” Instantly, she shot back, “I don’t see why not. You look to be in pretty good health to me!”

2 Posing Questions, Finding Answers These scientists, called lifespan beyond which we Aging Under the Micro- during the lifespan. However, gerontologists, ponder other cannot live no matter how scope: A Biological Quest this definition includes some Four brothers, below (a) 9 years old, (b) 7 years old, (c) 5 years old, and fundamental questions. Why optimal our environment describes what we know changes that aren’t necessarily (d) 3 years old; at lower right, the do we age? What happens as or favorable our genes? And so far about the answers problematic, and usually brothers pictured 52 years later. we age? Why do some people finally for all of us, the most to these questions. It offers don’t affect an individual’s Visible signs of aging can vary, even among family members, depending age faster or slower and in important question: How an overview of research viability. Gray hair and wrin- on a number of environmental and different ways than others? can insights into longevity on aging and longevity, kles, for instance, certainly are genetic factors. Is there a maximum human be used to fight the diseases describing the major puzzle manifestations of aging, but and disabilities associated pieces already in place neither is harmful. with old age to make sure and, to the extent possible, To differentiate these this period of life is healthy, the shapes of those that superficial changes from active, and independent? are missing. those that increase the risk b Researchers at the of disease, disability, or National Institute on Aging What Is Aging? death, gerontologists prefer a (NIA), part of the National What Is Senescence? to use a more precise term— Institutes of Health, are seek- Aging is a complex natural senescence—to describe ing answers to these and process potentially involving aging. Senescence is the other important questions. every molecule, cell, and progressive deterioration of Established by the Federal organ in the body. In its many bodily functions over Government in 1974, the broadest sense, aging merely time. This loss of function is NIA conducts and supports refers to changes that occur accompanied by decreased c research on aging and edu- fertility and increased risk d cates the public about its of mortality as an individual findings.

a

c

d b

3 Aging Under the Microscope turtle

Comparative Lifespans (in years) human oyster gets older. The rate and pro- sexual tissues atrophy with What is the gression of this process can increasing age. In men, Difference Between eagle Life Expectancy elephant vary greatly from person to sperm production decreases alligator ostrich person, but generally over and the prostate enlarges. and Lifespan? owl time every major organ of Why these and other When George Washington monkey th the body is affected. As we changes occur with advanc- celebrated his 60 birthday bear age, for instance, lung tissue ing age both intrigues and in 1792, he had outlived all dolphin loses much of its elasticity, perplexes gerontologists. of his male ancestors, dating lion bat dog and the muscles of the rib In fact, senescence is one of back for several generations. snail cage shrink. As a result, nature’s least understood bio- He had outlived a typical mouse maximum vital breathing logical processes. Gerontolo- Virginian of his era by about capacity progressively dimin- gists, for instance, disagree 15 years. To achieve this ishes in each decade of life, about when senescence relative “old age,” he had 4 18 20 24 30 30 47 50 62 66 68 70 80 100 122 150 beginning at about age 20. begins. Some argue it begins survived smallpox, mumps, With age, blood vessels accu- at birth. Others contend it pneumonia, dysentery, mulate fatty deposits and sets in after the peak repro- typhoid fever, a staphylococ- fairly primitive, and the life lose much of their flexibility, ductive years. But clearly, cal infection of the hip, four expectancy—the average resulting in arteriosclerosis or senescence, whether it begins bouts of malaria, and two number of years from birth “hardening of the arteries.” at birth or age 20, 30, or 40, nearly fatal encounters with that an individual can expect In the gastrointestinal leads to an accumulating influenza. to live—was still less than system, production of diges- loss of bodily functions, When Jeanne Calment 50 years worldwide. tive enzymes diminishes, and which ultimately increases was born in 1875, the illnesses Yet Mme. Calment, per- as a result, tissues lose much the probability of death, as that plagued Washington’s haps because she was born of their ability to break down we get older. generation still took many with a set of extraordinary and absorb foods properly. lives, health care was still genes or was simply fortunate In women, vaginal fluid enough to elude many of the production decreases and illnesses that claim so many others, beat the odds and set

4 Posing Questions, Finding Answers the benchmark for maximum As part of this quest, human lifespan—the greatest gerontologists are studying age reached by any member a variety of life forms includ- of a species. ing yeast, fruit flies, nema- Life expectancy in the todes, mice, and primates United States rose dramati- in search of clues applicable Why Do We Age? knowledge, all-encompass- cally in the 20th century, from to human aging. As they Gerontologists have pro- ing theories of aging are about 47 years in 1900 to explore the genes, cells, and posed many theories to giving way to a more about 73 years for males and organs involved in aging, explain the diversity of the diverse perspective. 79 years for females in 1999. they are uncovering more aging process in nature. Aging today is viewed This increase is mostly due and more of the secrets of Pacific salmon, for instance, as many processes, inter- to improvements in environ- longevity. As a result, life reproduce only once and die active and interdependent, mental factors—sanitation, extension may some day be within hours of spawning, that determine lifespan and the discovery of antibiotics, more than the stuff of myth. while at the other end of health, and gerontologists and medical care. Now, as In addition, as gerontologists the spectrum, sea anemones, are studying a multitude scientists make headway apply their expanding know- which reproduce asexually, of factors that may be against chronic diseases like ledge to medicine, the pre- show few, if any, outward involved. The rest of this cancer and heart disease, vention or retardation of the signs of deterioration until booklet describes what we some think life expectancy onset of some age-related the very end of their long know and don't know about can be extended even further diseases and disabilities lives. Most gerontologists many of these factors, and in the 21st century. may become realistic goals. now agree that no single where we think scientists theory can account for this are likely to find answers wide spectrum. In fact, with to questions about aging and longevity. “ the tools of biotechnology ext to the miracle of life itself, aging and death and an influx of new are perhaps the greatest mysteries.” N Pacific salmon, above, live about —Caleb Finch, Ph.D. 5 years and reproduce only once. They Gerontologist, University of Southern California undergo rapid physical deterioration and die soon after breeding. In contrast, Rougheye rockfish, right, are estimated to live more than 200 years, yet show few outward signs of aging and are apparently capable of reproducing fre- quently, even in late life. These differ- 5 ences intrigue some gerontologists. Aging Under the Microscope Theories of Aging

Theories of aging fall into two groups. The programmed ERROR THEORIES theories hold that aging follows a biological timetable, Wear and Tear. Cells and tissues have vital parts that perhaps a continuation of the one that regulates child- wear out. hood growth and development. The damage or error Rate of Living. The greater an organism's rate of oxygen theories emphasize environmental assaults to our systems basal metabolism, the shorter its life span. that gradually cause things to go wrong. Many of the theories of aging are not mutually exclusive. Here is a Crosslinking. An accumulation of crosslinked proteins brief and very simplified rundown of the major theories. damages cells and tissues, slowing down bodily processes.

PROGRAMMED THEORIES Free Radicals. Accumulated damage caused by oxygen radicals causes cells, and eventually organs, Programmed Longevity. Aging is the result of the sequen- to stop functioning. tial switching on and off of certain genes, with senescence being defined as the time when age-associated deficits are Somatic DNA Damage. Genetic mutations occur manifested. and accumulate with increasing age, causing cells to deteriorate and malfunction. Endocrine Theory. Biological clocks act through hormones In particular, damage to mitochondrial to control the pace of aging. DNA might lead to mitochondrial Immunological Theory. A programmed decline in immune dysfunction. system functions leads to an increased vulnerability to infectious disease and thus aging and death.

Four generations of a family. Although it is fairly easy to estimate the approximate ages of the women in this picture, gerontologists have not yet found any reliable way to measure these stark differences in human age under the microscope — either at the cellular or molecular level. Most gerontologists now believe no single theory fully explains the changes that occur in the aging body. 6 Posing Questions, Finding Answers Some families seem There is little doubt about human aging and can perform nearly 2,000 blessed with long lives. In that genes have a tremen- longevity (See Tracking roundworm studies in the fact, siblings of centenarians dous impact on aging and Down a Longevity Gene, time it would take them have a four times greater longevity. Based on studies page 9). to do one human study. Mary Lavigne, age 102, shares a laugh in her home with Thomas chance of living into their of identical twins, who share Under normal condi- Perls, M.D., founder and director early nineties than most peo- the exact same set of genes, Longevity Genes tions, some genes are of the New England Centenarian ple, according to researchers scientists now suspect that Researchers have found thought to manufacture Study. Ms. Lavigne has lived in three centuries. Perls and his The at the New England Cente- lifespan is determined by evidence of several genes proteins that limit lifespan. colleagues are studying centen- narian Study in Boston. A both environmental and that seem to be related to But when these same genes arians and their siblings for signs Genetic of longevity genes and other coincidence? Hardly. What genetic factors, with genetics longevity determination. are mutated, they either genetic traits. likely helps set these hardy accounting for up to 35 per- Longevity-related genes produce defective proteins individuals apart are extra- cent of this complex interac- have been found in tiny or no proteins at all. The ordinary sets of genes, the tion. Although different roundworms called nema- net effect is these mutations coded segments of DNA animal species vary up todes, in fruit flies, and even promote longevity. Connection (deoxyribonucleic acid), to 100 times in lifespan— in mice. Like yeast, nema- which are strung like beads humans live five times todes and fruit flies have along the chromosomes of longer than cats, for attracted a lot of attention nearly every living cell. In instance—scientists are dis- from gerontologists because humans, the nucleus of each covering some surprising their short lifespans and their cell holds 23 pairs of chromo- similarities between our well-characterized genetic Each year on her birthday, Jeanne Calment sent her lawyer somes, and together these genes and those of other composition make them chromosomes contain about species. Even single-celled relatively easy to study. a note, which read, “Excuse me if I’m still alive, but my 30,000 genes. yeast, one of nature’s Investigators, for instance, parents didn’t raise shoddy goods.” Her brother, who died simplest organisms, may provide scientists with at age 97, apparently wasn’t too “shoddy” himself. When important genetic clues another super centenarian, Sarah Knauss of Allentown, “ don’t think the trick is staying young. Pennsylvania, died in 1999 at age 119, her daughter was 96. I I think the trick is aging well.” — Thomas Perls, M.D. Director, New England Centenarian Study 8 The Genetic Connection Some families seem There is little doubt about human aging and can perform nearly 2,000 blessed with long lives. In that genes have a tremen- longevity (See Tracking roundworm studies in the fact, siblings of centenarians dous impact on aging and Down a Longevity Gene, time it would take them have a four times greater longevity. Based on studies page 9). to do one human study. Mary Lavigne, age 102, shares a laugh in her home with Thomas chance of living into their of identical twins, who share Under normal condi- Perls, M.D., founder and director early nineties than most peo- the exact same set of genes, Longevity Genes tions, some genes are of the New England Centenarian ple, according to researchers scientists now suspect that Researchers have found thought to manufacture Study. Ms. Lavigne has lived in three centuries. Perls and his The at the New England Cente- lifespan is determined by evidence of several genes proteins that limit lifespan. colleagues are studying centen- narian Study in Boston. A both environmental and that seem to be related to But when these same genes arians and their siblings for signs Genetic of longevity genes and other coincidence? Hardly. What genetic factors, with genetics longevity determination. are mutated, they either genetic traits. likely helps set these hardy accounting for up to 35 per- Longevity-related genes produce defective proteins individuals apart are extra- cent of this complex interac- have been found in tiny or no proteins at all. The ordinary sets of genes, the tion. Although different roundworms called nema- net effect is these mutations coded segments of DNA animal species vary up todes, in fruit flies, and even promote longevity. Connection (deoxyribonucleic acid), to 100 times in lifespan— in mice. Like yeast, nema- which are strung like beads humans live five times todes and fruit flies have along the chromosomes of longer than cats, for attracted a lot of attention nearly every living cell. In instance—scientists are dis- from gerontologists because humans, the nucleus of each covering some surprising their short lifespans and their cell holds 23 pairs of chromo- similarities between our well-characterized genetic Each year on her birthday, Jeanne Calment sent her lawyer somes, and together these genes and those of other composition make them chromosomes contain about species. Even single-celled relatively easy to study. a note, which read, “Excuse me if I’m still alive, but my 30,000 genes. yeast, one of nature’s Investigators, for instance, parents didn’t raise shoddy goods.” Her brother, who died simplest organisms, may provide scientists with at age 97, apparently wasn’t too “shoddy” himself. When important genetic clues another super centenarian, Sarah Knauss of Allentown, “ don’t think the trick is staying young. Pennsylvania, died in 1999 at age 119, her daughter was 96. I I think the trick is aging well.” — Thomas Perls, M.D. Director, New England Centenarian Study 8 The Genetic Connection Worms, Genes, and Aging For instance, a mutation of worms. One of these genes, Kenyon’s team found lifespan a gene whimsically named called daf-2, controls a special of well-fed worms, which did Tracking Down a Longevity Gene “I’m Not Dead Yet” or INDY, stage in the worm’s develop- not form a dauer, could be can double the lifespan of ment called dauer formation. doubled. Other investigators Investigators are finding clues to aging and longevity In his second experiment, Jazwinski mutated the gene. fruit flies. In studies sup- A dauer forms, if, in the first have detected mutations in in yeast, one-celled organisms that have some intrigu- When he introduced this non-working version into a ported by the NIA, these fruit few hours of its brief life, a similar daf genes that increase ing genetic similarities to human cells. In a laboratory group of yeast cells, they had only about 12 divisions. flies not only lived longer, worm finds food scarce. In nematode lifespan three or at Louisiana State University Medical Center in New The two experiments made it clear that the gene, they thrived. By the time that this state, C. elegans grows a even four-fold. Orleans, Michal Jazwinski, Ph.D., has found genes that now called LAG-1, influences the number of divisions 80 to 90 percent of normal cuticle for protection and The genes isolated so YOUNG WORM seem to promote longevity in these rapidly dividing, in yeast or, according to some researchers’ ways of flies were dead, many of the can go into hibernation for far are only a few of what Early in its brief lifespan, C. elegans, Yeast could help easy-to-study organisms. a small nematode (roundworm), gerontologists thinking, its longevity. (LAG-1 is short for longevity INDY flies were still vigorous several months. When the scientists think may be moves rapidly and feeds vigorously. understand the Yeast normally have about 21 cell divisions or genera- assurance gene.) But how it works is still a mystery. and capable of reproduction. food supply is ample again, dozens, perhaps hundreds, The worm is transparent, making it genetics of aging. At least two other life-extend- the worm emerges from of longevity- and aging- easier to study physiological and More than 14 genes tions. Jazwinski observed that over the course of that One small clue lies in its sequence of DNA bases— genetic changes that occur that appear to pro- lifespan, certain genes in the yeast are more active its genetic code—which suggests that it produces a ing genetic mutations have this metabolically slowed, related genes. But tracking during its lifespan. mote the longevity been detected in the fruit non-aging state and contin- them down in organisms of these single-celled or less active as the cells age; in the language of protein found in cell membranes. One next step is to organisms have been molecular biology, they are differentially expressed. study the function of that protein. Similar sequences fly genome. ues its normal life cycle. like nematodes and fruit flies OLD WORM discovered. In C. elegans, a nematode The protein produced by the is just the beginning. The Near the end of its typical 2-to-3-week So far, Jazwinski has found 14 such genes in yeast. have been found in human DNA, so a second inves- lifespan, the worm loses muscle tone tigative path is to clone the human gene and study its (roundworm), researchers daf-2 gene drives the worm’s next big question for many and eventually stops moving. By the Selecting one of these genes, Jazwinski tried function. If there turns out to be a human LAG-1 coun- have found yet another treas- development past or out of gerontologists is whether time it dies, its body appears tattered two different experiments. First, he intro- and worn out. But by altering certain terpart, new insights into aging may be uncovered. ure trove of genetic clues the dauer state. But Cynthia counterparts in people— genes, gerontologists have been able duced the gene into yeast cells in a form about the aging process. Kenyon, Ph.D., and her human homologs—of the to keep some of these worms sleek and that allowed him to control its activity. In another laboratory, Leonard Guarente, Ph.D., of By altering certain genes, colleagues at the University genes found in laboratory vibrant for much longer than normal. When the gene was activated to a the Massachusetts Institute of Technology found that researchers can substantially of California, San Francisco, animals have similar effects. greater degree than normal, or mutation of a silencing gene—a gene that “turns extend the normal 2-to-3- found that daf-2 does much The daf-2 gene in C. elegans, overexpressed, some of the yeast off” other genes—delayed aging 30 percent in yeast. week lifespan of these tiny more. It also can regulate the for instance, is similar to a cells went on dividing for 27 or 28 The gene, which is also found in C. elegans and other lifespan of normal, fertile gene found in humans that generations; their period of activity animals, produces an enzyme that alters the structure adults. By altering this gene functions in hormone control. was extended by 30 percent. of DNA, which, in turn, alters patterns of gene so that its activity is reduced, expression.

9 10 Aging Under the Microscope The Genetic Connection Worms, Genes, and Aging For instance, a mutation of worms. One of these genes, Kenyon’s team found lifespan a gene whimsically named called daf-2, controls a special of well-fed worms, which did Tracking Down a Longevity Gene “I’m Not Dead Yet” or INDY, stage in the worm’s develop- not form a dauer, could be can double the lifespan of ment called dauer formation. doubled. Other investigators Investigators are finding clues to aging and longevity In his second experiment, Jazwinski mutated the gene. fruit flies. In studies sup- A dauer forms, if, in the first have detected mutations in in yeast, one-celled organisms that have some intrigu- When he introduced this non-working version into a ported by the NIA, these fruit few hours of its brief life, a similar daf genes that increase ing genetic similarities to human cells. In a laboratory group of yeast cells, they had only about 12 divisions. flies not only lived longer, worm finds food scarce. In nematode lifespan three or at Louisiana State University Medical Center in New The two experiments made it clear that the gene, they thrived. By the time that this state, C. elegans grows a even four-fold. Orleans, Michal Jazwinski, Ph.D., has found genes that now called LAG-1, influences the number of divisions 80 to 90 percent of normal cuticle for protection and The genes isolated so YOUNG WORM seem to promote longevity in these rapidly dividing, in yeast or, according to some researchers’ ways of flies were dead, many of the can go into hibernation for far are only a few of what Early in its brief lifespan, C. elegans, Yeast could help easy-to-study organisms. a small nematode (roundworm), gerontologists thinking, its longevity. (LAG-1 is short for longevity INDY flies were still vigorous several months. When the scientists think may be moves rapidly and feeds vigorously. understand the Yeast normally have about 21 cell divisions or genera- assurance gene.) But how it works is still a mystery. and capable of reproduction. food supply is ample again, dozens, perhaps hundreds, The worm is transparent, making it genetics of aging. At least two other life-extend- the worm emerges from of longevity- and aging- easier to study physiological and More than 14 genes tions. Jazwinski observed that over the course of that One small clue lies in its sequence of DNA bases— genetic changes that occur that appear to pro- lifespan, certain genes in the yeast are more active its genetic code—which suggests that it produces a ing genetic mutations have this metabolically slowed, related genes. But tracking during its lifespan. mote the longevity been detected in the fruit non-aging state and contin- them down in organisms of these single-celled or less active as the cells age; in the language of protein found in cell membranes. One next step is to organisms have been molecular biology, they are differentially expressed. study the function of that protein. Similar sequences fly genome. ues its normal life cycle. like nematodes and fruit flies OLD WORM discovered. In C. elegans, a nematode The protein produced by the is just the beginning. The Near the end of its typical 2-to-3-week So far, Jazwinski has found 14 such genes in yeast. have been found in human DNA, so a second inves- lifespan, the worm loses muscle tone tigative path is to clone the human gene and study its (roundworm), researchers daf-2 gene drives the worm’s next big question for many and eventually stops moving. By the Selecting one of these genes, Jazwinski tried function. If there turns out to be a human LAG-1 coun- have found yet another treas- development past or out of gerontologists is whether time it dies, its body appears tattered two different experiments. First, he intro- and worn out. But by altering certain terpart, new insights into aging may be uncovered. ure trove of genetic clues the dauer state. But Cynthia counterparts in people— genes, gerontologists have been able duced the gene into yeast cells in a form about the aging process. Kenyon, Ph.D., and her human homologs—of the to keep some of these worms sleek and that allowed him to control its activity. In another laboratory, Leonard Guarente, Ph.D., of By altering certain genes, colleagues at the University genes found in laboratory vibrant for much longer than normal. When the gene was activated to a the Massachusetts Institute of Technology found that researchers can substantially of California, San Francisco, animals have similar effects. greater degree than normal, or mutation of a silencing gene—a gene that “turns extend the normal 2-to-3- found that daf-2 does much The daf-2 gene in C. elegans, overexpressed, some of the yeast off” other genes—delayed aging 30 percent in yeast. week lifespan of these tiny more. It also can regulate the for instance, is similar to a cells went on dividing for 27 or 28 The gene, which is also found in C. elegans and other lifespan of normal, fertile gene found in humans that generations; their period of activity animals, produces an enzyme that alters the structure adults. By altering this gene functions in hormone control. was extended by 30 percent. of DNA, which, in turn, alters patterns of gene so that its activity is reduced, expression.

9 10 Aging Under the Microscope The Genetic Connection Age-related Traits In the worm, this gene makes triggers alterations of genetic gerontologists study the The proteins expressed a protein that looks much activity. Caloric restriction genetics of mice, primates, by genes carry out a multi- Are All in the Family like the receptor for the hor- also may work, partially, by and other mammals that are tude of functions in each cell Microarrays in Action mone insulin. In humans, this altering metabolic pathways more closely related to us. and tissue in the body, and Finding longevity genes is only one of many goals for All cells have the same complement of genes. hormone controls functions involved in energy utilization. Some researchers are also some of these functions are gerontologists. An equally important mission is unraveling The form and function of any given cell is including food utilization (See The Next Step: Caloric studying human cells for related to aging. So, when the genetic processes involved in age-related traits and diseases. determined by which of these genes are turned pathways, glucose metabo- Restriction in Primates, page 36). more precise clues about we ask what longevity or on and off. As a cell grows, matures and ages, NIA and Italian investigators are focusing their attention on Sardinia, a lism, and cell growth. These Many investigators, how- how genes regulate human aging-related genes do, the pattern of genes turned on and off changes. secluded Mediterranean island. Since settlers first occupied the island thou- and other genetic linkages ever, interpret these findings longevity and aging. we are actually asking what Detecting these changes was once a tedious process sands of years ago, the population has grown without much immigration are under intense scrutiny, cautiously because there are Other unanswered their protein products do at that involved testing one gene at a time. No longer. from the outside world. Because they are more closely related than people and ultimately could yield important differences between questions concern the roles the cellular and tissue levels. living in other societies, Sardinians share much of the same genetic informa- clues about how genes human genes and those of played by these genes. What Increasingly, gerontologists Gene expression microarray technology, a potent scientific tion, which makes it easier to track genetic effects through generations. interact with environmental lower animals. In fact, the exactly do they do? How also are asking how alter- tool, is helping gerontologists rapidly clarify what genetic When a particular trait exists in a genetically isolated “founder” population factors to influence longe- structural similarity is only and when are they activated? ations in the process of changes occur in cells as they get older. Also known as “gene such as Sardinia, it is likely that the same few genes are responsible for the vity in humans and other about 30 percent, which means On one level, all genes gene expression itself may chips,” microarrays allow researchers to survey the expression trait in most or all affected individuals. Once the genes for a certain complex species. Caloric restriction, that comparing yeast genes to function by transcribing affect aging. Technological of thousands of genes at once. The match-box size glass chips trait are identified within the founder population, researchers can use this for example, is the only human genes, for instance, is their “codes”—actually advances, which allow contain DNA that has been exposed to messenger RNA information to isolate interacting genes and assess their importance in more known intervention shown like comparing a go-cart to a DNA base sequences—into researchers to observe the (mRNA), a nucleic acid that translates information contained genetically diverse cultures, like the United States. Other large founder to prolong life in species high-performance racing car. another nucleic acid called expression of thousands of in DNA into proteins. Each kind of mRNA binds to its corre- populations exist in Finland, Iceland, and French-speaking Quebec. ranging from yeast to The basic machinery may be messenger ribonucleic acid genes at once, are speeding sponding DNA probe, and the amount of mRNA that binds rodents. Scientists suspect similar, but one is far less or mRNA. Messenger the investigation of this to each gene’s DNA on the chip is an indicator of the activity In a study called the Progenia project, gerontologists are studying Sardinians this intervention works in complex than the other. So RNA is then translated into process. In time, this emerg- level of that gene. for evidence of genetic influences on two traits: severe arterial stiffness and yeast, worms, and other while yeast, worms, and proteins. Transcription and ing technology could help frequent positive emotions. Vascular stiffness may be an important predictor species, in part, because it other simple organisms are translation together consti- clarify what changes are Investigators using this technology have found relatively few of heart disease mortality. Reports also suggest that joyfulness and other helpful models of aging, they tute the process known as occurring simultaneously changes in gene expression occur in aging tissues. In some positive emotions can have profound impact on life satisfaction and health as probably don’t completely gene expression. in diverse cells, as they get studies, comparing tissue taken from young animals versus we age. Gerontologists suspect these traits have strong genetic components. mimic the process that occurs older. (See Microarrays older animals, fewer than two of every 100 genes have shown As the project progresses, investigators plan to conduct genetic analysis on in humans. For this reason, in Action, at right). major changes in activity over time. But these limited changes individuals who share extreme values of these traits and will attempt to may have significant impact on the ability of aging tissues identify the underlying genes. and organs to function properly. In time, microarrays might help gerontologists to more precisely characterize the genes Ultimately, gerontologists hope founder population studies yield results that Gerontologists study many involved in the aging of specific tissues or organs, and will help prevent certain age-related diseases. different animals including accelerate our understanding of its underlying mechanisms. zebrafish (left) and birds like 11 budgerigars (background) for 12 Aging Under the Microscope genetic clues about aging. The Genetic Connection Age-related Traits In the worm, this gene makes triggers alterations of genetic gerontologists study the The proteins expressed a protein that looks much activity. Caloric restriction genetics of mice, primates, by genes carry out a multi- Are All in the Family like the receptor for the hor- also may work, partially, by and other mammals that are tude of functions in each cell Microarrays in Action mone insulin. In humans, this altering metabolic pathways more closely related to us. and tissue in the body, and Finding longevity genes is only one of many goals for All cells have the same complement of genes. hormone controls functions involved in energy utilization. Some researchers are also some of these functions are gerontologists. An equally important mission is unraveling The form and function of any given cell is including food utilization (See The Next Step: Caloric studying human cells for related to aging. So, when the genetic processes involved in age-related traits and diseases. determined by which of these genes are turned pathways, glucose metabo- Restriction in Primates, page 36). more precise clues about we ask what longevity or on and off. As a cell grows, matures and ages, NIA and Italian investigators are focusing their attention on Sardinia, a lism, and cell growth. These Many investigators, how- how genes regulate human aging-related genes do, the pattern of genes turned on and off changes. secluded Mediterranean island. Since settlers first occupied the island thou- and other genetic linkages ever, interpret these findings longevity and aging. we are actually asking what Detecting these changes was once a tedious process sands of years ago, the population has grown without much immigration are under intense scrutiny, cautiously because there are Other unanswered their protein products do at that involved testing one gene at a time. No longer. from the outside world. Because they are more closely related than people and ultimately could yield important differences between questions concern the roles the cellular and tissue levels. living in other societies, Sardinians share much of the same genetic informa- clues about how genes human genes and those of played by these genes. What Increasingly, gerontologists Gene expression microarray technology, a potent scientific tion, which makes it easier to track genetic effects through generations. interact with environmental lower animals. In fact, the exactly do they do? How also are asking how alter- tool, is helping gerontologists rapidly clarify what genetic When a particular trait exists in a genetically isolated “founder” population factors to influence longe- structural similarity is only and when are they activated? ations in the process of changes occur in cells as they get older. Also known as “gene such as Sardinia, it is likely that the same few genes are responsible for the vity in humans and other about 30 percent, which means On one level, all genes gene expression itself may chips,” microarrays allow researchers to survey the expression trait in most or all affected individuals. Once the genes for a certain complex species. Caloric restriction, that comparing yeast genes to function by transcribing affect aging. Technological of thousands of genes at once. The match-box size glass chips trait are identified within the founder population, researchers can use this for example, is the only human genes, for instance, is their “codes”—actually advances, which allow contain DNA that has been exposed to messenger RNA information to isolate interacting genes and assess their importance in more known intervention shown like comparing a go-cart to a DNA base sequences—into researchers to observe the (mRNA), a nucleic acid that translates information contained genetically diverse cultures, like the United States. Other large founder to prolong life in species high-performance racing car. another nucleic acid called expression of thousands of in DNA into proteins. Each kind of mRNA binds to its corre- populations exist in Finland, Iceland, and French-speaking Quebec. ranging from yeast to The basic machinery may be messenger ribonucleic acid genes at once, are speeding sponding DNA probe, and the amount of mRNA that binds rodents. Scientists suspect similar, but one is far less or mRNA. Messenger the investigation of this to each gene’s DNA on the chip is an indicator of the activity In a study called the Progenia project, gerontologists are studying Sardinians this intervention works in complex than the other. So RNA is then translated into process. In time, this emerg- level of that gene. for evidence of genetic influences on two traits: severe arterial stiffness and yeast, worms, and other while yeast, worms, and proteins. Transcription and ing technology could help frequent positive emotions. Vascular stiffness may be an important predictor species, in part, because it other simple organisms are translation together consti- clarify what changes are Investigators using this technology have found relatively few of heart disease mortality. Reports also suggest that joyfulness and other helpful models of aging, they tute the process known as occurring simultaneously changes in gene expression occur in aging tissues. In some positive emotions can have profound impact on life satisfaction and health as probably don’t completely gene expression. in diverse cells, as they get studies, comparing tissue taken from young animals versus we age. Gerontologists suspect these traits have strong genetic components. mimic the process that occurs older. (See Microarrays older animals, fewer than two of every 100 genes have shown As the project progresses, investigators plan to conduct genetic analysis on in humans. For this reason, in Action, at right). major changes in activity over time. But these limited changes individuals who share extreme values of these traits and will attempt to may have significant impact on the ability of aging tissues identify the underlying genes. and organs to function properly. In time, microarrays might help gerontologists to more precisely characterize the genes Ultimately, gerontologists hope founder population studies yield results that Gerontologists study many involved in the aging of specific tissues or organs, and will help prevent certain age-related diseases. different animals including accelerate our understanding of its underlying mechanisms. zebrafish (left) and birds like 11 budgerigars (background) for 12 Aging Under the Microscope genetic clues about aging. The Genetic Connection Limits To Growth In the Lab of the For now, investigators 100 trillion cells, composing process have been identified. instance, senescent cells are changes in the genes they have found evidence that the organ systems that make This special aspect of cellular resistant to dying and, as a express might actually pro- For decades, researchers believed normal plant and Long-Lived Fruit Flies some proteins, such as our bodies. senescence is known as result, they occur more often mote unregulated growth animal cells could be propagated forever in test tubes A laboratory at the University of California, Irvine, is the home of antioxidant enzymes, prevent Early in life, nearly all replicative senescence. in aging bodies. Cellular and tumor formation. This (in vitro). But in 1961, Leonard Hayflick, Ph.D., (below) thousands of Drosophila melanogaster, or fruit flies, that routinely damage to cells, while others of the body’s cells can divide. However, we do not die senescence also triggers concept that genes, which disproved this idea in experiments with skin and lung live for 70 or 80 days, nearly twice the average Drosophila lifespan. may repair damaged DNA, But this process doesn’t go because we run out of cells important changes in gene have beneficial effects early fibroblast cells. Hayflick is a professor of anatomy at Here evolutionary biologist Michael Rose, Ph.D., has bred the long- regulate glucose metabolism, on indefinitely. Researchers (even the oldest people have expression. Normally, fibro- in life, can also have detri- the University of California, San Francisco. The eyes of these lived stocks by selecting and mating flies late in life. or help cells respond to have learned that cells have plenty of proliferating fibrob- blasts are responsible for mental effects later is known genetically altered stress. Other gene products finite proliferative lifespans, lasts and other types of cells). creating an underlying struc- as antagonistic pleiotropy. fruit flies appear To begin the process of genetic selection, Rose first collected eggs fluorescent under are thought to influence at least when studied in test In fact, most senescent cells ture, called the extracellular Some gerontologists specu- the microscope. laid by middle-age fruit flies and let them hatch in isolation. The replicative senescence. tubes—in vitro. After a cer- are not dead or dying. They matrix, which controls the late that a better understand- By altering gene progeny were then transferred to a communal plexiglass cage to expression in fruit tain number of divisions, continue to respond to hor- growth of other cells. But ing of antagonistic pleiotropy eat, grow, and breed under conditions ideal for mating. Once they flies and other Cellular Senescence they enter a state in which mones and other outside senescent fibroblasts secrete might reveal much about organisms, investi- had reached advanced ages, the eggs laid by older females (and During the process of cell they no longer proliferate stimuli, but can’t proliferate. enzymes that actually what aging is, and how gators are learning fertilized by older males) were again collected and removed to indi- much about aging. division or mitosis, a cell’s and DNA synthesis is Evidence suggests they can degrade this matrix. Geron- cellular senescence vidual hatching vials. The cycle was repeated, but with succeeding nucleus dissolves, and its blocked. For example, continue to work at many tologists suspect the break- contributes to it. generations, the day on which the eggs were collected was pro- chromosomes condense into young human fibroblasts— levels for some time after down of this structure may But for now, many YOUNG FIBROBLASTS gressively postponed. After 2 years and 15 generations, the visible thread-like structures structural cells that hold skin they cease dividing. Senes- contribute to the increased major questions about These human lung fibroblasts, laboratory had stocks of Drosophila with longer lifespans. shown after about the 10th that replicate. The resulting and other tissues together— cence, however, can cause risk of cancer as we age. So, cellular senescence remain in vitro population doubling, The next question is what genes and what gene products are 92 chromosomes separate, divide about 50 times and radical shifts in some impor- cellular senescence may be unanswered. Investigators, grow vigorously and complete the replication process more involved? Since the first experiments, Rose has bred longer life migrating to opposite sides then stop. This phenomenon tant cellular functions. For critical early in life because it for example, are uncertain rapidly than older cells. spans into fruit flies by selecting for other characteristics, such as of the cell where new nuclei— is known as the Hayflick limits cell proliferation and whether senescent cells ability to resist starvation, so the flies‘ long lifespans are not each with 46 chromosomes— limit, after Leonard Hayflick, helps suppress cancer. But as accumulate in all tissues necessarily tied to their fertility late in life. are formed. Once this occurs, who with Paul Moorhead we get older, senescent cells and organs with increasing the original cell, following described it in 1961 while at might be harmful because age, thus contributing to the OLD FIBROBLASTS One possibility is that the antioxidant enzyme, superoxide the chromosomes’ lead, the Wistar Institute in gradual loss of the body’s Nearing senescence, these lung dismutase (SOD), is involved. Two laboratory studies, fibroblasts are noticeably larger and pulls apart and forms two Philadelphia. At least capacity to heal wounds, tend to divide more slowly than their including work by John Tower, Ph.D., at the University of identical daughter cells. It is four genes involved in this maintain strong bones, and younger counterparts. After about 50 in vitro population doublings, these Southern California, have shown that genetically altered this process that allows us to CELL DIVISION fend off infections. Accumu- fruit flies that produce greater amounts of SOD have Daughter cells divide during cells stop dividing. This phenomenon grow from a single cell into mitosis. Early in life, nearly lation of senescent cells, if it is known as the Hayflick limit. extended lifespans. This finding has given a boost to the all cells can divide. But over hypothesis that antioxidant enzymes like SOD are linked time, this capacity diminishes. Cellular senescence is one of to aging or longevity. However, to date, similar experi- many biological processes ments in other species have been inconclusive. that gerontologists study. 14 The Genetic Connection Limits To Growth In the Lab of the For now, investigators 100 trillion cells, composing process have been identified. instance, senescent cells are changes in the genes they have found evidence that the organ systems that make This special aspect of cellular resistant to dying and, as a express might actually pro- For decades, researchers believed normal plant and Long-Lived Fruit Flies some proteins, such as our bodies. senescence is known as result, they occur more often mote unregulated growth animal cells could be propagated forever in test tubes A laboratory at the University of California, Irvine, is the home of antioxidant enzymes, prevent Early in life, nearly all replicative senescence. in aging bodies. Cellular and tumor formation. This (in vitro). But in 1961, Leonard Hayflick, Ph.D., (below) thousands of Drosophila melanogaster, or fruit flies, that routinely damage to cells, while others of the body’s cells can divide. However, we do not die senescence also triggers concept that genes, which disproved this idea in experiments with skin and lung live for 70 or 80 days, nearly twice the average Drosophila lifespan. may repair damaged DNA, But this process doesn’t go because we run out of cells important changes in gene have beneficial effects early fibroblast cells. Hayflick is a professor of anatomy at Here evolutionary biologist Michael Rose, Ph.D., has bred the long- regulate glucose metabolism, on indefinitely. Researchers (even the oldest people have expression. Normally, fibro- in life, can also have detri- the University of California, San Francisco. The eyes of these lived stocks by selecting and mating flies late in life. or help cells respond to have learned that cells have plenty of proliferating fibrob- blasts are responsible for mental effects later is known genetically altered stress. Other gene products finite proliferative lifespans, lasts and other types of cells). creating an underlying struc- as antagonistic pleiotropy. fruit flies appear To begin the process of genetic selection, Rose first collected eggs fluorescent under are thought to influence at least when studied in test In fact, most senescent cells ture, called the extracellular Some gerontologists specu- the microscope. laid by middle-age fruit flies and let them hatch in isolation. The replicative senescence. tubes—in vitro. After a cer- are not dead or dying. They matrix, which controls the late that a better understand- By altering gene progeny were then transferred to a communal plexiglass cage to expression in fruit tain number of divisions, continue to respond to hor- growth of other cells. But ing of antagonistic pleiotropy eat, grow, and breed under conditions ideal for mating. Once they flies and other Cellular Senescence they enter a state in which mones and other outside senescent fibroblasts secrete might reveal much about organisms, investi- had reached advanced ages, the eggs laid by older females (and During the process of cell they no longer proliferate stimuli, but can’t proliferate. enzymes that actually what aging is, and how gators are learning fertilized by older males) were again collected and removed to indi- much about aging. division or mitosis, a cell’s and DNA synthesis is Evidence suggests they can degrade this matrix. Geron- cellular senescence vidual hatching vials. The cycle was repeated, but with succeeding nucleus dissolves, and its blocked. For example, continue to work at many tologists suspect the break- contributes to it. generations, the day on which the eggs were collected was pro- chromosomes condense into young human fibroblasts— levels for some time after down of this structure may But for now, many YOUNG FIBROBLASTS gressively postponed. After 2 years and 15 generations, the visible thread-like structures structural cells that hold skin they cease dividing. Senes- contribute to the increased major questions about These human lung fibroblasts, laboratory had stocks of Drosophila with longer lifespans. shown after about the 10th that replicate. The resulting and other tissues together— cence, however, can cause risk of cancer as we age. So, cellular senescence remain in vitro population doubling, The next question is what genes and what gene products are 92 chromosomes separate, divide about 50 times and radical shifts in some impor- cellular senescence may be unanswered. Investigators, grow vigorously and complete the replication process more involved? Since the first experiments, Rose has bred longer life migrating to opposite sides then stop. This phenomenon tant cellular functions. For critical early in life because it for example, are uncertain rapidly than older cells. spans into fruit flies by selecting for other characteristics, such as of the cell where new nuclei— is known as the Hayflick limits cell proliferation and whether senescent cells ability to resist starvation, so the flies‘ long lifespans are not each with 46 chromosomes— limit, after Leonard Hayflick, helps suppress cancer. But as accumulate in all tissues necessarily tied to their fertility late in life. are formed. Once this occurs, who with Paul Moorhead we get older, senescent cells and organs with increasing the original cell, following described it in 1961 while at might be harmful because age, thus contributing to the OLD FIBROBLASTS One possibility is that the antioxidant enzyme, superoxide the chromosomes’ lead, the Wistar Institute in gradual loss of the body’s Nearing senescence, these lung dismutase (SOD), is involved. Two laboratory studies, fibroblasts are noticeably larger and pulls apart and forms two Philadelphia. At least capacity to heal wounds, tend to divide more slowly than their including work by John Tower, Ph.D., at the University of identical daughter cells. It is four genes involved in this maintain strong bones, and younger counterparts. After about 50 in vitro population doublings, these Southern California, have shown that genetically altered this process that allows us to CELL DIVISION fend off infections. Accumu- fruit flies that produce greater amounts of SOD have Daughter cells divide during cells stop dividing. This phenomenon grow from a single cell into mitosis. Early in life, nearly lation of senescent cells, if it is known as the Hayflick limit. extended lifespans. This finding has given a boost to the all cells can divide. But over hypothesis that antioxidant enzymes like SOD are linked time, this capacity diminishes. Cellular senescence is one of to aging or longevity. However, to date, similar experi- many biological processes ments in other species have been inconclusive. that gerontologists study. 14 The Genetic Connection TELOMERES: The Cancer Connection does occur, could, in turn, anti-proliferative gene came research and cancer research as telomere shortening influ- telomeres become so short while others with long, but enabling cells to replace indirectly increase an indi- from an eye tumor called intersect. When tumor sup- ence replicative senescence. that their function is dis- “frayed” telomeres under- lost telomeric sequences Certain cells, such as egg and sperm cells, use telomerase, vidual’s vulnerability to retinoblastoma. When one pressor genes are inacti- rupted, and this, in turn, go senescence. Telomere and divide indefinitely. This an enzyme, to restore telomeres to the ends of their chro- the diseases and disabilities of the genes from retinoblas- vated, investigators theorize Telomeres leads the cell to stop prolif- researchers also are explor- finding has led to speculation mosomes, insuring that they can continue to reproduce often associated with aging. toma cells—later called the it turns on a complex process Every chromosome has tails erating. Average telomere ing other possible ways in that if a drug could be devel- and promote survival of the species. But most adult cells However, no feature of aging RB gene—became inactive, that leads to development of at its ends that get shorter length, therefore, gives some which these chromosome oped to block telomerase lack this capacity, and when telomeres reach a critical has yet been unequivocally the cells went on dividing a tumor. So replicative senes- as a cell divides. These tails, indication of how many ends regulate cellular life- activity, it might aid in length, these cells stop proliferating. In immortal cancer explained by in vitro cellular indefinitely and produced cence apparently has been called telomeres, all have the divisions the cell has already span, and believe that cancer treatment. cells, telomeres act abnormally—they cease shortening senescence. a tumor. But when the RB retained through evolution same short sequence of DNA undergone and how many proteins associated with Whether cell senescence with each cell division. Investigators suspect telomerase gene product was activated, as a defense against cancer. bases (TTAGGG in humans remain before it can no telomeres play a role. is explained by abnormal is somehow activated in cancer cells. Proliferative Genes the cells stopped dividing. Scientists are unraveling and other vertebrates) longer replicate. Telomere research is gene products, telomere Searching for explanations of This gene’s product, in other how the products of these repeated thousands of times. This apparent counting another territory where can- shortening, or other factors, proliferation and senescence, words, appeared to suppress genes promote and suppress These repetitive snippets do mechanism, almost like an cer and aging research merge. the question of what Germ Cell scientists have found certain proliferation. Another well- cell proliferation. There are not contain any vital genetic abacus keeping track of In immortal cancer cells, senescence has to do telomerase genes that appear to trigger characterized gene of this indications that a multi-layer information, but acting much the cell’s age, has led to telomeres act abnormally— with the aging of cell proliferation. One exam- type is the p53 gene, which control system is at work, like the hard, plastic cover- speculation that telomeres they no longer shrink with organisms continues ple of such a proliferative produces a protein that involving a host of intricate ing on the ends of shoe- serve as molecular meters each cell division. In the to be the focus of gene is c-fos, which encodes also limits cell proliferation. mechanisms that interact to strings, they help keep of cell division. But some search for clues to this phe- rigorous study. telomere chromosomes a short-lived protein that These genes are called maintain a balance between chromosomes intact. scientists suspect telomere nomenon, researchers have is thought to regulate the tumor suppressor genes. the two kinds of genes. Some During mitosis, the length is just one aspect discovered an enzyme called Adult Cell expression of other genes Limited proliferation genes, for instance, appear molecular machinery that of a complex mechanism. telomerase. This enzyme, important in cell division. is the norm in the world of to suppress or silence other replicates DNA can’t com- Elizabeth Blackburn, Ph.D., which is not active in most Proliferative genes, such human cells. In some cases, genes. Mutations in these pletely copy the extreme of the University of Califor- adult cells (egg and sperm as c-fos and others of its kind, however, a cell somehow silencing genes have been ends of chromosomes. So nia, San Francisco, for cells are among the excep- are countered by anti-prolif- escapes this control mecha- shown to affect the lifespan each time a cell divides, the instance, has accumulated tions), seems to swing into Senescent Cell erative genes, which seem nism and goes on dividing, of C. elegans and yeast. telomeres get shorter. Over evidence that some cells action in advanced cancers, to interfere with division. becoming, in the terms of Many gerontologists are time, scientists theorize, with extremely short, but The first evidence of an cell biology, immortal. And studying how silencing structurally sound telomeres TELOMERES because immortal cells even- and other mechanisms such continue to proliferate, At each end of every chromosome (blue) Cell Immortality are telomeres (red), repetitive DNA and Cancer tually form tumors, this is sequences that appear to help regulate one area in which aging cellular replication. Gerontologists are working to learn more about telomere structure and function.

15 16 Aging Under the Microscope The Genetic Connection TELOMERES: The Cancer Connection does occur, could, in turn, anti-proliferative gene came research and cancer research as telomere shortening influ- telomeres become so short while others with long, but enabling cells to replace indirectly increase an indi- from an eye tumor called intersect. When tumor sup- ence replicative senescence. that their function is dis- “frayed” telomeres under- lost telomeric sequences Certain cells, such as egg and sperm cells, use telomerase, vidual’s vulnerability to retinoblastoma. When one pressor genes are inacti- rupted, and this, in turn, go senescence. Telomere and divide indefinitely. This an enzyme, to restore telomeres to the ends of their chro- the diseases and disabilities of the genes from retinoblas- vated, investigators theorize Telomeres leads the cell to stop prolif- researchers also are explor- finding has led to speculation mosomes, insuring that they can continue to reproduce often associated with aging. toma cells—later called the it turns on a complex process Every chromosome has tails erating. Average telomere ing other possible ways in that if a drug could be devel- and promote survival of the species. But most adult cells However, no feature of aging RB gene—became inactive, that leads to development of at its ends that get shorter length, therefore, gives some which these chromosome oped to block telomerase lack this capacity, and when telomeres reach a critical has yet been unequivocally the cells went on dividing a tumor. So replicative senes- as a cell divides. These tails, indication of how many ends regulate cellular life- activity, it might aid in length, these cells stop proliferating. In immortal cancer explained by in vitro cellular indefinitely and produced cence apparently has been called telomeres, all have the divisions the cell has already span, and believe that cancer treatment. cells, telomeres act abnormally—they cease shortening senescence. a tumor. But when the RB retained through evolution same short sequence of DNA undergone and how many proteins associated with Whether cell senescence with each cell division. Investigators suspect telomerase gene product was activated, as a defense against cancer. bases (TTAGGG in humans remain before it can no telomeres play a role. is explained by abnormal is somehow activated in cancer cells. Proliferative Genes the cells stopped dividing. Scientists are unraveling and other vertebrates) longer replicate. Telomere research is gene products, telomere Searching for explanations of This gene’s product, in other how the products of these repeated thousands of times. This apparent counting another territory where can- shortening, or other factors, proliferation and senescence, words, appeared to suppress genes promote and suppress These repetitive snippets do mechanism, almost like an cer and aging research merge. the question of what Germ Cell scientists have found certain proliferation. Another well- cell proliferation. There are not contain any vital genetic abacus keeping track of In immortal cancer cells, senescence has to do telomerase genes that appear to trigger characterized gene of this indications that a multi-layer information, but acting much the cell’s age, has led to telomeres act abnormally— with the aging of cell proliferation. One exam- type is the p53 gene, which control system is at work, like the hard, plastic cover- speculation that telomeres they no longer shrink with organisms continues ple of such a proliferative produces a protein that involving a host of intricate ing on the ends of shoe- serve as molecular meters each cell division. In the to be the focus of gene is c-fos, which encodes also limits cell proliferation. mechanisms that interact to strings, they help keep of cell division. But some search for clues to this phe- rigorous study. telomere chromosomes a short-lived protein that These genes are called maintain a balance between chromosomes intact. scientists suspect telomere nomenon, researchers have is thought to regulate the tumor suppressor genes. the two kinds of genes. Some During mitosis, the length is just one aspect discovered an enzyme called Adult Cell expression of other genes Limited proliferation genes, for instance, appear molecular machinery that of a complex mechanism. telomerase. This enzyme, important in cell division. is the norm in the world of to suppress or silence other replicates DNA can’t com- Elizabeth Blackburn, Ph.D., which is not active in most Proliferative genes, such human cells. In some cases, genes. Mutations in these pletely copy the extreme of the University of Califor- adult cells (egg and sperm as c-fos and others of its kind, however, a cell somehow silencing genes have been ends of chromosomes. So nia, San Francisco, for cells are among the excep- are countered by anti-prolif- escapes this control mecha- shown to affect the lifespan each time a cell divides, the instance, has accumulated tions), seems to swing into Senescent Cell erative genes, which seem nism and goes on dividing, of C. elegans and yeast. telomeres get shorter. Over evidence that some cells action in advanced cancers, to interfere with division. becoming, in the terms of Many gerontologists are time, scientists theorize, with extremely short, but The first evidence of an cell biology, immortal. And studying how silencing structurally sound telomeres TELOMERES because immortal cells even- and other mechanisms such continue to proliferate, At each end of every chromosome (blue) Cell Immortality are telomeres (red), repetitive DNA and Cancer tually form tumors, this is sequences that appear to help regulate one area in which aging cellular replication. Gerontologists are working to learn more about telomere structure and function.

15 16 Aging Under the Microscope The Genetic Connection Biochemistry andAging As important as genes are, they do not act in a vacuum. Everyday metabolic activities—even breathing—expose cells to biochemical substances that can promote random DNA damage and other cellular breakdowns. Of these factors, oxygen radicals and crosslinking of proteins have become focal points of scientific exploration. Gerontologists also are studying other important proteins—heat shock proteins, hormones, and growth factors—that may play a role in aging and longevity. In short, the biochemistry of aging is a rich territory with an expanding frontier. Oxygen Radicals by–products are called oxy- and combine readily with Oxygen sustains us. Every gen free radicals, also known other molecules. cell in the body needs it to as reactive oxygen species. This process, called survive. Yet, paradoxically, A free radical can be oxidation, can spark a chain oxygen also wreaks havoc produced from almost any reaction resulting in a series in the body and may be a molecule when it loses an of products, some of which primary catalyst for much electron from one or more are actually beneficial. The of the damage we associate of its atoms. In cells, they immune system, for instance, with aging. This damage are commonly created when uses free radicals to destroy occurs as a direct result of mitochondria combine oxy- bacteria and other patho- how cells metabolize it. gen with hydrogen to form gens. Another oxidizing Oxygen is processed water. This transformation molecule, called nitric oxide, within a cell by tiny ogan- releases energy into the helps nerve cells in the brain elles called mitochondria. cell, but it also can shred communicate with each other. Mitochondria convert oxy- electrons from oxygen. Free radicals, however, gen and food into adenosine When this happens it leaves also can be vandals that triphosphate (ATP), an the oxygen atom—now cause extensive damage to energy-releasing molecule an unstable oxygen free proteins, membranes, and that powers most cellular radical—with one unpaired DNA. Mitochondria are processes. In essence, mito- electron. Because electrons particularly prone to free chondria are furnaces, and are most stable when they radical damage. The major like all furnaces, they pro- are paired, oxygen free source of free radical duce potentially harmful radicals steal mates for their by–products. In cells, these lone electrons from other molecules. These molecules, This mitochondrion is a cellular power- house, continuously generating ATP, an in turn, become unstable energy-releasing molecule, as well as potentially harmful by-products such as oxygen free radicals. Hundreds of mito- chondria exist in every cell. With age, increasing oxidative damage to these organelles may decrease their efficiency.

18 Biochemistry and Aging Antioxidants and production in the body, they substances called antioxi- are also one of its prime tar- dants to counteract them. Aging Nematodes gets. As the damage mounts, These substances including A worm barely the size of a comma printed on this page mitochondria become less nutrients—the familiar may change how investigators think about oxygen radicals, efficient, progressively gen- vitamins C and E—as well antioxidants, and aging. C. elegans nematodes immersed in a erating less ATP and more as enzymes produced in liquid containing a potent antioxidant drug lived 44 percent free radicals. Over time, the cell, such as superoxide longer than worms not treated with this substance. It was according to the free radical dismutase (SOD), catalase, the first time that any drug had extended the lifespan of any theory, oxidative damage and glutathione peroxidase, multi-cellular organism. The finding lends credence to the accumulates in our cells prevent most oxidative dam- hypothesis that oxygen radicals have a significant role in and tissues, triggering many age. Nonetheless, some free the aging process. of the bodily changes that radicals manage to circum- occur as we age. Free radicals vent these defenses and do In addition, the international team of investigators, led by have been implicated not harm. As a result, cellular Simon Melov, Ph.D., of the Buck Center for Research in Aging only in aging but also in repair mechanisms eventu- in California, restored a normal lifespan to mutant worms degenerative disorders, ally falter and some internal that had a mitochondrial defect, which caused increased including cancer, athero- breakdowns are inevitable. oxygen radical production and accelerated aging. The sclerosis, cataracts, and These breakdowns can lead worms showed no apparent ill effects from the treatment. neurodegeneration. to cellular senescence, and But free radicals, which eventually may trigger EUK-134, the drug used in the experiment, was a also can be produced by apoptosis, a form of synthetic form of superoxide dismutase (SOD) and cata- tobacco smoke, sun expo- programmed cell death. lase, two enzymes that counteract the effects of oxidative sure, and other environ- stress. Like other antioxidants, such as vitamin E, these mental factors, do not go compounds convert oxygen radicals to water. But they are unchecked. Cells utilize much more potent.

While it is only one study, and its results have not been con- firmed in other species, this investigation supports the concept that antioxidant defenses may be critical during aging. It also suggests that one day it may be possible to use similar Oxygen free radicals, the bright yellow spots in this interventions to treat age-related conditions in humans. illustration, can attack and damage DNA, leading to mutations.

19 Aging Under the Microscope Protein Crosslinking Support for the free extended their normal life- Protein Crosslinking radical theory, first proposed span. (See Antioxidants and Blood sugar—glucose—is Human rib cartilage shows the effects of protein in 1956 by chemist Denham Aging Nematodes, page 19). another suspect in cellular crosslinks, which slowly accumulate through complex Harman, M.D., Ph.D., comes The discovery of anti- deterioration. In a process pathways and eventually disrupt cellular function. from studies of antioxidants, oxidants raised hopes that called non-enzymatic glyco- With age, as glucose binds to its proteins, the cartilage particularly SOD. SOD con- people could retard aging sylation or glycation, glucose turns brown and becomes less supple. This process, verts an oxygen radical simply by adding them to molecules attach themselves called the Maillard reaction, is similar to what happens known as superoxide anion the diet. So far, studies of to proteins, setting in motion when bread is toasted. into hydrogen peroxide, antioxidant-laden foods and a chain of chemical reactions which can be degraded by supplements in humans that ends in the proteins an enzyme, called catalase, have yielded little support binding together or cross- into oxygen and water. Stud- for this premise. Further linking, thus altering their ies have shown that insert- research, including large- biological and structural Infant Age 17 ing extra copies of the SOD scale epidemiological stud- roles. The process is slow gene into fruit flies extends ies, might clarify whether and complex, but cross- their average lifespan by as dietary antioxidants can help linked proteins accumulate much as 30 percent. people live longer, healthier with time and eventually Other experimental evi- lives. For now, however, disrupt cellular function. dence lends support to the the effectiveness of dietary Investigators suspect free radical hypothesis. For antioxidant supplementation that glycation and oxidation example, higher levels of remains controversial. In are interdependent processes Age 45 Age 64 SOD and catalase have been the meantime, gerontologists since free radicals and cross- found in long-lived nema- are investigating other links seem to accelerate the todes. In one compelling intriguing biochemical formation of one another. study, giving nematodes processes affected by free synthetic forms of these radicals, including protein antioxidants significantly crosslinking.

Age 76 Age 88

20 Biochemistry and Aging Research on Sunlight May Help Explain Crosslinks, also known as kidney function (nephropa- advanced glycation end thy), and age-related neuro- What Happens to Skin as We Age products (AGEs), seem to logical disorders including As anyone who reads beauty magazines knows, sunlight damages “stiffen” tissues and may Alzheimer’s disease. skin in ways that seem similar to aging. It’s well-established that cause some of the deteriora- These conditions appear long-term, sunlight-induced damage causes wrinkles. And in both tion associated with aging. at younger ages in people normal aging and photoaging—the process initiated by sunlight— Collagen, for instance, the with diabetes, who have the skin becomes drier and loses elasticity. Although geron- most common protein mole- high glucose levels (hyper- tologists think that the normal or intrinsic aging process is cule in our bodies, forms the glycemia). Glycosylated probably not the same as photoaging, there are enough connective tissue that pro- hemoglobin in red blood similarities to make this a tantalizing field of study. vides structure and support cells, for instance, is an for organs and joints. When important marker doctors The process of photoaging may hold clues to normal aging glucose binds with colla- use to measure hyper- because many of the same cells are affected. Photoaging, gen—as it tends to do as we glycemia. While the physio- for example, damages collagen and elastin, the two proteins age—this normally supple logical effects of glycosylated that give skin its elasticity. These proteins decline as we age, protein loses much of its hemoglobin are unclear, along with the fibroblast cells that manufacture them. In flexibility. As a result, lungs, the disease it helps doctors addition, the enzymes that break down collagen and arteries, tendons, and other detect—diabetes—is some- elastin increase. tissues stiffen and become times considered an accele- Other changes occur in keratinocytes, upper-layer skin less efficient. In the circula- rated model of aging. Not cells that are shed and renewed regularly. In the normal tory system, AGEs may help only do the complications aging process the turnover of keratinocytes slows down trap LDL (the so-called of diabetes mimic the and in photoaging they are damaged. Still other skin cells, “bad”) cholesterol in artery physiologic changes that called melanocytes, are also affected by both processes: they walls, and thus contribute to can accompany old age, but decline with normal aging and are killed in photoaging. (Stopped in the development of athero- people with this condition their tracks by sunlight, these normally migratory cells show up as sclerosis. They also have have shorter-than-average freckles in light skin.) been linked to clouded life expectancies. As a result, lenses (cataracts), reduced much research on cross- What we don’t know yet is exactly how photoaging damages linking has focused on its cells. Ultraviolet light can damage DNA and could be the culprit. relationship to diabetes as Free radicals could be involved in some way. Researchers continue well as aging. to explore these and other factors in the effort to understand photoaging. 21 Aging Under the Microscope Werner’s Syndrome Just as the body has Why this happens is not crosslinking may play a role gradually accumulates, leads antioxidants to fight free- known, but immunologists in damage to DNA, which is to malfunctioning genes, radical damage, it has other are beginning to learn more another important focus for proteins, cells, and, as the guardians, immune cells about how the immune sys- research on aging. years go by, deteriorating called macrophages, which tem affects, and is affected tissues and organs. combat glycation. Macro- by aging (See The Immune DNA Repair Not surprisingly, numer- phages with special recep- System, page 31). And in and Synthesis ous enzyme systems in the tors for AGEs seek out and the meantime, diabetes In the normal wear and tear cell have evolved to detect engulf them. Once AGEs researchers are investigating of cellular life, DNA under- and repair damaged DNA. are broken down, they are drugs that could supplement goes continual damage. For repair, transcription, ejected into the blood stream the body’s natural defenses Attacked by oxygen radicals, and replication to occur, the WS patient age 14 where they are filtered out by blocking AGEs formation. ultraviolet light, and other double-helical structure that by the kidneys and elimi- Crosslinking interests toxic agents, it suffers dam- makes up DNA must be par- nated in urine. gerontologists for several age in the form of deletions, tially unwound. Enzymes The only apparent reasons. It is associated with or deleted sections, and called helicases do the drawback to this defense disorders that are common mutations, or changes in the unwinding. Investigators system is that it is not com- among older people, such as sequence of DNA bases that have found that people who plete and levels of AGEs diabetes and heart disease; make up the genetic code. have Werner’s syndrome increase steadily with age. it progresses with age; and In addition, sometimes the (WS), a rare disease with One reason is that kidney AGEs are potential targets DNA replication machinery several features of premature function tends to decline for drugs. In addition, makes an error. aging, have a defect in one with advancing age. Another Biologists theorize that of their helicases. George WS patient age 48 is that macrophages, like this DNA damage, which Martin, M.D., of the Univer- certain other components sity of Washington and other Genetic defects are believed to be responsible for Werner’s syndrome of the immune system, investigators are exploring (WS), a disease in which people at a become less active. the mechanisms involved young chronological age develop some characteristics associated with aging, in DNA repair in WS and such as gray hair, wrinkled skin, diabetes, heart disease, and cancer. Because of the apparent acceleration of aging in WS, gerontologists are delv- Macrophages, such as the one shown ing into its causes, hoping to shed light here, recognize foreign bodies such as on the disease and the degenerative bacteria, or altered molecules such as processes that occur with normal aging. crosslinked proteins, and remove them from circulation. 22 Biochemistry and Aging “ he remarkable increase in our similar disorders, collectively bility to cancer. If DNA production, and cells have T th known as progeroid syn- repair processes decline with hundreds of them. Investiga- life span during the 20 Century dromes. This research could age while damage accumu- tors suspect mitochondrial has been due, in large part to the help explain why DNA repair lates as scientists hypothe- DNA is injured at a much becomes less efficient during size, it could help explain greater rate than nuclear contributions of basic biomedical normal human aging. why cancer is more common DNA, possibly because the st research…In the 21 Century, The repair process among older people. mitochondria produce a interests gerontologists for Gerontologists who stream of damaging oxygen the advances in these basic many reasons. It is known study DNA damage and radicals during metabolism. sciences should lead to effective that an animal’s ability to repair have begun to uncover Adding to its vulnerability, repair certain types of DNA numerous complexities. Even mitochondrial DNA is treatments of diseases of our damage is directly related within a single organism, unprotected by the protein aging population.” to the lifespan of its species. repair rates can vary among coat that helps shield DNA Humans repair DNA, for cells, with the most efficient in the nucleus from damage. —Julius Axelrod, Ph.D. example, more quickly and repair going on in germ Research has shown 1970 Nobel Laureate in Medicine efficiently than mice or other (sperm and egg) cells. that mitochondrial DNA animals with shorter life- Moreover, certain genes are damage increases exponen- spans. This suggests that repaired more quickly than tially with age, and as a DNA damage and repair others, including those that result, energy production are in some way part of regulate cell proliferation. in cells diminishes over time. the aging puzzle. Especially intriguing These changes may cause In addition, researchers is repair to a kind of DNA declines in physiological have found defects in DNA that resides not in the cell’s performance, and may play repair in people with a nucleus but in its mitochon- a role in the development genetic or familial suscepti- dria. These small organelles are the principal sites of metabolism and energy

DNA, the double helix cellular molecule that contains thousands of genes necessary for life, is constantly being damaged and repaired. Gerontologists suspect DNA repair mechanisms become less efficient with age. Accumulating DNA damage, including breaks in its structure or changes in its nucleotide sequences, can lead to some of the physical changes we associate with aging.

23 Aging Under the Microscope Heat Shock Proteins of age-related diseases. plants, bacteria, worms, of a heat shock protein des- action of HSP-70 in specific Investigators are examining mice, and yes, humans. ignated HSP-70 than young sites, such as the adrenal In the Aorta how much mitochondrial Today, the role of these animals under similar stress. cortex (the outer layer of the DNA damage occurs in spe- substances, known as heat Moreover, in laboratory cul- adrenal gland). In this gland cific parts of the body such shock proteins, in the aging tures of cells, researchers as well as in blood vessels as the brain, what causes process is under scrutiny. have found a striking decline and possibly other sites, Unstressed Adult the damage, and whether Despite their name, in HSP-70 production as the expression of HSP-70 it can be prevented. heat shock proteins (HSPs) cells approach senescence. appears closely related are produced when cells are Exactly what role HSPs to hormones released in Heat Shock Proteins exposed to various stresses, play in the aging process response to stress, such In the early 1960s, investiga- not only heat. Their expres- is not yet clear. They are as the glucocorticoids and tors noticed fruit flies did sion can be triggered by known to help cells disman- catecholamines. Eventually, Stressed Adult something unusual. When exposure to toxic substances tle and dispose of damaged answers to the puzzle of these insects were exposed such as heavy metals and proteins. They also facilitate HSPs may throw light on to a burst of heat, they pro- chemicals and even by the making and transport some parts of the neuro- duced proteins that helped behavioral and psycho- of new proteins. But what endocrine system, whose their cells survive the tem- logical stress. proteins are involved and hormones and growth In the perature change. Intrigued, What attracts aging how they relate to aging is factors might have an Adrenal Gland researchers looked for these researchers to HSPs is the still the subject of specula- important influence on proteins in other animals, finding that the levels at tion and study. the aging process. and found them in virtually which they are produced While at the NIA, Nikki every living thing including depend on age. Old animals Holbrook, Ph.D., and other Unstressed Aged placed under stress—short- researchers investigated the term, physical restraint, for example—have lower levels In certain circumstances, plants and animals produce heat shock proteins Plants Bacteria Worms Mice Humans (HSPs). These proteins are believed to have an important role in helping cells respond to stress. The dark areas Stressed Aged Since they were first discovered in these illustrations show increased in fruit flies, heat shock proteins expression of HSPs in short term, physi- have been found in virtually cally restrained rats. With age, genetic every living thing. expression of these proteins diminishes.

24 Biochemistry and Aging Testosterone

Hormones and immune function. increased their lean body hot flashes, long-term use of Hormones are powerful These glands, including the (and presumably muscle) these hormones may increase chemicals that help keep our pituitary, thyroid, adrenal, mass, reduced excess fat, risk for several major age- bodies working normally. ovaries, and testes, release and thickened skin. When related diseases in some Made by specialized groups various hormones into the the injections stopped, these women, especially when In this colored transmission of cells called glands, hor- body as needed. changes reversed, and the treatment is started years electron micrograph, growth hormone granules (brown) mones stimulate, regulate, As we age, production signs of aging returned. after menopause. The finding are visible in the cytoplasm and control the function of of certain hormones, such What the men were taking that levels of testosterone in (yellow) of a growth-hormone secreting endocrine cell from various tissues and organs. as testosterone and estrogen, was recombinant human men decreased with aging the pituitary gland. Visible cell They are involved in virtu- tends to decrease. Hormones growth hormone (hGH), raised the question of whether organelles include mitochondria ally every biological process with less familiar names, a synthetic version of the they too might benefit from (round, green) and the nucleus (purple, center). including sexual reproduc- like melatonin and dehy- hormone that is produced sex hormone treatment. tion, growth, metabolism, droepiandrosterone (DHEA) in the pituitary gland and As a result of these are also not as abundant in plays a critical part in nor- preliminary observational older people as in younger mal childhood growth and findings, the NIA launched a adults. But what influence, if development. At the same series of research initiatives any, these natural hormonal time, evidence was accumu- to clarify what influence declines have on the aging lating that menopausal hor- hormone replacement therapy process is unclear. mone therapy with estrogen might have on the aging (alone or in combination process. So far, most of these Hormone with a progestin in women studies have been inconclu- Replacement with a uterus) could benefit sive, but have led many In the late 1980s, at Veterans postmenopausal women by investigators to question Administration hospitals in reducing cardiovascular dis- whether the risks of hormone Milwaukee and Chicago, ease, colon cancer, and other replacement may outweigh 12 men age 60 and older diseases of aging. Further began receiving injections studies have indicated that, three times a week that although estrogen remains dramatically reversed some an effective way to control signs of aging. The injections Estrogen

25 Agiing Under the Miicroscope Hormones and Research on Aging Produced by glands, organs, and tissues, hormones are the body’s chemical messengers, flowing through the blood stream and searching out cells fitted with special receptors. Each receptor, like a lock, can be opened by the specific hormone that fits it and also, to a lesser extent, by closely related hormones. Here are some of the hormones and other growth factors of special interest to gerontologists.

ESTROGEN > Although it is primarily associated with women, men also produce small amounts of this sex hormone. hormone, which is produced in the brain. It works, in part, Among its many roles, estrogen slows the bone thinning by stimulating the production of insulin-like growth factor, that accompanies aging. In premenopausal women the which comes mainly from the liver. All three hormones are ovaries are the main manufacturers of estrogen (image being studied for their potential to strengthen muscle and above). After menopause, fat tissue is the major source bones and prevent frailty among older people. For now, of smaller amounts and weaker forms of estrogen than however, there is no convincing evidence that taking that produced by the ovaries. While many women with growth hormone will improve the health of those who do menopausal symptoms are helped by hormone therapy not suffer a profound deficiency of this hormone. during and after menopause, some are placed at higher MELATONIN > Contrary to some claims, secretion risk for certain diseases if they take it. The results of the of this hormone, made by the pineal gland, does not WHI are prompting further studies about the usefulness necessarily diminish with age. Instead, a number of factors, and safety of this therapy when used by younger meno- including light, can affect production of this hormone, pausal and postmenopausal women to control symptoms, which seems to regulate various seasonal changes in the such as hot flashes, and to prevent chronic diseases. body. Current research does indicate that melatonin in low dosages may help some older individuals with their sleep. However, it is recommended that a physician knowledge- GROWTH HORMONE> This product of the pituitary able in sleep medicine be consulted before self-medication. gland appears to play a role in body composition and mus- Claims that melatonin can slow or reverse aging are far cle and bone strength. It is released through the action of from proven. another trophic factor called growth hormone releasing continued >>

26 Biochemistry and Aging any benefit. Supplements of Estrogen is perhaps the hGH, for instance, can promote most well studied of all hor- continued >> Hormones and Research diabetes, joint pain, carpal mones. Yet results from the tunnel syndrome, and pooling Women’s Health Initiative TESTOSTERONE> In men, testosterone (image of fluid in the skin and other (WHI), the first major below) is produced in the testes (women also produce tissues, which may lead to placebo-controlled, random- small amounts of this hormone). Production peaks in early high blood pressure and heart ized clinical trial of estrogen adulthood. However, the range of normal testosterone failure. Studies in mice have therapy with or without production is vast. So while there are some declines in raised other concerns about progestin to prevent some testosterone production with age, most older men stay the hormone. Investigators chronic diseases of aging, well within normal limits. The NIA is investigating the have found that mice deficient surprised the medical com- in growth hormone produc- munity. There were more role of testosterone supplementation in delaying or tion live substantially longer cases of stroke, blood clots, preventing frailty. Preliminary results have been than normal mice, while heart disease, and breast inconclusive, and it remains unclear if supplementation mice overproducing growth cancer in postmenopausal of this hormone can sharpen memory or help men hormone live shorter than women using estrogen and maintain stout muscles, sturdy bones, and robust average lives. This finding progestin in the study, and sexual activity. Investigators are also looking at its suggests that even if hGH more cases of possible side effects, which may include an increased risk of replacement therapy is ini- dementia in women over certain cancers, particularly prostate cancer. A small tially beneficial, ultimately it age 65, than in those using may be harmful and actually the placebo. But, there were percentage of men with profound deficiencies may be helped might curtail longevity. also fewer bone fractures by prescription testosterone supplements. Similarly, there is scant and cases of colon cancer. In evidence that testosterone postmenopausal supplementation has any women using DHEA > Short for dehydroepiandrosterone, DHEA is pro- positive impact in healthy estrogen alone, duced in the adrenal glands. It is a precursor to some other older men. In fact, some there were hormones, including testosterone and estrogen. Production studies suggest supplemen- more cases peaks in the mid-20s, and gradually declines with age. What tation might trigger excessive of stroke red blood cell production in this drop means or how it affects the aging process, if at all, some men. This can increase is unclear. Investigators are working to find more definite a man’s risk of stroke. answers about DHEA’s effects on aging, muscles, and the immune system. DHEA supplements, even when taken briefly, may cause liver damage and have other detrimental effects on the body. 27 Aging Under the Microscope “ riends…drinking lots of good water, no alcohol, -f staying positive, and lots of singing will keep you alive for a long time.” and fewer bone fractures than many of the actions of hGH. in those women on placebo. Another trophic factor of —Chris Mortensen (1882-1998), Other studies indicate that interest to gerontologists is America’s oldest man, on his 115th birthday. menopausal hormone growth hormone releasing therapy is effective in con- hormone, which stimulates trolling moderate-to-severe the release of hGH. Growth stimulating production of action of growth hormone menopausal symptoms, factors might have an impor- IGF-I. Produced primarily also may be intertwined with so research is ongoing to tant role in longevity deter- in the liver, IGF-I enters and a cluster of other factors— evaluate benefits and risks mination. In nematodes, for flows through the blood exercise, for example, which in menopausal and younger instance, mutations in at stream, seeking out special stimulates a certain amount postmenopausal women. least two genes in the IGF-I IGF-I receptors on the surface of hGH secretion on its own, As research continues, pathway result in extended of various cells, including and obesity, which depresses the pros and cons of hormone lifespan. muscle cells. Through these production of hGH. Even the replacement may become The mechanisms—how receptors it signals the way fat is distributed in the more precisely defined. These hormones and growth factors muscle cells to increase in body may make a difference; hormonal supplements produce their effects—are size and number, perhaps lower levels of hGH have appear to increase risk and still a matter of intense specu- by stimulating their genes been linked to excess provide few clear-cut bene- lation and study. Scientists to produce more of special, abdominal fat but not to fits for healthy individuals know that these chemical muscle-specific proteins. Also lower body fat. and do not seem to slow messengers selectively involved at some point in this the aging process. stimulate cell activities, process are one or more of which in turn affect critical the six known proteins that events, such as the size and specifically bind with IGF-I; functioning of skeletal mus- their regulatory roles are still Growth Factors cle. However, the pathway a mystery. As if the cellular com- Some types of hormonesfrom can hormone to muscle is plexities weren’t enough, the be referred to as growthcomplex or and still unclear. trophic factors. These factorsConsider growth include substances suchhormone. as It begins by insulin-like growth factor (IGF-I), which mediates Like many hormones, blood levels of progesterone, a reproductive hormone, (right) diminish with age. But what influence, if any, the natural decline in progesterone and other hormones has on the aging process in middle and late life is unclear. 28 Biochemistry and Aging Physiologic Clues

We don’t know very much about the few men and women who have lived to 115 years of age or more, but we can assume that they eluded the diseases that kill many people in their 70s and 80s. At 122, Jeanne Calment, for instance, had lived a relatively disease-free life. In fact, escape from infectious disease is the most common reason that all of us can now expect to live longer than our grandparents. Chronic diseases and disabil- Normal Aging establish definitive measures ity were once thought insep- Unlike most of us, Satchel of physiological aging. In arable from old age. This Paige was never quite sure theory, these biomarkers view is changing rapidly as of his birth year. “My birth would be more precise one disease after another certificate was in our (fam- indicators of aging than joins the ranks of those that ily) Bible, and the goat ate chronological age itself. can be prevented or at least the Bible,” he said. But even Once established, these controlled, often through had he known his chrono- biomarkers could make it changes in lifestyle. logical age, it may not have easier to study normal aging, We now know, for exam- shed much light on how diseases, and possible inter- ple, that most people can old he was physiologically. ventions. So far, however, avoid lung disease by not In fact, gerontologists are no such biomarkers have smoking. And heart disease discovering that age in years been identified in humans. and stroke rates have fallen doesn’t necessarily correlate at the same time that Ameri- with physiological age. cans have lowered their fat For decades, investiga- consumption, begun to exer- tors at the NIA have com- cise more, and quit smoking. piled data on heart function, So if chronic disease is lung capacity, and numerous not intrinsic to the aging other bodily functions in process, as many gerontolo- hopes that this information gists now believe, then what may one day be used to is? Are there universal or “normal” aging processes?

“ ow old would you be if you didn’t know how old you were?” —Leroy “Satchel” Paige Member, Baseball Hall of Fame. The oldest person to pitch

in the major leagues—he was in his late 50s. 30 Physiologic Clues In fact, normal Although this diversity Scientists have long known physiological aging is lessens the likelihood of that these defenses decline quite variable, according finding biomarkers of aging with age; now, some of the to investigators involved in in humans, the quest for underlying mechanisms are the Baltimore Longitudinal these indicators has yielded coming to light. Study of Aging, a long-term many insights into the A multiplicity of cells, NIA study begun in 1958 that physiology of two organ substances, and organs make has tracked the lives of more systems that may have up the immune system. The than 1,000 people from age important roles in the aging thymus, spleen, tonsils, bone 20 to 90 and beyond. Not process. One of these is marrow, and lymphatic sys- only do individuals age over- the endocrine system (See tem, for example, produce, all at vastly different rates, Hormones and Research store, and transport a host it is quite likely that age- on Aging, page 26). The of cells and substances— related changes in various other is the immune system. B-lymphocytes and T-lym- cells, tissues, and organs phocytes, antibodies, inter- differ as well. For instance, The Immune System leukins, and interferon, to kidney function may decline When Shigechiyo Izumi of name a few. Several are of more rapidly in some indi- Japan contracted pneumonia special interest to gerontolo- In the Baltimore Longitudinal Study of viduals. In others, bone and died in 1986 at the gists. These include the class Aging (BLSA), volunteers, age 20 to 90, strength may diminish faster. reputed age of 120, it was of white blood cells called are screened every 2 years for physiologi- cal and psychological changes. They The organs that age fastest in his immune system that lymphocytes, which fight undergo a complete physical exam and a one person may not age as failed. One of the many invading bacteria and other series of tests including muscle strength (shown), bone density, aerobic capacity, rapidly in another. This sug- bacteria or viruses that foreign cells. and glucose tolerance. Each assessment gests that genes, lifestyle, and cause pneumonia broke adds detail and focus to the BLSA’s disease can all affect the rate through the elaborate, natu- slowly growing picture of how we age. of aging and that several dis- ral defenses that protect tinct processes are involved. humans from infection.

The organs of the immune system are located throughout the body. White blood cells—lymphocytes—are key operatives of this system. With age, these cells become less active, making the body more vulnerable to bacteria, viruses and other pathogens.

31 Aging Under the Microscope What is Normal Aging? Individuals age at extremely different rates. In fact even within one person, organs and organ systems show different rates of decline. However, some generalities can be made, based on data from the Baltimore Longitudinal Study of Aging.

HEART > Heart muscle thickens with age. Maximal BRAIN > With age, the brain loses some of the oxygen consumption during exercise declines in men structures (axons) that connect nerve cells (neurons) by about 10 percent with each decade of adult life and to each other, although the actual number of neurons in women by about 7.5 percent. This decline occurs seems to be less affected. The ability of individual because the heart’s maximum pumping rate and the neurons to function may diminish with age. Recent body’s ability to extract oxygen from blood both studies indicate that the adult nervous system is diminish with age. capable of producing new neurons, but the exact conditions that are critical for this have yet to be ARTERIES > Arteries tend to stiffen with age. determined. The older heart, in turn, needs to supply more force to propel the blood forward through the less elastic KIDNEYS > Kidneys gradually become less arteries. efficient at extracting wastes from the blood.

LUNGS > Maximum breathing (vital) capacity may BLADDER > Bladder capacity declines. Urinary decline by about 40 percent between the ages of incontinence, which may occur after tissues atrophy, 20 and 70. particularly in women, can often be managed through exercise and behavioral techniques. continued >>

32 Physiologic Clues continued >> What is Normal Aging?

BODY FAT > Typically, body fat gradually SIGHT > Difficulty focusing close up may begin in increases in adulthood until individuals reach middle the 40s; the ability to distinguish fine details may age. Then it usually stabilizes until late life, when begin to decline in the 70s. From 50 on, there is body weight tends to decline. As weight falls, older increased susceptibility to glare, greater difficulty individuals tend to lose both muscle and body fat. in seeing at low levels of illumination, and more With age, fat is redistributed in the body, shifting difficulty in detecting moving objects. from just beneath the skin to deeper organs. Women typically have a higher percentage of body fat than HEARING > It becomes more difficult to hear men. However, because of differences in how this fat higher frequencies with age. Even older individuals is distributed—on the hips and thighs in women and who have good hearing thresholds may experience on the abdomen in men—women may be less suscep- difficulty in understanding speech, especially in situa- tible to certain conditions including heart disease. tions where there is background noise. Hearing declines more quickly in men than in women. MUSCLES > Without exercise, estimated muscle mass declines 22 percent for women PERSONALITY > Personality is extraordinarily and 23 percent for men between the ages of stable throughout adulthood. Generally, it does 30 and 70. Exercise can slow this rate of loss. not change radically, even in the face of major events in life such as retirement, job loss, or death BONES > Bone mineral is lost and replaced of loved ones. However, there are exceptions. throughout life; loss begins to outstrip replace- Certain individuals facing these and other life- ment around age 35. This loss accelerates in altering circumstances can and do show signs of women at menopause. Regular weight bearing personality change during the final years of life. exercise—walking, running, strength training— An easy-going individual who loses a job after can slow bone loss. many years, for instance, may become disillusioned and develop a sullen disposition. But these out-of- character reversals of personality are relatively rare.

33 Aging Under the Microscope “ o lengthen thy life, lessen thy meals.” T —Benjamin Franklin, (1706-1790) Lymphocytes fall into powerful chemicals, called Most research on the immune system as well two major classes: B-cells lymphokines, that mobilize aging immune system now as in other physiological and T-cells. B-cells mature in other immune system centers on these cells. One systems of aging animals. the bone marrow, and one of substances and cells. group of T-cell products, their functions is to secrete T-cells and their lym- interleukins, is found at Caloric Restriction antibodies in response to phokine products have different levels as people An inventor, statesman, infectious agents or antigens. intrigued gerontologists age. The interleukins—there diplomat, and scientist, T-cells develop in the thy- ever since it was learned are more than 20 identified Benjamin Franklin was a true mus, which shrinks in size as that T-cells—or more pre- so far—serve as messengers, Renaissance man renowned

people age; they are divided cisely the functioning popu- relaying signals that regulate for his sage advice. Among Feeding animals 30 to 40 percent into cytotoxic T-cells and lation of T-cells—declines the immune response. Some, his many pearls of wisdom: fewer calories than normal appears helper T-cells. Cytotoxic with age. While the number like interleukin-6, rise with “To lengthen thy life, lessen to delay age-related degeneration of nearly every physiological system. T-cells attack infected or of T-cells remains about the age, and it is speculated that thy meals.” Nearly 275 But it remains uncertain whether damaged cells directly. same, the proportion of them they interfere in some way years later, gerontologists caloric restriction could have the same effect in humans. Helper T-cells produce that proliferate and function with the immune response. are finding those words may declines. Studies have also Others, like interleukin-2, turn out to be amazingly shown that in older people, which stimulates T-cell pro- prophetic. T-cells destroyed by stresses liferation, tend to fall with Since the 1930s, investi- such as irradiation or cancer age. Gerontologists study gators have consistently 1 chemotherapy take longer the interleukins, not only found that laboratory rats to renew than they do in for clues to the mechanisms and mice live up to 40 percent younger people. of aging, but also for their longer than usual when fed potential in the detection a diet that has at least 30 per- 2 The Immune System and treatment of immune cent fewer calories than they problems. would normally consume. 3 1 Tonsils and Adenoids Meanwhile, compelling The animals that eat this 3 2 Thymus evidence suggests one inter- nutritionally balanced diet, 4 3 Lymph Nodes vention—caloric restriction— which provides healthful 4 Spleen may counteract some of the natural declines in the 5 Appendix 6 6 Peyer’s Patches 5 7 Lymphatic Vessels 8 8 Bone Marrow 34 7 Physiologic Clues amounts of protein, fat, and reduce oxidative damage Many gerontologists However, whether caloric vitamins and minerals, also to cells. Calorie restricted are particularly intrigued restriction might have the Data from animal studies suggests appear to be more resistant to animals also have less by findings suggesting that same effect in primates caloric restriction may help neurons resist dysfunction and death (top). age-related diseases. In fact, glucose circulating in their animals on calorie restricted remains a major question. Caloric restriction also might help caloric restriction appears to blood than their freely feed- diets have reduced rates of In studies underway at NIA, the body fend off cancer (center), delay normal age-related ing counterparts. This may disease. In one of the largest rhesus and squirrel monkeys and other age-related cellular changes (bottom). degeneration of almost all lessen the potential for studies to date, Roderick are growing up on a calori- physiological systems. And protein crosslinking, a bio- Bronson, D.V.M., at Tufts cally restricted diet. Similar so far, caloric restriction has chemical process implicated University found that caloric studies are also ongoing at increased the lifespans of in cellular aging. And restriction not only extended the University of Wisconsin nearly every animal species because caloric restriction lifespan in mice, but also and the University of Mary- studied including protozoa, lowers body temperature prevented or slowed down land. Preliminary results fruit flies, mice, and other slightly, cells may sustain development of every dis- from these studies show laboratory animals. Now less genetic damage than at ease and all types of tumors. some promising early signs of investigators are exploring normal body temperature. In Other rodent studies have improved health—including whether and how caloric addition, scientists speculate found that caloric restriction greater resistance to diabetes restriction will affect aging that caloric restriction pre- may increase resistance and heart disease—in these in monkeys and other non- serves the capacity of cells of neurons in the brain to primates as they age. (See human primates, our closest to proliferate, and that it dysfunction and death. The Next Step: Caloric relatives in the animal keeps the immune system These results, described Restriction in Primates, kingdom. functioning at youthful as “stunning” by geron- page 36). Why calorically levels. Caloric restriction tologists, have raised hope restricted animals live also may work through that further study of caloric

far beyond their normal other mechanisms. It may, restriction will help uncover In the 1930s, investigators discovered lifespans remains unclear. for instance, influence hor- the mechanisms responsible that rats and mice fed fewer calories Because cutting down on monal balance, cell senes- for disease in old age. lived longer than rodents allowed to eat as much as they liked. Since then, caloric calories slows metabolism, cence, or gene expression. restriction has increased the lifespan of and free radicals are by- Or, it might work through nearly every animal species studied. products of metabolism, a combination of all of caloric restriction may these mechanisms, plus other factors.

35 Aging Under the Microscope The Next Step: Caloric Restriction in Primates

At the NIH Animal Center in Poolesville, Maryland, being compared with those of the monkeys in the about 75 rhesus and squirrel monkeys are on diets; control group and should provide leads to some of they eat 30 percent less than they would normally the mechanisms at work in caloric restriction. but get all the necessary nutrients. Another 75 mon- The monkeys on the restricted diet are smaller and keys, the control group, are eating as much as they weigh about 20 percent less than monkeys in the want. The differences between the two groups, as control group. However, the calorically restricted they age, are beginning to provide insights into how monkeys are no less physically active than animals caloric restriction influences lifespan. allowed to eat at will. The monkeys that arrived at the Poolesville labora- So far, some positive trends have been detected, tory in 1987 have responded to caloric restriction as including the possibility of reduced incidence of expected; their maturation, measured by factors heart disease and cancer in the calorically such as skeletal development and onset of puberty, restricted monkeys. But it is important to has been delayed by about a year or year and a half. keep in mind that these data are pre- This is comparable to the delays in maturation seen liminary, and investigators caution in calorically restricted rodents. that it may be many more years As the monkeys continue to grow into middle before it can be determined if age and beyond, Donald Ingram, Ph.D., and his caloric restriction does indeed colleagues at the NIA’s Gerontology Research Center improve the health and extend in Baltimore, where the project is coordinated, are the lifespan of aging primates. monitoring dozens of signs of aging, ranging from immune response to activity level to antioxidant levels to fingernail growth. The measurements are

36 Physiologic Clues Yet even if caloric restric- tion is successful in primates, Exercise: It Works at Any Age it is unlikely that most peo- ple could maintain a diet Regular physical activity may be the most of 30 percent fewer calories important thing an older person can do without drastic and, in all to stay healthy and self-reliant. In probability, unpalatable fact, the more exercise you can do changes in their eating in later life, the better off you’ll be. habits. For this reason, most Studies suggest regular, sustained exercise can help gerontologists doubt that prevent or delay some diseases and disabilities as caloric restriction will ever people grow older. And, in some cases, it can actually become a widespread means improve some of these conditions in older people older adults: falls. Flexibility or of extending the human life- who already have them. In a study conducted at stretching exercises help keep your span. But investigators are Tufts University in Boston, for instance, some people body limber. As part of a daily exploring the question of age 80 and older were able to progress from using routine, these exercises and whether drugs might mimic walkers to using canes after doing simple muscle- other physical activities its effects, negating the need building exercises for just 10 weeks. In addition, you enjoy can make a for sweeping alterations in physical activity can improve your mood, lessen your difference in your life as diet. In rodent and other risk of developing adult-onset diabetes, slow bone you get older. animal studies, gerontolo- loss, and reduce your risk of heart attack and stroke. gists are testing a number For a nominal fee, an exercise book and a 48-minute of synthetic substances that Endurance exercises such as brisk companion video are available from NIA. For more walking increase your stamina information about the book and video contact: and improve the health of your NIA Information Center heart, lungs and circulatory sys- P.O. Box 8057 tem. Strength exercises build Gaithersburg, MD muscles and reduce your risk of 1-(800)-222-2225 osteoporosis. Balance exercises help 1-(800)-222-4225 TTY prevent a major cause of disability in

37 Aging Under the Microscope produce some of the same age. These include higher example, help reduce the thin- effects as caloric restriction, levels of fats or lipids in the ning of bones that accompa- such as reducing body blood, changing levels of nies aging in almost everyone temperature and lowering blood sugar and insulin, a but particularly in older the amount of insulin in the tendency toward obesity, women, many of whom are blood. So far, the preliminary and increased central body at high risk for osteoporosis. results have been promising. fat that settles around the Researchers are also However, none of these waist and abdomen. These studying exercise as a behav- of exercise to reduce the substances has yet proved changes are so prevalent ioral factor that may have risk of osteoporosis. This to extend lifespan, and some among older people that an impact on how long condition, with its fragile, have potentially toxic side they have been given a we live or at least on how easily broken bones, is a effects that may make human name, syndrome X. Many healthy we are in old age. major cause of fractures use impractical. Still, the gerontologists are studying One landmark study at Tufts among older people, fre- search goes on. Meanwhile, the possible relationship University in Boston has quently resulting in disabil- it is becoming increasingly between this syndrome and shown that exercise can ity, and eventually leading to clear that lifestyle—particu- cardiovascular diseases. strengthen muscles, improve institutionalization for many. larly diet and exercise—can Syndrome X may be mobility, and reduce frailty In some cases, drugs called have a powerful influence preventable through low-fat even among 90-year-olds. bisphosphonates help by on how people age. and low-cholesterol diets, Exercises that put weight slowing calcium loss in bone. but these are not the only on bones, such as jogging,

Behavioral Factors aspects of nutrition that may walking, and weight-lifting, A balanced diet and regular Diet and exercise are thought influence life expectancy. have been shown to strengthen exercise can help strengthen bone and prevent osteoporosis in later to have a major impact on a Gerontologists have been them. Researchers, as a result, life. Normal bone (bottom inset) constellation of changes that scrutinizing a wide range of are exploring the potential and osteoporotic bone (top). are common with advancing nutrients with an eye toward Reproduced from J Bone Miner their role in aging processes. Res 1986; 1:16-21 with permision of the American Society for Calcium and vitamin D, for Bone and Mineral Research.

38 Physiologic Clues he question has been asked countless times in the T12 months since her 100th birthday…“What’s the secret?” This remarkable burst of others predict that robust longevity, unprecedented health in later life will be —The Independence (Mo.) Examiner on centenarian in human history, has been more common as fewer and longevity determination. Audrey Stubbart’s 101st birthday. possible because of equally fewer older Americans live Experiments involving yeast, The remarkable improvements in with disabilities. Whether fruit flies, nematodes, mice, Future sanitation, health care, and any of these visions become and primates continue to Audrey Stubbart, shown at right in 1920, lifestyle. These advances reality will greatly depend yield insights into various and below with her great-great grand- have led to much conjecture on the emerging science aspects of aging that could daughter, told friends work kept her alive. During her long life, she taught school, about how aging will evolve of aging. one day be applicable to raised five children, and operated a 2,000- in the 21st century. Some As investigators delve humans. acre sheep ranch in Wyoming with her of husband. At 66, she took a job at the Aging gerontologists suspect an more deeply into how and Still, many of the funda- Independence (Mo.) Examiner, where average life expectancy of why we age, its secrets are mental underpinnings of she was a copy editor and columnist 85 years or more may be being deciphered at an aging and longevity determi- for nearly 40 years. She retired shortly before her death at age 105. possible in the not-so-distant unparalleled rate. Scientific nation remain elusive. The The aging boom is upon us. Life expectancy nearly doubled future. Others have specu- understanding of the genetic, role of telomeres in cellular lated that the first person biochemical, and physiologi- senescence and aging, for in the 20th century. Since 1900, the number of Americans age destined to live 130 years cal aspects of this dynamic instance, is poorly under- or more is alive today. Still process has never been stood. It is unclear what, 65 and older has increased 10-fold. The oldest-old—people greater. Microarray technol- if any, effects diminishing Gerontologists have unraveled many ogy has enabled gerontolo- hormone levels in later age 85 and older—constitute the fastest growing segment of the secrets of aging thanks to experi- gists to characterize the life have on aging, ments with simple organisms such as yeast (below, left). Still, much remains expression of vast numbers longevity, and health. of the U.S. population. By 2050, this population— currently unknown about the processes that of genes potentially impor- underlie the journey from young to old, tant in human aging and including the roles that macrophages, about 4 million people—could top 19 million. Living to 100 a part of the immune system (center) and telomeres (right) may play. likely will become more commonplace. In 1950, only about 3,000 Americans were centenarians; by 2050, there could be nearly one million.

40 The Future of Aging he question has been asked countless times in the T12 months since her 100th birthday…“What’s the secret?” This remarkable burst of others predict that robust longevity, unprecedented health in later life will be —The Independence (Mo.) Examiner on centenarian in human history, has been more common as fewer and longevity determination. Audrey Stubbart’s 101st birthday. possible because of equally fewer older Americans live Experiments involving yeast, The remarkable improvements in with disabilities. Whether fruit flies, nematodes, mice, Future sanitation, health care, and any of these visions become and primates continue to Audrey Stubbart, shown at right in 1920, lifestyle. These advances reality will greatly depend yield insights into various and below with her great-great grand- have led to much conjecture on the emerging science aspects of aging that could daughter, told friends work kept her alive. During her long life, she taught school, about how aging will evolve of aging. one day be applicable to raised five children, and operated a 2,000- in the 21st century. Some As investigators delve humans. acre sheep ranch in Wyoming with her of husband. At 66, she took a job at the Aging gerontologists suspect an more deeply into how and Still, many of the funda- Independence (Mo.) Examiner, where average life expectancy of why we age, its secrets are mental underpinnings of she was a copy editor and columnist 85 years or more may be being deciphered at an aging and longevity determi- for nearly 40 years. She retired shortly before her death at age 105. possible in the not-so-distant unparalleled rate. Scientific nation remain elusive. The The aging boom is upon us. Life expectancy nearly doubled future. Others have specu- understanding of the genetic, role of telomeres in cellular lated that the first person biochemical, and physiologi- senescence and aging, for in the 20th century. Since 1900, the number of Americans age destined to live 130 years cal aspects of this dynamic instance, is poorly under- or more is alive today. Still process has never been stood. It is unclear what, 65 and older has increased 10-fold. The oldest-old—people greater. Microarray technol- if any, effects diminishing Gerontologists have unraveled many ogy has enabled gerontolo- hormone levels in later age 85 and older—constitute the fastest growing segment of the secrets of aging thanks to experi- gists to characterize the life have on aging, ments with simple organisms such as yeast (below, left). Still, much remains expression of vast numbers longevity, and health. of the U.S. population. By 2050, this population— currently unknown about the processes that of genes potentially impor- underlie the journey from young to old, tant in human aging and including the roles that macrophages, about 4 million people—could top 19 million. Living to 100 a part of the immune system (center) and telomeres (right) may play. likely will become more commonplace. In 1950, only about 3,000 Americans were centenarians; by 2050, there could be nearly one million.

40 The Future of Aging “ or the first time in human history the prospect - of living a long, healthy and productive flife has become a reality for the majority of people... Stem Cells: Great Expectations, but Many Barriers Remain What was the privilege of the few has become the destiny of the many.” From the moment they were first isolated in the late 1990s, human —Robert Butler, M.D., Gerontologist stem cells mesmerized gerontologists. And for good reason. Further study is needed to they will likely uncover These versatile cells intrigue investigators because Investigators suspect that embryonic stem cells can brains of the rodents clarify how caloric restriction many more secrets of aging. they are capable of transforming themselves develop into almost any of the many known special- and within 1-to-6 months works, and to determine These discoveries may lead into many different kinds of body tissue. ized cell types in the body, including bone, blood, and became neuronal cells. A whether this intervention— to extended life-spans, and Because of this flexibility, stem cells hold brain cells. However, these stem cells are not embryos, second study showed that or drugs that mimic its almost certainly will con- enormous potential for cell replacement or and cannot themselves develop into embryos. Adult adult mouse bone marrow cells could also develop effects—might be effective tribute to better health, tissue repair in many age-associated degen- stem cells apparently help repair or replace those into heart cells and vascular structures, resulting in and safe for humans. less disability, and greater erative disorders where loss of cells is cur- tissues lost through natural attrition, or when they the substantial replacement of damaged heart tissue These and other linger- independence in later life. rently irreversible, including diabetes, are damaged by injury or disease. Adult stem cells in within 2 weeks. ing research challenges stroke, heart disease, and Alzheimer’s and bone marrow, for instance, regularly replenish the underscore the enormity Despite these preliminary successes, many formidable Parkinson’s disease. With millions of older body’s supply of red blood cells. Similarly, intestinal of the quest facing geron- hurdles must be overcome. Investigators still under- Will robust aging as shown by Americans suffering from these conditions, stem cells help maintain the lining of the intestines, tologists. It is becoming this man, be the norm in the stand very little about how stem cells work, so deter- gerontologists are scrambling to find out if which is frequently sloughed off in a natural process. increasingly clear that aging future? Jeanne Calment, the mining how to get stem cells to do what investigators world’s longest-lived person, these cells will yield any practical interventions is an intricate bundle of It is not clear, however, if adult stem cells can fully want them to do in the body remains a mystery. In still rode a bicycle at age 100. that might help promote healthy aging. interdependent processes, match embryonic stem cells’ capacity to differentiate adults, stem cells appear to become less spontaneously some of which are better Stem cells can be derived from an embryo or an adult. into vast arrays of replacement cells and tissues. In active with age, and some gerontologists suspect that understood than others. Unlike most cells in the body, such as skin or heart animal studies, certain adult stem cells have shown inactivation of these cells may play a prominent role in As gerontologists untangle cells, which are dedicated to perform a specific func- some potential to develop into multiple cell types, the normal aging process. For investigators, finding Colorized scanning electron micrograph of these interconnecting tion, stem cells are not specialists. But under certain suggesting that both embryonic and adult stem cells ways to reactivate these cells and get them to where stem cells collected from human bone mar- genetic, biochemical, and row. Stem cells are primitive cells that can circumstances, they can differentiate into specialized could have therapeutic applications. NIA-supported they are needed in the body are significant challenges. multiply indefinitely, migrate to different cells. Another unique characteristic of stem cells is investigators who injected adult mouse bone marrow physiological processes, parts of the body, and develop into different Still, the discovery of human stem cells is an important types of tissue. Bone marrow retains the their ability to replicate for indefinite periods without cells into the circulatory systems of mice, for instance, scientific breakthrough that clearly has the potential to ability to generate stem cells throughout life. becoming senescent. discovered that these cells found their way into the Bone marrow stem cells typically give rise to improve the quality and length of life. bone, blood, and cartilage.

41 42 Aging Under the Microscope The Future of Aging “ or the first time in human history the prospect - of living a long, healthy and productive flife has become a reality for the majority of people... Stem Cells: Great Expectations, but Many Barriers Remain What was the privilege of the few has become the destiny of the many.” From the moment they were first isolated in the late 1990s, human —Robert Butler, M.D., Gerontologist stem cells mesmerized gerontologists. And for good reason. Further study is needed to they will likely uncover These versatile cells intrigue investigators because Investigators suspect that embryonic stem cells can brains of the rodents clarify how caloric restriction many more secrets of aging. they are capable of transforming themselves develop into almost any of the many known special- and within 1-to-6 months works, and to determine These discoveries may lead into many different kinds of body tissue. ized cell types in the body, including bone, blood, and became neuronal cells. A whether this intervention— to extended life-spans, and Because of this flexibility, stem cells hold brain cells. However, these stem cells are not embryos, second study showed that or drugs that mimic its almost certainly will con- enormous potential for cell replacement or and cannot themselves develop into embryos. Adult adult mouse bone marrow cells could also develop effects—might be effective tribute to better health, tissue repair in many age-associated degen- stem cells apparently help repair or replace those into heart cells and vascular structures, resulting in and safe for humans. less disability, and greater erative disorders where loss of cells is cur- tissues lost through natural attrition, or when they the substantial replacement of damaged heart tissue These and other linger- independence in later life. rently irreversible, including diabetes, are damaged by injury or disease. Adult stem cells in within 2 weeks. ing research challenges stroke, heart disease, and Alzheimer’s and bone marrow, for instance, regularly replenish the underscore the enormity Despite these preliminary successes, many formidable Parkinson’s disease. With millions of older body’s supply of red blood cells. Similarly, intestinal of the quest facing geron- hurdles must be overcome. Investigators still under- Will robust aging as shown by Americans suffering from these conditions, stem cells help maintain the lining of the intestines, tologists. It is becoming this man, be the norm in the stand very little about how stem cells work, so deter- gerontologists are scrambling to find out if which is frequently sloughed off in a natural process. increasingly clear that aging future? Jeanne Calment, the mining how to get stem cells to do what investigators world’s longest-lived person, these cells will yield any practical interventions is an intricate bundle of It is not clear, however, if adult stem cells can fully want them to do in the body remains a mystery. In still rode a bicycle at age 100. that might help promote healthy aging. interdependent processes, match embryonic stem cells’ capacity to differentiate adults, stem cells appear to become less spontaneously some of which are better Stem cells can be derived from an embryo or an adult. into vast arrays of replacement cells and tissues. In active with age, and some gerontologists suspect that understood than others. Unlike most cells in the body, such as skin or heart animal studies, certain adult stem cells have shown inactivation of these cells may play a prominent role in As gerontologists untangle cells, which are dedicated to perform a specific func- some potential to develop into multiple cell types, the normal aging process. For investigators, finding Colorized scanning electron micrograph of these interconnecting tion, stem cells are not specialists. But under certain suggesting that both embryonic and adult stem cells ways to reactivate these cells and get them to where stem cells collected from human bone mar- genetic, biochemical, and row. Stem cells are primitive cells that can circumstances, they can differentiate into specialized could have therapeutic applications. NIA-supported they are needed in the body are significant challenges. multiply indefinitely, migrate to different cells. Another unique characteristic of stem cells is investigators who injected adult mouse bone marrow physiological processes, parts of the body, and develop into different Still, the discovery of human stem cells is an important types of tissue. Bone marrow retains the their ability to replicate for indefinite periods without cells into the circulatory systems of mice, for instance, scientific breakthrough that clearly has the potential to ability to generate stem cells throughout life. becoming senescent. discovered that these cells found their way into the Bone marrow stem cells typically give rise to improve the quality and length of life. bone, blood, and cartilage.

41 42 Aging Under the Microscope The Future of Aging Glossaryand Bibliography Amino acid—A chemical building block of proteins. There DNA—Abbreviation for deoxyribonucleic acid, the molecule are 20 standard amino acids. A protein consists of a specific that contains the genetic code for all life forms except for a sequence of amino acids. few viruses. It consists of two long, twisted chains made up of nucleotides. Each nucleotide contains one base, one phos- Antioxidants—Compounds that neutralize oxygen radicals. phate molecule, and the sugar molecule deoxyribose. The Some are enzymes like superoxide dismutase (SOD) and bases in DNA nucleotides are adenine, thymine, guanine, and catalase, while others are nutrients such as vitamin C. cytosine. Anti-proliferative genes—Genes that inhibit cell division or Enyzme—A protein that promotes a specific biochemical reac- proliferation. These genes can act as tumor suppressor genes. tion in the body without itself being permanently changed or Base—Part of a nucleotide. In DNA, the bases are adenine destroyed. Enzymes, for instance, are involved in blood clot- (abbreviated A), thymine (T), cytosine (C), and guanine (G). ting and initiate the process of breaking down food. RNA contains uracil (U) instead of thymine. Fibroblast— One of the major cell types found in skin. Scien- Biomarkers—Biological changes that characterize the aging tists utilize human fibroblast cell cultures to study aging at process. So far, no reliable biomarkers have been identified the cellular level. in humans. Free radicals—Molecules with unpaired electrons that react Caloric restriction—An experimental intervention that readily with other molecules. Oxygen-free radicals, produced is being studied to determine its impact on longevity. In labo- during metabolism, damage cells and may be responsible for ratory settings, the lifespans of animals have been extended aging in tissues and organs. by reducing calories while maintaining the necessary levels Gene—A segment of DNA that contains the “code” for a spe- of nutrients. cific protein. Centenarian—a person who has lived at least 100 years. Gene expression—The process by which the information Chromosome—A cellular structure containing genes. Chro- contained in the genes is transcribed and translated into pro- mosomes are composed of DNA and proteins. Humans have teins. Age-related changes in gene expression may account 23 pairs of chromosomes in each body cell, one of each pair for some of the phenomena of aging. from the mother and the other from the father. Glycation—A process by which glucose links with proteins Cytokines—Proteins that are secreted by cells and regulate and causes these proteins to bind together. In some circum- the behavior of other cells by binding to receptors on their stances, this can result in “stiffening” of tissues and may lead surfaces. This binding triggers a variety of responses, to certain complications of diabetes, and perhaps some of the depending on the nature of the cytokine and the target cell. physiological problems associated with aging.

44 Glossary and Bibliography Hayflick limit—The finite number of divisions a cell is Nucleotide—A building block of DNA or RNA. It includes capable of when cultured in a laboratory setting (in vitro). one base, one phosphate molecule, and one sugar molecule A cell reaching this limit is considered to be senescent, at (deoxyribose in DNA, ribose in RNA). least when in vitro. However, to date there is no evidence Photoaging—The process initiated by sunlight through that replicative senescence plays a physiologically significant which the skin becomes drier and loses elasticity. Photoaging role in normal aging or age-related disorders. is being studied for clues to aging because it has the same Interleukins—A type of cytokine involved in regulation of effect as normal aging on certain skin cells. immune function. The levels of some interleukins present in Proliferative genes—Genes that promote cell division or the body are reported to change with age, but it is unclear proliferation. These genes can act as oncogenes (genes that whether these fluctuations are due to aging itself or are a promote cancer growth). manifestation of the many conditions and diseases associated with aging. Proteins—Molecules composed of amino acids arranged in a specific order determined by the DNA sequence of the gene. Lymphocytes—Small white blood cells that are important to Proteins are essential for all life processes. Certain ones, such the immune system. A decline in lymphocyte function with as the enzymes that protect against free radicals and the lym- advancing age is being studied for insights into aging and phokines, produced in the immune system, are being studied disease. extensively by gerontologists. Maximum lifespan—The greatest age reached by any mem- Replicative senescence—The stage at which a cell has per- ber of a given species. manently stopped dividing. Mean lifespan—The average number of years that members RNA—Abbreviation for ribonucleic acid, the molecule that of a species live; also known as life expectancy. carries out DNA’s instructions for making proteins. It con- Mitochondria—Cell organelles that metabolize glucose and sists of one long chain made up of nucleotides. There are other sugars to produce biochemical energy. Mitochondria three main types of RNA: messenger RNA, transfer RNA, also contain DNA, which is damaged by the high level of and ribosomal RNA. free radicals produced during this process. Telomeres—Repeated short DNA sequences occurring at the Mitosis—The process of replicating DNA, and dividing it end of the chromosomes; telomeres shorten each time a cell into two equal parts to generate two identical “daughter” divides. cells from one “mother” cell. Tumor suppressor genes—Genes that inhibit cell division or proliferation.

45 Aging Under the Microscope Posing Questions, Finding Answers The Genetic Connection Selected Readings Selected Readings Clark,W.R., AMeans to an End: The Biological Basis of Aging and Blackburn, E.H., “Telomere States and Cell Fates,” Nature Death, New York: Oxford University Press, 2002. 408(6808):53-56, 2000. Ricklefs, R.E., and Finch, C.E., Aging: A Natural History, New Sprott, R.L, and Pereira-Smith, O.M. eds., “The Genetics of York: W.H. Freeman and Company, 1995. Aging,” Generations: Journal of the American Society on Aging, 24:11-88, 2000. Austad, S.N., Why We Age: What Science Is Discovering about the Body’s Journey Through Life, New York: John Wiley & Sons, 1997. Guarente, L., and Kenyon, C., “Genetic Pathways That Regulate Aging in Model Organisms,” Nature 408(6809): 255- Kirkwood, T., Time of Our Lives, New York: Oxford University 262, 2000. Press, 2000. Finch C.E., and Tanzi, R.E., “Genetics of Aging,” Science, Rowe, J.W., and Kahn, R.L., Successful Aging, New York: 278(5337): 407-411, 1997. Random House, 1998. Rudolph, K.L., et al., “Longevity, Stress Response, and Cancer Hayflick, L., How and Why We Age, New York: Ballantine, 1994. in Aging Telomerase-Deficient Mice,” Cell, 965: 701-12, 1999. Finch, C.E., Longevity, Senescence and the Genome, Chicago: Hodes, R.J., McCormick, A.M., and Pruzan, M., “Longevity University of Chicago Press, 1991. Assurance Genes: How Do They Influence Aging and Lifes- Institute of Medicine, Extending Life, Enhancing Life: A National pan,” Journal of the American Geriatrics Society, 448:988-991, 1996. Research Agenda on Aging, Washington, DC: National Academy Rubin, H., “Cell Aging In Vivo and In Vitro,” Mechanisms of Press, 1991. Aging and Development, 981:1-35, 1997. Martin, G.R., Baker, G.T., “Aging and the Aged: Theories of Perls, T., et al., “Exceptional Familial Clustering for Extreme Aging and Life Extension,” Encyclopedia of Bioethics, New York: Longevity in Humans,” Journal of the American Geriatrics MacMillan, 1993. Society, 48(11):1483-1485, 2000. Warner, H.R., Butler, R.N., Sprott, R.L., and Schneider, E.L., eds., Harley, C.B., Futcher, A.B., and Greider, C.W., “Telomeres Modern Biological Theories of Aging, New York: Raven, 1987. Shorten During Aging of Human Fibroblasts,” Nature 345:458- 460, 1990.

46 Glossary and Bibliography Hayflick, L., and Moorhead, P.S., “The Serial Cultivation Tower, J., “Transgenic Methods for Increasing Drosophila Life of Human Diploid Cell Strains,” Experimental Cell Research Span,” Mechanisms of Aging and Development 118(1-2):1-14, 2000. 25:585-621, 1961. Melov, S., et al., “Extension of Life-Span with Superoxide Dis- Jazwinski, S.M., “Genes of Youth: Genetics of Aging in Baker’s mutase/Catalase Mimetics,” Science 289(5484):1567-1569, 2000. Yeast,” ASM News 59:172-178, 1993. Knight, J.A., “The Biochemistry of Aging,” Advances In Johnson, T.E., “Aging Can Be Genetically Dissected Clinical Chemistry, 35:1-62, 2000. into Component Processes Using Long-Lived Lines of Campisi, J., and Warner, H.R., “Aging in Mitotic and Post- Caenorhabditis elegans,” Proceedings of the National Academy of Mitotic Cells,” in Gilchrest, B.A., and Bohr, V.A., eds., The Role Sciences 84:3777-3781, 1987. of DNA Damage and Repair in Cell Aging, New York: Elsevier McCormick, A.M., and Campisi, J., “Cellular Aging and Science, 2001. Senescence,” Current Opinion in Cell Biology 3:230-234, 1991. Ames, B.N., “Endogenous DNA Damage as Related to Nutri- Pereira-Smith, O.M., and Smith, J.R., “Genetic Analysis tion and Aging,” in Ingram, D.K., Baker, G.T., and Shock, N.W., of Indefinite Division in Human Cells: Identification of eds., The Potential for Nutritional Modulation of Aging Processes, Four Complementation Groups,” Proceedings of the National Trumbull, CT: Food and Nutrition Press, 1991. Academy of Sciences 85:6042-6046, 1988. Blake, M.J., Udelsman, R., Feulner, G.J., Norton, D.D., and Rose, M.R., “Laboratory Evolution of Postponed Senescence in Holbrook, N.J., “Stress-Induced HSP70 Expression in Adrenal Drosophila Melanogaster,” Evolution 38:1004-1010, 1984. Cortex: A Glucocorticoid Sensitive, Age-Dependent Response,” Proceedings of the National Academy of Sciences 87:846-850, 1991. Biochemistry and Aging Cerami, A., “Hypothesis: Glucose as a Mediator of Aging,” Selected Readings Journal of the American Geriatrics Society 33:626-634, 1985. Finkel, T., and Holbrook, N.J., “Oxidants, Oxidative Stress and Daynes R.A., and Araneo, B.A., “Prevention and Reversal the Biology of Aging,” Nature 408(6809):239-247, 2000. of Some Age-Associated Changes in Immunologic Responses Beckman, K.B., and Ames, B.N., “The Free Radical Theory of by Supplemental Dehydroepiandrosterone Sulfate Therapy,” Aging Matures,” Physiological Reviews 78(2): 547-581, 1998. Aging: Immunology, and Infectious Disease 3:135-153, 1992. Phillips, J.P., Parkes, T.L., and Hilliker, A.J., “Targeted Harman, D., “The Free Radical Theory of Aging,” in Warner, Neuronal Gene Expression and Longevity in Drosophila,” H.R., et al., eds., Modern Biological Theories of Experimental Gerontology 35(9-10):1157-1164, 2000. Aging, New York: Raven, 1987.

47 Aging Under the Microscope Rudman, D., Feller, A.G., Nagraj, H.S., et al., “Effects of Fiatarone, M.A., and Marks, E.C., et al., “High-Intensity Human Growth Hormone in Men Over 60 Years Old,” Strength Training in Nonagenarians,” Journal of the American The New England Journal of Medicine 323(1):1-6, 1990. Medical Association 263:3029-3034, 1990. Stadtman, E.R., “Protein Oxidation and Aging,” National Institute on Aging, Research on Older Women: Science 257:1220-1224, 1992. Highlights from the Baltimore Longitudinal Study of Aging, Bethesda, MD: National Institutes of Health, 1991. Wallace, D.C., “Mitochondrial Genetics: A Paradigm for Aging and Degenerative Diseases?” Science 256:628-632, 1992. Shock, N.W., Greulich, R.G., Andres, R.A., Arenberg, D., Costa, P.T., Lakatta, E.G., and Tobin, J.P., Normal Physiologic Clues Human Aging: The Baltimore Longitudinal Study of Aging, Selected Readings Washington, DC: U.S. Government Printing Office, 1984. Biomarkers of Aging: From Primitive Organisms to Man, Warner, H.R., and Kim, S.K., “Dietary Factors Modulating the Workshop Report, International Longevity Center, 2001. Rate of Aging,” in Goldberg, I., ed., Functional Foods, New York: Van Nostrand Reinhold, 1993. The Aging Factor in Health and Disease, Workshop Report, Inter- national Longevity Center, 1999. Weindruch, R., and Walford, R.L., The Retardation of Aging and Disease by Dietary Restriction, Springfield, IL: Charles C. Roth, G.S., Ingram, D.K., and Lane, M.A., “Calorie Restriction Thomas, 1988. in Primates: Will It Work and How Will We Know?” Journal of the American Geriatrics Society, 47(7):896-903, 1999. The Future of Aging Mattson, M.P., “Neuroprotective Signaling and the Aging Selected Readings Brain: Take Away My Food and Let Me Run,” Brain Research K. Kinsella and V.A. Velkoff, U.S. Census Bureau, Series 886(1-2):47-53, 2000. P95/01-1, An Aging World: 2001, U.S. Government Printing Ramsey, J.J., et al., “Dietary Restriction and Aging in Rhesus Office, Washington, D.C. 2001. Monkeys: The University of Wisconsin Study,” Experimental Federal Interagency Forum on Aging-Related Statistics. Gerontology 35(9-10):1131-1149, 2000. Older Americans 2000: Key Indicators of Well-Being. Federal Adler, W., Song, L., Chopra, R.K., Winchurch, R.A., Waggie, Interagency Forum on Aging-Related Statistics, Washington, K.S., and Nagel, J.E., “The Immune Deficiency of Aging,” in DC: U.S. Government Printing Office. August 2000. Powers, D., Morley, J., and Coe, R., eds., Aging, Immunity, and Stem Cells: Scientific Progress and Future Research Directions, Infection, New York: Springer, 1993. National Institutes of Health, Department of Health and Human Services, June 2001. http://www.nih.gov/news/ stemcell/scireport.htm 48 Glossary and Bibliography Acknowledgements

WRITER Page 10, 19 — Aging worm photos, courtesy Page 23 — DNA stock art, courtesy of Dr. Paul A. Doug Dollemore, Office of Communications and Public of Dr. Cynthia Kenyon, University of California, Thiessen, www.Chemicalgraphics.com Liaison, National Institute on Aging San Francisco Page 24 — Heat shock protein illustrations, courtesy of Page 11 — Sardinian man, courtesy of Askos Edizioni, Dr. Nikki Holbrook, Yale University, New Haven, CT DESIGN and Dr. Giuseppe Pilia of the L’Instituto sulle Randi L. Wright, Levine & Associates, Inc., Page 26, 27, 28 — Hormones and Molecular Talassemie ed Anemie Mediterranee, Cagliari, Washington, D.C. Expressions, Michael W. Davidson, Sardinia, Italy http://micro.magnet.fsu.edu PHOTOGRAPHY / ILLUSTRATIONS Page 11 — Zebrafish, courtesy of Dr. Glenn Gerhard, Page 31 — BLSA participant, courtesy of Kay Churnush Cover, inside front and back covers, page 4, 5, 13, 17, VA Medical Center, White River Junction, VT 18, 19, 20, 21, 23, 26, 27, 29, 30, 34, 35, 37, 39, 42, 43 — Page 35 — Illustration of neurons, courtesy of Page 12 — Microarray photo, courtesy of courtesy of Getty Images, Inc. Dr. Mark Mattson, Laboratory of Neurosciences, Dr. Minoru Ko, Laboratory of Genetics, National Institute on Aging Introduction — Robert Byrd photos, reproduced from National Institute on Aging Growing Old Is Not For Sissies II: Portraits of Senior Page 36 — Monkey illustrations, courtesy of Page 13-14 — Dividing cell, courtesy of Athletes, by Etta Clark, Pomegranate Art Books, Dr. Don Ingram, Laboratory of Neurosciences, Dr. Elizabeth Blackburn, University of California, San Francisco, (1995) with permission of Etta Clark National Institute on Aging San Francisco Page 2, 30 — Jeanne Calment and Leroy “Satchel” Page 37 — Rowers, reproduced from Growing Old Is Page 13 — Fruit Fly photo, courtesy of Dr. John Tower, Paige, courtesy of the Associated Press Not For Sissies II: Portraits of Senior Athletes, by Etta University of Southern California, Los Angeles Page 3 — Four brothers photos, courtesy of Clark, Pomegranate Art Books, San Francisco, (1995) Doug Dollemore, National Institute on Aging Page 14 — Fibroblast photos and Dr. Leonard Hayflick with permission of Etta Clark photo, courtesy of Dr. Leonard Hayflick, University of Page 38 — reproduced from J. Bone Miner Res., 1986; Page 5 — Rockfish, courtesy of Dr. Gregor M. Cailliet, California, San Francisco Moss Landing Marine Laboratories, California State 1:16-21 with permission of the American Society for University, Moss Landing, CA Page 15, 18 — Scientists, courtesy of Max Hirshfeld Bone and Mineral Research Page 6 — Four generations photo, courtesy of Page 18, 22, 25, 31, 35, 40, 41 — Photo Researchers Inc. Page 40 — Audrey Stubbart photos, courtesy of Carol Kroeck and The Examiner Dr. Huber Warner, Biology of Aging Program, Page 19 — Free radical illustration, courtesy of National Institute on Aging Stacy Janis Back cover — Electron microscope, courtesy of Max Hirshfeld Page 8 — Dr. Thomas T. Perls and centenarian, Page 20 — Protein crosslinking photos, courtesy of Rick Friedman Photography, © 2002 Rick Friedman Dr. John W. Baynes, University of South Carolina, All other photos from the Office of Communications All Rights Reserved Columbia, SC and Public Liaison, National Institute on Aging Page 9, 40 — Yeast photos, courtesy of Page 22 — Werner’s syndrome photos, courtesy of Dr. Michal S. Jazwinski, Louisiana State University Dr. George Martin, University of Washington, Seattle Special thanks to Dr. Huber Warner, Associate Medical Center, New Orleans Director, Biology of Aging Program, National Institute on Aging “ row old along with me! gThe best is yet to be, The last of life, for which the first was made.”

—Robert Browning, (1812-1889)

A Biological Quest National Institutes of Health National Institute on Aging Office of Communications and Public Liaison Building 31, Room 5C27 Bethesda, MD 20892-2292 Phone: 301-496-1752 Website: www.nia.nih.gov

NIH Publication No. 02-2756 June 2006 edition Originally printed September 2002 NATIONAL INSTITUTE ON AGING NATIONAL INSTITUTES OF HEALTH