Page 2 - Aging and Long Term Care


What Is Aging?

Aging is a complex natural process potentially involving every molecule, cell, and organ in the body. In its broadest sense, aging merely refers to changes that occur during the lifespan. However, this definition includes some changes that aren’t necessarily problematic, and usually don’t affect an individual’s viability. Gray hair and wrinkles, for instance, certainly are manifestations of aging, but neither is harmful.

To differentiate these superficial changes from those that increase the risk of disease, disability, or death, gerontologists prefer to use a more precise term—senescence—to describe aging. Senescence is the progressive deterioration of many bodily functions over time. This loss of function is accompanied by decreased fertility and increased risk of mortality as an individual gets older. The rate and progression of this process can vary greatly from person to person, but generally over time every major organ of the body is affected. As we age, for instance, lung tissue loses much of its elasticity, and the muscles of the rib cage shrink. As a result, maximum vital breathing capacity progressively diminishes in each decade of life, beginning at about age 20. With age, blood vessels accumulate fatty deposits and lose much of their flexibility, resulting in arteriosclerosis or “hardening of the arteries.” In the gastrointestinal system, production of digestive enzymes diminishes, and as a result, tissues lose much of their ability to break down and absorb foods properly. In women, vaginal fluid production decreases and sexual tissues atrophy with increasing age. In men, sperm production decreases and the prostate enlarges.

Why these and other changes occur with advancing age both intrigues and perplexes gerontologists. In fact, senescence is one of nature’s least understood biological processes. Gerontologists, for instance, disagree about when senescence begins. Some argue it begins at birth. Others contend it sets in after the peak reproductive years. But clearly, senescence, whether it begins at birth or age 20, 30, or 40, leads to an accumulating loss of bodily functions, which ultimately increases the probability of death, as we get older.

What is the Difference Between Life Expectancy and Lifespan?

When George Washington celebrated his 60th birthday in 1792, he had outlived all of his male ancestors, dating back for several generations. He had outlived a typical Virginian of his era by about 15 years. To achieve this relative “old age,” he had survived smallpox, mumps, pneumonia, dysentery, typhoid fever, a staphylococcal infection of the hip, four bouts of malaria, and two nearly fatal encounters with influenza.

When Jeanne Calment was born in 1875, the illnesses that plagued Washington’s generation still took many lives, health care was still fairly primitive, and the life expectancy—the average number of years from birth that an individual can expect to live—was still less than 50 years worldwide.

Yet Mme. Calment, perhaps because she was born with a set of extraordinary genes or was simply fortunate enough to elude many of the illnesses that claim so many others, beat the odds and set the benchmark for maximum human lifespan—the greatest age reached by any member of a species.

Life expectancy in the United States rose dramatically in the 20th century, from about 47 years in 1900 to about 73 years for males and 79 years for females in 1999. This increase is mostly due to improvements in environmental factors—sanitation, the discovery of antibiotics, and medical care. Now, as scientists make headway against chronic diseases like cancer and heart disease, some think life expectancy can be extended even further in the 21st century.

As part of this quest, gerontologists are studying a variety of life forms including yeast, fruit flies, nematodes, mice, and primates in search of clues applicable to human aging. As they explore the genes, cells, and organs involved in aging, they are uncovering more and more of the secrets of longevity. As a result, life extension may some day be more than the stuff of myth. In addition, as gerontologists apply their expanding knowledge to medicine, the prevention or retardation of the onset of some age-related diseases and disabilities may become realistic goals.

Why Do We Age?

Gerontologists have proposed many theories to explain the diversity of the aging process in nature. Pacific salmon, for instance, reproduce only once and die within hours of spawning, while at the other end of the spectrum, sea anemones, which reproduce asexually, show few, if any, outward signs of deterioration until the very end of their long lives. Most gerontologists now agree that no single theory can account for this wide spectrum. In fact, with the tools of biotechnology and an influx of new knowledge, all-encompassing theories of aging are giving way to a more diverse perspective.

Aging today is viewed as many processes, interactive and interdependent, that determine lifespan and health, and gerontologists are studying a multitude of factors that may be involved. The rest of this booklet describes what we know and don't know about many of these factors, and where we think scientists are likely to find answers to questions about aging and longevity.

Theories of aging fall into two groups. The programmed theories hold that aging follows a biological timetable, perhaps a continuation of the one that regulates childhood growth and development. The damage or error theories emphasize environmental assaults to our systems that gradually cause things to go wrong. Many of the theories of aging are not mutually exclusive. Here is a brief and very simplified rundown of the major theories.



Programmed Longevity. Aging is the result of the sequential switching on and off of certain genes, with senescence being defined as the time when age-associated deficits are manifested.

Endocrine Theory. Biological clocks act through hormones to control the pace of aging.

Immunological Theory. A programmed decline in immune system functions leads to an increased vulnerability to infectious disease and thus aging and death.


Wear and Tear. Cells and tissues have vital parts that wear out.

Rate of Living. The greater an organism's rate of oxygen basal metabolism, the shorter its life span.

Crosslinking. An accumulation of crosslinked proteins damages cells and tissues, slowing down bodily processes.

Free Radicals. Accumulated damage caused by oxygen radicals causes cells, and eventually organs, to stop functioning.

Somatic DNA Damage. Genetic mutations occur and accumulate with increasing age, causing cells to deteriorate and malfunction. In particular, damage to mitochondrial DNA might lead to mitochondrial dysfunction.

Each year on her birthday, Jeanne Calment sent her lawyer a note, which read, “Excuse me if I’m still alive, but my parents didn’t raise shoddy goods.” Her brother, who died at age 97, apparently wasn’t too “shoddy” himself. When another super centenarian, Sarah Knauss of Allentown, Pennsylvania, died in 1999 at age 119, her daughter was 96.

Some families seem blessed with long lives. In fact, siblings of centenarians have a four times greater chance of living into their early nineties than most people, according to researchers at the New England Centenarian Study in Boston. A coincidence? Hardly. What likely helps set these hardy individuals apart are extraordinary sets of genes, the coded segments of DNA (deoxyribonucleic acid), which are strung like beads along the chromosomes of nearly every living cell. In humans, the nucleus of each cell holds 23 pairs of chromosomes, and together these chromosomes contain about 30,000 genes.

There is little doubt that genes have a tremendous impact on aging and longevity. Based on studies of identical twins, who share the exact same set of genes, scientists now suspect that lifespan is determined by both environmental and genetic factors, with genetics accounting for up to 35 percent of this complex interaction. Although different animal species vary up to 100 times in lifespan—humans live five times longer than cats, for instance—scientists are discovering some surprising similarities between our genes and those of other species. Even single-celled yeast, one of nature’s simplest organisms, may provide scientists with important genetic clues about human aging and longevity.

Investigators are finding clues to aging and longevity in yeast, one-celled organisms that have some intriguing genetic similarities to human cells. In a laboratory at Louisiana State University Medical Center in New Orleans, Michal Jazwinski, Ph.D., has found genes that seem to promote longevity in these rapidly dividing, easy-to-study organisms.


Yeast normally have about 21 cell divisions or generations. Jazwinski observed that over the course of that lifespan, certain genes in the yeast are more active or less active as the cells age; in the language of molecular biology, they are differentially expressed. So far, Jazwinski has found 14 such genes in yeast.

Selecting one of these genes, Jazwinski tried two different experiments. First, he introduced the gene into yeast cells in a form that allowed him to control its activity. When the gene was activated to a greater degree than normal, or overexpressed, some of the yeast cells went on dividing for 27 or 28 generations; their period of activity was extended by 30 percent.

In his second experiment, Jazwinski mutated the gene. When he introduced this non-working version into a group of yeast cells, they had only about 12 divisions.

The two experiments made it clear that the gene, now called LAG-1, influences the number of divisions in yeast or, according to some researchers’ ways of thinking, its longevity. (LAG-1 is short for longevity assurance gene.) But how it works is still a mystery. One small clue lies in its sequence of DNA bases—its genetic code—which suggests that it produces a protein found in cell membranes. One next step is to study the function of that protein. Similar sequences have been found in human DNA, so a second investigative path is to clone the human gene and study its function. If there turns out to be a human LAG-1 counterpart, new insights into aging may be uncovered.

In another laboratory, Leonard Guarente, Ph.D., of the Massachusetts Institute of Technology found that mutation of a silencing gene—a gene that “turns off” other genes—delayed aging 30 percent in yeast. The gene, which is also found in C. elegans and other animals, produces an enzyme that alters the structure of DNA, which, in turn, alters patterns of gene expression.

Longevity Genes

Researchers have found evidence of several genes that seem to be related to longevity determination. Longevity-related genes have been found in tiny roundworms called nematodes, in fruit flies, and even in mice. Like yeast, nematodes and fruit flies have attracted a lot of attention from gerontologists because their short lifespans and their well-characterized genetic composition make them relatively easy to study. Investigators, for instance, can perform nearly 2,000 roundworm studies in the time it would take them to do one human study.

Under normal conditions, some genes are thought to manufacture proteins that limit lifespan. But when these same genes are mutated, they either produce defective proteins or no proteins at all. The net effect is these mutations promote longevity.

For instance, a mutation of a gene whimsically named “I’m Not Dead Yet” or INDY, can double the lifespan of fruit flies. In studies supported by the NIA, these fruit flies not only lived longer, they thrived. By the time that 80 to 90 percent of normal flies were dead, many of the INDY flies were still vigorous and capable of reproduction. At least two other life-extending genetic mutations have been detected in the fruit fly genome.

In C. elegans, a nematode (roundworm), researchers have found yet another treasure trove of genetic clues about the aging process. By altering certain genes, researchers can substantially extend the normal 2-to-3-week lifespan of these tiny worms. One of these genes, called daf-2, controls a special stage in the worm’s development called dauer formation. A dauer forms, if, in the first few hours of its brief life, a worm finds food scarce. In this state, C. elegans grows a cuticle for protection and can go into hibernation for several months. When the food supply is ample again, the worm emerges from this metabolically slowed, non-aging state and continues its normal life cycle. The protein produced by the daf-2 gene drives the worm’s development past or out of the dauer state. But Cynthia Kenyon, Ph.D., and her colleagues at the University of California, San Francisco, found that daf-2 does much more. It also can regulate the lifespan of normal, fertile adults. By altering this gene so that its activity is reduced, Kenyon’s team found lifespan of well-fed worms, which did not form a dauer, could be doubled. Other investigators have detected mutations in similar daf genes that increase nematode lifespan three or even four-fold.

Finding longevity genes is only one of many goals for gerontologists. An equally important mission is unraveling the genetic processes involved in age-related traits and diseases.

NIA and Italian investigators are focusing their attention on Sardinia, a secluded Mediterranean island. Since settlers first occupied the island thousands of years ago, the population has grown without much immigration from the outside world. Because they are more closely related than people living in other societies, Sardinians share much of the same genetic information, which makes it easier to track genetic effects through generations.

When a particular trait exists in a genetically isolated “founder” population such as Sardinia, it is likely that the same few genes are responsible for the trait in most or all affected individuals. Once the genes for a certain complex trait are identified within the founder population, researchers can use this information to isolate interacting genes and assess their importance in more genetically diverse cultures, like the United States. Other large founder populations exist in Finland, Iceland, and French-speaking Quebec.

In a study called the Progenia project, gerontologists are studying Sardinians for evidence of genetic influences on two traits: severe arterial stiffness and frequent positive emotions. Vascular stiffness may be an important predictor of heart disease mortality. Reports also suggest that joyfulness and other positive emotions can have profound impact on life satisfaction and health as we age. Gerontologists suspect these traits have strong genetic components. As the project progresses, investigators plan to conduct genetic analysis on individuals who share extreme values of these traits and will attempt to identify the underlying genes.

The genes isolated so far are only a few of what scientists think may be dozens, perhaps hundreds, of longevity- and agingrelated genes. But tracking them down in organisms like nematodes and fruit flies is just the beginning. The next big question for many gerontologists is whether counterparts in people—human homologs—of the genes found in laboratory animals have similar effects. The daf-2 gene in C. elegans, for instance, is similar to a gene found in humans that functions in hormone control.

In the worm, this gene makes a protein that looks much like the receptor for the hormone insulin. In humans, this hormone controls functions including food utilization pathways, glucose metabolism, and cell growth. These and other genetic linkages are under intense scrutiny, and ultimately could yield clues about how genes interact with environmental factors to influence longevity in humans and other species. Caloric restriction, for example, is the only known intervention shown to prolong life in species ranging from yeast to rodents. Scientists suspect this intervention works in yeast, worms, and other species, in part, because it triggers alterations of genetic activity. Caloric restriction also may work, partially, by altering metabolic pathways involved in energy utilization. (See The Next Step: Caloric Restriction in Primates).

Many investigators, however, interpret these findings cautiously because there are important differences between human genes and those of lower animals. In fact, the structural similarity is only about 30 percent, which means that comparing yeast genes to human genes, for instance, is like comparing a go-cart to a high-performance racing car. The basic machinery may be similar, but one is far less complex than the other. So while yeast, worms, and other simple organisms are helpful models of aging, they probably don’t completely mimic the process that occurs in humans. For this reason, gerontologists study the genetics of mice, primates, and other mammals that are more closely related to us. Some researchers are also studying human cells for more precise clues about how genes regulate human longevity and aging.


Other unanswered questions concern the roles played by these genes. What exactly do they do? How and when are they activated? On one level, all genes function by transcribing their “codes”—actually DNA base sequences—into another nucleic acid called messenger ribonucleic acid or mRNA. Messenger RNA is then translated into proteins. Transcription and translation together constitute the process known as gene expression.

The proteins expressed by genes carry out a multitude of functions in each cell and tissue in the body, and some of these functions are related to aging. So, when we ask what longevity or aging-related genes do, we are actually asking what their protein products do at the cellular and tissue levels. Increasingly, gerontologists also are asking how alterations in the process of gene expression itself may affect aging. Technological advances, which allow researchers to observe the expression of thousands of genes at once, are speeding the investigation of this process. In time, this emerging technology could help clarify what changes are occurring simultaneously in diverse cells, as they get older. (See Microarrays in Action, at right).

For now, investigators have found evidence that some proteins, such as antioxidant enzymes, prevent damage to cells, while others may repair damaged DNA, regulate glucose metabolism, or help cells respond to stress. Other gene products are thought to influence replicative senescence.

Cellular Senescence

During the process of cell division or mitosis, a cell’s nucleus dissolves, and its chromosomes condense into visible thread-like structures that replicate. The resulting 92 chromosomes separate, migrating to opposite sides of the cell where new nuclei—each with 46 chromosomes—are formed. Once this occurs, the original cell, following the chromosomes’ lead, pulls apart and forms two identical daughter cells. It is this process that allows us to grow from a single cell into 100 trillion cells, composing the organ systems that make our bodies.

Early in life, nearly all of the body’s cells can divide. But this process doesn’t go on indefinitely. Researchers have learned that cells have finite proliferative lifespans, at least when studied in test tubes—in vitro. After a certain number of divisions, they enter a state in which they no longer proliferate and DNA synthesis is blocked. For example, young human fibroblasts—structural cells that hold skin and other tissues together—divide about 50 times and then stop. This phenomenon is known as the Hayflick limit, after Leonard Hayflick, who with Paul Moorhead described it in 1961 while at the Wistar Institute in Philadelphia. At least four genes involved in this process have been identified. This special aspect of cellular senescence is known as replicative senescence.

However, we do not die because we run out of cells (even the oldest people have plenty of proliferating fibroblasts and other types of cells). In fact, most senescent cells are not dead or dying. They continue to respond to hormones and other outside stimuli, but can’t proliferate. Evidence suggests they can continue to work at many levels for some time after they cease dividing. Senescence, however, can cause radical shifts in some important cellular functions. For instance, senescent cells are resistant to dying and, as a result, they occur more often in aging bodies. Cellular senescence also triggers important changes in gene expression. Normally, fibroblasts are responsible for creating an underlying structure, called the extracellular matrix, which controls the growth of other cells. But senescent fibroblasts secrete enzymes that actually degrade this matrix. Gerontologists suspect the breakdown of this structure may contribute to the increased risk of cancer as we age. So, cellular senescence may be critical early in life because it limits cell proliferation and helps suppress cancer. But as we get older, senescent cells might be harmful because changes in the genes they express might actually promote unregulated growth and tumor formation. This concept that genes, which have beneficial effects early in life, can also have detrimental effects later is known as antagonistic pleiotropy. Some gerontologists speculate that a better understanding of antagonistic pleiotropy might reveal much about what aging is, and how cellular senescence contributes to it.

But for now, many major questions about cellular senescence remain unanswered. Investigators, for example, are uncertain whether senescent cells accumulate in all tissues and organs with increasing age, thus contributing to the gradual loss of the body’s capacity to heal wounds, maintain strong bones, and fend off infections. Accumulation of senescent cells, if it does occur, could, in turn, indirectly increase an individual’s vulnerability to the diseases and disabilities often associated with aging. However, no feature of aging has yet been unequivocally explained by in vitro cellular senescence.

Proliferative Genes

Searching for explanations of proliferation and senescence, scientists have found certain genes that appear to trigger cell proliferation. One example of such a proliferative gene is c-fos, which encodes a short-lived protein that is thought to regulate the expression of other genes important in cell division.

Proliferative genes, such as c-fos and others of its kind, are countered by anti-proliferative genes, which seem to interfere with division. The first evidence of an anti-proliferative gene came from an eye tumor called retinoblastoma. When one of the genes from retinoblastoma cells—later called the RB gene—became inactive, the cells went on dividing indefinitely and produced a tumor. But when the RB gene product was activated, the cells stopped dividing. This gene’s product, in other words, appeared to suppress proliferation. Another well characterized gene of this type is the p53 gene, which produces a protein that also limits cell proliferation. These genes are called tumor suppressor genes.

Limited proliferation is the norm in the world of human cells. In some cases, however, a cell somehow escapes this control mechanism and goes on dividing, becoming, in the terms of cell biology, immortal. And because immortal cells eventually form tumors, this is one area in which aging research and cancer research intersect. When tumor suppressor genes are inactivated, investigators theorize it turns on a complex process that leads to development of a tumor. So replicative senescence apparently has been retained through evolution as a defense against cancer.

Scientists are unraveling how the products of these genes promote and suppress cell proliferation. There are indications that a multi-layer control system is at work, involving a host of intricate mechanisms that interact to maintain a balance between the two kinds of genes. Some genes, for instance, appear to suppress or silence other genes. Mutations in these silencing genes have been shown to affect the lifespan of C. elegans and yeast. Many gerontologists are studying how silencing and other mechanisms such as telomere shortening influence replicative senescence.

Oxygen Radicals

Oxygen sustains us. Every cell in the body needs it to survive. Yet, paradoxically, oxygen also wreaks havoc in the body and may be a primary catalyst for much of the damage we associate with aging. This damage occurs as a direct result of how cells metabolize it.

Oxygen is processed within a cell by tiny oganelles called mitochondria. Mitochondria convert oxygen and food into adenosine triphosphate (ATP), an energy-releasing molecule that powers most cellular processes. In essence, mitochondria are furnaces, and like all furnaces, they produce potentially harmful by–products. In cells, these by–products are called oxygen free radicals, also known as reactive oxygen species.

A free radical can be produced from almost any molecule when it loses an electron from one or more of its atoms. In cells, they are commonly created when mitochondria combine oxygen with hydrogen to form water. This transformation releases energy into the cell, but it also can shred electrons from oxygen. When this happens it leaves the oxygen atom—now an unstable oxygen free radical—with one unpaired electron. Because electrons are most stable when they are paired, oxygen free radicals steal mates for their lone electrons from other molecules. These molecules, in turn, become unstable and combine readily with other molecules.

This process, called oxidation, can spark a chain reaction resulting in a series of products, some of which are actually beneficial. The immune system, for instance, uses free radicals to destroy bacteria and other pathogens. Another oxidizing molecule, called nitric oxide, helps nerve cells in the brain communicate with each other.

Free radicals, however, also can be vandals that cause extensive damage to proteins, membranes, and DNA. Mitochondria are particularly prone to free radical damage. The major source of free radical production in the body, they are also one of its prime targets. As the damage mounts, mitochondria become less efficient, progressively generating less ATP and more free radicals. Over time, according to the free radical theory, oxidative damage accumulates in our cells and tissues, triggering many of the bodily changes that occur as we age. Free radicals have been implicated not only in aging but also in degenerative disorders, including cancer, atherosclerosis, cataracts, and neurodegeneration.

But free radicals, which also can be produced by tobacco smoke, sun exposure, and other environmental factors, do not go unchecked. Cells utilize substances called antioxidants to counteract them. These substances including nutrients—the familiar vitamins C and E—as well as enzymes produced in the cell, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, prevent most oxidative damage. Nonetheless, some free radicals manage to circumvent these defenses and do harm. As a result, cellular repair mechanisms eventually falter and some internal breakdowns are inevitable. These breakdowns can lead to cellular senescence, and eventually may trigger apoptosis, a form of programmed cell death.

The discovery of antioxidants raised hopes that people could retard aging simply by adding them to the diet. So far, studies of antioxidant-laden foods and supplements in humans have yielded little support for this premise. Further research, including largescale epidemiological studies, might clarify whether dietary antioxidants can help people live longer, healthier lives. For now, however, the effectiveness of dietary antioxidant supplementation remains controversial. In the meantime, gerontologists are investigating other intriguing biochemical processes affected by free radicals, including protein crosslinking.

Protein Crosslinking

Blood sugar—glucose—is another suspect in cellular deterioration. In a process called non-enzymatic glycosylation or glycation, glucose molecules attach themselves to proteins, setting in motion a chain of chemical reactions that ends in the proteins binding together or crosslinking, thus altering their biological and structural roles. The process is slow and complex, but crosslinked proteins accumulate with time and eventually disrupt cellular function.

Investigators suspect that glycation and oxidation are interdependent processes since free radicals and crosslinks seem to accelerate the formation of one another.

Crosslinks, also known as advanced glycation end products (AGEs), seem to “stiffen” tissues and may cause some of the deterioration associated with aging. Collagen, for instance, the most common protein molecule in our bodies, forms the connective tissue that provides structure and support for organs and joints. When glucose binds with collagen—as it tends to do as we age—this normally supple protein loses much of its flexibility. As a result, lungs, arteries, tendons, and other tissues stiffen and become less efficient. In the circulatory system, AGEs may help trap LDL (the so-called “bad”) cholesterol in artery walls, and thus contribute to the development of atherosclerosis. They also have been linked to clouded lenses (cataracts), reduced kidney function (nephropathy), and age-related neurological disorders including Alzheimer’s disease.

These conditions appear at younger ages in people with diabetes, who have high glucose levels (hyperglycemia). Glycosylated hemoglobin in red blood cells, for instance, is an important marker doctors use to measure hyperglycemia. While the physiological effects of glycosylated hemoglobin are unclear, the disease it helps doctors detect—diabetes—is sometimes considered an accelerated model of aging. Not only do the complications of diabetes mimic the physiologic changes that can accompany old age, but people with this condition have shorter-than-average life expectancies. As a result, much research on crosslinking has focused on its relationship to diabetes as well as aging.

Just as the body has antioxidants to fight freeradical damage, it has other guardians, immune cells called macrophages, which combat glycation. Macrophages with special receptors for AGEs seek out and engulf them. Once AGEs are broken down, they are ejected into the blood stream where they are filtered out by the kidneys and eliminated in urine.

The only apparent drawback to this defense system is that it is not complete and levels of AGEs increase steadily with age. One reason is that kidney function tends to decline with advancing age. Another is that macrophages, like certain other components of the immune system, become less active.

Why this happens is not known, but immunologists are beginning to learn more about how the immune system affects, and is affected by aging (See The Immune System). And in the meantime, diabetes researchers are investigating drugs that could supplement the body’s natural defenses by blocking AGEs formation.

Crosslinking interests gerontologists for several reasons. It is associated with disorders that are common among older people, such as diabetes and heart disease; it progresses with age; and AGEs are potential targets for drugs. In addition, cross-linking may play a role in damage to DNA, which is another important focus for research on aging.

DNA Repair and Synthesis

In the normal wear and tear of cellular life, DNA undergoes continual damage. Attacked by oxygen radicals, ultraviolet light, and other toxic agents, it suffers damage in the form of deletions, or deleted sections, and mutations, or changes in the sequence of DNA bases that make up the genetic code. In addition, sometimes the DNA replication machinery makes an error.

Biologists theorize that this DNA damage, which gradually accumulates, leads to malfunctioning genes, proteins, cells, and, as the years go by, deteriorating tissues and organs.

Not surprisingly, numerous enzyme systems in the cell have evolved to detect and repair damaged DNA. For repair, transcription, and replication to occur, the double-helical structure that makes up DNA must be partially unwound. Enzymes called helicases do the unwinding. Investigators have found that people who have Werner’s syndrome (WS), a rare disease with several features of premature aging, have a defect in one of their helicases. George Martin, M.D., of the University of Washington and other investigators are exploring the mechanisms involved in DNA repair in WS and similar disorders, collectively known as progeroid syndromes. This research could help explain why DNA repair becomes less efficient during normal human aging.

The repair process interests gerontologists for many reasons. It is known that an animal’s ability to repair certain types of DNA damage is directly related to the lifespan of its species. Humans repair DNA, for example, more quickly and efficiently than mice or other animals with shorter lifespans. This suggests that DNA damage and repair are in some way part of the aging puzzle.

In addition, researchers have found defects in DNA repair in people with a genetic or familial susceptibility to cancer. If DNA repair processes decline with age while damage accumulates as scientists hypothesize, it could help explain why cancer is more common among older people.

Gerontologists who study DNA damage and repair have begun to uncover numerous complexities. Even within a single organism, repair rates can vary among cells, with the most efficient repair going on in germ (sperm and egg) cells. Moreover, certain genes are repaired more quickly than others, including those that regulate cell proliferation.

Especially intriguing is repair to a kind of DNA that resides not in the cell’s nucleus but in its mitochondria. These small organelles are the principal sites of metabolism and energy production, and cells have hundreds of them. Investigators suspect mitochondrial DNA is injured at a much greater rate than nuclear DNA, possibly because the mitochondria produce a stream of damaging oxygen radicals during metabolism. Adding to its vulnerability, mitochondrial DNA is unprotected by the protein coat that helps shield DNA in the nucleus from damage.

Research has shown that mitochondrial DNA damage increases exponentially with age, and as a result, energy production in cells diminishes over time. These changes may cause declines in physiological performance, and may play a role in the development of age-related diseases. Investigators are examining how much mitochondrial DNA damage occurs in specific parts of the body such as the brain, what causes the damage, and whether it can be prevented.

Heat Shock Proteins

In the early 1960s, investigators noticed fruit flies did something unusual. When these insects were exposed to a burst of heat, they produced proteins that helped their cells survive the temperature change. Intrigued, researchers looked for these proteins in other animals, and found them in virtually every living thing including plants, bacteria, worms, mice, and yes, humans. Today, the role of these substances, known as heat shock proteins, in the aging process is under scrutiny.

Despite their name, heat shock proteins (HSPs) are produced when cells are exposed to various stresses, not only heat. Their expression can be triggered by exposure to toxic substances such as heavy metals and chemicals and even by behavioral and psychological stress.

What attracts aging researchers to HSPs is the finding that the levels at which they are produced depend on age. Old animals placed under stress—short term, physical restraint, for example—have lower levels of a heat shock protein designated HSP-70 than young animals under similar stress. Moreover, in laboratory cultures of cells, researchers have found a striking decline in HSP-70 production as cells approach senescence.

Exactly what role HSPs play in the aging process is not yet clear. They are known to help cells dismantle and dispose of damaged proteins. They also facilitate the making and transport of new proteins. But what proteins are involved and how they relate to aging is still the subject of speculation and study.

While at the NIA, Nikki Holbrook, Ph.D., and other researchers investigated the action of HSP-70 in specific sites, such as the adrenal cortex (the outer layer of the adrenal gland). In this gland as well as in blood vessels and possibly other sites, the expression of HSP-70 appears closely related to hormones released in response to stress, such as the glucocorticoids and catecholamines. Eventually, answers to the puzzle of HSPs may throw light on some parts of the neuroendocrine system, whose hormones and growth factors might have an important influence on the aging process.


Hormones are powerful chemicals that help keep our bodies working normally. Made by specialized groups of cells called glands, hormones stimulate, regulate, and control the function of various tissues and organs. They are involved in virtually every biological process including sexual reproduction, growth, metabolism, and immune function. These glands, including the pituitary, thyroid, adrenal, ovaries, and testes, release various hormones into the body as needed.

As we age, production of certain hormones, such as testosterone and estrogen, tends to decrease. Hormones with less familiar names, like melatonin and dehydroepiandrosterone (DHEA) are also not as abundant in older people as in younger adults. But what influence, if any, these natural hormonal declines have on the aging process is unclear.

Hormone Replacement

In the late 1980s, at Veterans Administration hospitals in Milwaukee and Chicago, 12 men age 60 and older began receiving injections three times a week that dramatically reversed some signs of aging. The injections increased their lean body (and presumably muscle) mass, reduced excess fat, and thickened skin. When the injections stopped, these changes reversed, and the signs of aging returned. What the men were taking was recombinant human growth hormone (hGH), a synthetic version of the hormone that is produced in the pituitary gland and plays a critical part in normal childhood growth and development. At the same time, evidence was accumulating that menopausal hormone therapy with estrogen (alone or in combination with a progestin in women with a uterus) could benefit postmenopausal women by reducing cardiovascular disease, colon cancer, and other diseases of aging. Further studies have indicated that, although estrogen remains an effective way to control hot flashes, long-term use of these hormones may increase risk for several major age-related diseases in some women, especially then treatment is started years after menopause. The finding that levels of testosterone in men decreased with aging raised the question of whether they too might benefit from sex hormone treatment.

As a result of these preliminary observational findings, the NIA launched a series of research initiatives to clarify what influence hormone replacement therapy might have on the aging process. So far, most of these studies have been inconclusive, but have led many investigators to question whether the risks of hormone replacement may outweigh any benefit. Supplements of hGH, for instance, can promote diabetes, joint pain, carpal tunnel syndrome, and pooling of fluid in the skin and other tissues, which may lead to high blood pressure and heart failure. Studies in mice have raised other concerns about the hormone. Investigators have found that mice deficient in growth hormone production live substantially longer than normal mice, while mice overproducing growth hormone live shorter than average lives. This finding suggests that even if hGH replacement therapy is initially beneficial, ultimately it may be harmful and actually might curtail longevity.

Similarly, there is scant evidence that testosterone supplementation has any positive impact in healthy older men. In fact, some studies suggest supplementation might trigger excessive red blood cell production in some men. This side effect can increase a man’s risk of stroke.

Estrogen is perhaps the most well studied of all hormones. Yet results from the Women’s Health Initiative (WHI), the first major placebo-controlled, randomized clinical trial of estrogen therapy with or without progestin to prevent some chronic diseases of aging, surprised the medical community. There were more cases of stroke, blood clots, heart disease, and breast cancer in postmenopausal women using estrogen and progestin in the study, and more cases of possible dementia in women over age 65, than in those using the placebo. But, there were also fewer bone fractures and cases of colon cancer. In postmenopausal women using estrogen alone, there were more cases of stroke and fewer bone fractures than in those women on placebo. Other studies indicate that menopausal hormone therapy is effective in controlling moderate-to-severe menopausal symptoms, so research is ongoing to evaluate benefits and risks in menopausal and younger postmenopausal women.

As research continues, the pros and cons of hormone replacement may become more precisely defined. These hormonal supplements appear to increase risk and provide few clear-cut benefits for healthy individuals and do not seem to slow the aging process.

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. Among its many roles, estrogen slows the bone thinning that accompanies aging. In premenopausal women the ovaries are the main manufacturers of estrogen (see image). After menopause, fat tissue is the major source of smaller amounts and weaker forms of estrogen than that produced by the ovaries. While many women with menopausal symptoms are helped by hormone therapy during and after menopause, some are placed at higher risk for certain diseases if they take it. The results of the WHI are prompting further studies about the usefulness and safety of this therapy when used by younger menopausal and postmenopausal women to control symptoms, such as hot flashes, and to prevent chronic diseases.

GROWTH HORMONE > This product of the pituitary gland appears to play a role in body composition and muscle and bone strength. It is released through the action of another trophic factor called growth hormone releasing hormone, which is produced in the brain. It works, in part, by stimulating the production of insulin-like growth factor, which comes mainly from the liver. All three hormones are being studied for their potential to strengthen muscle and bones and prevent frailty among older people. For now, however, there is no convincing evidence that taking growth hormone will improve the health of those who do not suffer a profound deficiency of this hormone.

MELATONIN > Contrary to some claims, secretion of this hormone, made by the pineal gland, does not necessarily diminish with age. Instead, a number of factors, including light, can affect production of this hormone, which seems to regulate various seasonal changes in the 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 knowledgeable in sleep medicine be consulted before self-medication. Claims that melatonin can slow or reverse aging are far from proven.

TESTOSTERONE > In men, testosterone (see image) is produced in the testes (women also produce small amounts of this hormone). Production peaks in early adulthood. However, the range of normal testosterone production is vast. So while there are some declines in testosterone production with age, most older men stay well within normal limits. The NIA is investigating the role of testosterone supplementation in delaying or preventing frailty. Preliminary results have been inconclusive, and it remains unclear if supplementation of this hormone can sharpen memory or help men maintain stout muscles, sturdy bones, and robust sexual activity. Investigators are also looking at its side effects, which may include an increased risk of certain cancers, particularly prostate cancer. A small percentage of men with profound deficiencies may be helped by prescription testosterone supplements.

DHEA > Short for dehydroepiandrosterone, DHEA is produced in the adrenal glands. It is a precursor to some other hormones, including testosterone and estrogen. Production peaks in the mid-20s, and gradually declines with age. What this drop means or how it affects the aging process, if at all, is unclear. Investigators are working to find more definite 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.

Growth Factors

Some types of hormones can be referred to as growth or trophic factors. These factors include substances such as insulin-like growth factor (IGF-I), which mediates many of the actions of hGH. Another trophic factor of interest to gerontologists is growth hormone releasing hormone, which stimulates the release of hGH. Growth factors might have an important role in longevity determination. In nematodes, for instance, mutations in at least two genes in the IGF-I pathway result in extended lifespan.

The mechanisms—how hormones and growth factors produce their effects—are still a matter of intense speculation and study. Scientists know that these chemical messengers selectively stimulate cell activities, which in turn affect critical events, such as the size and functioning of skeletal muscle. However, the pathway from hormone to muscle is complex and still unclear.

Consider growth hormone. It begins by stimulating production of IGF-I. Produced primarily in the liver, IGF-I enters and flows through the blood stream, seeking out special IGF-I receptors on the surface of various cells, including muscle cells. Through these receptors it signals the muscle cells to increase in size and number, perhaps by stimulating their genes to produce more of special, muscle-specific proteins. Also involved at some point in this process are one or more of the six known proteins that specifically bind with IGF-I; their regulatory roles are still a mystery.

As if the cellular complexities weren’t enough, the action of growth hormone also may be intertwined with a cluster of other factors—exercise, for example, which stimulates a certain amount of hGH secretion on its own, and obesity, which depresses production of hGH. Even the way fat is distributed in the body may make a difference; lower levels of hGH have been linked to excess abdominal fat but not to lower body fat.



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