Photo of Mary Lavigne
Aging Under the Microscope
A Biological Quest
Introduction
Posing Questions, Finding Answers
» The Genetic Connection
Biochemistry and Aging
Physiologic Clues
The Future of Aging
Glossary
Bibliography
Acknowledgements
 
National Institute on Aging > Health > Publications > Aging Under the Microscope
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Chapter 2: The Genetic Connection

  Mary Lavigne, age 102, shares a laugh in her home with Thomas Perls, M.D., founder and director of the New England Centenarian Study. Ms. Lavigne has lived in three centuries. Perls and his colleagues are studying centenarians and their siblings for signs of longevity genes and other genetic traits.
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.

Tracking Down a Longevity Gene
  Yeast could help gerontologists understand the genetics of aging. More than 14 genes that appear to promote the longevity of these single-celled organisms have been discovered.
 
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.

  Worms, Genes, and Aging
 

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.
Age-related Traits Are All in the Family

Photo of a Sardinia ancestorFinding 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.

Microarrays in Action

Photograph of microarraysAll cells have the same complement of genes. The form and function of any given cell is determined by which of these genes are turned on and off. As a cell grows, matures and ages, the pattern of genes turned on and off changes. Detecting these changes was once a tedious process that involved testing one gene at a time. No longer.

Gene expression microarray technology, a potent scientific tool, is helping gerontologists rapidly clarify what genetic changes occur in cells as they get older. Also known as “gene chips,” microarrays allow researchers to survey the expression of thousands of genes at once. The match-box size glass chips contain DNA that has been exposed to messenger RNA (mRNA), a nucleic acid that translates information contained in DNA into proteins. Each kind of mRNA binds to its corresponding DNA probe, and the amount of mRNA that binds to each gene’s DNA on the chip is an indicator of the activity level of that gene.

Investigators using this technology have found relatively few changes in gene expression occur in aging tissues. In some studies, comparing tissue taken from young animals versus older animals, fewer than two of every 100 genes have shown major changes in activity over time. But these limited changes may have significant impact on the ability of aging tissues and organs to function properly. In time, microarrays might help gerontologists to more precisely characterize the genes involved in the aging of specific tissues or organs, and accelerate our understanding of its underlying mechanisms.

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.

In the Lab of the Long-Lived Fruit Flies
  Photograph of genetically altered fruit flies
 
The eyes of these genetically altered fruit flies appear fluorescent under the microscope. By altering gene expression in fruit flies and other organisms, investigators are learning much about aging.
A laboratory at the University of California, Irvine, is the home of thousands of Drosophila melanogaster, or fruit flies, that routinely live for 70 or 80 days, nearly twice the average Drosophila lifespan. Here evolutionary biologist Michael Rose, Ph.D., has bred the longlived stocks by selecting and mating flies late in life.

To begin the process of genetic selection, Rose first collected eggs laid by middle-age fruit flies and let them hatch in isolation. The progeny were then transferred to a communal plexiglass cage to eat, grow, and breed under conditions ideal for mating. Once they had reached advanced ages, the eggs laid by older females (and fertilized by older males) were again collected and removed to individual hatching vials. The cycle was repeated, but with succeeding generations, the day on which the eggs were collected was progressively postponed. After 2 years and 15 generations, the laboratory had stocks of Drosophila with longer lifespans.

The next question is what genes and what gene products are involved? Since the first experiments, Rose has bred longer life spans into fruit flies by selecting for other characteristics, such as ability to resist starvation, so the flies‘ long lifespans are not necessarily tied to their fertility late in life.

One possibility is that the antioxidant enzyme, superoxide dismutase (SOD), is involved. Two laboratory studies, including work by John Tower, Ph.D., at the University of Southern California, have shown that genetically altered fruit flies that produce greater amounts of SOD have extended lifespans. This finding has given a boost to the hypothesis that antioxidant enzymes like SOD are linked to aging or longevity. However, to date, similar experiments in other species have been inconclusive.

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.

  Limits to Growth
 

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.

  Telomeres: The Cancer Connection
 

Telomeres
Every chromosome has tails at its ends that get shorter as a cell divides. These tails, called telomeres, all have the same short sequence of DNA bases (TTAGGG in humans and other vertebrates) repeated thousands of times. These repetitive snippets do not contain any vital genetic information, but acting much like the hard, plastic covering on the ends of shoestrings, they help keep chromosomes intact.

During mitosis, the molecular machinery that replicates DNA can’t completely copy the extreme ends of chromosomes. So each time a cell divides, the telomeres get shorter. Over time, scientists theorize, telomeres become so short that their function is disrupted, and this, in turn, leads the cell to stop proliferating. Average telomere length, therefore, gives some indication of how many divisions the cell has already undergone and how many remain before it can no longer replicate.

This apparent counting mechanism, almost like an abacus keeping track of the cell’s age, has led to speculation that telomeres serve as molecular meters of cell division. But some scientists suspect telomere length is just one aspect of a complex mechanism. Elizabeth Blackburn, Ph.D., of the University of California, San Francisco, for instance, has accumulated evidence that some cells with extremely short, but structurally sound telomeres continue to proliferate, while others with long, but “frayed” telomeres undergo senescence. Telomere researchers also are exploring other possible ways in which these chromosome ends regulate cellular lifespan, and believe that proteins associated with telomeres play a role.

Telomere research is another territory where cancer and aging research merge. In immortal cancer cells, telomeres act abnormally—they no longer shrink with each cell division. In the search for clues to this phenomenon, researchers have discovered an enzyme called telomerase. This enzyme, which is not active in most adult cells (egg and sperm cells are among the exceptions), seems to swing into action in advanced cancers, enabling cells to replace lost telomeric sequences and divide indefinitely. This finding has led to speculation that if a drug could be developed to block telomerase activity, it might aid in cancer treatment.

Whether cell senescence is explained by abnormal gene products, telomere shortening, or other factors, the question of what senescence has to do with the aging of organisms continues to be the focus of rigorous study.

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Page last updated Jan 31, 2008