Biology of Aging: Research Today for a Healthier Tomorrow PDF

BIOLOGY OF Research Today for a Healthier Tomorrow AGING NATIONAL INSTITUTE ON AGING NATIONAL INSTITUTES OF HEALTH U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES BIOLOGY OF AGING Research Today for a Healthier Tomorrow AGING U...

BIOLOGY OF Research Today for a Healthier Tomorrow AGING NATIONAL INSTITUTE ON AGING NATIONAL INSTITUTES OF HEALTH U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES BIOLOGY OF AGING Research Today for a Healthier Tomorrow AGING UNDER THE METABOLISM The National Institute on Aging MICROSCOPE (NIA), part of the National 23 Does stress really shorten Institutes of Health at the 4 What is aging? your life? U.S. Department of Health and Human Services, was established 6 Living long and well: 27 Does how much you eat to help improve the health and Can we do both? Are affect how long you live? well-being of older people through they the same? research. NIA conducts and IMMUNE SYSTEM supports research on the medical, 9 Is what’s good for mice good for men? 31 Can your immune system social, and behavioral aspects still defend you as you age? of aging. This mission is carried GENETICS out through NIA’s Intramural THE PROMISE OF RESEARCH Research Program composed 13 Is aging in our genes? of staff scientists in Baltimore 35 Past, present, and future and Bethesda, Maryland, and 14 How can we find aging through its Extramural Research genes in humans? 36 GLOSSARY Program, which funds researchers at major institutions across the 18 What happens when DNA 37 BIBLIOGRAPHY United States and internationally. becomes damaged? Biology of Aging: Research Today for a Healthier Tomorrow describes some of NIA’s exciting findings about the basic biology of aging and points to directions for future investigation. BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 1 PHOTO CREDIT: MARTY KATZ, WWW.MARTYKATZ.COM 2 AGING UNDER THE MICROSCOPE We marvel at the 90-year-old who still gets up every day and goes to work. And, it is a genuine thrill to celebrate a relative’s 100th birthday. Yet our feelings about aging are complex. We may want to live forever, but who looks about this magical transformation. These forward to getting old? We hope we’re vigor- are the types of questions and kinds of experi- ous right up until the very end. Still, day-to- ences that could stimulate a lifelong quest to day, many of us make unhealthy choices that explore what happens as we age. could put our future at risk. Since the National Institute on Aging (NIA) From the beginning of time, people was established at the National Institutes of have tried to understand aging. Almost Health (NIH) in 1974, scientists asking just every culture has a mythology to explain it. such questions have learned a great deal As we grow up, tales of eternal youth pique about the processes associated with the our curiosity. And, it is these musings that biology of aging. For scientists who study may provide just the spark needed to ignite aging—called gerontologists—this is an excit- a budding scientist. There’s the little girl, ing time. Technology today supports research excited to visit her grandmother, who asks that years ago would have seemed possible her parents how someone so spunky and only in a science fiction novel. And, a scientific fun could be so old. Or, the 3rd grader who, community that values active collaboration as after watching in awe as a caterpillar spins well as individual scientific achievement has a cocoon and then days later emerges as a helped to move research forward faster than butterfly, peppers the teacher with questions ever before. BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 3  Over centuries, theories about aging have literally slowed down the runners. Although emerged and faded, but the true nature of the some physical decline may be a normal result aging process is still uncertain. The fact is— of aging, the reasons for these changes are of aging is a part of everyone’s life. But the facts particular interest to gerontologists. of aging—what is happening on a biochemi- Gerontologists look for what distinguishes cal, genetic, and physiological level—remain normal aging from disease, as well as explore rich for exploration. why older adults are increasingly vulnerable This booklet introduces some key areas of to disease and disability. They also try to research into the biology of aging. Each area understand why these health threats take is a part of a larger field of scientific inquiry. a higher toll on older bodies. Since 1958, You can look at each topic individually, or you NIA’s Baltimore Longitudinal Study of Aging can step back to see how they fit together in (BLSA) has been observing and reporting on a lattice-work, interwoven to help us better these kinds of questions. As with any longi- understand aging processes. Research on aging tudinal study, the BLSA repeatedly evaluates is dynamic, constantly evolving based on new people over time rather than comparing discoveries, and so this booklet also keeps an a group of young people to a group of old open eye on the future, as today’s research people, as in a cross-sectional study. Using this provides the strongest hints of things to come. approach, BLSA scientists have observed, for example, that people who have no evidence of ear problems or noise-induced hearing What is aging? loss still lose some of their hearing with In the broadest sense, aging reflects all the age—that’s normal. Using brain scans to learn changes that occur over the course of life. if cognitive changes can be related to struc- You grow. You develop. You reach maturity. tural changes in the brain, BLSA scientists To the young, aging is exciting—it leads to discovered that even people who remain later bedtimes and curfews, and more inde- healthy and maintain good brain function pendence. By middle age, another candle late in life lose a significant amount of brain seems to fill up the top of the birthday cake. volume during normal aging. It’s hard not to notice some harmless cosmetic However, some changes that we have long changes like gray hair and wrinkles. Middle thought of as normal aging can be, in fact, age also is the time when people begin to the signs of a potential disease. Take, for notice a fair amount of physical decline. example, sudden changes in personality. Even the most athletically fit cannot escape A common belief is that people become these changes. Take marathon runners, for cranky, depressed, and withdrawn as they get example. An NIA-funded study found that older. But an analysis of long-term data from their record times increased with age—aging the BLSA showed that an adult’s personality 4 AGING UNDER THE MICROSCOPE  POSSIBLE PATHWAYS LEADING TO AGING SIGNALS ENTERING THE CELL CELL NUCLEUS DNA ILLUSTRATION AND INFORMATION ADAPTED FROM WWW.GENOME.GOV SIGNALS TO OTHER CELLS To answer questions about why and how we age, some scientists look for mechanisms or pathways in the body that lead to aging. Our cells constantly receive cues from both inside and outside the body, prompted by such things as injury, infection, stress, or even food. To react and adjust to these cues, cells send and receive signals through biological pathways. Some of the most common are involved in metabolism, the regulation of genes, and the transmission of signals. These pathways may also be important to aging. BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 5  generally does not change much after age 30. occurs, and what are the biological processes People who are cheerful and assertive when underlying these changes. Scientists look they are younger will likely be the same when deep into our cells and the cells of laboratory they are age 80. The BLSA finding suggests animals to find answers. What they learn today that significant changes in personality are not about aging at the cellular and molecular due to normal aging, but instead may be early levels may, ultimately, lead to new and better signs of disease or dementia. ways to live a longer, healthier life. The rate and progression of cellular aging can vary greatly from person to person. But generally, over time, aging affects the cells of Living long and well: Can we every major organ of the body. Changes can do both? Are they the same? start early. Some impact our health and func- You can hardly turn on your computer these tion more seriously than others. For instance, days without being bombarded with adver- around the age of 20, lung tissue starts to lose tisements that pop up trying to convince you elasticity, and the muscles of the rib cage slowly of the power of a pill that will make you live begin to shrink. As a result, the maximum longer or a cream that will help to revive your amount of air you can inhale decreases. In the youthful vigor and appearance. The search for gut, production of digestive enzymes dimin- ishes, affecting your ability to absorb foods properly and maintain a nutritional balance. Blood vessels in your heart accumulate fatty deposits and lose flexibility to varying degrees, resulting in what used to be called “hardening of the arteries” or atherosclerosis. Over time, women’s vaginal fluid production decreases, and sexual tissues atrophy. In men, aging decreases sperm production, and the prostate can become enlarged. Scientists are increasingly successful at detailing these age-related differences because of studies like the BLSA. Yet studies that observe aging do not identify the reasons for age-related changes, and, therefore, can only go so far toward explaining aging. Questions remain at the most basic level about what triggers aging in our tissues and cells, why it 6 AGING UNDER THE MICROSCOPE ways to stop or reverse the aging process is a FACTORS CONTRIBUTING TO LIFESPAN near-obsession in popular culture. The likeli- hood of discovering a scientifically proven “anti-aging” elixir is slim, but researchers GENES believe their work will reveal ways to improve a person’s ability to live a longer, healthier life. They express these goals in terms of “lifespan” and “health span,” respectively. ENVIRONMENT Lifespan is the length of life for an organism. For instance, if you live to age 99, that would be your lifespan. Maximal lifespan is the BEHAVIORAL TRAITS maximum number of years of life observed in a specific population. It differs from species to species. The maximum recorded lifespan for humans, reported in 2010, was 122.5 years for females and 116 years for males. Lifespan is a common measurement in aging research. That’s because it is clear-cut and easy to measure—an organism is either Researchers are finding that lifespan alive or dead. Scientists look for factors such may be influenced by external factors, as well. as genes, environment, and behavioral traits This has been demonstrated in animal stud- (including diet) that may contribute to an ies. NIA’s Interventions Testing Program (ITP) organism’s lifespan. Altering a factor to see if examines a variety of compounds for their it changes lifespan can provide evidence about effects on the lifespan of mice. Compounds whether or not that specific factor is impor- studied include dietary supplements, tant for aging. For instance, when researchers hormones, and anti-inflammatory drugs. suspect that a specific gene has an effect on In one ITP study, male mice treated with lifespan, they may test their hypothesis by aspirin, an anti-inflammatory drug, displayed modifying the activity of that gene (perhaps a moderately increased lifespan. In another lower its activity by deleting the gene or ITP study, masoprocol, an anti-inflammatory increase its activity by adding an extra copy drug that has antioxidant properties, was of it). If the life of the animal with the modified found to increase longevity of male, but not gene activity is longer or shorter, then the gene female, mice. These and other findings may probably does play a role in lifespan. help scientists identify compounds to test in BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 7  UNCOVERING FAMILY humans for their effects on aging. While some of the SECRETS TO A LONG LIFE compounds tested in the ITP already have a clinical use for humans, scientists are clear: These compounds should be used only as prescribed and not for lifespan Most of what we know about factors extension at this time. that can contribute to a long lifespan The ability to withstand disease could also be and health span is based on research central to lifespan. Studies of exceptionally long-lived in animal models. However, NIA- people are helping to establish patterns of health funded research like the Long Life decline and increased disease (called morbidity) with Family Study is taking what we’ve old age. For example, do health problems start around learned in animals and seeing if it the same age in all people and expand over extra years applies to human aging. This study of life for the long-lived, or are the problems delayed, is collecting data from families with occurring closer to the end of life among exceptional at least two siblings who have lived agers? Evidence from a Danish longitudinal study of to a very old age in relatively good 92- to 100-year-olds found that health problems seem health. Along with asking questions to be delayed, appearing closer to the end of life. This is about their family and health history, not a certain outcome, but in many studies, the average the researchers conduct physical centenarian seems to be in better health than the aver- assessments and health screenings age 80-year-old. However, living to 100 does not mean and collect a small blood sample never having any health issues. In the New England for genetic tests. What researchers Centenarian Study, researchers have developed three learn about common characteristics categories for their long-lived participants. They are shared by these families could one characterized as “survivors,” “delayers,” or “escapers,” day be used to guide lifestyle advice depending on whether they have survived a life-threaten- and medical treatments. ing disease, delayed a serious health problem until much later in life, and/or escaped any serious health events. Scientists used to think that long life was a good indicator of health span, or years of good health and function. However, some experiments, particularly in mice, demonstrate significant improvements in health, without actually increasing lifespan. For example, NIA scientists and grantees (that is, scientists at a university or other institution whose research is funded by NIA) examining the effects of the wine-derived compound resveratrol in mice on a normal diet found the 8 AGING UNDER THE MICROSCOPE  ANIMAL MODELS Here are some animals commonly studied in aging research. compound positively influenced the health of the mice—resveratrol-treated mice had better bone health, heart function, strength, vision, coordination, and cholesterol than the control group. But, resveratrol did ROUNDWORM C. elegans not increase lifespan. (Lifespan was increased, however, in mice on a high-fat diet supplemented with resveratrol.) Understanding how to extend health span—apart from its impact on longevity—is a growing focus of many studies, and for good reason. Imagine a society where a majority of people live to be 100, but along with the added years comes considerably more physical decline. While there is still a place for lifespan research, health span research holds promise for revealing ways to delay FRUIT FLY or prevent disease and disability so that we can live Drosophila melanogaster healthier longer. Is what’s good for mice good for men? A lot of research findings seem to tell us what is good—or bad—for yeast, mice, roundworms (C. elegans), or fruit MOUSE flies (Drosophila melanogaster). Does that mean it will Mus musculous work for you? Animal models are essential to research in the biology of aging. Fruit flies and roundworms, along with more complex organisms like mice, rats, and nonhuman primates, have many biological mechanisms and genes that are similar to humans. They also experience many of the same physiological changes (changes in the body) with aging. Therefore, these animals can be used as models of human aging and human physiology, despite the obvious differences in appearance. Scientists can use some exploratory approaches (like modifying a gene to measure its effects on health or longevity) in animal RHESUS MONKEY models such as worms, flies, and mice that would not be Macaca mulatta possible in humans. They also can better isolate the variable BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 9  they want to investigate because animal studies biological pathway. Sometimes it does not. are conducted in tightly controlled environ- Part of the reason might be that while mice, ments. The animals typically have a very struc- for example, have only a slightly larger number tured daily regimen with limited exposure to of genes than worms, and the genes in mice pollutants, stressors, or other elements that and worms serve similar functions, the activ- could otherwise affect lifespan and health span. ity of mouse genes is different and somewhat Different types of studies use different more complex than that of worms. As a result, animal models. Animal models with a short a genetic intervention that increases a worm’s lifespan take less time and fewer resources lifespan by fourfold might have a significantly to study from birth to death and to test inter- less impressive effect on a mouse’s lifespan. ventions that might affect the aging process. For similar reasons, an intervention might be Scientists might favor a fruit fly when studying promising in mice, but that does not mean it a possible genetic target for an intervention to will work the same way or at all in humans. increase longevity, for example, because their Studies in animal models closer to average lifespan is only 30 days. This allows humans, such as monkeys or other nonhuman researchers to measure the effects in about a primates, can be key to understanding how month. The roundworm’s 2- to 3-week lifespan basic discoveries might apply to humans. makes it another ideal model for identifying and They are essential for pre-clinical studies, studying genes that might affect longevity. In a an intermediary step between research in landmark study, NIA-funded researchers found animal models like mice and clinical studies that reducing the activity of a set of genes, called in humans. Studies in nonhuman primates, for daf, increased roundworm lifespan by three- or example, have demonstrated to NIA researchers even fourfold. Daf genes are involved in the how normal age-related changes in the heart roundworm’s ability to enter a type of hiberna- influence risk of heart disease. They have also tion stage, called diapause, to survive periods of been important for testing interventions to food scarcity. This research would not have been lower risks of heart disease, such as drugs to as feasible if conducted using an animal model decrease blood vessel stiffness. with an average lifespan of 10 or 20 years. So, if something works to slow aging in After scientists establish a possible inter- mice, worms, fruit flies, or monkeys, does vention in one animal model, they then apply that mean it will definitely work for you? the intervention to increasingly complex The answer is no. Certainly, data from animal organisms. They might work their way up studies provide critical insights to the aging from worms or flies to mice and then to larger process and can form the basis for testing mammals, such as nonhuman primates. At each potential interventions. But direct testing in step, researchers carefully study if the interven- humans is essential before an intervention tion has the same effect on the comparable can be considered safe and effective.  10 AGING UNDER THE MICROSCOPE  A DIFFERENT APPROACH: COMPARATIVE BIOLOGY NAKED MOLE RAT PHOTO CREDIT: COURTESY OF THOMAS PARK, PH.D., UNIVERSITY OF ILLINOIS AT CHICAGO MOUSE NAKED MOLE RAT Lifespan: 4 years Lifespan: 17 to 28 years One approach to aging biology research The naked mole rat, a mouse-size rodent is called “comparative biology.” It involves that lives underground, has been widely used comparing two or more similar species that have in comparative research. It lives approximately very different lifespans—one lives much longer 17 years in the wild and more than 28 years than the other—to understand how the longer- in captivity. Its relative, the mouse, lives a lived species has, as one NIA-funded researcher maximum of 4 years. What accounts for this puts it, “exceptional resistance to basic aging startling difference? Naked mole rats have lower processes.” Comparative biology studies metabolic rates and body temperature, meaning generally focus on species that live at least twice that they require less energy to survive. They as long as their close relatives. have low concentrations of blood glucose (blood A few possible theories explain what may be sugar), insulin, and thyroid hormone, so they are taking place among these longer-lived animals: less susceptible to certain diseases. Naked mole ►►They experience a slower rate of rats are better able to withstand some types age-related decline. of biological stress and, at this point, there has ►► They can survive even when their organs and/or never been a case of cancer reported in these systems break down and have minimal function. animals. All these factors and likely others yet to ►►They are better able to tolerate cellular be determined contribute to their healthier and damage or diseases. longer life. BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 11 12 GENETICS Is aging in our genes? You may get your hair color from your father’s side of the family and your great math skills from your mother. These traits are “in the genes,” so to speak. Likewise, longevity tends to “run in families”—your genetic make-up plays an important role in how you age. You can see evidence of this genetic connection in families with siblings who live into their 90s or families that have generation after generation of centenarians. These long-lived families are the basis for many genetic studies. Identifying the genes associated with any trait is difficult. First, just locating the gene requires a detailed understanding of the trait, including knowledge of most, if not all, of the contributing factors and pathways related to that trait. Second, scientists must have clear ways of determining whether the gene suspected to have a relationship with the trait has a direct, indirect, or even no effect on that trait. BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 13  Identifying longevity genes is even more a gene influences aging in humans, a relation- complex than determining genes for height or ship, or “association,” may be inferred based hair color, for example. Scientists do not know upon whether a genetic variant is found more all the factors and pathways that contribute frequently among successful agers, such as to longevity, and measuring a gene’s effect on centenarians, compared with groups of people long-lived animals, including humans, would who have an average or short lifespan and literally take a lifetime! Instead, scientists health span. have identified hundreds of genes that affect Several approaches are used to identify longevity in short-lived animal models, like possible genes associated with longevity in worms and flies. Not all of these genes pro- humans. In the candidate gene approach, mote long life. Sometimes mutating or elimi- scientists look for genes in humans that serve nating a gene increases lifespan, suggesting similar functions in the body as genes already that the normal function of the gene limits associated with aging in animal models, so- longevity. Findings in animal models point to called “homologs” or “orthologs” to animal places for scientists to look for the genes that genes. For instance, after finding longevity may influence longevity in humans. genes involved in the insulin/IGF-1 pathway of animal models, researchers look for the How can we find aging comparable genes in the insulin/IGF-1 path- way of humans. Scientists then determine genes in humans? whether the genes are linked to longevity in The human genetic blueprint, or genome, humans by looking to see if a variant of the consists of approximately 25,000 genes made genes is prevalent among people who live up of approximately 3 billion letters (base healthy, long lives but not for people who have pairs) of DNA. Small deviations in the base an average health span and lifespan. pairs naturally occur about once in every In one NIA-funded project, researchers 1,000 letters of DNA code, generating small studied 30 genes associated with the insulin/ genetic variants. Scientists are finding that IGF-1 pathway in humans to see if any vari- some of these variants (polymorphisms) are ants of those genes were more common in actually associated with particular traits or women over 92 years old compared to women chance of developing a specific disease. People who were less than 80 years old. Variants with a certain trait, for example, those living of certain genes—like the FOXO3a gene— past age 100, may be more likely to have one predominated among long-lived individuals, variant of a gene, while people without the suggesting a possible role with longer lifespan. same trait may be more likely to have another This finding provides evidence that, like in variant. While it is very difficult to prove that animal models, the insulin/IGF-1 pathway has 14 GENETICS  HUMAN GENETIC BLUEPRINT CELL 23 PAIRS OF CHROMOSOMES GENES NUCLEUS ILLUSTRATION ADAPTED FROM ALZHEIMER'S DISEASE: UNRAVELING THE MYSTERY C G A T C T G A DNA STRAND BASES The human genetic blueprint, or genome, consists of approximately 25,000 genes made up of approximately 3 billion letters (base pairs) of DNA. Base pair sequences: guanine (G) pairs with cytosine (C); adenine (A) pairs with thymine (T). BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 15  PATHWAYS OF LONGEVITY GENES Most longevity genes identified thus far influence one of three pathways in a cell: insulin/IGF-1, sirtuins, or mTOR. In the 1980s, scientists discovered the first gene a role in human aging. These genes may be shown to limit lifespan in roundworms, which they named important to future development of thera- age-1. Further investigation revealed that the effects of pies to support healthy aging. age-1 are involved with the insulin/IGF-1 pathway. When Another approach, the genome-wide scientists “silenced” the age-1 gene’s activity, the insulin/ association study, or GWAS, is particularly IGF-1 pathway’s activity also decreased and the worms productive in finding genes involved in lived longer. Since then, many other genes associated diseases and conditions associated with with the insulin/IGF-1 pathway have been found to aging. In this approach, scientists scan affect the lifespan of fruit flies and mice, strengthening the entire genome looking for variants the hypothesis that the insulin/IGF-1 pathway plays an that occur more often among a group important role in the aging process. More research is with a particular health issue or trait. In needed to determine if inhibiting this pathway could one GWAS study, NIH-funded researchers increase longevity in humans or create insulin-related identified genes possibly associated with health problems like diabetes. A recent report suggests that high and low blood fat levels, cholesterol, people with a mutation related to the insulin/IGF-1 pathway and, therefore, risk for coronary artery may have less risk of developing diabetes and cancer. disease. The data analyzed were collected from Sardinians, a small genetically alike There is also a great deal of interest in the sirtuin population living off the coast of Italy in pathway. Sirtuin genes are present in all species and the Mediterranean, and from two other regulate metabolism in the cell. They are crucial for international studies. The findings cell activity and cell life. In the 1990s, scientists at the revealed more than 25 genetic variants Massachusetts Institute of Technology found that in 18 genes connected to cholesterol and inserting an extra copy of a sirtuin equivalent, called Sir2, lipid levels. Seven of the genes were not increased the lifespan of yeast. Extension of lifespan has previously connected to cholesterol/lipid been replicated in other organisms, including flies and worms. levels, suggesting that there are possibly However, studies in mice have yielded conflicting results. other pathways associated with risk for The mTOR pathway—an abbreviation of “mammalian coronary artery disease. Heart disease is target of rapamycin”—plays a role in aging of yeast, a major health issue facing older people. worms, flies, and mice. This pathway controls the cell’s Finding a way to eliminate or lower risk rate of protein synthesis, which is important for proper cell for heart disease could have important function. Researchers have found that inhibiting the pathway ramifications for reducing disability in mice genetically or pharmacologically (using rapamycin) and death from this particular age- leads to increased longevity and improved health span. related condition. Scientists are also currently using GWAS to find genes directly associated with aging and longevity. Because the 16 GENETICS  THE FUTURE OF AGING RESEARCH EPIGENETICS An emerging area of research called “epigenetics” opens the door to a scientific blending of two worlds that for decades were thought of as totally separate— that is nature and nurture, or more specifically genetics and the environment. Epigenetics research looks at how your environment, over time, can affect how your genes work and influence your development, health, and aging. At the center of this research is the Epigenetics might also explain variations epigenome—chemical modifications, or in lifespan among laboratory mice that are marks, on our DNA, or in proteins that genetically identical and seemingly raised interact with DNA, that tell it what to do, in the exact same environment. Scientists where to do it, and when to do it. The marks theorize that the difference in their that make up the epigenome are affected lifespans may result from a disparity in the by your lifestyle and environment and may amount of nurturing they received when change, for example, based on what you eat very young. The mice with the shorter and drink, if you smoke, what medicines lifespan might have been less adept at feed- you take, and what pollutants you encounter. ing and, therefore, got less of their mother’s Changes in the epigenome can cause milk, or their mother may have licked them changes in gene activity. Most epigenetic less, or they may have slept farther away from changes are likely harmless, but some could the center of the litter. Receiving less nurtur- trigger or exacerbate a disease or condition, ing may have influenced their epigenetics, such as your risk for age-related diseases. marking the genes that control aging. In some cases, scientists find that these As epigenetic research moves forward, epigenetic changes driven by the environ- scientists hope to answer three key questions: ment can be inherited by the offspring. Identical, maternal twins are ideal for How do changes in the epigenome trans- late into long-term differences in health epigenetic research. At birth, twins have and aging? nearly the same genetic blueprint; however, over time, they may have fewer identical Do single events influence the epigenome? traits. Careful study of these changes may If single events can change the epigenome, help scientists better understand environ- does the organism’s age (or stage of devel- mental and lifestyle’s influence on genes. opment) at the time of the change matter? BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 17  GWAS approach does not require previous ing condition. But by the time it reaches the knowledge of the function of the gene or its 100,000 mile mark, the car doesn’t run quite potential relationship with longevity, it could like it used to. Or, that lovely walking path possibly uncover genes involved in cellular you discovered when you first moved into processes and pathways that were not previ- your home has now become weathered, ously thought to play roles in aging. Since no the weeds are overgrown, and some of the single approach can precisely identify each asphalt has buckled. and every gene involved in aging, scientists Like the car and the walking path, over will use multiple methods, including a com- time your DNA accumulates damage. That’s bination of the GWAS and candidate gene normal. Our DNA suffers millions of damaging approaches to identify genes involved events each day. Fortunately, our cells have in aging. powerful mechanisms to repair damage and, As scientists continue to explore the genetics by and large, these mechanisms remain active of aging, its complexity becomes increasingly and functional through old age. However, evident. Further studies could illustrate the over time, some damage will fail to be repaired varying ways genes influence longevity. For and will stay in our DNA. Scientists think this example, some people who live to a very old damage—and a decrease in the body’s ability age may have genes that better equip them to fix itself—may be an important component to survive a disease; others may have genes of aging. Most DNA damage is harmless—for that help them resist getting a disease in the example, small errors in DNA code, called first place. Some genes may accelerate the rate mutations, are harmless. Other types of DNA of aging, others may slow it down. Scientists damage, for example, when a DNA strand breaks, investigating the genetics of aging do not can have more serious ramifications. Fixing a foresee a “Eureka!” moment when one gene break in a DNA strand is a complex operation is discovered as the principal factor affecting and it is more likely the body will make mistakes health and lifespan. It is more likely that we when attempting this repair—mistakes that will identify several combinations of many could shorten lifespan. genes that affect aging, each to a small degree. Another kind of DNA damage build-up occurs when a cell divides and passes its What happens when DNA genetic information on to its two daughter cells. During cell division, the telomere, a becomes damaged? stretch of DNA at each end of a chromosome The impact of age, of course, is not limited that doesn’t encode any proteins but instead to organisms. You drive a brand new car protects the protein-encoding part of the off the lot, and ideally it’s in perfect work- DNA, becomes shorter. When the telomere 18 GENETICS  TELOMERASE Telomeres shorten each time a cell divides. In most cells, the telomeres becomes too short, it can no longer protect the cell’s eventually reach a critical length DNA, leaving the cell at risk for serious damage. In when the cells stop proliferating and most cells, telomere length cannot be restored. Extreme become senescent. telomere shortening triggers an SOS response, and But, in certain cells, like sperm and egg the cell will do one of three things: stop replicating cells, the enzyme telomerase restores by turning itself off, becoming what is known as telomeres to the ends of chromo- senescent; stop replicating by dying, called apoptosis; somes. This telomere lengthening or continue to divide, becoming abnormal and poten- insures that the cells can continue to tially dangerous (for example, leading to cancer). safely divide and multiply. Investiga- Scientists are interested in senescent cells because, tors have shown that telomerase is although they are turned off, they still work on many activated in most immortal cancer levels. For instance, they continue to interact with cells, since telomeres do not shorten other cells by both sending and receiving signals. when cancer cells divide. However, senescent cells are different from their TELOMERE earlier selves. They cannot die, and they release molecules that lead to an increased risk for diseases, particularly cancer. CHROMOSOME OF ADULT CELL The relationship among cell senescence, cancer, and aging is an area of ongoing investigation. When we are TELOMERE SHORTENS AFTER young, cell senescence may be critical in helping to MULTIPLE REPLICATIONS suppress cancer. Senescence makes the cell stop replicating when its telomeres become too short, or when the cell cannot repair other damage to its DNA. Thus, senescence prevents severely damaged cells from producing abnormal and perhaps cancer- TELOMERE AT ous daughter cells. However, later in life, cell senes- SENESCENCE cence may actually raise the risk of cancer by releasing certain molecules that make the cells more vulnerable to abnormal function. Consider fibroblasts, cells that divide about 60 times TELOMERASE before turning off. Normally, fibroblasts hold skin and other tissues together via an underlying structure, a scaffold outside the cell, called the extracellular matrix. CHROMOSOME OF IMMORTAL CELL The extracellular matrix also helps to control the growth of other cells. When fibroblasts turn off, they BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 19  FIBROBLASTS PHOTO CREDIT: COURTESY OF LEONARD HAYFLICK, PH.D., UNIVERSITY OF CALIFORNIA, SAN FRANCISCO TELOMERE LENGTH: HEALTH SPAN VS. LIFESPAN? Aging biologists are investigating whether humans' telomere length is associated with lifespan, health span, or both. In one study of people age 85 years and older, researchers found telomere length was not associated with longevity, at least not in the oldest-old. In another study, YOUNG FIBROBLASTS researchers analyzing DNA samples from centenarians found that telomeres of healthy centenarians were significantly longer than those of unhealthy centenarians, suggesting that telomere length may be associated with health span. OLD FIBROBLASTS, NEARING SENESCENCE emit molecules that can change the extracellular matrix and cause inflammation. This disturbs the tissue’s function and contributes to aging. At the same time, the breakdown of the extracellular matrix may contribute to increased risk of cancer with age. Learning why—on a biological level—cell senescence goes from being beneficial early in life to having detri- mental effects later in life may reveal some important clues about aging.  20 GENETICS  THE FUTURE OF AGING RESEARCH STEM CELLS & REGENERATIVE MEDICINE Imagine if doctors were able to reverse age-related, chronic degeneration and bring the body back to its original health and vigor. While far too early to know if regenerative medicine will ever be a reality, research on stem cells opens up the possibility. Stem cells can come from a variety of sources. people with severe burns on the outmost Adult stem cells are candidates for regen- layer of their eyes (the cornea) by using erative medicine approaches for several stem cells grown in the laboratory. reasons—doctors can use the patient’s own Researchers are also looking for alterna- stem cells; stem cells can develop into nearly tives to stem cells that have similar healing any type of cell based on where they are abilities and can be used in regenerative inserted and other factors; and stem cells medicine. It appears that certain cells, continue to function normally during an like skin cells, can be reprogrammed to almost infinite number of cell divisions, act as artificial stem cells, called induced making them essentially immortal. There- pluripotent cells. fore, in theory, if stem cells were inserted in a damaged part of the body, they could develop Many questions about stem cell (and into area-specific cells that could potentially induced pluripotent cell) therapy need to be restore function. But does that work? That’s answered: Do older adults have enough stem what researchers are trying to find out. cells for this type of therapy or do they need to be donated from someone else? Would Findings from early research on regen- creating stem cells from an older person’s erative medicine, primarily in animal skin cells work? Would stem cell therapy restore models, show potential for stem cell treat- health and vigor to an older person or only ment. For example, inserting mouse ovarian work in a younger person? How would stem cells created from a female donor’s stem cell therapy work on the cellular level—would cells into infertile mice restored the mice’s stem cells replace the non-functioning cells ability to reproduce. Another study in mice found that function could be restored or would they reactivate and repair the dam- to injured muscle tissue by reactivating aged cells? Would stem cell therapy work in existing stem cells rather than transplanting all areas of the body, or only in some areas? new ones. The ability to reactivate dormant While many questions remain, the prospect adult stem cells continues to be investigated. of regenerative medicine could have impor- In a 2010 Italian study with human partici- tant implications for the treatment of many pants, researchers restored vision to some degenerative diseases. BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 21 22 METABOLISM Does stress really shorten your life? Have you ever looked at side-by-side photos of a person before and after a particularly trying time in his or her life, for instance, before and a few years after starting a highly demanding job? The person likely appears much older in the later photo. The stress of the job is thought to contribute to the prematurely aged appearance. You might feel stress from work or other aspects of your daily life, too. Stress is everywhere. Even when you feel relaxed, your body is still experiencing considerable stress—biological stress. And, it is this type of stress that is widely studied by gerontologists for its effects on aging and longevity. Biological stress begins with the very basic processes in the body that produce and use energy. We eat foods and we breathe, and our body uses those two vital elements (glucose from food and oxygen from the air) to produce energy, in a process known as metabolism. You may already think of metabolism as it pertains to eating—“My metabolism is fast, so I can eat dessert," or “My metabolism has slowed down over the years, so I’m gaining weight.” Since metabolism is all about energy, it also encompasses breathing, circulating blood, eliminating waste, controlling body temperature, contracting muscles, oper- ating the brain and nerves, and just about every other activity associated with living. BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 23  FREE RADICALS Oxidation chain reaction. These everyday metabolic activities that sustain life also create “metabolic stress,” which, over time, results in damage to our bodies. A B Take breathing—obviously, we could not survive without oxygen, but oxygen is a catalyst for much of the damage associated with aging because of the way it is metabolized inside our cells. Tiny parts of the cell, called mitochondria, use oxygen to convert food into energy. While mitochondria are extremely efficient in doing this, they produce potentially harmful by- products called oxygen free radicals. A variety of environmental factors, including tobacco A B smoke and sun exposure, can produce them, too. The oxygen free radicals react with and create instability in surrounding molecules. This process, called oxidation, occurs as a chain reaction: the oxygen free radical reacts with molecule “A” causing molecule “A” to become unstable; molecule “A” attempts to stabilize itself by reacting with neighboring molecule “B”; then molecule “B” is unstable and attempts to B C become stable by reacting with neighboring molecule “C”; and so on. This process repeats itself until one of the molecules becomes stable by breaking or rearranging itself, instead of passing the instability on to another molecule. Some free radicals are beneficial. The immune system, for instance, uses oxygen free radicals to destroy bacteria and other harmful organisms. Oxidation and its by-products also B C help nerve cells in the brain communicate. But, in general, the outcome of free radicals is damage (breaks or rearrangements) to other molecules, including proteins and DNA. Because mitochondria metabolize oxygen, 24 METABOLISM  HEAT SHOCK PROTEINS In the early 1960s, scientists discovered that fruit flies exposed to a burst of heat they are particularly prone to free radical produced proteins that helped their cells damage. As damage mounts, mitochondria survive the temperature change. Over the may become less efficient, progressively years, scientists have found these “heat generating less energy and more free radicals. shock proteins” in virtually every living organism, including plants, bacteria, worms, Scientists study whether the accumulation mice, and even humans. Scientists have of oxidative (free radical) damage in our cells learned that, despite their name, heat shock and tissues over time might be responsible for proteins are produced when cells are ex- many of the changes we associate with aging. posed to a variety of stresses, not just heat. Free radicals are already implicated in many The proteins can be triggered by oxidative disorders linked with advancing age, includ- stress and by exposure to toxic substances ing cancer, atherosclerosis, cataracts, and neurodegeneration. (for example, some chemicals). When heat shock proteins are produced, they help cells Fortunately, free radicals in the body do dismantle and dispose of damaged proteins not go unchecked. Cells use substances called and help other proteins keep their structure antioxidants to counteract them. Antioxidants and not become unraveled by stress. They include nutrients, such as vitamins C and E, as also facilitate making and transporting new well as enzyme proteins produced naturally in proteins in the body. the cell, such as superoxide dismutase (SOD), Heat shock response to stress changes catalase, and glutathione peroxidase. with age. Older animals have a higher every- Many scientists are taking the idea that anti- day level of heat shock proteins, indicating oxidants counter the negative effects of oxygen that their bodies are under more biological free radicals a step further. Studies have tested stress than younger animals. On the other whether altering the antioxidant defenses of the hand, older animals are unable to produce cell can affect the lifespan of animal models. an adequate amount of heat shock proteins These experiments have had conflicting results. to cope with fleeting bouts of stress from NIA-supported researchers found that insert- the environment. ing extra copies of the SOD gene into fruit flies Heat shock proteins are being consid- extended the fruit flies’ average lifespan by as ered as a possible aging biomarker— much as 30 percent. Other researchers found something that could predict lifespan or that immersing roundworms in a synthetic development of age-related problems— form of SOD and catalase extended their in animal models like worms and fruit flies. lifespan by 44 percent. However, in a com- However, the exact role heat shock proteins prehensive set of experiments, increasing or play in the human aging process is not yet clear. decreasing antioxidant enzymes in laboratory mice had no effect on lifespan. Results from a BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 25  limited number of human clinical trials involv- diet will support longer life. Antioxidant ing antioxidants generally have not supported supplementation remains a topic of the premise that adding antioxidants to the continuing investigation. THE FUTURE OF AGING RESEARCH STRESS The first C. elegans worm genetically manipulated to have a longer lifespan was resistant to stress caused by heat. Subsequently, researchers learned that a common thread among all long-lived animals is that their cells (and in some cases the animals as a whole) are more resistant to a variety of stresses, compared to animals with an average or shorter lifespan. Scientists also found that age-related dam- and if these longer-lived animals are resis- age to DNA and proteins is often reversible tant to all or only certain sources of stress. and does not cause problems until the dam- In addition, researchers are studying age evokes a stress response. This suggests the relationship between psychological that the stress response, rather than the stress and aging. In one study, mothers of damage itself, is partially responsible for severely and chronically sick children had age-related deterioration. shorter telomeres, relative to other women. Some biologists have started looking In other research, caregivers of people with at stress resistance when choosing animal Alzheimer’s disease were found to have models to study as examples of successful shortened telomeres. These findings could aging. Researchers can test stress resistance suggest that emotional or psychological in young animals and then continue study- stress might affect the aging process. More ing only those animals demonstrating high research on the mechanisms involved is resistance. Ongoing studies will determine needed before scientists can make any if there is a direct cause-effect relationship conclusions about clinical implications. between stress resistance and longevity, 26 METABOLISM  calorie consumption from the normal diet with a balanced amount of protein, fat, vita- mins, and minerals. In the 1930s, investigators found that laboratory rats and mice lived up to 40 percent longer when fed a calorie- restricted diet, compared to mice fed a normal diet. Since that time, scientists observed that calorie restriction increased the lifespan of many other animal models, including yeast, worms, flies, some (but not all) strains of mice, and maybe even nonhuman primates. In addition, when started at an early age or as a young adult, calorie restriction was found to increase the health span of many animal models by delaying onset of age-related dis- ease and delaying normal age-related decline. Two studies of calorie restriction in non- human primates (the animals most closely Does how much you eat related to humans) have had intriguing results. In a study conducted at NIA, monkeys affect how long you live? fed a calorie-restricted diet had a notably decreased and/or delayed onset of age-related Your body needs food to survive. However, the diseases, compared to the control group of very process of extracting energy from food— “normal” eaters. In a University of Wisconsin metabolizing food—creates stress on your body. study supported by NIA, calorie-restricted Overeating creates even more stress on the rhesus monkeys had three times fewer age- body. That’s part of the reason why it can lead to related diseases compared to the control a shorter lifespan and serious health problems group. The Wisconsin study also found that common among older people, including cardio- rhesus monkeys on a restricted diet had fewer vascular disease and type 2 diabetes. age-related deaths compared to their normal Calorie restriction, an approach primarily fed controls. In 2007, when the findings from (but not exclusively) used in a research set- the study conducted at NIA were published, ting, is more tightly controlled than normal it was too early to determine whether calo- healthy eating or dieting. It is commonly rie restriction had any effects on lifespan. defined by at least a 30 percent decrease in Research in primates continues. BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 27  Despite its apparent widespread acceptance, Given that ample studies have demon- calorie restriction does not increase lifespan strated mostly positive effects of calorie in all animals. In studies of non-laboratory restriction in many organisms, today’s (wild) mice, researchers found that on aver- scientific studies focus on finding the mecha- age, calorie restriction did not have any effect nisms and pathways by which calorie restric- on lifespan. Some of the calorie-restricted tion works. Researchers are also studying mice actually lived shorter than average lives. compounds that might act the same way This may be due to differences in the genetics in the body, mimicking the benefits of of the wild mice. A 2010 NIA-funded study calorie restriction. provides further evidence that genetics may A wide range of possible mechanisms for play a role in whether or not calorie restric- calorie restriction are being investigated. tion will have a positive effect on longevity. Some scientists are exploring the possibility Looking at 42 closely related strains of labora- that metabolizing fewer calories results in less tory mice, researchers found that only about a oxidative damage to the cells. Other scientists third of the strains on a calorie-restricted diet are looking at how the relative scarcity of had an increase in longevity. One-third of the nutrients caused by calorie restriction might strains of mice on a calorie-restricted diet had induce heat shock proteins and other defense a shortened lifespan, and the other third had mechanisms that allow the body to better no significant difference in lifespan com- withstand other stresses and health problems. pared to mice on a normal diet. Some researchers wonder if the effects of calo- While animal studies are ongoing, researchers rie restriction are controlled by the brain and are also exploring calorie restriction in humans nervous system. In one NIA-conducted study, to test its safety and practicality, as well as to calorie restriction increased the production see if it will have positive effects on health. of brain-derived neurotrophic factor, or Participants in a 2002 pilot of the Compre- BDNF, a protein that protects the brain from hensive Assessment of Long-term Effects of dysfunction and degeneration, and supports Reducing Intake of Energy (CALERIE) study increased regulation of blood sugar and heart had, after 1 year, lowered their fasting glucose, function in animal models. Still other studies total cholesterol, core body temperature, body indicate calorie restriction may influence weight, and fat. At the cellular level, they had hormonal balance, cell senescence, or gene better functioning mitochondria and reduced expression. It is likely that calorie restriction DNA damage. However, in terms of practi- works through a combination of these mecha- cality, scientists observed that adapting and nisms, and others yet to be identified. adhering to the regimen could be difficult. There is an intriguing overlap between A longer-term trial is underway. the pathways that control normal aging and 28 METABOLISM those that scientists think may be pertinent or maximum lifespan. These findings suggest to calorie restriction. The most relevant are that resveratrol does not affect all aspects of the sirtuins and mTOR (mammalian target the basic aging process and that there may of rapamycin) pathways as discussed on be different mechanisms for health versus page 16. In several, but not all cases, disrupting lifespan. Research on resveratrol continues these pathways means the organism no lon- in mice, along with studies in nonhuman ger responds positively to calorie restriction. primates and people. These two pathways have been important Rapamycin, another possible calorie for identifying at least two compounds that restriction mimetic, acts on the mTOR path- may mimic the effects of calorie restriction: way. This compound’s main clinical use is to resveratrol and rapamycin. help suppress the immune system of people Resveratrol, found naturally in grapes, who have had an organ transplant so that wine, and nuts, activates the sirtuin pathway. the transplant can succeed. A study by NIA’s It has been shown to increase the lifespan Interventions Testing Program, as discussed of yeast, flies, worms, and fish. In 2006, NIA on page 7, reported in 2009 that rapamycin researchers, in collaboration with university extended the median and maximum lifespan scientists funded by NIA, reported on a study of mice, likely by inhibiting the mTOR path- comparing mice fed a standard diet, a high way. Rapamycin had these positive effects fat-and-calorie diet, or a high fat-and-calorie even when fed to the mice beginning at diet supplemented with resveratrol beginning early-old age (20 months), suggesting that at middle age. Resveratrol appeared to lessen an intervention started later in life may still the negative effects of the high fat-and-calorie be able to increase longevity. Researchers are diet, both in terms of lifespan and disease. In now looking at rapamycin’s effects on health a 2008 follow-up study, investigators found span and if there are other compounds that that resveratrol improved the health of aging may have similar effects as rapamycin on mice fed a standard diet. It prevented age- and the mTOR pathway. obesity-related decline in heart function. Scientists do not yet know how resveratrol, Mice on resveratrol had better bone health, rapamycin, and other compounds that dem- reduced cataract formation, and enhanced onstrate effects similar to calorie restriction balance and motor coordination compared to will influence human aging. Learning more non-treated mice. In addition, resveratrol was about these calorie restriction mimetics, and found to partially mimic the effects of calorie the mechanisms and pathways underlying restriction on gene expression profiles of calorie restriction, may point the way to future liver, skeletal muscle, and adipose (fatty) tissue healthy aging therapies.  in the mice. However, the compound did not have an impact on the mice’s overall survival BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 29 30 IMMUNE SYSTEM Can your immune system still defend you as you age? Elementary schools are breeding grounds for the common cold. Kids pass their germs around as often as they share their lunch. For children, catching a cold may not be a big deal. They might take it easy for a few days while their immune system kicks into action and fights off infection. But for their older teachers and grandparents, each cold can be more of a challenge. It may take a week or longer to get back to feeling 100 percent. Does that mean that the immune system gets weaker as we age? That’s what gerontologists are trying to figure out. Our immune system is a complicated network of cells, tissues, and organs to keep us healthy and fight off disease and infection. The immune system is composed of two major parts: the innate immune system and the adaptive immune system. Both change as people get older. Studies to better understand these changes may lead to ways of supporting the aging immune system. BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 31  Innate immunity is our first line of problem—may help gerontologists find ways defense. It is made up of barriers and certain to temper its associated diseases. cells that keep harmful germs from entering The adaptive immune system is more the body. These include our skin, the cough complex than the innate immune system reflex, mucous membranes, and stomach and includes the thymus, spleen, tonsils, bone acid. If germs are able to pass these physical marrow, circulatory system, and lymphatic barriers, they encounter a second line of system. These different parts of the body innate defense, composed of specialized cells work together to produce, store, and transport that alert the body of the impending danger. specific types of cells and substances to combat Research has shown that, with age, innate health threats. T cells, a type of white blood immune cells lose some of their ability to cell (called lymphocytes) that fights invading communicate with each other. This makes bacteria, viruses, and other foreign cells, are it difficult for the cells to react adequately to of particular interest to gerontologists. potentially harmful germs called pathogens, T cells attack infected or damaged cells including viruses and bacteria. directly or produce powerful chemicals that Inflammation is an important part of mobilize an army of other immune system our innate immune system. In a young substances and cells. Before a T cell gets person, bouts of inflammation are vital programmed to recognize a specific harmful for fighting off disease. But as people age, germ, it is in a “naïve” state. After a T cell is they tend to have mild, chronic inflamma- assigned to fight off a particular infection, it tion, which is associated with an increased becomes a “memory” cell. Because these cells risk for heart disease, arthritis, frailty, remember how to resist a specific germ, they type 2 diabetes, physical disability, and help you fight a second round of infection dementia, among other problems. Research- faster and more effectively. Memory T cells ers have yet to determine whether inflam- remain in your system for many decades. mation leads to disease, disease leads to A healthy young person’s body is like a inflammation, or if both scenarios are true. T cell producing engine, able to fight off Interestingly, centenarians and other people infections and building a lifetime storehouse who have grown old in relatively good health of memory T cells. With age, however, people generally have less inflammation and a produce fewer naïve T cells, which makes more efficient recovery from infection and them less able to combat new health threats. inflammation when compared to people This also makes older people less responsive who are unhealthy or have average health. to vaccines, because vaccines generally Understanding the underlying causes of require naïve T cells to produce a protective chronic inflammation in older individuals— immune response. One exception is the shingles and why some older people do not have this vaccine. Since shingles is the reactivation 32 IMMUNE SYSTEM  ORGANS OF THE IMMUNE SYSTEM BARRIERS — TONSILS NOSE, MUCOUS LYMPH NODES LYMPHATIC VESSELS THYMUS LYMPH NODES SPLEEN ADAPTED FROM WWW.NIAID.NIH.GOV BONE MARROW LYMPH NODES LYMPHATIC VESSELS BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 33  of the chickenpox virus, this particular ute to immunosenescence. Radiation, chemi- vaccine relies on existing memory T cells cal exposure, and exposure to certain diseases and has been particularly effective in older can also speed up the deterioration of the people. Researchers are investigating ways to immune system. Studying the intricacies of develop other vaccines that are adjusted for the immune system helps researchers better the changes that happen in an older person’s understand immunosenescence and deter- immune system. mine which areas of the immune system are Negative, age-related changes in our innate most vulnerable to aging. Ongoing research and adaptive immune systems are known may shed light on whether or not there is any collectively as immunosenescence. A lifetime way to reverse the decline and boost immune of stress on our bodies is thought to contrib- protection in older individuals.  THE FUTURE OF AGING RESEARCH ALTERING OLDER ADULTS' IMMUNITY Our ability to survive the germs in older people, or is immunosenescence around us is based on a tightly somehow beneficial within the context of controlled immune system. Too the aging body? little of an immune response Given the delicate balance of the makes us susceptible to infection, immune system, gerontologists suspect that, including life-threatening pneumonia. along with its more obvious negative con- Conversely, an overactive immune response sequences, immunosenescence might have is at the root of autoimmune diseases a protective role in seniors. More research common among older people and may is needed before scientists fully understand contribute to age-related chronic diseases the aging immune system and determine like Alzheimer’s disease, osteoarthritis, whether changing an immune response diabetes, and heart disease. So, should sci- would lead to an increase or a decrease in entists try to change the immune response health span and lifespan in humans. 34 IMMUNE SYSTEM  THE PROMISE OF RESEARCH Past, present, and future So, in the end, what causes aging? As the field of gerontology matures, Clearly this question has fascinated scientists will continue to learn about medical researchers, philosophers, what happens deep inside our bodies anthropologists, and the general public during our passage from child to older for centuries. This booklet offers you just adult. Experiments involving animal a glimpse of the journey to understand models that on the surface seem so the science of aging. different from us—yeast, fruit flies, In a sense, we are all aging experts— worms, and mice—will yield insights into every day we get older. It’s true that most aspects of aging that could one day lead of us cannot explain what’s happening to important clinical, pharmacological, or under the microscope, but the little girl behavioral interventions for humans. can still be curious about her vivacious What is the future of biology of aging grandmother without knowing that research? It is not likely that we will see the grandmother’s good health may a modern-day fountain of youth, that PHOTO CREDIT: WWW.BILLDENISONPHOTO.COM be a sign of what to expect during her mythical elixir promised to restore people own golden years. And, the man in to their younger selves. But research may middle age can know that he looks and very well offer us the means to a healthier, feels better when making healthy food longer life. And, with that, we may have choices and staying physically active the opportunity to spend more time with without understanding the intricacies our loved ones, the opportunity to meet of metabolism and biological stress. our great-great-grandchildren, and the Aging is part of us, it’s part of life. opportunity to enjoy more life experiences.  BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 35  GLOSSARY Antioxidants – Compounds that may protect Enzyme – A protein that increases the rate of a cells from oxygen free radicals by preventing or specific chemical reaction. slowing the process of oxidation. Some anti- oxidants are enzyme proteins like superoxide Fibroblast – One of the major cell types found dismutase (SOD) and catalase, while others are in skin and other tissues. Fibroblasts secrete nutrients, such as vitamin C. molecules that have important structural properties for tissues and organs, and they Calorie restriction – A diet that is lower by a change with age. specific percent of calories than the normal diet, but includes all essential nutrients. At this time Free radicals – Unstable molecules that react calorie restriction is an experimental interven- readily with other molecules to try to become tion being studied to determine its impact on stable. Oxygen free radicals are produced nor- health and longevity. mally when food is metabolized and may cause damage to cells. Over a lifetime, this damage Cell senescence – A process in which a cell may contribute to aging. turns off its capacity to produce new cells, stops dividing, and has limited function. Cell senes- Gene – A region of DNA containing code that cence may contribute to aging, but it may also can be read to make proteins in the cell. Genes be a protective mechanism against cancer (a are responsible for many heritable traits. disease state in which cells continue to divide without control). Immunosenescence – The age-related decline in functions of the immune system. Centenarian – A person who has lived at least 100 years. Life expectancy – The average number of years that members of a population (or species) Chromosome – A structure inside cells contain- live; also known as average lifespan. ing DNA, which carries our genetic information and is responsible for heritable traits. Lymphocytes – White blood cells that are important to the immune system. A decline in DNA – Abbreviation for deoxyribonucleic acid; lymphocyte function with advancing age is be- DNA contains the genetic code for all animals ing studied for insights into aging and disease. and plants, from single-cell organisms to humans. Maximum lifespan – The greatest age reached by any member of a given population (or species). 36  BIBLIOGRAPHY Mitochondria – Cell organelles that Austad, S.N., “Comparative Biology of Aging,” Journal of Gerontology: Biological Sciences, 64A(2): 199-201, 2009. produce energy necessary for life from the foods we eat. Mitochondria contain DNA, Bartke, A., “Insulin and Aging,” Cell Cycle, 7(21): which may be damaged by oxygen free radi- 3338-3343, 2008. cals produced during this process. Damage Bartke, A., “The Somatotropic Axis and Aging: Mechanisms of mitochondrial DNA may contribute to and Persistent Questions about Practical Implications,” aging. Mitochondria also are involved in Experimental Gerontology, 44(6-7): 372-374, 2009. controlling cell death. Barzilai, N. and Bartke, A., “Biological Approaches to Proteins – Molecules arranged in a specific Mechanistically Understand the Healthy Life Span Exten- sion Achieved by Calorie Restriction and Modulation of order determined by DNA. Proteins are Hormones,” Journal of Gerontology: Biological Sciences, essential for all life processes. Certain proteins, 64A(2): 187-191, 2009. such as those protecting against free radicals Bauer, M.E., “Chronic Stress and Immunosenescence: A and those produced by the immune system, Review,” NeuroImmunoModulation, 15: 241-250, 2008. are studied extensively by gerontologists. Baur, J.A., Pearson, K.J., Price, N.L., et al., “Resveratrol Stem cells – Cells with the potential Improves Health and Survival of Mice on a High-Calorie to become many different types of cells Diet,” Nature, 444: 337-342, 2006. found in the body. Stem cells are also able Blagozklonny, M.V. and Campisi, J., “Cancer and Aging,” to replicate almost indefinitely without Cell Cycle, 7(17): 2615-2618, 2008. becoming abnormal. Buffenstein, R., “The Naked Mole-Rat: A New Long-Living Telomerase – An enzyme that restores Model for Human Aging Research,” Journal of Gerontology: Biological Sciences, 60A(11): 1369-1377, 2005. telomeres to the ends of chromosomes in certain cells, such as egg and sperm cells. This Calvanese, V., Lara, E., Kahn, A., and Fraga, M.F., “The Role telomere lengthening insures that the cells of Epigenetics in Aging and Age-Related Diseases,” Ageing can continue to divide and multiply. Research Reviews, 8: 268-276, 2009. Campisi, J. and Yaswen, P., “Aging and Cancer Cell Biology, Telomeres – Repeated short, non-coding 2009,” Aging Cell, 8: 221-225, 2009. sequences of DNA at each end of a chromo- some. Telomeres protect the chromosome from Centers for Disease Control and Prevention, Health, United States, 2008, p. 208, http://www.cdc.gov/ damage and shorten each time a cell divides. nchs/data/hus/hus08.pdf#026 BIOLOGY OF AGING: RESEARCH TODAY FOR A HEALTHIER TOMORROW 37  BIBLIOGRAPHY (continued) Chen, W.H., Kozlovsky, B.F., Eff