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  Cover Story  
  August 23,  2004
Volume 82, Number 34
pp. 30-35

Scientists attempt to understand the triggers, timing, and molecular basis for aging as they try to stave off humanity's most intractable scourge


What causes aging? Scientists don't know for sure, but there appear to be many contributing factors. It's possible that aging is an unintended side effect of the mechanisms that reduce vulnerability to cancer. Cellular maintenance and repair mechanisms may also gradually break down, permitting damage to build up over time. At the same time, evolution is unlikely to favor the investment of resources in organisms that can no longer reproduce. And natural selection is unable to weed out genes whose deleterious effects don't occur until later in life.

In a sense, aging begins at birth. But it is more commonly associated with the wrinkles; gray hair; and declines in strength, mental sharpness, reproductive ability, wound healing, immunity, and other functions that occur after reaching adulthood. Other conditions that often accompany aging include cancer, dementia, osteoporosis, and arteriosclerosis.

The average life expectancy for humans has increased over the centuries with improvements in sanitation, health care, and food quality and availability. But maximum lifespan hasn't grown much, leading some scientists to speculate that there may be some kind of barrier around the age of 120. Others believe that, with the right technological advances, humans will be able to live much longer than that.

Of course, those additional years would be a burden if many of them were spent in ill health. So delaying aging while maintaining good overall health is the ultimate goal of researchers in this field. In fact, they have found several such treatments that can extend the life of organisms in the lab while maintaining their health. However, none of these treatments has yet been proven to work in humans.

GERIATRIC MOUSE Yoda (left), who passed away in April at the age of four years and 12 days, was the world's oldest mouse. Part of a colony maintained at the University of Michigan, Ann Arbor, the dwarf mouse was housed with a companion, Princess Leia, for warmth.
IN THE LAB, one of the most powerful ways to extend life is to reduce food intake while satisfying nutritional needs. Organisms ranging from yeast to mammals enjoy much longer and healthier lives if they consume just two-thirds of the calories they normally eat. Experiments with rodents, for instance, have increased life span by 50% through dietary restrictions. The National Institute on Aging is now sponsoring a trial to test whether humans can stick with this kind of dietary regimen. Fortunately, cutting back on calories may not require a lifelong commitment. Mice whose caloric intake isn't reduced until they are 19 months old--equivalent to late middle age in humans--still show significant life span and health benefits after just a couple of months on the new diet, according to Stephen R. Spindler, a biochemistry professor at the University of California, Riverside, and colleagues [Proc. Natl. Acad. Sci. USA, 101, 5524 (2004)].

Mice that start the diet late show many of the same gene expression changes in the liver that characterize mice on a long-term restricted diet. Affected genes include those associated with metabolism, signal transduction, growth factors, immune response, inflammation, and stress response. On the other hand, the genomic profile of mice that are initially raised on a restricted diet and then switched to a normal diet quickly reverts to resembling that of better fed mice.

Spindler's findings contradict those from earlier studies of late-life calorie restriction. In fact, he notes on his website that his results "go against prevailing theories that say slow, incremental changes in gene expression and metabolism are the cause of aging. They suggest that the key genomic effects of caloric restriction are rapid, readily reversible, and do not seem to result from the long-term accrual of irreversible molecular damage."

Spindler is one of the scientific founders of BioMarker Pharmaceuticals, a firm based in Campbell, Calif., that is developing therapies for the treatment and prevention of age-related disease. In particular, the company and its partners are developing drugs that will mimic the effects of calorie restriction.

How does a severely limited food intake--which intuitively would seem harmful--increase life span?

One theory has it that cutting calories reduces the production during respiration of reactive oxygen species that cause oxidative stress and damage in the body. These compounds can inflict damage on DNA that, over time, may accumulate to produce the ravages of age. Researchers working in this area include Simon Melov, director of genomics at Buck Institute, a Novato, Calif., nonprofit organization that conducts research on aging.

THE SKINNY ON AGING Guarente (left) and Frédéric Picard study the effect of SIRT1--a protein that links calorie restriction and aging--on mammalian fat cells.
Leonard P. Guarente, a biology professor at Massachusetts Institute of Technology, backs an alternate premise based on experiments involving yeast (Saccharomyces cerevisiae). Life span in yeast is equated with the number of times a mother cell can bud off a smaller daughter cell--typically an average of some 20 divisions and a maximum of about 40 divisions for normal, or wild-type, yeast.

Guarente and his colleagues have found that growing yeast on media containing 0.5% glucose instead of the normal 2% increases life span by about 25%. They have determined that the effect is related to the SIR2 gene. The gene codes for Sir2 proteins, which deacetylate the lysine groups of histones as well as many other proteins. Histones are components of chromatin, the tightly bundled complexes of DNA, RNA, and protein that make up chromosomes. When Sir2 deacetylates histones, it compresses the structure of chromatin, silencing various stretches of DNA by making the regions less accessible for gene transcription. One benefit for yeast is a reduction in the production of DNA fragments during cell division--structures that cause aging.

Sir2 acts in concert with nicotinamide adenine dinucleotide (NAD). Yeast cells produce NAD from its reduced form, NADH, through respiration. According to the researchers, calorie restriction tips the yeast's metabolism of glucose from fermentation to respiration. Therefore, Guarente and
colleagues suggest that calorie restriction drives the conversion of NADH to NAD, lowering the NADH concentration and boosting the NAD:NADH ratio [Genes Dev., 18, 12 (2004)]. Because NADH is a Sir2 inhibitor, they reason, its reduction increases Sir2 activity.

Other researchers believe that Sir2 activity is controlled not by NAD:NADH levels but by levels of the NAD derivative nicotinamide, another Sir2 inhibitor. David A. Sinclair, an assistant professor of pathology at Harvard Medical School, and his colleagues have proposed that calorie restriction increases the expression of PNC1 [Nature, 423, 181 (2003)]. This longevity gene codes for an enzyme that deaminates nicotinamide, converting it to nicotinic acid. The paper offers evidence that "nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity" in yeast.

WHATEVER the true mechanism, Harvard geneticists Siu S. Lee and Gary Ruvkun caution in a July 2002 commentary in Nature that "what applies in yeast won't necessarily apply in animals." However, there are similarities between the response of yeast and animals to calorie restriction. In addition, the life span of Caenorhabditis elegans worms and other organisms is also affected by genes similar to SIR2. A few years ago, Guarente and then-postdoc Heidi A. Tissenbaum reported that C. elegans possessing an extra copy of the worm's version of the SIR2 gene, known as sir-2.1, live as much as 50% longer than normal [Nature, 410, 227 (2001)]. This worm gene codes for the protein SIR-2.1.

The mammalian version of Sir2 is SIRT1. This protein is an important component of a complex network of reactions that control an organism's response to the environment. "In mammals, it is becoming increasingly apparent that SIRT1 is a key regulator of cell defenses and survival in response to stress," write Sinclair and colleagues in a recent article [Science, 305, 390 (2004)]. "In response to damage or stress, cells attempt to repair and defend themselves, but if unsuccessful, they often undergo programmed cell death, or apoptosis. Numerous studies show that aging is associated with increased rates of stress-induced apoptosis. ... Consistent with this, rodents subjected to caloric restriction and long-lived genetic mutants ... are typically less prone to stress-induced apoptosis."

In the Science paper, the Sinclair team reports that SIRT1 expression is higher in rats with restricted diets than in animals that eat as much as they want. In addition, cells grown in serum from rats on restricted diets are less vulnerable to stress-induced apoptosis than cells grown in serum from well-fed rats.

The scientists believe that SIRT1 operates through its interaction with the DNA repair factor Ku70. Ku70 ordinarily binds to the protein Bax, interfering with Bax's ability to promote apoptosis. Under stressful conditions, however, two lysines in Ku70 become acetylated, and it loses its hold on Bax. That allows Bax to migrate from the cell's cytoplasm into the mitochondria, where it initiates apoptosis.

The Sinclair team discovered that SIRT1 maintains the two Ku70 residues in a deacetylated state "to keep Bax sequestered from mitochondria. Thus, caloric restriction induces SIRT1 expression in a wide array of tissues, and this shifts the balance away from cell death toward cell survival."

The researchers also note that levels of insulin and another hormone called insulin-like growth factor 1 (IGF-1) are lower in rodents that are fed less than normal. And they found that cells grown in serum from underfed rats reduced SIRT1 expression when treated with insulin or IGF-1. Sinclair's team concludes that these data "indicate that the systemic regulation of mammalian SIRT1 is mediated, in part, by insulin and IGF-1, two serum factors that are involved in life span regulation in a variety of species" including worms, flies, and mice.

Sinclair and his colleagues believe that other targets of SIRT1 may also be affected by caloric restriction and other stresses. For instance, Sinclair has collaborated with Michael E. Greenberg, director of the neuroscience division at Children's Hospital Boston, to explore the connection between SIRT1 and FOXO3, a member of the FOXO family of Forkhead transcription factors. These proteins serve as sensors of the insulin signaling pathway and also activate genes related to DNA repair, detoxification of reactive oxygen species, cell cycle arrest, and cell death.

SIRT1 apparently controls the cellular response to stress by regulating the FOXO transcription factors, report Greenberg, Sinclair, and their colleagues [Science, 303, 2011 (2004)]. In response to oxidative stress, SIRT1 deacetylates FOXO3, which "increases FOXO3's ability to induce cell cycle arrest ... possibly allowing more time for cells to detoxify reactive oxygen species and to repair damaged DNA." Deacetylation also "inhibits FOXO3's ability to induce cell death. Thus, one way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance."

Although these threads of evidence indicate that a low-calorie regimen might have beneficial effects for humans, such a diet would prove too ascetic for all but the most dedicated. Sinclair may have another solution. He has found a way to stimulate sirtuins, the family of proteins that includes Sir2 and SIR-2.1, without cutting calorie intake. The technique relies on "sirtuin-activating compounds" (STACs), which increase the rate at which sirtuins deacetylate their protein targets, such as Ku70.

Sinclair and his colleagues found that STACs such as resveratrol can extend the life span of yeast, human cells, C. elegans, and the fruit fly Drosophila melanogaster that are nourished with a normal amount of food [Nature, 430, 686 (2004)]. Unlike some other techniques such as dietary restriction, treatment with STACs lengthens life without reducing fertility.


IF SUCH RESULTS apply to humans, antiaging treatment could be quite popular, because resveratrol and other plant polyphenols are found in red wine. Sinclair has formed a biotech firm, Sirtris Pharmaceuticals, to look for other small molecules that can stimulate production of sirtuins.

Sinclair's team has determined that organisms fed STACs such as resveratrol don't live even longer if their food intake is curtailed, implying that STACs and calorie restriction work through a similar pathway.

But not all antiaging treatments work via just one mechanism. For instance, Andrzej Bartke, a physiology professor at Southern Illinois University School of Medicine, Springfield, and colleagues reported on an additive effect between a longevity gene and calorie reduction [Nature, 414, 412 (2001)]. The researchers found that dwarf mice, which already enjoy long lives because of the gene Prop1df, live even longer when their diet is restricted. Their evidence suggests that this particular longevity gene and dietary restrictions extend life via two independent pathways. "Calorie restriction seems to decelerate aging, whereas Prop1df seems to delay it," the researchers note.

In some cases, longevity treatments appear to be downright synergistic. Cynthia Kenyon, a professor in the biochemistry and biophysics department at UC San Francisco, and colleagues reported in Science [302, 611 (2003)] that their genetically modified C. elegans lived an astonishing six times longer than normal worms. The researchers began with worms that had mutations in daf-2. This gene codes for a receptor for insulin and IGF-1 and also affects reproduction. When food is scarce and conditions are thus inhospitable for reproduction, daf-2 activity drops off, and young worms enter a state of suspended animation known as the dauer. This stage presumably improves a worm's odds of reproducing by halting aging until food reappears. In adult worms, a decline in daf-2 activity doesn't initiate the dauer or affect reproduction, but it does extend life span.

The daf-2 mutation of Kenyon's worms reduces insulin/IGF-1 signaling. The researchers reduce daf-2 activity further through RNA interference. They then remove the worms' reproductive systems, which may alter endocrine signaling.

"Whereas the mean life span of wild type was 20 days, these animals had mean life spans of 124 days," Kenyon's team reports. "In fact, only 15% of the animals died in the first three months." What's more, the worms are "quite active for most of their lives." The authors compare the long-lived worms to "healthy, active 500-year-old" humans.

"These findings in C. elegans show that remarkable life span extensions can be produced with no apparent loss of health or vitality by perturbing a small number of genes and tissues in an animal," Kenyon's team writes. These life span extensions, which they claim are among the longest ever produced in any organism, "are particularly intriguing because the insulin/IGF-1 pathway controls longevity in many species, including mammals."

Kenyon, along with Guarente, Thomas T. Perls--an associate professor of medicine at Boston University School of Medicine who is also affiliated with the Boston Medical Center's geriatrics section--and other partners, have formed Elixir Pharmaceuticals to develop antiaging therapies. The treatments will target longevity genes and their associated proteins, including those involved in the daf-2/insulin/IGF-1 signaling pathway. Such compounds could also prevent or delay the onset of diabetes.

The daf-2 pathway targets DAF-16, a member of the FOXO family of Forkhead transcription factors that help to regulate production of superoxide dismutase (SOD) and catalase. These free-radical scavengers ward off oxidative damage that can contribute to aging. When daf-2 activity is suppressed, DAF-16 activity cranks up and boosts SOD and catalase expression. Eukarion, a biopharmaceutical firm based in Bedford, Mass., is testing small synthetic mimics of SOD and catalase as potential antiaging candidates.

Richard A. Miller, a pathology professor and associate director for research in the Geriatrics Center at the University of Michigan, Ann Arbor, and colleagues have studied mice with a mutation at the Pit1 locus, which codes for a transcription factor necessary for pituitary development. These dwarf mice show defects in growth hormone stimulation of IGF-1 and live more than 40% longer than control animals. The mutant mice also show delays in age-dependent cross-linking of connective tissue and in six age-sensitive indices of immune system status [Proc. Natl. Acad. Sci. USA, 98, 6736 (2001)].


REGARDLESS OF the mechanism, one sure sign of aging is a loss in ability to regenerate muscle mass. Stanford University researchers believe this diminished capacity is related to changes in the Notch signaling pathway. Notch genes code for transmembrane proteins that serve as receptors for ligands such as Delta. Signaling associated with the binding of ligands to Notch proteins is involved in numerous cellular processes ranging from the formation of muscle to the development of blood cells.

Inadequate activation of Notch by Delta is responsible for the loss of regenerative potential in old skeletal muscle in mice, report Thomas A. Rando, an associate professor in the department of neurology and neurological sciences at Stanford University School of Medicine, and colleagues [Science, 302, 1575 (2003)]. They also find that forced reactivation of Notch "restores regenerative potential to old muscle." The researchers think that their findings have implications beyond deteriorating muscles. "We propose that a decline in Notch signaling necessary for cell proliferation and cell fate determination may also occur in progenitor cells and stem cells in other tissues with age and may be a general mechanism underlying the diminished regenerative properties of aged tissues."

Muscle mass diminishes and body fat increases as the levels of human growth hormone decline with age. Injections of growth hormone can counter this trend in the elderly, according to some studies. But the benefits are accompanied by side effects such as diabetes, and some physicians believe that growth hormone is not ready for use as an antiaging formula.

Rather than risking the possible side effects of hormones, those who wish to live longer may one day be able to take a compound such as 4-phenylbutyrate. Currently used to treat several diseases such as sickle cell anemia and cystic fibrosis, it has been shown to extend the life and maintain the vigor of fruit flies. The compound is an inhibitor of histone deacetylase that may work by affecting chromatin structure and thus gene transcription.

Foods high in antioxidants may also be able to slow age-related conditions such as a decline in learning ability and memory. Antioxidants may rein in the increase in production of proinflammatory cytokines that normally accompanies aging.

Dietary supplements may also help. Acetyl-l-carnitine and lipoic acid--compounds that are found in mitochondria--improve vigor, metabolic function, resistance to oxidative stress, and memory in old rats, report Bruce N. Ames, a molecular and cell biology professor at UC Berkeley, and colleagues [Proc. Natl. Acad. Sci. USA, 99, 1870 (2002)]. Ames's company, Juvenon, markets this combination of supplements. The researchers believe the supplements fight mitochondrial damage caused by reactive oxygen species generated as by-products during normal metabolism.

8234coverstory_sinclair 8234coverstory_Miller
Consumption of coenzyme Q, a lipid component of cellular membranes required for respiration, can also affect life span. In addition to other functions, Q transports electrons and protons across the mitochondrial membrane to enable the synthesis of ATP. Pamela L. Larsen, an associate professor in the department of cellular and structural biology at the University of Texas Health Science Center, San Antonio, and Catherine F. Clarke, a biochemistry professor at UC Los Angeles, report that worms live about 60% longer if their Q intake is limited [Science, 295, 120 (2002)]. The researchers attribute the results to a diminished production of reactive oxygen species in mitochondria.

While most people will want to wait and see whether such compounds prove useful for humans, a lucky few can shrug off such external factors because they have won the genetic lottery. Perls and colleagues report that brothers and sisters of centenarians are respectively at least 17 and eight times as likely to reach the age of 100 as the average person born in 1900 in the U.S. [Proc. Natl. Acad. Sci. USA, 99, 8442 (2002)]. In addition, siblings of centenarians have a death rate at all ages of about half the national level.

Perls and colleagues have identified a region on human chromosome 4 that appears to be associated with reaching exceptional age. Uncovering the genes responsible will be doubly valuable because "many centenarians live the majority of their exceptionally long lives in good health, demonstrating a rapid decline only near the end of life," they write. Perls's firm, Elixir, continues the search for the specific genes involved.

Of course, scientists want to track down the human versions of many of the genes that have been implicated in aging in other animals. In addition to the ones already described, some of the most well known include age-1, chico, clk-1, clk-2, clk-3, Indy, and methuselah.

Genes figure in another area of aging research involving telomeres, protective structures of DNA and protein that cap the ends of chromosomes in eukaryotic cells. Telomeres shield the chromosomes from cellular mechanisms that would interpret the ends of the chromosomes as broken DNA and attempt to repair them, leading to chromosome fusion and genomic instability.

Along with the rest of the cell's DNA, telomeres are copied during cell division. However, the replication machinery is unable to copy the very tip of the DNA molecules. This means that the telomeres become shorter every time the cell divides. After several cycles of cell division, the telomeres become too short to protect the remaining DNA. The cell then stops dividing (a stage referred to as senescence) and ages.

Telomeres can thus be thought of as a kind of cellular clock. Furthermore, "it has been proposed, but not proven, that shortened telomeres in dividing cells may be responsible for some of the changes we associate with normal aging," according to Jerry W. Shay, a cell biology professor at the University of Texas Southwestern Medical Center, Dallas. If the clock could be stopped, the thinking goes, aging could also be stopped--or at least slowed.

One possible method would be to re-extend the telomeres. Most human cells don't have this capability or have it only to a limited extent. But some cells--including fetal tissue cells, adult male germ cells, and hematopoietic stem cells--can add telomeric DNA onto the ends of chromosomes with the assistance of telomerase. This reverse transcriptase was discovered in 1985 by Elizabeth H. Blackburn, a professor of biochemistry and biophysics at UC San Francisco, and Carol W. Greider, a professor of molecular biology and genetics at Johns Hopkins University.

So there's biochemical precedent for lengthening telomeres. There's a hitch, however. A cancer cell continues to divide indefinitely because its telomeres are constantly refreshed. Shay notes that cellular senescence may have developed to protect long-lived organisms from cancer. Hence, the trick is to find a mechanism to lengthen the telomeres without letting cell growth get out of control.

Junho Lee, a biology professor at Yonsei University, Seoul, South Korea, and colleagues recently took on this challenge. The researchers first identified HRP-1 as a protein that can lengthen telomeres in the cells of worms. Lee's team then engineered worms to overexpress the protein. The worms--and their offspring--live longer than their normal fellows [Nat. Genet., 36, 607 (2004)]. Surprisingly, the mutants' cells don't undergo more divisions than those in wild-type worms. Instead, the worms with longer telomeres appear to live longer because they are more resistant to heat stress.

Cellular response to numerous stresses is controlled by the tumor suppressor p53. This protein is entwined with the aging process through its ability to initiate senescence or apoptosis in response to stress. Lawrence A. Donehower, a professor in the departments of molecular virology and microbiology and molecular and cellular biology at Baylor College of Medicine, Houston, and colleagues report on a project in which they create mice with enhanced p53 activity [Nature, 415, 45 (2002)]. Although the mice benefit from a significantly reduced cancer risk compared with wild-type mice, they suffer from some symptoms of premature aging. The Donehower team speculates that the enhanced p53 activity suppresses the proliferation of stem cells, diminishing their ability to replace cells in organs and eventually reducing organ viability.

The protein may have many routes by which it is linked with the aging process. For instance, Sir2 can suppress p53 activity, while radiation doses that promote premature aging in mice activate p53.

The response of organisms to such stresses may prove the adage that what doesn't kill you makes you stronger. "Sustained stress definitely is not good for you, but an occasional burst of stress or low levels of stress can be very protective," according to Richard I. Morimoto, a biology professor at Northwestern University.

DNA GUARDIANS Telomeres (yellow) cap the ends of chromosomes to protect them from inappropriate "repair" mechanisms.

STRESSORS such as high temperature, infections, and toxic compounds activate a protein known as heat shock factor (HSF-1). HSF-1 mobilizes an army of molecular chaperones that repair or eliminate damaged and misfolded proteins. In turn, this prevents or delays cell damage, prolonging life, Morimoto and graduate student James F. Morley report [Mol. Biol. Cell, 15, 657 (2004)].

Prior research indicates that "heat shock gene expression is induced poorly in aged animals," the researchers note. In that context, they write, their studies "provide a new perspective on the way in which decreased ability to sense and respond to stress in old animals may contribute to declining cellular function and, in particular, increased susceptibility to diseases of protein misfolding observed during aging."

Aging makes itself felt throughout the body. One site is the immune system. Miller's lab is studying why the immune system weakens with advancing years. He works with T cells (lymphocytes that protect the body from viruses, bacteria, and cancer). Miller has found that specific enzymes and surface molecules, which are usually activated soon after a T cell gets turned on, are less able to react if the T cell comes from an old mouse.

When a T cell recognizes an antigen, Miller explains, "the proteins in the membrane of the T cell all rush to the point where the T cell is in contact with the antigen-presenting cell." About half of the T cells from a young mouse are capable of that response, he says, but only about one-fourth of the T cells from an old mouse can muster it.

T cells from older mice are also less capable of dragging inhibitory molecules out of the contact zone. One such inhibitor is CD43, a huge molecule that sits on the T cell surface. As mice age, their CD43s become increasingly glycosylated. Once these polysaccharide chains clutter up enough of the CD43s, they block antigen-presenting cells from approaching the T cells, hindering immune response.

In an in vitro test, Miller's colleague Gonzalo G. Garcia found that cleaving the polysaccharide chains restores the immune activity of T cells from old mice. "We don't know whether this will work in an intact animal," Miller says, "but it certainly gives us ideas about ways we might be able to restore the immune function of lymphocytes in older mice and people." Miller and Garcia published their work in the European Journal of Immunology [33, 3464 (2003)].

Whatever technique is ultimately used, attempts to alter life span must be done carefully. "There is a very real danger that enhancing biological attributes associated with extended survival late in life might compromise biological properties important to growth and development early in life," note S. Jay Olshansky, a professor of epidemiology and biostatistics in the School of Public Health at the University of Illinois, Chicago; Leonard Hayflick, an adjunct professor of anatomy at UCSF; and Bruce A. Carnes, a senior research scientist at the University of Chicago's Center on Aging, in the Journal of Gerontology [57A, B292 (2002)].

Extending life also shouldn't come with a toll of living longer with the illnesses associated with old age such as cancer, Alzheimer's disease, and cardiovascular disease. "For most people, quality of life seems to be preferred to quantity of life," according to the trio.

"In the ideal case, the healthy citizens of a modern society will survive to an advanced age with their vigor and functional independence maintained, and morbidity and disability will be compressed into a relatively short period," note Shay and Woodring E. Wright, a cell biology professor at the University of Texas Southwestern Medical Center, on their website. Such was the case for Jeanne Calment of France, the oldest documented human, who died at the age of 122 in 1997.

"We have been increasing the maximum life span of rats and mice by 30 or 40% over the last 70 years," Sinclair says. "So unless we're fundamentally different from a rat--and most biologists don't believe so--then it should be possible to go past 120. I don't know how far past 120. I'd be happy with 125 myself."


Early-Aging Disorders May Shed Light on Normal Aging

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