Ponce De Leon and the Telomere of Youth

Evolutionary Anthropology 13:82–88 (2004)

CROTCHETS & QUIDDITIES

Ponce de Leon and the Telomere of Youth

KENNETH WEISS

The explorer went to the ends of the earth looking for immortality. Did he only tion are indirectly screened through have to go to the ends of his chromosomes? their life-history effects. One net re- sult is that species have characteristic aging rates, making questions like, “If the drug industry has a commer- “How long do dogs live?” evolutionar- cial Holy Grail, it might be an anti- ily meaningful. Perhaps the fact that aging pill, one that would let you live lifespan is a somewhat colloquial longer and prolong your youthful rather than scientific term has led to vigor,” wrote Gina Kolata in a recent the notion of that each species has article in the New York Times.1 Genes what has been called a Maximum have recently been found that have Lifespan Potential (MLP), so that in- similar effects on aging processes in dividuals who avoid exogenous causes yeast, flies, nematodes, and humans. of death-like predation or infection This suggests that aging might be an will eventually succumb to a species- easily modifiable phenomenon and specific internal clock at its MLP, the drug industry is eager to discover making room for a fresh generation. the magic potion for eternal youth. We can illustrate aspects of life-his- Of course the icon of the search for tory evolution by the survivorship the Fountain of Youth is Juan Ponce, curve, the age-specific probability of known as Ponce de Leon. A comrade Figure 1. Ponce de Leon in his younger surviving from birth to each age (Fig- of Columbus, who successfully fought years. ure 2). The impression that there is an the Moors and helped subjugate His- MLP is an understandable illusion of pan˜ ola as a base for Spanish con- such data (Figure 2, first 2 curves). Trends in causes of mortality over quests, Ponce became governor of Leon looked over the far horizon for Puerto Rico in the early 1500s. Later, simple cures for death. In the scien- time made it seem that the survivor- faced with age and the fading of his tific age we seek our dreams on the ship curve was becoming “squared,” glory days, he heard of crystal waters, inner horizon of our genome, and approaching a limit—the MLP—that among trees bearing golden fruit we’re in an age when we can stop hy- the rapid acceleration of mortality tended by lovely maidens, that be- pothesizing about aging-related genes rates with age make it impossible to stowed eternal youth upon those who and, if they exist (unlike the Fountain survive. The reason for the illusion, bathed in them. Who could resist? Af- of Youth), find them. But before see- which was widely accepted by the bio- ter searching in vain in the Bahamas, ing what is now known about such medical aging research community in 1512 Ponce followed magnolia- genes, we first need to consider just until quite recently, was that early ex- scented offshore breezes to what he what kind of phenomenon aging actu- trinsic causes of mortality like infec- hence named “Florida,” where his ally is. tion were being reduced by public search also failed—but he would re- health measures. If we could finally turn. remove those causes we would have In longing for long life, Ponce de WHAT KIND OF EVOLUTIONARY something rather squarish (curve C), because the remaining intrinsic aging PHENOMENON IS “AGING”? processes would then predominate. The fitness associated with any trait However, the MLP was far beyond Kenneth Weiss is Evan Pugh Professor of is a life-history phenomenon. Age-spe- ages most people ever attained, so it Anthropology and Genetics, at Penn Uni- was always difficult for evolutionary versity. cific timing of reproductive maturity, fertility, and mortality determine life- biologists to accept the notion, in part time reproductive success. Life-his- also because one of its rather incredi- © 2004 Wiley-Liss, Inc. tory traits are complex, because they ble implications was that the known DOI 10.1002/evan.20008 Published online in Wiley InterScience can be affected by selection and drift causes of death were biologically un- (www.interscience.wiley.com). directly, but even traits like locomo- related to the determination of life- CROTCHETS & QUIDDITIES Ponce de Leon 83

Why would the idea that aging is a unified biological trait, or that there could be a simple genetic MLP-direct- ing switch, seem plausible in the first place? One oft-cited reason is that among vertebrate species there is a systematic relationship between estimated lifespan and measures like mean body or brain size (Figure 3). Indeed, the same age-patterns of diseases that fail to support the notion of a fixed MLP to kill us, suggest that there must be some common underlying processes that evolution (or we) might play with to preserve us. At any given age, the absolute risk of death from different causes varies by orders of magnitude. But the change in those risks with age are very similar (Figure 4); diverse causes rise in risk at roughly the 5th power of age. Similar diseases strike mice, mon- Figure 2. A survivorship history, in percent surviving from birth each succeeding age. keys, and men, who share largely the General pattern of U.S. mortality by age in 1900, 1950, and (curve C) the continuation of same genome, yet are scaled to each that trend giving the appearance of a squared survivorship curve at the hypothetical species’ lifespan, indicating that evo- human MLP. Curve D shows an “extended” life history without the squaring, as has been seen in recent years, leading to the suggestion that human life can be indefinitely ex- lution may somehow calibrate the tended. Schematic. overall rate of aging, rather than specifically of death. The tapering off of span, and without them we could all live in good health until our MLPth birthday.2 Aging research might not make us immortal, but we’d at least be able to have a well-planned Last Sup- per. Instead, and more plausibly, recent mortality data show that death rates do not rapidly accelerate at very old ages (Figure 2, “extended” curve D). This means that the oldest old do not drop off suddenly, but gradually: there is no “squaring” of survivorship. The MLP vanishes—and the unrepen- tant research lobby now touts its new insight that human life can be extended indefinitely. But this too is a Leonid dream. Life expectancy and health at older ages have recently in- creased, in part because of life-extend- ing intervention like less physical stress, better nutrition, drugs and vac- cines, bypass surgery, cancer chemo- therapy, bronchial ventilators, more effective long-term and emergency room care, and the like. But a visit to a senior center reveals the sobering truth that old people are “old” in roughly the same complexity of ways Figure 3. Age and lifespan: something’s going on here. Relationship between body size and as always. estimated lifespan among vertebrate species. 84 Weiss CROTCHETS & QUIDDITIES

Figure 4. Different causes of death vary greatly in absolute risk but share similar patterns of acceleration with age. Risk is on a log scale. 1999–2001 U.S. mortality.3

some causes seen here reflects the sec- would seem obvious that the rest of natural selection. But wearing out ular trends (curve D) in Figure 3 and our cells, with the same genome, don’t does not explain our long post-repro- is due, at least in part, to the differen- have to wear out either. To bowdlerize ductive persistence, and a variety of tial loss with age of individuals genet- James Hutton, a founder of modern theories and controversies, have been ically susceptible to the various dis- geology, all life today is composed of advanced for that, some in the context eases. Thus, those who survive cell lineages that are about 3–4 billion of the broader evolution of primate represent their own longevity, but not years old, with “some vestige of a be- life-histories.4–7 that of people generally. ginning—no prospect of an end.” Evolutionary explanations almost If these data reflect an underlying always rest on the assumption that if aging process, that might account for aging is highly organized it must have another curious aspect of Figure 3, WHAT IS THE LIKELY been molded by selective forces, and that suggests that humans live longer, EVOLUTIONARY EFFECT ON the genes involved are routinely hy- by an amount roughly equaling the AGING-RELATED GENES? pothesized (“Suppose a mutation in- length of our post-reproductive sur- Everything here seems to cut both creases lifespan;...”). I think this vival, than a mammal our size has any ways. Does evolution kill us off or view of life is overdone, but it is worth right to expect. Although this could keep us going? One general theory for considering the likely resulting im- just be an artifact of multiple causes, the evolution of senescence is that pact of those forces, whatever they the possibility of a common underly- nothing evolved specifically to kill us are. ing cause understandably raises the off, but that the price of genes that First, however, we should not over- hope for a Gene Therapy of Youth. give us plenty at twenty is to become interpret statistical data, especially Immortality! What in the Devil’s weighty at eighty. This is known as with a measure like lifespan. A spe- Dictionary Ambrose Bierce quipped negative pleiotropy, and the idea is that cies-specific lifespan or MLP is the ex- that people would apply on their genes selected for early fitness can tremum of a population phenomenon, knees and be eternally proud to die have deleterious effects in later life, whose estimation depends on sample for, is clearly possible at the cell level. when events can become just a matter size. We’ve observed hundreds of mil- Since the germ line never ages, it of wearing-out, beyond the reach of lions of human lifespans, vastly more CROTCHETS & QUIDDITIES Ponce de Leon 85 than for other species, biasing the hu- the chances, and hence evolutionary ing” gene should affect underlying man estimate towards the extreme of fitness, of her children or grandchil- processes we associate with getting rare genotype or luck relative to what dren.5 Trans-generational resource old. The first genes known to affect we’ve observed for other species. transfer is undeniable, but only a frac- aging probably were those causing Though above the trend in Figure 3, tion of fitness remains in the Darwin- numerous progerias, including Down’s we’re not dramatically longevous for ian arena by the ages at which it oc- syndrome. Progerias commonly affect our body size, no more aberrant than curs. Although the overall heritability connective tissue, which is found in rhesus, reindeer, and African buffalo, of longevity in humans is about 25%, skin, bone, muscle, heart, and blood for whom no special evolutionary ex- showing that there is potentially rele- vessels, and by affecting multiple planations have seemed necessary. So vant variation, that heritability de- traits in similar ways can appear to at least some of the excess might be clines with age: genetic effects are accelerate general aging. simply a sample size artifact. weakest at the ages when trans-gener- Free oxygen radicals, or oxidants, Another potential illusion is that ational effects are most important. interact with cellular components even the modest post-reproductive And as to the human specificity of ag- causing damage to any tissue, includ- survival found in contemporary tribal ing, baboons have roughly the same ing mutations in DNA, damage that cultures may be misleadingly long, be- heritability, in both sexes, and as accumulates with age.9 Various dis- cause they probably have far better in other mammals the pattern of eases, especially cancer, have been cultural protection (arrows, sharper senescence in baboons resembles thought to be accelerated by such stone blades, metal, agriculture, that in humans, despite very differ- damage. Dietary antioxidants have maybe even antibiotics or antimalari- ent lifespans. been thought to reduce a variety of als) than was available when our life The transfer of resources to the next such diseases and hence general aging history evolved. Studies of traits like generation involves not the direct fit- rates, and oxidant-scavenging genes hominid fossil dental eruption suggest ness of a parent, but her inclusive— are viewed as longevity-promoting that our maturation rates evolved long indirect—fitness achieved via others candidates. ago, but this need not apply at the who bear her genes. But her specific In a wide variety of experimental other end of life when selection was selective advantage would be less than laboratory animals, and probably hu- weaker. And if the historical, anthro- it might seem because small local mans, modest restriction of dietary pological, and fictional literature is demes consisted mainly of cousin-like caloric intake increases the length of any guide, in prior times people were kin, who care for a woman’s children life (maybe the secret is not to seek the widely seen as pretty worn out by if she dies, and communal necessity Fountain of Youth but to shun the their 50s. I’ve been reading Don Quix- makes hunter-gatherers share re- Soda Fountain). Some genetic mech- ote, in which the Don is described as sources like food, defense, tool-mak- anisms are known that probably con- “about fifty years old, of a strong com- ing technology, and so on. Ultimately tribute to this observation. In re- culture is enabled by genes, but in the plexion, dry flesh, and a withered sponse to calorie intake, genes in the search for a biomedical elixir of face.” Yet people from all cultures liv- insulin-like, pituitary, and related hor- youth, we seek a genetic cause of the ing in modern environments like, say, monal signaling systems can shunt biology of aging itself, not of the cul- Mohawks in Toronto (or knights of La metabolic energy either to growth and ture that protects old people. Mancha in La Mancha), stay equally reproduction or, when suppressed, to For these reasons, late-age selection fit, for equally long. As anthropolo- extended lifespan. Genes in the Sir- effects were probably weak, and if gists we should keep in mind the trap tuin gene family10 indirectly affect many different genes contribute to of viewing the world through our own these pathways by modifying the his- longevity, the net selective advantage cultural lenses; for example, we rou- tone proteins that package DNA, af- at any one of them would have been tinely apply skin cosmetics to prevent fecting gene expression. One sirtuin, even smaller. In our small ancestral “premature” aging. The difference be- Sir2, affects yeast lifespan through ef- populations this means that genetic tween what is possible and what actu- fects on mating and cell division cy- drift would have been a stronger, if ally occurred or was selected for in the cles, and in some species Sir2 affects not predominant effect on the fre- past is an important distinction in expression in the insulin-like system. quencies of alleles related to late-age evolutionary biology that may well ap- A human homolog, SIRT1, affects the survival. This high genetic noise-to- ply here. The fact that Bonzai trees signal ratio in turn means that we cell cycle and programmed cell death. can be made does not mean trees should not expect the kind of simple In laboratory animals the senes- evolved to be tiny. genetic aging mechanism—the phar- cence-delaying effects of mutations in How old was old in days of old is maceutical dream—that one might these genes resemble the empirical ef- 5,7,8 debatable, but the question is what expect after rapid, strong selection. fects of calorie restriction: stretching happens to those who do live to be But what do we actually find? out the survivorship curve to more old, and the most prevalent explana- like the “extended” curve D in Figure tions for long human survival involve “SUPPOSE A MUTATION 2. This has been interpreted as show- trans-generational resource transfer. ing that aging can be manipulated INCREASES LIFESPAN ...” An older adult has reduced needs for through only a few genetic pathways herself and can contribute enough In fact, genes have been found that that are highly conserved among ani- food, safety, or other care to enhance satisfy a key requirement that an “ag- mals, and may have evolved long ago 86 Weiss CROTCHETS & QUIDDITIES

Figure 5. Telomerase complexed with proteins like TERT and dyskerin adds TTAGGG sequence caps to chromosomes. Modiﬁed after.12

as survival responses to environmen- erase does not code for a protein, but been suggested as anti-aging magic, tal stresses.9 But while natural and ex- for a type of RNA that is directly active which could backfire by making small perimental mutations in these energy- on its own, complexing with several tumors more aggressive. Cell cultures related genes in laboratory animals proteins, causing the addition of the that die, at least partly, because of loss show delayed senescence, they can repeat sequence by complementary of telomeres do not accurately mirror also have a variety of deleterious ef- base-pairing, as shown in Figure 5. natural causes of death, in part be- fects,11 some of which are also seen in A reduction of telomerase activity cause when a cell dies for that reason naturally occurring mutations in hu- and shortening of telomeres occurs in a real organism, its place is taken mans (who don’t gain the longevity with age in cultured cells and because by neighboring cells with sufficiently benefits). all cells have chromosomes, telomere long telomeres. Viewing telomerase as Probably the most highly touted ag- length has been viewed as the general a long-life gene is at least somewhat ing-related gene is one involved with calibrator of longevity, and telomere problematic. the aging of chromosomes—the very loss is associated with a number of I can’t resist adding that de Leon13 heart of life—and in particular their age-related diseases. But if this is a has recently confirmed an expected ends, or telomeres. Telomeres are true story it is a complicated one, be- neurodegenerative effect, on cogni- TTAGGG sequences concatenated in cause mice have longer telomeres tion, of variation in another aging-re- thousands of copies at the ends of (20–50 kb) but shorter lives (2–3 yrs) lated gene, ApoE. That’s not Ponce, chromosomes. These sequence caps than we do, and die, as we do, at com- but it does keep it in the family! protect the chromosomes from being parable ages relative to their lifespans If aging-related genes tell an aging chemically chewed up, as could other- whether from telomere-related dis- story, it is an incomplete story, a com- wise occur during the many rounds of eases or not. A further irony is that a plex story—and not the whole story. cell division during life. Chromo- main disease effect is that failure shut What these genes have in common is somes without telomeres cannot be down telomerase expression allows the segmental nature of their ef- replicated all the way to the ends, cells to proliferate, including cancers, fects—on some but not all age-related leading to cells that misbehave or can- the archetype of age-related diseases. changes. We see just what we should not successfully divide. The gene te- In this sense telomerase, by keeping expect: an aggregate of many genetic lomerase is a main factor responsible cells viable, might be viewed as a gene effects on different aspects of aging for installing and maintaining telo- for cellular immortality. Thus, thera- leading to a variable, largely probabi- mere sequence.12 Interestingly, telom- peutic application of telomerase has listic, gradual aging pattern. Nonethe- CROTCHETS & QUIDDITIES Ponce de Leon 87

Figure 6. Darwin’s Study in Grey: elephants on Malthusian parade (population growth at an annual rate of 2.5%).

less, these “aging” genes suggest how other forms of stress for decades, but win calculated that a single pair of life-history events could be broadly pays us back later in the form of heart elephants, the slowest of breeders, calibrated by natural selection trim- disease, hypertension, and diabetes. would produce 19 million descen- ming alleles that lead to deaths so Grants are nutrition for scientists who dants in only 750 years (he was innu- early as to affect fitness. The resulting are happy to feed the public hunger merate and changed his numbers in net species-specific aggregate of ef- for a genetic life-extension Teflon so different editions of Origin but got fects reduces the probability of sur- we can safely eat at will and smoke them wrong anyway, so Figure 6 illus- vival with age until it becomes so low like chimneys. As the Times article trates a growth rate of 2.5%). as to generate the illusion of a death- noted, if such pills were available “The That’s assuming the elephants even- switch at that age. market would be huge.” I have the tually died! The genetically engi- image of force-fed insect queens and neered near-immortality often prom- st WHEN ENOUGH IS TOO MUCH Sumo wrestlers, and that would not ised for the 21 century would be be all. Malthusian growth without Malthu- There is another point worth mak- Against the Church’s defense of an sian checks. If we think 6 bil- ing. We already have a built-in foun- Earth-centered universe, Galileo ob- lion...12 billion...18 billion im- tain of youth. This is because the main mortals on Earth would be paradise served that “Those who so greatly ex- social transfer of dotage benefits goes on Earth, even if it were possible, alt incorruptibility, inalterability, etc. the other way, from children to their we’re more deluded than Ponce de are reduced to talking this way, I be- parents when they become too old to Leon. Maybe that was why the Amer- lieve, by their great desire to go on defend or feed themselves—Golden indians met him when he arrived at living, and by the terror they have of Years on Golden Pond without any the Florida coast in 1521 to resume death. They do not reflect that if men help from our genes. Even today, a his search for eternal life—and killed were immortal, they themselves child’s death can threaten the life of him. its parents. would never have come into the We may yearn for immortality for- Life can doubtlessly be even further world.” This personal nightmare sug- ever. But because of the way evolution extended by biomedical manipula- gests the real-world tragedy that, like works, there is no simple Fountain of tion. But whether the quality of life an ET, lies within the womb of any Youth, and in the complex seasons of can be comparably extended is less Fountain-of-Youth dream. Because life, no eternal spring. clear, and Ponce de Leon’s dream is that dream incubates a Malthusian just a REM cycle away from a night- horror. Malthus estimated that un- NOTES mare. Our dietary surfeit allows us to constrained human populations were live long, healthy lives in which we capable of doubling in 25 years, an I welcome comments on this col- can survive infection, trauma, and annual growth rate of 2.5%, and Dar- umn: [email protected]. I have a 88 Weiss CROTCHETS & QUIDDITIES feedback page at http://www.anthro. Deaths: final data for 2001. National Vital Statis- 9 Arking R. 2003. Aging: a biological perspective. psu.edu/weiss lab/index.html where tics Report, US Centers for Disease Control 52. Am Sci 91:508–515. additional references can be found. I 4 Weiss KM. 1981. Evolutionary perspectives on 10 Hekimi S, Guarente L. 2003. Genetics and the human aging. In: Amoss P, Harrell S, editors. specificity of the aging process. Science 299:1351– thank John Fleagle and Anne Other ways of growing old. Stanford, CA: Stan- 1354. Buchanan for editorial assistance. ford University Press. p. 25–52. 11 Longo VD, Finch CE. 2003. Evolutionary 5 Hawkes K. 2003. Grandmothers and the evolu- medicine: from dwarf model systems to healthy tion of human longevity. Am J Hum Biol 15:380– centenarians? Science 299:1342–1346. REFERENCES 400. 12 Wong JM, Collins K. 2003. Telomere mainte- 6 Charnov EL, Berrigan D. 1993. Why do female nance and disease. Lancet 362:983–988. Many things discussed here can be primates have such long lifespans and so few 13 de Leon MJ, Convit A, Wolf OT, Tarshish CY, profitably explored by web searching. babies? Or life in the slow lane. Evolutionary DeSanti S, Rusinek H, Tsui W, Kandil E, Scherer Anthropology 1:191–194. AJ, Roche A, Imossi A, Thorn E, Bobinski M, 1 Kolata G. The drug industry’s holy grail. New 7 Kaplan H, Hill K, Lancaster J, Hurtado AM. Caraos C, Lesbre P, Schlyer D, Poirier J, Reisberg York Times 2003 November 9; Sect. 12. p 1. 2000. A theory of human life history evolution: B, et al. 2001. Prediction of cognitive decline in 2 Weiss KM. 1989. Are the known chronic dis- diet, intelligence, and longevity. Evolutionary normal elderly subjects with 2-[(18)F]fluoro-2- eases related to the human lifespan and its evo- Anthropology 9:153–185. deoxy-D-glucose/poitron-emission tomography lution? Am J Hum Biol 1:307–319. 8 Weiss KM. 1973. Demographic models for an- (FDG/PET). Proc Natl Acad Sci USA 98:10966– 3 Arias E, Anderson R, Kung H-CK. 2001. thropology. Washington. 10971.

Books Received

• Cremo, M.A. (2003) Human netic, Idiosyncratic, and Geo- Rainbow: Diversity, Gender, and Devolution: A Vedic Alternative graphic Variation in Recent Sexuality in Nature and People. to Darwin’s Theory. xxxϩ554pp. Homo, Great Apes, and Fossil Berkeley: University of Califor- Imperial Beach: Torchlight Pub- Hominids. viiϩ113pp. Oxford: nia Press. ISBN 0-520-24073-1 lishing. ISBN 0-892-13334-1 John and Erica Hedges Ltd. (cloth) $27.50. (cloth) $35.00. ISBN 1-841-71333-3 (paper) • Sussman, R.W. and Chapman, • Dumit, J. (2003) Picturing Per- £30.00. A.R. (2004) The Origins and Na- sonhood: Brain Scans and Bio- • Boaz, N.T. and Ciochon, R.L. ture of Sociality. xiiϩ340pp. medical Identity. xiiϩ251pp. (2004) Dragon Bone Hill: An Ice- Hawthorne: Aldine de Gruyter. Princeton: Princeton University Age Saga of Homo Erectus. ISBN 0-202-30731-X (paper) Press. ISBN 0-691-11398-X (pa- xviiϩ232pp. New York: Oxford $32.95. per) $19.95. University Press. ISBN 0-195- • Wallace, D. (2004) Beasts of • Leroi, A.M. (2003) Mutants: On 15291-3 (cloth) $30.00. Eden: Walking Whales, Dawn Genetic Variety and the Human • Broom, D.M. (2003) The Evolu- Horses, and Other Enigmas of Body. xvϩ431pp. New York: Vi- tion of Morality and Religion. Mammal Evolution. xviiiϩ340pp. king Press. ISBN 0-670-03110-0 xiiϩ259pp. New York: Cam- Berkeley: University of California (cloth) $25.95. bridge University Press. ISBN Press. ISBN 0-520-23731-5 (cloth) • Neal, D. (2003) Introduction to 0-521-52924-7 (paper) $28.00. $24.95. Population Biology. xivϩ393pp. • Felsenstein, J. (2004) Inferring • Wiley, A. (2004) An Ecology of New York: Cambridge Univer- Phylogenies. xxϩ664pp. Sun- High-Altitude Infancy: A Biocul- sity Press. ISBN 0-521-53223-X derland: Sinauer Associates, tural Perspective. xxiiϩ245pp. (paper) $40.00. Inc. ISBN: 0-878-93177-5 (pa- New York: Cambridge Univer- • Palmer, D. (2003) Prehistoric per) $59.95. sity Press. ISBN 0-521-83000-1 Past Revealed: The Four Billion • Finlayson, C. (2004) Neander- (cloth) $80.00. Year History of Life on Earth. thals and Modern Humans: An • Wuketits, F.M. and Antweiler, C. 176pp. Berkeley: University of Ecological and Evolutionary (2004) Handbook of Evolution: California Press. ISBN 0-520- Perspective. xϩ255pp. New Volume I: The Evolution of Hu- 24105-3 (cloth) $29.95. York: Cambridge University man Societies and Cultures. • Richards, G.D., Jabbour, R.S., Press. ISBN 0-521-82087-1 xiϩ341pp. Hoboken: John Wiley Anderson, J.Y. (2003) Medial (cloth) $85.00. & Sons. ISBN 3-527-30839-3 Mandibular Ramus: Ontoge- • Roughgarden, J. Evolution’s (cloth) $240.00.