Ponce de Leon and the telomere of youth

CROTCHETS & QUIDDITIES

Ponce de Leon and the Telomere of YouthKENNETH WEISS

“If the drug industry has a commer-cial Holy Grail, it might be an anti-aging pill, one that would let you livelonger and prolong your youthfulvigor,” wrote Gina Kolata in a recentarticle in the New York Times.1 Geneshave recently been found that havesimilar effects on aging processes inyeast, flies, nematodes, and humans.This suggests that aging might be aneasily modifiable phenomenon andthe drug industry is eager to discoverthe magic potion for eternal youth.

Of course the icon of the search forthe Fountain of Youth is Juan Ponce,known as Ponce de Leon. A comradeof Columbus, who successfully foughtthe Moors and helped subjugate His-panola as a base for Spanish con-quests, Ponce became governor ofPuerto Rico in the early 1500s. Later,faced with age and the fading of hisglory days, he heard of crystal waters,among trees bearing golden fruittended by lovely maidens, that be-stowed eternal youth upon those whobathed in them. Who could resist? Af-ter searching in vain in the Bahamas,in 1512 Ponce followed magnolia-scented offshore breezes to what hehence named “Florida,” where hissearch also failed—but he would re-turn.

In longing for long life, Ponce de

Leon looked over the far horizon forsimple cures for death. In the scien-tific age we seek our dreams on theinner horizon of our genome, andwe’re in an age when we can stop hy-pothesizing about aging-related genesand, if they exist (unlike the Fountainof Youth), find them. But before see-ing what is now known about suchgenes, we first need to consider justwhat kind of phenomenon aging actu-ally is.

WHAT KIND OF EVOLUTIONARYPHENOMENON IS “AGING”?

The fitness associated with any traitis a life-history phenomenon. Age-spe-cific timing of reproductive maturity,fertility, and mortality determine life-time reproductive success. Life-his-tory traits are complex, because theycan be affected by selection and driftdirectly, but even traits like locomo-

tion are indirectly screened throughtheir life-history effects. One net re-sult is that species have characteristicaging rates, making questions like,“How long do dogs live?” evolutionar-ily meaningful. Perhaps the fact thatlifespan is a somewhat colloquialrather than scientific term has led tothe notion of that each species haswhat has been called a MaximumLifespan Potential (MLP), so that in-dividuals who avoid exogenous causesof death-like predation or infectionwill eventually succumb to a species-specific internal clock at its MLP,making room for a fresh generation.

We can illustrate aspects of life-his-tory evolution by the survivorshipcurve, the age-specific probability ofsurviving from birth to each age (Fig-ure 2). The impression that there is anMLP is an understandable illusion ofsuch data (Figure 2, first 2 curves).Trends in causes of mortality overtime made it seem that the survivor-ship curve was becoming “squared,”approaching a limit—the MLP—thatthe rapid acceleration of mortalityrates with age make it impossible tosurvive. The reason for the illusion,which was widely accepted by the bio-medical aging research communityuntil quite recently, was that early ex-trinsic causes of mortality like infec-tion were being reduced by publichealth measures. If we could finallyremove those causes we would havesomething rather squarish (curve C),because the remaining intrinsic agingprocesses would then predominate.

However, the MLP was far beyondages most people ever attained, so itwas always difficult for evolutionarybiologists to accept the notion, in partalso because one of its rather incredi-ble implications was that the knowncauses of death were biologically un-related to the determination of life-

Kenneth Weiss is Evan Pugh Professor ofAnthropology and Genetics, at Penn Uni-versity.

© 2004 Wiley-Liss, Inc.DOI 10.1002/evan.20008Published online in Wiley InterScience(www.interscience.wiley.com).

The explorer went to the ends of the earth looking for immortality. Did he onlyhave to go to the ends of his chromosomes?

Figure 1. Ponce de Leon in his youngeryears.

Evolutionary Anthropology 13:82– 88 (2004)

span, and without them we could alllive in good health until our MLPth

birthday.2 Aging research might notmake us immortal, but we’d at least beable to have a well-planned Last Sup-per.

Instead, and more plausibly, recentmortality data show that death ratesdo not rapidly accelerate at very oldages (Figure 2, “extended” curve D).This means that the oldest old do notdrop off suddenly, but gradually:there is no “squaring” of survivorship.The MLP vanishes—and the unrepen-tant research lobby now touts its newinsight that human life can be ex-tended indefinitely. But this too is aLeonid dream. Life expectancy andhealth at older ages have recently in-creased, in part because of life-extend-ing intervention like less physicalstress, better nutrition, drugs and vac-cines, bypass surgery, cancer chemo-therapy, bronchial ventilators, moreeffective long-term and emergencyroom care, and the like. But a visit toa senior center reveals the soberingtruth that old people are “old” inroughly the same complexity of waysas always.

Why would the idea that aging is aunified biological trait, or that therecould be a simple genetic MLP-direct-ing switch, seem plausible in the firstplace? One oft-cited reason is thatamong vertebrate species there is asystematic relationship between esti-mated lifespan and measures likemean body or brain size (Figure 3).Indeed, the same age-patterns of dis-eases that fail to support the notion ofa fixed MLP to kill us, suggest thatthere must be some common underly-ing processes that evolution (or we)might play with to preserve us.

At any given age, the absolute riskof death from different causes variesby orders of magnitude. But thechange in those risks with age are verysimilar (Figure 4); diverse causes risein risk at roughly the 5th power of age.Similar diseases strike mice, mon-keys, and men, who share largely thesame genome, yet are scaled to eachspecies’ lifespan, indicating that evo-lution may somehow calibrate theoverall rate of aging, rather than spe-cifically of death. The tapering off of

Figure 2. A survivorship history, in percent surviving from birth each succeeding age.General pattern of U.S. mortality by age in 1900, 1950, and (curve C) the continuation ofthat trend giving the appearance of a squared survivorship curve at the hypotheticalhuman MLP. Curve D shows an “extended” life history without the squaring, as has beenseen in recent years, leading to the suggestion that human life can be indefinitely ex-tended. Schematic.

Figure 3. Age and lifespan: something’s going on here. Relationship between body size andestimated lifespan among vertebrate species.

CROTCHETS & QUIDDITIES Ponce de Leon 83

some causes seen here reflects the sec-ular trends (curve D) in Figure 3 andis due, at least in part, to the differen-tial loss with age of individuals genet-ically susceptible to the various dis-eases. Thus, those who surviverepresent their own longevity, but notthat of people generally.

If these data reflect an underlyingaging process, that might account foranother curious aspect of Figure 3,that suggests that humans live longer,by an amount roughly equaling thelength of our post-reproductive sur-vival, than a mammal our size has anyright to expect. Although this couldjust be an artifact of multiple causes,the possibility of a common underly-ing cause understandably raises thehope for a Gene Therapy of Youth.

Immortality! What in the Devil’sDictionary Ambrose Bierce quippedthat people would apply on theirknees and be eternally proud to diefor, is clearly possible at the cell level.Since the germ line never ages, it

would seem obvious that the rest ofour cells, with the same genome, don’thave to wear out either. To bowdlerizeJames Hutton, a founder of moderngeology, all life today is composed ofcell lineages that are about 3–4 billionyears old, with “some vestige of a be-ginning—no prospect of an end.”

WHAT IS THE LIKELYEVOLUTIONARY EFFECT ON

AGING-RELATED GENES?

Everything here seems to cut bothways. Does evolution kill us off orkeep us going? One general theory forthe evolution of senescence is thatnothing evolved specifically to kill usoff, but that the price of genes thatgive us plenty at twenty is to becomeweighty at eighty. This is known asnegative pleiotropy, and the idea is thatgenes selected for early fitness canhave deleterious effects in later life,when events can become just a matterof wearing-out, beyond the reach of

natural selection. But wearing outdoes not explain our long post-repro-ductive persistence, and a variety oftheories and controversies, have beenadvanced for that, some in the contextof the broader evolution of primatelife-histories.4–7

Evolutionary explanations almostalways rest on the assumption that ifaging is highly organized it must havebeen molded by selective forces, andthe genes involved are routinely hy-pothesized (“Suppose a mutation in-creases lifespan; . . . ”). I think thisview of life is overdone, but it is worthconsidering the likely resulting im-pact of those forces, whatever theyare.

First, however, we should not over-interpret statistical data, especiallywith a measure like lifespan. A spe-cies-specific lifespan or MLP is the ex-tremum of a population phenomenon,whose estimation depends on samplesize. We’ve observed hundreds of mil-lions of human lifespans, vastly more

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

84 Weiss CROTCHETS & QUIDDITIES

than for other species, biasing the hu-man estimate towards the extreme ofrare genotype or luck relative to whatwe’ve observed for other species.Though above the trend in Figure 3,we’re not dramatically longevous forour body size, no more aberrant thanrhesus, reindeer, and African buffalo,for whom no special evolutionary ex-planations have seemed necessary. Soat least some of the excess might besimply a sample size artifact.

Another potential illusion is thateven the modest post-reproductivesurvival found in contemporary tribalcultures may be misleadingly long, be-cause they probably have far bettercultural protection (arrows, sharperstone blades, metal, agriculture,maybe even antibiotics or antimalari-als) than was available when our lifehistory evolved. Studies of traits likehominid fossil dental eruption suggestthat our maturation rates evolved longago, but this need not apply at theother end of life when selection wasweaker. And if the historical, anthro-pological, and fictional literature isany guide, in prior times people werewidely seen as pretty worn out bytheir 50s. I’ve been reading Don Quix-ote, in which the Don is described as“about fifty years old, of a strong com-plexion, dry flesh, and a witheredface.” Yet people from all cultures liv-ing in modern environments like, say,Mohawks in Toronto (or knights of LaMancha in La Mancha), stay equallyfit, for equally long. As anthropolo-gists we should keep in mind the trapof viewing the world through our owncultural lenses; for example, we rou-tinely apply skin cosmetics to prevent“premature” aging. The difference be-tween what is possible and what actu-ally occurred or was selected for in thepast is an important distinction inevolutionary biology that may well ap-ply here. The fact that Bonzai treescan be made does not mean treesevolved to be tiny.

How old was old in days of old isdebatable,5,7,8 but the question is whathappens to those who do live to beold, and the most prevalent explana-tions for long human survival involvetrans-generational resource transfer.An older adult has reduced needs forherself and can contribute enoughfood, safety, or other care to enhance

the chances, and hence evolutionaryfitness, of her children or grandchil-dren.5 Trans-generational resourcetransfer is undeniable, but only a frac-tion of fitness remains in the Darwin-ian arena by the ages at which it oc-curs. Although the overall heritabilityof longevity in humans is about 25%,showing that there is potentially rele-vant variation, that heritability de-clines with age: genetic effects areweakest at the ages when trans-gener-ational effects are most important.And as to the human specificity of ag-ing, baboons have roughly the sameheritability, in both sexes, and asin other mammals the pattern ofsenescence in baboons resemblesthat in humans, despite very differ-ent lifespans.

The transfer of resources to the nextgeneration involves not the direct fit-ness of a parent, but her inclusive—indirect—fitness achieved via otherswho bear her genes. But her specificselective advantage would be less thanit might seem because small localdemes consisted mainly of cousin-likekin, who care for a woman’s childrenif she dies, and communal necessitymakes hunter-gatherers share re-sources like food, defense, tool-mak-ing technology, and so on. Ultimatelyculture is enabled by genes, but in thesearch for a biomedical elixir ofyouth, we seek a genetic cause of thebiology of aging itself, not of the cul-ture that protects old people.

For these reasons, late-age selectioneffects were probably weak, and ifmany different genes contribute tolongevity, the net selective advantageat any one of them would have beeneven smaller. In our small ancestralpopulations this means that geneticdrift would have been a stronger, ifnot predominant effect on the fre-quencies of alleles related to late-agesurvival. This high genetic noise-to-signal ratio in turn means that weshould not expect the kind of simplegenetic aging mechanism—the phar-maceutical dream—that one mightexpect after rapid, strong selection.But what do we actually find?

“SUPPOSE A MUTATIONINCREASES LIFESPAN . . .”

In fact, genes have been found thatsatisfy a key requirement that an “ag-

ing” gene should affect underlyingprocesses we associate with gettingold. The first genes known to affectaging probably were those causingnumerous progerias, including Down’ssyndrome. Progerias commonly affectconnective tissue, which is found inskin, bone, muscle, heart, and bloodvessels, and by affecting multipletraits in similar ways can appear toaccelerate general aging.

Free oxygen radicals, or oxidants,interact with cellular componentscausing damage to any tissue, includ-ing mutations in DNA, damage thataccumulates with age.9 Various dis-eases, especially cancer, have beenthought to be accelerated by suchdamage. Dietary antioxidants havebeen thought to reduce a variety ofsuch diseases and hence general agingrates, and oxidant-scavenging genesare viewed as longevity-promotingcandidates.

In a wide variety of experimentallaboratory animals, and probably hu-mans, modest restriction of dietarycaloric intake increases the length oflife (maybe the secret is not to seek theFountain of Youth but to shun theSoda Fountain). Some genetic mech-anisms are known that probably con-tribute to this observation. In re-sponse to calorie intake, genes in theinsulin-like, pituitary, and related hor-monal signaling systems can shuntmetabolic energy either to growth andreproduction or, when suppressed, toextended lifespan. Genes in the Sir-tuin gene family10 indirectly affectthese pathways by modifying the his-tone proteins that package DNA, af-fecting gene expression. One sirtuin,Sir2, affects yeast lifespan through ef-fects on mating and cell division cy-cles, and in some species Sir2 affectsexpression in the insulin-like system.A human homolog, SIRT1, affects thecell cycle and programmed cell death.

In laboratory animals the senes-cence-delaying effects of mutations inthese genes resemble the empirical ef-fects of calorie restriction: stretchingout the survivorship curve to morelike the “extended” curve D in Figure2. This has been interpreted as show-ing that aging can be manipulatedthrough only a few genetic pathwaysthat are highly conserved among ani-mals, and may have evolved long ago


as survival responses to environmen-tal stresses.9 But while natural and ex-perimental mutations in these energy-related genes in laboratory animalsshow delayed senescence, they canalso have a variety of deleterious ef-fects,11 some of which are also seen innaturally occurring mutations in hu-mans (who don’t gain the longevitybenefits).

Probably the most highly touted ag-ing-related gene is one involved withthe aging of chromosomes—the veryheart of life—and in particular theirends, or telomeres. Telomeres areTTAGGG sequences concatenated inthousands of copies at the ends ofchromosomes. These sequence capsprotect the chromosomes from beingchemically chewed up, as could other-wise occur during the many rounds ofcell division during life. Chromo-somes without telomeres cannot bereplicated all the way to the ends,leading to cells that misbehave or can-not successfully divide. The gene te-lomerase is a main factor responsiblefor installing and maintaining telo-mere sequence.12 Interestingly, telom-

erase does not code for a protein, butfor a type of RNA that is directly activeon its own, complexing with severalproteins, causing the addition of therepeat sequence by complementarybase-pairing, as shown in Figure 5.

A reduction of telomerase activityand shortening of telomeres occurswith age in cultured cells and becauseall cells have chromosomes, telomerelength has been viewed as the generalcalibrator of longevity, and telomereloss is associated with a number ofage-related diseases. But if this is atrue story it is a complicated one, be-cause mice have longer telomeres(20–50 kb) but shorter lives (2–3 yrs)than we do, and die, as we do, at com-parable ages relative to their lifespanswhether from telomere-related dis-eases or not. A further irony is that amain disease effect is that failure shutdown telomerase expression allowscells to proliferate, including cancers,the archetype of age-related diseases.In this sense telomerase, by keepingcells viable, might be viewed as a genefor cellular immortality. Thus, thera-peutic application of telomerase has

been suggested as anti-aging magic,which could backfire by making smalltumors more aggressive. Cell culturesthat die, at least partly, because of lossof telomeres do not accurately mirrornatural causes of death, in part be-cause when a cell dies for that reasonin a real organism, its place is takenby neighboring cells with sufficientlylong telomeres. Viewing telomerase asa long-life gene is at least somewhatproblematic.

I can’t resist adding that de Leon13

has recently confirmed an expectedneurodegenerative effect, on cogni-tion, of variation in another aging-re-lated gene, ApoE. That’s not Ponce,but it does keep it in the family!

If aging-related genes tell an agingstory, it is an incomplete story, a com-plex story—and not the whole story.What these genes have in common isthe segmental nature of their ef-fects—on some but not all age-relatedchanges. We see just what we shouldexpect: an aggregate of many geneticeffects on different aspects of agingleading to a variable, largely probabi-listic, gradual aging pattern. Nonethe-

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


less, these “aging” genes suggest howlife-history events could be broadlycalibrated by natural selection trim-ming alleles that lead to deaths soearly as to affect fitness. The resultingnet species-specific aggregate of ef-fects reduces the probability of sur-vival with age until it becomes so lowas to generate the illusion of a death-switch at that age.

WHEN ENOUGH IS TOO MUCH

There is another point worth mak-ing. We already have a built-in foun-tain of youth. This is because the mainsocial transfer of dotage benefits goesthe other way, from children to theirparents when they become too old todefend or feed themselves—GoldenYears on Golden Pond without anyhelp from our genes. Even today, achild’s death can threaten the life ofits parents.

Life can doubtlessly be even furtherextended by biomedical manipula-tion. But whether the quality of lifecan be comparably extended is lessclear, and Ponce de Leon’s dream isjust a REM cycle away from a night-mare. Our dietary surfeit allows us tolive long, healthy lives in which wecan survive infection, trauma, and

other forms of stress for decades, butpays us back later in the form of heartdisease, hypertension, and diabetes.Grants are nutrition for scientists whoare happy to feed the public hungerfor a genetic life-extension Teflon sowe can safely eat at will and smokelike chimneys. As the Times articlenoted, if such pills were available “Themarket would be huge.” I have theimage of force-fed insect queens andSumo wrestlers, and that would notbe all.

Against the Church’s defense of anEarth-centered universe, Galileo ob-served that “Those who so greatly ex-alt incorruptibility, inalterability, etc.are reduced to talking this way, I be-lieve, by their great desire to go onliving, and by the terror they have ofdeath. They do not reflect that if menwere immortal, they themselveswould never have come into theworld.” This personal nightmare sug-gests the real-world tragedy that, likean ET, lies within the womb of anyFountain-of-Youth dream. Becausethat dream incubates a Malthusianhorror. Malthus estimated that un-constrained human populations werecapable of doubling in 25 years, anannual growth rate of 2.5%, and Dar-

win calculated that a single pair ofelephants, the slowest of breeders,would produce 19 million descen-dants in only 750 years (he was innu-merate and changed his numbers indifferent editions of Origin but gotthem wrong anyway, so Figure 6 illus-trates a growth rate of 2.5%).

That’s assuming the elephants even-tually died! The genetically engi-neered near-immortality often prom-ised for the 21st century would beMalthusian growth without Malthu-sian checks. If we think 6 bil-lion . . . 12 billion . . . 18 billion im-mortals on Earth would be paradiseon Earth, even if it were possible,we’re more deluded than Ponce deLeon. Maybe that was why the Amer-indians met him when he arrived atthe Florida coast in 1521 to resumehis search for eternal life—and killedhim.

We may yearn for immortality for-ever. But because of the way evolutionworks, there is no simple Fountain ofYouth, and in the complex seasons oflife, no eternal spring.

NOTES

I welcome comments on this col-umn: [email protected]. I have a

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


feedback page at http://www.anthro.psu.edu/weiss lab/index.html whereadditional references can be found. Ithank John Fleagle and AnneBuchanan for editorial assistance.

REFERENCES

Many things discussed here can beprofitably explored by web searching.

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Deaths: final data for 2001. National Vital Statis-tics Report, US Centers for Disease Control 52.

4 Weiss KM. 1981. Evolutionary perspectives onhuman aging. In: Amoss P, Harrell S, editors.Other ways of growing old. Stanford, CA: Stan-ford University Press. p. 25–52.

5 Hawkes K. 2003. Grandmothers and the evolu-tion of human longevity. Am J Hum Biol 15:380–400.

6 Charnov EL, Berrigan D. 1993. Why do femaleprimates have such long lifespans and so fewbabies? Or life in the slow lane. EvolutionaryAnthropology 1:191–194.

7 Kaplan H, Hill K, Lancaster J, Hurtado AM.2000. A theory of human life history evolution:diet, intelligence, and longevity. EvolutionaryAnthropology 9:153–185.

8 Weiss KM. 1973. Demographic models for an-thropology. Washington.

9 Arking R. 2003. Aging: a biological perspective.Am Sci 91:508–515.

10 Hekimi S, Guarente L. 2003. Genetics and thespecificity of the aging process. Science 299:1351–1354.

11 Longo VD, Finch CE. 2003. Evolutionarymedicine: from dwarf model systems to healthycentenarians? Science 299:1342–1346.

12 Wong JM, Collins K. 2003. Telomere mainte-nance and disease. Lancet 362:983–988.

13 de Leon MJ, Convit A, Wolf OT, Tarshish CY,DeSanti S, Rusinek H, Tsui W, Kandil E, SchererAJ, Roche A, Imossi A, Thorn E, Bobinski M,Caraos C, Lesbre P, Schlyer D, Poirier J, ReisbergB, et al. 2001. Prediction of cognitive decline innormal elderly subjects with 2-[(18)F]fluoro-2-deoxy-D-glucose/poitron-emission tomography(FDG/PET). Proc Natl Acad Sci USA 98:10966–10971.

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• Dumit, J. (2003) Picturing Per-sonhood: Brain Scans and Bio-medical Identity. xii�251pp.Princeton: Princeton UniversityPress. ISBN 0-691-11398-X (pa-per) $19.95.

• Leroi, A.M. (2003) Mutants: OnGenetic Variety and the HumanBody. xv�431pp. New York: Vi-king Press. ISBN 0-670-03110-0(cloth) $25.95.

• Neal, D. (2003) Introduction toPopulation Biology. xiv�393pp.New York: Cambridge Univer-sity Press. ISBN 0-521-53223-X(paper) $40.00.

• Palmer, D. (2003) PrehistoricPast Revealed: The Four BillionYear History of Life on Earth.176pp. Berkeley: University ofCalifornia Press. ISBN 0-520-24105-3 (cloth) $29.95.

• Richards, G.D., Jabbour, R.S.,Anderson, J.Y. (2003) MedialMandibular Ramus: Ontoge-

netic, Idiosyncratic, and Geo-graphic Variation in RecentHomo, Great Apes, and FossilHominids. vii�113pp. Oxford:John and Erica Hedges Ltd.ISBN 1-841-71333-3 (paper)£30.00.

• Boaz, N.T. and Ciochon, R.L.(2004) Dragon Bone Hill: An Ice-Age Saga of Homo Erectus.xvii�232pp. New York: OxfordUniversity Press. ISBN 0-195-15291-3 (cloth) $30.00.

• Broom, D.M. (2003) The Evolu-tion of Morality and Religion.xii�259pp. New York: Cam-bridge University Press. ISBN0-521-52924-7 (paper) $28.00.

• Felsenstein, J. (2004) InferringPhylogenies. xx�664pp. Sun-derland: Sinauer Associates,Inc. ISBN: 0-878-93177-5 (pa-per) $59.95.

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Rainbow: Diversity, Gender, andSexuality in Nature and People.Berkeley: University of Califor-nia Press. ISBN 0-520-24073-1(cloth) $27.50.

• Sussman, R.W. and Chapman,A.R. (2004) The Origins and Na-ture of Sociality. xii�340pp.Hawthorne: Aldine de Gruyter.ISBN 0-202-30731-X (paper)$32.95.

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• Wiley, A. (2004) An Ecology ofHigh-Altitude Infancy: A Biocul-tural Perspective. xxii�245pp.New York: Cambridge Univer-sity Press. ISBN 0-521-83000-1(cloth) $80.00.

• Wuketits, F.M. and Antweiler, C.(2004) Handbook of Evolution:Volume I: The Evolution of Hu-man Societies and Cultures.xi�341pp. Hoboken: John Wiley& Sons. ISBN 3-527-30839-3(cloth) $240.00.


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Ponce de Leon and the telomere of youth