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 TABLE 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.