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Confronting the boundaries of human longevity

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Unformatted text preview: Confronting the Boundaries of Human Longevity Many people now live beyond their natural lifespans through the intervention of medical technology and improved lifestyles—a form of “manufactured time” 8. Jay Olshansky, Bruce A. Carnes and Douglas Grahn lthough historical records indicate that older people have always exist- ed in human societies, survival beyond age 50 for most members of a popula— tion was a rare event until the 20th cen- tury. Today, 95 percent of all babies born in the developed world live past this age. This unprecedented survival means that almost everyone either experiences or is witness to senescence, the variety of physiological changes that accompany the passage of time. Senescence on such a grand scale arising from conditions f; - vorable for extended survival is a pro— fOundly new experience for our species and probably represents a unique phe nomenon in the history of life. We are attempting to understand why senescence and death occur when they do within populations. For example, why is the incidence of death highest be- low 1,000 days for most strains of labora— tory mice, below 5,000 days for the bea- gle and below about 30,000 days for most human beings? Why do some indi- viduals die shortly after birth while oth- 5. joy Olslianslcy is a hioileinograplier in the Depart.— inent ofMerlicine and Center on Aging, University ofCliieago. He has published numerous articles on such issues as estimating practical limits to human longevity, global population aging, mortality and the rc—eniergeiasi' ofinfi’ctioirs and parasitic diseases. Bruce A. (limes is a biologist at the Center for Mechanistic Biology and Biotechnology at Argonne National laboratory. His research interests include biatleinography, suroirnl analysis anaI the inter- species prediction of mortality patterns. Douglas Grain-i is a senior biologist at the Center fiir Mecha— nistic Biology and Biolecliriolofl at Amen-ire. l-t'is re— seairli interests include mammalian naiiatioii genet— ins and radiation toxicology. Address for Olslianslni: Department of Medicine, University of Chicago, 584.1 South Maryland Avenue, Chicago, it. 60637. lnlernet: [email protected]'caqoeiiti. 52 American Scientist, Volume 86 ers live to a ripe old age? Why does the risk of death for human beings and other species decline to its lowest point at sex- ual maturity, and then increase along a predictable path thereafter? Could these regularities in the timing of death reflect a "law of mortality” that might explain why species differ in how long they live and why some members of the same species live longer than others? If a law of mortality does exist, an even more in— triguing question is whether it can be modified (or perhaps has already been altered) so that individuals live beyond their biological potential. The Law of Mortality In 1825 a British actuary, Benjamin Gompertz, discovered a consistent age pattern in human mortality statistics. He found that the probability of dying was high at birth, declined rapidly during the first year of life, continued declining until the age of sexual matu— rity and then increased thereafter at an exponential rate until very old age. Gompertz and others speculated that the exponential rise in the risk of death following sexual maturity was the re— Sult of a law of mortality—a natural and inevitable phenomenon character- ized by “a deterioration, or an in— creased inability to withstand destruc— tion” as one grows older. One hundred years after Compertz’s discovery, scientists began looking for a “universal” law of mortality that ap- plied to all living things. Despite great differences in longevity, species were thought to have a similar pattern in their age distribution of death. Our re search, conducted by a team of scien— tists at Argonne National Laboratory and the University of Chicago, suggests that not only may a law of mortality ex- ist, but that the lifespan of sume people may have already exceeded the limits implied by such a law—a product of survival time manufactured by medical technology and lifestyle modifications (Carries, Olshansky and Grahn 1996}. Why Not Immortality? Questions concerning why senescence exists, when it occurs and what biologi— cal processes may be responsible for how it happens have been the focus of con- siderable attention in the field of evolu— tionary biology (Finch 1990, Rose 1991). We have been interested in determining whether the evolutionary logic used to explain the senescence of individuals has implications for patterns of mortality that are observed in populations. Our re— search in this area has led us to suggest that the evolutionary forces thought to be responsible for the senescence of indi— viduals have left a detectable imprint on the schedule of agesspecific death rates for populations. We call this imprint an intrinsic mortality signature and believe it to be as characteristic of a species as the species” physical appearance. One of the earliest attempts at a Dar— winian explanation for the duration of life was provided by biologist August Weismann (1891). Weismann adhered to the traditional views of his time when he described the “purpose of life“ for an individual as "the attainment of maturity and the reproduction of the species." The replacement of older indi— viduals by younger ones (reproduction) was viewed as necessary for the good of the species, because as individuals age they cannot avoid a progressive ac- cumulation of debilitating bodily in- juries that arise from a never—ending Figure 1. Death may strike at any stage of human life by various means and with differing degrees of effectiveness. The authors explore the in- teraction between the life-history strategy of our species, as sculpted by natural selection, and medical interventions and alternative lifestyles, which affect human survival. In this painting, dating from the late 19th century, infants, young children and the elderly are easily killed by the accurate aim of Death (using respectively a skull, a machine gun and a rifle), whereas adolescents and the middle-aged are killed in relatively smaller proportions by less accurate weapons (a bow and arrow and a musket). The abrupt end to the bridge implies a biological limit to the hu- man lifespan. The painting, entitled The Bridge of Life, was commissioned by the British statistician Karl Pearson. (From Pearson 1897.) barrage of environmental damage ac- quired during the course of life. Weis- mann noted that reproductive cells ap- pear to have a "power of reproduction” that is without limit (immortality), whereas the cells of the body (somatic cells) possess an existence that is limit- ed by a fixed number of cell genera- tions (known today as the Hat/flick lim- it). He went on to argue that although it “may be but poor consolation to the conscious individual,” the immortality of the reproductive cells means that death for individuals should be expect— ed once reproduction “ensured the preservation of the species.” Although his conclusions were couched in group- selection arguments, Weismann was one of the first biologists to explicitly link the necessity of reproduction with the utility of death for individuals. Theories based on group selection and “good'of-thc-species" arguments are no longer invoked by evolutionary biolo— gists (Carnes and Olshansky 1993). In- stead, modcrn theories of senescence in- variably revolve around the influence that natural selection can have on the timing of gene expression—a concept ruravailable to Weismann in the 19th cen- tury. Selection is now viewed as a process by which the frequency of favor— able variants of a gene (alleles) increase in a population at the expense of unfa- vorable alleles. The changes in frequency are brought about by differences in the survival and reproductive success of the individuals carrying the alleles. The ability of natural selection to influ- ence the relative abundance of a particu- lar allele in a population, whether favor— able or unfavorable, depends on when in the lifespan it is expressed. For example, an allele that causes the death of an indi- vidual before sexual maturity would or- dinarily be quickly eliminated from a population, except in the case of harmful or lethal alleles that “hide” from natural selection by being paired with a normal allele (a condition referred to as heterozy- gosity). Genes responsible for lethal dis— eases such as Huntington’s chorea and ataxia can also evade the influence of se- lection because by the time they are typi— cally expressed (the fourth and fifth decades of life), these genes have already been passed on to the next generation through progeny produced earlier. This interplay between when a gene is ex— pressed and its ability to be represented in the next generation creates a gradient of decline for the effectiveness of natural selection during the characteristic age range of reproduction for a species (Pigmr' 2). This concept is the foundation for most modern evolutionary theories of why senescence exists and when in the lifespan it should be observed. Restricting the influence of natural selection to only a portion of the poten- tial lifespan has led evolutionary biolo- gists to speculate on how senescence 1998 ,Ia11uary-—Fcbrrmr'y 53 'Pre' -. reproductive ' period ' ' IonI —-—» high human age [years] l I of” / / f ./ Figure 2. Effectiveness of natural selection declines as an individual achieves reproductive suc~ cess. Evolutionary perspectives on aging view senescence as an inadvertent consequence of ex- tending survival beyond the post-reproductive period, where the organism becomes “evolu- tionarily disposable." [Adapted from Cames, Olshansky and Crahn 1996.) might have arisen. Evolutionary biolo— gist George Williams has argued that it should be possible for alleles with harmful effects (when expressed late in life) to accumulate in a population if they enhance survival and reproductive success early in life (Williams .1957). The late Sir Peter Medawar of the University of London described the post—reproduc- tive period of the lifespan as a genetic “dustbin” for the expression of genes whose harmful effects during this peri— od are beyond the reach of natural se- lection (Medawar 1952). Under normal survival conditions, the harmful effects of these genes would not be observed because most animals die either before or shortly after reproducing. Thomas Kirkwood of the University of Man— chester has noted that immortality of the individual would not even be evo— lutionarily desirable if the physiological costs required for such extended sur- vival were not translated into greater re— 1.0 H AustraliaO” _ Japan Q 0-3 _ h.— Neiherlands OZ fl — Sweden Q gm _ United States 0” a G) a 0.4 — / E m g . 0.2 — I ::/,::7 it | l | ' productive output (Kirkwood 1992). Thus, like Weismaim before them, mod- ern evolutionary biologists link senes— cence to reproduction and conclude that senescence may simply be an inadver— tent consequence of survival extended into the post-reproductive period where the individual becomes disposable. Racing to the Checkered Flag A simple analogy to the longevity of an Indianapolis 500 race car will make the evolutionary theories of senescence easi~ er to understand. In this case, the length of the race is known beforehand. Given the importance of the race and the huge financial investments made in these cars, the racing teams strive to engineer a car so that even its weakest link will operate for at least 500 miles. Because these cars are not operated beyond the end of the race, the failure of parts after 500 miles is neither observed by the mechanics nor important to the engineers. Now we will conduct a thought ex— periment. Instead of ("timing the engines off at the end of 500 miles, we will con— tinue the race until every car fails. Seine cars will fail almost immediately, a handful of “’Methuselah" cars will con- tinue. to operate well beyond the end of the race, and. the remainder will break down somewhere between these two extremes. By operating the cars beyond the normal duration of the race we have created. the opportunity to see things go wrong that would not ordinarily be ob— served—giving rise to a pattern of fail- ure times that is remarkably similar to that observed for living organisms. Several observations follow from this example. First, damage is an unavoid- able price paid for operating a mechani— cal device. Second, an investigation of the cars will reveal that damage tends to accumulate in a few crucial parts—what might be called. the weak links. This oc— curs because the nature of the race im— poses a similar engineering strategy on the developers of the cars and because the weak links typically involve a limit— ed number of parts (such as tires, pis- tons and so on) that require continuous movement and contact with the envi— ronment. Third, the failure times of the cars will vary not only because of subtle differences in engineering but also be- cause of damage to parts that arises ran— domly. Fourth, there is no advantage to engineering an immortal race car be- cause the cost of doing so would be enormous (perhaps impossible) and un- necessary under normal conditions be— cause the engines are turned off once the race is over. Finally, it is important to re— alize that the cars are not intentionally Figure 3. Lowest intrinsic mortality rates (for deaths caused by genetic damage that is inherited or endogenously acquired) are observed at the on— set of sexual maturity, suggesting that natural selection has sculpted our species’ life-history strategy. 54 American Scientist, Volume so Owen l"('mlkt':il,-"C(.\l'bi5 0 msfil‘ifn" "ti" fixaifli reproducfive success death Figure 4. Life-history strategy of a species can be likened to a car race. Neither race cars nor biological organisms are intentionally engineered to fall apart, they are simply not designed to run indefinitely beyond the end of the race. Intrinsic failures and unrepaired or improperly repaired darn- age that accumulates over the course of the race ultimately account for the demise of race cars and individuals. engineered to fall apart—they are sim- ply not designed to run indefinitely be— yond the end of the race. Now let us extend the race-car analo- gy to species that reproduce sexually (Figure 4). The engineer is natural selec— tion and the end of the race is a mea- sure of time rather than distance. From an evolutionary perspective, the race is to reproduction, which includes a time for the production of offspring, a possi— ble child-rearing period and for snow species (for instance human beings) a grandparentng period where parental contributions can be made to the repro— ductive success of their own offspring. However, in order to even have a chance to participate in this race, organ- isms must reach the age of sexual matu— rity. From conception to sexual maturity, there are biological clocks that have been molded by natural selection to govern the tempo of growth and devel- opmental processes. These genetically controlled events are reminders of a carefully orchestrated set of biological processes—collectively referred to as a life—history strategy—that evolved in re— sponse to environmental conditions that prevailed when the species arose. It is a genetic legacy from the past carried by virtually every member of a species, in— cluding our own. What happens in our thought expen iment when we create conditions that permit most members of a species to survive beyond the age range normally experienced—that is, beyond the end of the reproductive period? First, the genetic uniqueness of individuals and the random accumulation of damage (both genetic and physical) will com— bine to create a distribution of failure times. Some members of the popula- tion will die before sexual maturity, a handful of Methuselahs will live to ex— treme old age, and most will die some- where between these two extremes. Second, as with a mechanical device, the accumulation of damage is an un— avoidable price that must be paid for operating a living machine. Damage to molecules and tissues accrues from many sources, including the by-prod- ucts of metabolisrn, exposure to toxic agents and personal behavior. Even though some damage may be random, the basic body plan shared by mem- bers of a species ensures that vulnera- ble sites (joints, sense organs, DNA) will also be shared. Third, an immortal animal has no selective advantage be- cause under natural conditions the force of extrinsic mortality is so strong that a genetic program for immortality, even if possible, could never realize its potential. Under these conditions, a strategy based on perfect maintenance Figure 5. Reproductive success (in terms of inclusive fitness) can be increased by helping one’s children have their own children. The authors’ notion of the human reproductive period in- chides an individual’s contributions to his or her own inclusive fitness. (Photograph courtesy of Ann Williams of Durham, NC.) 1998 January—February 55 Corbis—Iiettmann incidence of death for a cohort—he young 6—— age at death —> old Figure 6. Variation in the age at death from intrinsic mortality for a cohort of individuals (con- ceived at the same time) can be largely accounted for by a combination of genetic diversity and interactions between genes and the environment. Death rates are very high in the early stages af- ter conception {in embryo, baby 1) and in the post-reproductive period of an individual’s life (baby 3). Comparatively fewer individuals in a cohort die in their youth (baby 2) or in very old age (beyond about 85 years, baby 4). and repair will always lose out to one that sacrifices long-term survival for investment in early reproduction. As in our race~car analogy, organisms are not designed by natural selection to fail. instead, sexually reproducing or— ganisms are a product of a genetic legacy that was not designed for ex- tended survival. At least for human be- ings and a few other species, our thought experiment has become a re- ality. We have entered a unique era of human history where unprecedented survival to ages rarely experienced in the past permit us to observe the con— sequences of senescence. An important part of the explanation for why senescence exists needs further elaboration. Namely, why should re— as American Scientist, Volume 86 production be restricted to only an ear- ly part of the potential lifespan of an or- ganism? The probable answer lies in the ubiquitous array of “extrinsic mor- tal i ty” pres su res—acciden ts, predation and infectious and parasitic diseases— that paradoxically have both nothing and everything to do with senescence (Carnes and Olshansky 1997). A fundamental premise of this argu— ment is that extrinsic causes of death have always been a significant source of mortality and have forced organisms to reproduce early if they are going to re- produce at all. The biological response to these forces has been a genetic pro- gram of growth and development geared toward achieving sexual maturi- ty as early as possible. Once sexual nia- turity has been achieved, extrinsic forces of mortality also define a probabilistic (as opposed. to biological) age range within which reproduction must occur. Thus, forces of extrinsic mortality have played a major role in molding the growth, development and reproductive biology of sexually reproducing species. A reproductive period circumscribed to a restricted portion of the potential lifespan has the profound effect of creat— ing a selection gradient that gives rise to an age-related pattern of gene expres— sion that manifests itself as senescence and senescent—related mortality when survival extends beyond the reproduc- tive window. Historically, senescence probably had little evolutionary signifiv cance because so few organisms ever lived long enough to experienc...
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