The Molecular Face of Aging

Consider a human baby, so young she cannot distinguish herself from the world. Her parents, beset by the fears and longings of adulthood, gaze anxiously upon their daughter's knitted brow. Her serious expression, at once reminiscent of her mother and comical on an infant's face, causes the parents to fret: When will the crease become a wrinkle? When will the physical assault of being alive begin? Their concern might seem absurdly premature, but the fleeting nature of life has long prompted people to wonder about the process of aging, and its impact on health. Contemporary science is wondering, too, and is rejuvenating these ancient inquiries. The direction such investigations should take was indicated a few years ago by evolutionary biologist George C. Williams at State University of New York (SUNY), Stony Brook. He warned that modern gerontological research focuses on death rather than on senescence or "the decreasing effectiveness of mechanisms by which adult organisms avoid death and loss of fitness."1 Williams dubbed this "the Tithonus error," after the Greek hero who became the lover of Eos, goddess of the dawn. She begged Zeus to give him immortality and Zeus complied, but Eos had forgotten to include eternal youthfulness in her request. As Tithonus aged, she locked him away, finally turning him into a cicada that could amuse her with its chirruping and shed its old skin every year. Alfred Lord Tennyson's poem about Tithonus suggests that the loss of youth and beauty, and the difficulties of very old age, eventually find relief: "And after many a summer dies the swan." Yet today, the retention of youth, the preservation of beauty, and the defiance of death are billion-dollar industries. Their bases are a curious mixture of science and nostrums, the latter no more effective than those peddled for centuries off the backs of carts in village squares. Amid an adulation of youthfulness by the advertising and entertainment industries that is so ubiquitous, its very mention is cliché, the triumphs and the promise of biomedical research have raised huge expectations about its ultimate goal: longer, healthier human lives. It's a moving target. In the United States, advances during the 20th century in public health and medicine greatly reduced the risks of death among children and younger adults. Average life expectancy rose from about 45 to 78, slightly more for women and less for men.2 But further improvements in those statistics will require success against diseases of the elderly. This historically unprecedented challenge presents biomedicine with a realistic alternative to the Tithonus request: If youthful immortality is unattainable, can extreme old age exist without its infirmities? If biomedical interventions were to eliminate the major scourges of the elderly—cardiovascular disease, stroke, and cancer—an estimated 15 years would be added to average life expectancy.3 That won't happen in the near future, but assuming an eventual best-case scenario, the next question is how much longer could human life be extended? How far can the target move? A benchmark for average life expectancy is the longest authenticated life, that of Frenchwoman Jeanne Louise Calment, who died in 1997 at age 122. When two American aging specialists made a wager last year on how old the longest-lived human would be in 2150, one guessed 130 and the other, 150.4 Whatever the average and maximum longevities might be in the future, the true objective will be to age well. Genetics could help. Aging and Families Boston University Medical CenterThomas T. Perls The conventional scientific wisdom has been that old age does not run in families. Deriving largely from studies that attributed more than 65% of the variance in twins' life spans to environmental factors, this theory was challenged in 2000, when the first four families ever documented with high clusterings of extreme longevity were reported.5 The study was led by geriatrician Thomas T. Perls of Beth Israel Deaconess Medical Center and Harvard Medical School. Last year, he and colleagues published the results of a genome-wide scan of 308 nonagenarians and centenarians, each of whom was a sibling of at least one other person in the study. A total of 137 families were represented. The researchers found that a locus on chromosome 4 is "highly suggestive" of genetic susceptibility to age well and to achieve exceptional longevity.6 Perls notes that the previous studies suggested that effects on aging are primarily under the individual's control. He says, "I don't necessarily disagree with that point of view, because the oldest people in those studies were in their late 70s to early 80s." That research told what the majority of people's genes can do, but his group's work has shown that, in extraordinary circumstances, relatively few polymorphisms can exert distinct effects on senescence. University of Nebraska Medical CenterDenham Harman These rare people are not only blessed with longevity-enabling genes, but they seem to lack certain disease genes. They also tend to fight off age-related diseases better than most people. Perhaps they cope more effectively than other people do with free radicals, the harmful byproducts of metabolism originally linked to aging by Denham Harman, now emeritus professor of medicine at the University of Nebraska Medical Center.7 In any case, Perls notes, "We see these people markedly escape or delay a broad range of age-related diseases." He thinks there might be about 10 longevity genes, and his team is continuing its search in other suggestive regions of the genome. Ultimately, sequences from centenarians might be used as a kind of comparative filter, to identify age-related disease genes in other people. All this could help to increase longevity, but what do scientists know of the role aging plays in disease? Is this where the touted telomere biology enters? The answer, according to biogerontologist Leonard Hayflick, requires making a distinction between aging and longevity determination. In 1961, Hayflick and Paul S. Moorhead showed that normal human fetal cell strains are limited to between 40 and 60 population doublings before they enter senescence,8 a finding now known as the "Hayflick Limit." The paper has been cited more than 3,000 times, and the work catalyzed a field of inquiry that eventually led to the identification of telomeres, the repeat nucleotide sequences at the ends of chromosomes that shorten with each population doubling. But Hayflick, a professor of anatomy at the University of California, San Francisco, cautions, "I don't think telomere shortening is necessarily telling us something about the aging process. I think that it is more likely telling us something about longevity determination." Aging in all objects, living and inanimate, is characterized by increasing molecular disorder, he explains. This occurs because energy is lost in the process of maintaining the molecules' structural integrity, and the result is a gradual diminution of functional integrity. People don't age or die because their cells stop dividing; hundreds of studies show that cells begin deteriorating in many ways that resemble organismal aging long before they stop replicating. Such findings lead Hayflick to observe, "You don't die from what's written on your death certificate." Old people die, he adds, from an increase in molecular disorder that correspondingly increases their vulnerability to the diseases associated with advanced age. Although telomere shortening probably does not give information about aging or molecular deterioration, it does help to explain how an organism's cellular longevity is determined. Not everyone agrees. Microbiologist Guido Krupp at the University of Kiel in Germany, coeditor of a forthcoming book on cancer and telomeres,9 is among those who believe that telomere shortening could influence aging. He comments in an E-mail, "The central problem in understanding the aging process is the detection of the signals that start and control aging processes." He says he thinks these signals could include telomere shortening within each aging tissue, along with oxidative damage of the genome and other cell components. "Another possibility is the control of the process by central tissue[s] that serve as life span sensor[s]—again, possibly by telomere shortening and oxidative damage—and that act as effector[s] in controlling aging in other tissues via neuronal signals or hormones." Controversial Hypothesis The hypothesis that cellular senescence contributes to organismal aging "has engendered far too much passion," declares Judith Campisi, head of the life sciences division in the department of cell and molecular biology at Lawrence Berkeley National Laboratory. She traces this strong feeling to private industry's involvement in telomere biology, claiming "money corrupts." Telomere shortening is only one way that the cell enters senescence, she adds. Oxidative damage during metabolic events, DNA breaks, and changes in telomere binding proteins are other triggers. "Senescence is a cellular response, like apoptosis, in the sense that if cells experience damage or any kind of stimulus that puts them at risk of undergoing transformation into cancer cells, they can do one of two things: go into senescence or die." © Clayton Ryder She rejects the telomere-shortening hypothesis, citing a lack of correlation between telomere length and life span in many species. For example, the mouse has longer telomeres and a shorter life than the human. Campisi says a paradigm is emerging in telomere biology that suggests it is not the length that matters, but the structure. A cell undergoing replicative arrest is trying to maintain its telomeric structure. Otherwise, the chromosome ends "will fuse to anything" and the cell will be ripped apart with the next mitosis, creating the genomic instability that precedes cancer. Under this scenario, the longer telomeres and shorter life of the mouse compared to the human is not so problematic. She does think there may be merit in the notion that limited cellular replication contributes to organismal aging. Although the arrest of a cell's division protects it from tumorigenic transformation, cancer nevertheless almost inevitably develops when mammals grow old, she notes. As mutations and dysfunctional senescent cells accumulate over time, the tissue microenvironment may be disrupted, eventually leading to the increased risk of developing cancer that characterizes aging.10 Her argument follows evolutionary reasoning fleshed out by SUNY's Williams. The idea is that only recently have advancements in public health and medicine allowed contemporary humans to far exceed the life span of their forebears. In the past, natural selection found it unnecessary to eliminate genes that, while useful in early life, later cause disease. People died before these pathological phenotypes ever appeared, just as other mammals in the wild rarely live long enough to acquire, say, tumors or cardiovascular disease. In Hayflick's apt phrase, "Aging is an artifact of civilization." Williams calls this effect of good genes turning bad "antagonistic pleiotropy," and it's why Campisi thinks that cellular senescence could suppress oncogenesis earlier in life and contribute to cancer in old age. The hypothesis was bolstered in January by evidence linking the p53 tumor suppressor gene to aging in mice.11 The potential consequences of someday fully understanding senescence raise another set of questions. Just imagine if it ever became possible to slow the rate at which people age; the price of manipulating this normal life process would be an ethical burden almost beyond reckoning. Consider again the newborn child. Let's say she eventually chooses to age normally, while her anxious parents elect to age slowly. Would the family's fate be less eerie than that of Eos and Tithonus? Steve Bunk (sbunk@the-scientist.com)is a contributing editor. References 1. G.C. Williams, "The Tithonus error in modern gerontology," Quarterly Review of Biology, 74:405-15, 1999. 2. S.J. Olshansky, B.A. Carnes, The Quest for Immortality, New York: W.W. Norton, 2001. 3. L. Hayflick, "The future of aging," Nature, 408:267-9, 2000. 4. J. McCann, "Wanna bet?" The Scientist, 15[3]:8, Feb. 5, 2001. 5. T. Perls et al., "Exceptional familial clustering for extreme longevity in humans," Journal of the American Geriatrics Society, 48:1483-5, 2000. 6. A.A. Puca et al., "A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4," Proceedings of the National Academy of Sciences, 98:10505-8, Aug. 28, 2001. 7. A. Mack, "Trying to unlock the mysteries of free radicals and antioxidants," The Scientist, 10[19]:13, 1996. 8. L. Hayflick, P.S. Moorehead, "Serial cultivation of human diploid cell strains." Experimental Cell Research, 25:585, 1961. 9. G. Krupp, R. Parwaresch, eds., Human Cancer and Biology of Telomeres and Telomerases, Georgetown, Texas: Eurekah.com, in press. 10. J. Campisi, "Cancer, aging, and cellular senescence," In vivo, 14:183-8, 2000. 11. S.D. Tyner et al., "p53 mice that display early ageing-associated phenotypes," Nature, 415:45-53, Jan. 3, 2002.

The Molecular Face of Aging

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