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: sjayo@ciceio.spc.uclu'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 experience its ef— fects. l'lowever, evolutionary neglect during the post-reproductive period has enormous societal and health conse— quences for a species that, by learning to control the very forces that have shaped its biology, has a population that is ex- panding rapidly into this rarely explored older region of the lifespan (Olshansky, Centres and Cassel 1993). So far we have provided a generic recipe for senescence with ingredients that include extrinsic causes of mortali- ty, a circumscribed reproductive period and a selection gradient. If we follow this recipe, why is it that some members of a population die young while others live to old age? The answer lies in the genetic variation that inevitably arises from sexual reproduction. A pool of ge netic diversity can be an adaptive bonus for a population living in a potentially hostile and rapidly changing environ— ment. However, genetic diversity also means that for any given time and place, some individuals are better suited to that time and place than others. Thus, as natural selection sifts through the ge netic diversity provided by Sexual re- production, soine individuals will in— evitably die young while others have the potential to live to older ages. Empirical Tests for a Law of Mortality In the early pa rt of the 20th century, bi- ologist Raymond Pearl was searching for a “universal law of mortality" that would extend to other species the con— sistent age pattern of death described for people by Benjamin Gompertz in 1825. Eventually, Pearl was forced to give up his search for a law because the mortality data he worked with did not contain the pathology information needed. to distinguish causes of death that were aging-related from those that were environmentally influenced. A unique collection of mortality data at Argonne National Laboratory for a variety of mouse strains, the beagle and a well—studied human population al- lowed us to continue Pearl’s search for a “law of mortality” In so doing, we tried to meld together concepts that have been developed over the past 172 years by biologists and demographers who were la rgely u nawa re of their common interests and insights on this issue. Using the pathology diagnoses con— tained within the Argonne data, causes of death for the three species were parti— tioned into what we called intrinsic (ge- netically based) and extrinsic (environ— mentally influenced) mortality. Such a step was simply not available to Pearl. in the early 20th century and most of the scientists who followed him. Several predictions arose from our comparative study of these mortality data {Ct-1151165, Olshansky and Grahn 1996). First, species possess a character- istic schedule of age-specific death rates associated with intrinsic mortalityw what we call an intrinsic mortality sig— nature. Second, intrinsic mortality sig- natures are normally hidden by a high incidence of extrinsic mortality that pre— cludes survival past youth for most members of a species. Third, the intrin- sic mortality signature of a species should remain invariant over time even though. mortality pressures from extrin— sic causes of death may vary. Fourth, a common intrinsic mortality signature should be revealed when species are compared on a biologically comparable time scale. This happens because the in— trinsic mortality signature is an evolu— tionary imprint arising from the univer- sal action of natural selection that imposes a link between the reproduc- tive biology of a species and the dispos~ at time of individuals in a population. An unintended experiment permitted us to test the first three predictions. Ani— mal studies involving laboratory mice were conducted at Argonne over a 50— year period from l945 to 1995. In the ea r— ly years of these studies, infectious dis~ eases would periodically sweep through the animal colony, taking a heavy death toll. As better tech niques for animal hus— bandry became available, dramatic gains in survival were achieved as deaths Caused by infectious diseases were near- 1y elirnina ted. As a consequetioe, the sur- vival curves based on all causes of death for these two populations of the same mouse strain look totally different. A much different picture emerges when the survival curves are estimated for in— trinsic causes of death. Now, as predict- ed, the survival moves are so similar that they can be represented by a single curve (Figure 7). This is consistent with the no- tion that an intrinsic mortality signature does indeed exist. For the fourth prediction, we made the assumption that the forces of selec- tion would cause the median age at death from intrinsic causes to be found at a comparable point within the relative lifespan of different species. if the medi— an ag-i of intrinsic death has biological meaning, and the distribution of deaths around this median are the same for dif— ferent‘ species, then their intrinsic mortal- ity signatures should converge to a com— mon signature after the death times are normalized to the medians. We inter— preted the inability to statistically distin- guish death—rate curves estimated with adequate sampling statistics to be a re- sult consistent with Pearl’s vision of a “law of mortality” Here the one caveat is that comparable patterns of agerelated mortality across species are only expect- ed for intrinsic causes of death. Evidence for Manufactured Time Although we were technically unable to distinguish between the mortality curves 0.010 0.008 deaths/unit time 1.0 0.3 —' ‘ intrinsic— 0.6 — Improved H. survival environment curve 0.4- — cumulative survival 0'2 _ suboptimal .— " environment 0. I I | I I £280 400 600 380 1.0001.2001.400 age at death {days} Figure 'i'. Different survival curves for two pop- ulations of a genetically pure strain of mouse in different environmental conditions (blue and gm»: lines) reveal the efifect of extrinsic [or en- vironmental) causes on their death rate. The predicted rate of death from intrinsic (geneti- cally based) causes in both populations can be represented by a single curve (red line), the mouse strain’s intrinsic iirortulity signature. (From Carries, Olshansky and Grahn 1996.) of the three species (as we p1edicted), the higher death rates at older ages for hu— man beings relative to the mice and dogs bothered us (i-‘igiire 8). We had expected the mortality curves for the three species to literally fall on top of each other, just as in the unintended experiment with the mouse. Ultimately, our explanation for why the human—mortality curve ap— peared elevated provided the motivation for writing this article. a 200 300 400 50:: one too But are 1.000 age at death (mouse days) r'——1 "—“1 "_l_‘ "1—— —1 | 950 1,450 1,950 .1450 2.950 3,4'50 3,950 4,450 $30 age at death (dog days) bj—l—wfi—r—l—hW—l—fi—‘H—l—ih‘I—r—l—v-fi 1'3 30 45 60 75 90 age at death {human years) Figure 8. Cumulative death rates for human beings, dogs and mice on a biologically comparable time scale represent the intrinsic mortality signatures of the reapective species and are a graphic representation of a "law of mortal ity." The relatively higher incidence of death at the later stages of the human lifespan (light—brown shade) is evidence that medical technologies and alternative lifestyles have modified the intrinsic mortality signature of our species by extending the period of human senescence—what the authors call manufactured time. 1998 January—February 5? — Australia 0’" 1135 _ Japan O” 0.30 _ w NetherlandsQ g — Sweden Q 3 0.25 — United States 0” £0.20 — d g 0.15 — S U 010 —\ 0'05 _ KW 0——|—|—"— 1950 19m 1930 1990 year A 10 g 9— _ Japan Q E — NetherlandsOa g —— Sweden Q 2 3— ' ' g United StaiesO” g \g g W O E .g 6 — s 5 | | 1963 1970 1930 1990 year Hilllon— sch Collection rICorhis Figure 9. Decreases in the intrinsic death rates of adolescents [ages 10 to 14, top) and the mortal- ity rate doubling lime (bottom) between 1960 and 1.990 provide evidence that the intrinsic mor- tality signature of our species is being modified in certain industrialized nations. Medical tech- nologies and changes in lifestyles have greatly decreased the death rate of children. (Graphs adapted from Carries, Olshansky and Grahn 1996.) The laboratory animals used in our study were control animals from ex.— perlments conducted at Argonne Na- tional Laboratory. Although these ani— mals were well cared for and many lived to extreme old age, no heroic measures were used to extend their lives. The same. cannot be said for the human population, where medical in— terventions intended to prolong life are commonplace. Thus, the median age for intrinsic mortality used. to scale death times for people must have been overestimated relative to the median age for the mouse and the dog. in our scaling approach, this leads to an ap— parent acceleration of failure times for human beings. The intrinsicanortality curves of the three species can con— verge on one another by “reducing” the median age of intrinsic mortality for the human population. We believe that the extent to which the median age of human-death times must be re— duced is a measure of the survival time that has been manufactured. 58 American Scientist, Volume 86 An examination of other mortality data for human beings revealed a similar story: The intrinsic mortality signature of our species appears to have been modified. For example, contrary to our predictions, death rates from intrinsic causes among males and females aged 10 to 14 in various countries declined From 1960 to 1990 (Figure 9, tsp). Another standard demographic statistic, the mor— tality rate doubling time (the number of years it takes for death rates to double), also exhibited change over this time pe nod (Figure 9, bottom). The change is ow— ing largely to the relatively rapid de- crease in the mortality of young people compared to the slower decrease in the mortality of middle-aged and older peo— ple. if the death rates at younger ages stabilize and the death rates at older ages continue their decline, the mortality rate doubling- time will eventually increase— indicating a slower age progression in death rates. The change in rates indicates that the intrinsic mortality signature of human beings, something that we once thought was intractable, is being modi— fied. One of our current research efforts is to estimate the additional months and years of survival time that specific med— ical technologies add to peoples lives. This includes treatments for end—stage renal disease and early-onset diabetes, as well as chemotherapy and radiation therapy for various cancers. An intrinsic mortality signature sets lower limits to agespecific death rates— it is a mortality schedule that does not include the inevitable force of extrinsic mortality and, therefore, places upper limits on the life expectancy that are bio- logically plausible. We found that a me— dian age at death of about 83 years for human beings was required to make the intrinsic~mortality curves of the three species overlap. This is about two years lower than an empirical estimate we had made for a practical upper limit to human life expectancy (Olshansky, Carnes and Cassel “1990). Furthermore, when prevailing levels of extrinsic mor— tality are folded back into the intrinsic- mortality schedule, the resulting life ex— pectancy actually falls below those cur- rently observed in low—mortality popu— lations. if a biologically based upper limit to life expectancy exists, then in low-mortality populations such as Western Europe, japan and the United States it may have already been sur- passed rather than lying somewhere be- yond the observed longevity horizon, as commonly believed. it appeared to us that the remarkable insight Benjamin Gompertz had for hu— man mortality in 1825 could be general- ized to other species as well. Namely, that there is a consistent age pattern of death for a population of sexually re- producing organisms when survival ex— tends into the post-reproductive period of the lifespan. This pattern of mortality has been revealed only recently for our Species, as greater numbers of people survive beyond their reproductive years. It does, however, raise a paradox: lf evolutionary theories of senescence are correct and survival into the post- reproductivc period serves no useful purpose, why is human life expectancy so much greater than the age when re— production ceases? Manufacturing Survival Time Nobody knows with certainty what the life expectancy of human beings was even a few thousand years ago. However, reports of death tolls from infectious and parasitic diseases that occurred prior to the modern era of antibiotics strongly suggest that very few people lived much beyond age 50. By implication, the effective end of re— production for the vast majority of in- dividuals would have occurred at a much earlier age. Human-mediated selection experi— ments (agricultural plants, farm animals, pets) suggest that altering the genome of an organism to favor a particular trait (such as growth or milk production) can have unintended and often negative con— sequences on other aspects of the organ- ism’s biology. Ilowever, if senescence is in fact the product of evolutionary ne- glect rather than evolutionary intent, then there is every reason to be opti- mistic that the prooess is inherently mod- ifiable, an extremely important implica— tion for an aging population. Although great care will be required, it is probable that aspects of the senescent process can be modifiable either through a direct ma— nipulation of crucial. genes (rare but al- ready taking place) or more indirectly by controlling or manipulating the products of gene expression (a major focus of cur— rent biomedical research). The one cau- tionary note in this optimistic vision of a brave new world is that there may be a price to pay when only the progression or expression of senescent diseases is modified—namely, our interventions may simply shift the burden of series cence to other forms of lethal. or debilitat— ing senescent diseases. Regardless of the outcome, the su I'Vl val time purchased for individuals who would otherwise have died at younger ages is what we call manufactqu time. We contend that survival time has al- ready been manufactured by interven— ing in the expression of intrinsic diseases and disorders. Among many examples, consider the dietary modification of in~ fants born with phenylketonuria (I’KU) and medical interventions for children and young adults with early onset dia— betes, middle—aged and older adults cli- agnosed with colon cancer, end-stage re— nal disease or coronary heart disease and stroke victims. Such interventions have no doubt contributed to declines in death rates throughout the age structure of the population. In part, such declines in mortality have contributed to the most recent increases in life expectancy at birth (now approaching 80 years in some parts of the world). One reason human beings live so far beyond the end of their reproductive years may be robust engineering. Main— Figure 10. Rate of senescence can be manipulated by human behavior, much as an individual ad- justs the throttles of an aircraft composed of separate Functional systems. Some types of behavior (such as cigarette smoking] appear to accelerate senescence for an organ system, whereas omers (ex- ercise and low-fat diets} may serve to decelerate the rate of senescence. Much like an aircraft that runs out of fuel, the fate of an individual is determined by the weakest component in the system. tainng the biological integrity of an or- ganism in a hostile environment re- quires the evolution of highly effective maintenance, repair and protection processes, such as wound healing, cell replacement and DNA maintenance and repair. These mechanisms are re— markably efficient but they are not per— fect. Unrepaired damage does accumu— late over time and may be a major contributor to many of the diseases and the physiological changes of old age. Our species has become extraordinar— ily effective at creating shelters from en— vironmental extremes, providing med— ical care that converhs what would have been health crises in the past into minor inconveniences today and developing chemicals that combat many of the or— ganisms that affect human health and hygiene. Despite this technological progress, we retain a genetic legacy passed down to us from ancestors who lived under much harsher environmen- tal conditions. It is a legacy with both ad vantages and disadvantages for health and longevity. Consider the human body’s ability to store fat when excess calories are consumed. In today’ 3 world of grocery stores laden with food sup- plies, what was an adaptation for out an- cestors is now a burden that often leads to such senescent disorders as diabetes, cardiovascular diseases and artluitis. Unprecedented survival extended into the post—reproductive region of the lifespan now permits our species to ob- serve how our bodies change and dete- riorate with time. The loss of boue and muscle mass, degeneration of the macula in the eye, hearing loss, Alzheimer’s disease, prostate cancer, osteoarthritis and a host of other ail- ments that afflict today’s elderly could not have been a major problem in the past because so few individuals lived long enough to experience them. A range of inherited diseases—such as some breast and colon cancers, ataxia and late—onset diabetes, amyotrophic lateral sclerosis and familial hypercho- lesterolemia-uhave probably always 1998 Jamiary—February 59 Owen lira)! kenr’Corbis Figure 11. Medical interventions have extended the lives of many people suffering from various disorders—including kidney failure, diabetes, certain cancers, heart disease and appendicitis— that would have otherwise taken the individual's life. The extent to which biomedical advances can extend survival is as yet unknown, as are the consequences for human society of manufac- turing more survival time. been a part of the human genome, but they were largely hidden from previ— ous generations by higher mortality at younger ages. The extent of our genet- ic legacy is becoming progressively more evident as our knowledge of the effects of genes rapidly expands. Methods of manufacturing survival time that already exist may be classified into three categories: senescence accel— erators, senescence decelerators and ge— netic manipulation. Scnescence acceler— ators are behaviors or substances that hasten the aging process, with prema— ture death as a result. imagine yourself in the cockpit of an aircraft controlling a bank of throttles that permit you to ac— celerate or decelerate the usage of cm- as American Scientist, Volume 86 cial individual components of the craft. The default settings on the throttles were determined when the aircraft was constructed. Pushing any single throttle forward accelerates senescence for the specified component. When a compo— nent fails, the aircraft can no longer op- erate. identifying senescence accelera— tors and avoiding them improves the chance that an individual will survive to his or her biological potential. Known and suspected examples of senescence accelerators include cigarette smoking, radiation (such as exposure to the sun), excessive alcohol consumption, psycho— logical stress and environmental toxins. Other senescence accelerators will un- doubtedly be identified in the future. It is far easier to accelerate the aging process than to decelerate it. Acceler- ating senescence can be accomplished by pushing any one of the many throt— tles forward. Decelerating senescence, however, requires that all or at least the most crucial throttles be pulled back si— multaneously. Otherwise, the weakest system components will determine when death occurs. Moreover, there must be inherent biological constraints that place limits on how far the decel- eration throttles can be pulled back. Despite the difficulty in decelerating senescence, scientists are rapidly learn— ing how to manipulate some of the throttles that govern senescence. Mod~ ifying diets to include more antioxi— dants (natural sources like fruits and vegetables or vitamin supplements such as A, C and E) may decelerate senescence at its source—at the cellular and molecular level. Consuming more calcium during yOuth may postpone the possible effects of bone loss (osteo- porosis) by building up a larger reser- voir of bone before the loss of bone be- gins in the third decade of life. Other promising senescence decelerators in— clude pharmaceuticals that (like fruits and vegetables) either protect DNA directly or enhance natural repair processes (which is potentially impor- tant because damage to nuclear and nfitochondrial DNA has been implicated in the eventual expression of numerous senescent—related diseases and disor— ders). Bruce Ames of the University of California at Berkeley has recently shown that accumulated damage to the mitochondrial DNA of rats can even be reversed by pharmaceuticals (personal communication). Chemicals that reverse DNA dam— age, while promising, are not necessar- ily elixirs that will reverse the aging process. Hormone therapies and vita— min supplements have been heralded as the key to extreme longevity and to reversing the aging process. These claims—made by longevity gurus who make money by preying on a common fear of death—have proved to be exag- gerated. The conceptual flaw is mak- ing claims for senescence decelerators that are comparable to the longevity gains observed when senescence accel- erators are avoided. Despite numerous anecdotal stories, there is no scientific evidence to support the claim that any hormone or vitamin supplement cur~ rently on the market will have any sig- nificant affect on human longevity. The good news is that scientific re- search has confirmed that simple exer- cise is one of the best ways to maintain health and vigor, if not youth. Aerobic, weight-bearing and resistance exercises have been shown to have beneficial ef- fects on such crucial senescent "throt- tles" as the cardiovascular and immune systems. Exercise also reduces the risk of diabetes and its associated complica- tions, cuts the death rate from some forms of cancer, slows the rate of bone loss and improves mental acuity. Maria Fiatarone of Harvard University has demonstrated that muscle mass can be increased at any age, even among the extreme elderly. Simple resistance exer- cises have been shown to improve physical functioning among those with even the most severe disabilities. In the absence of a genetically controlled pro- gram for death, we are free to manipu- late our inherited senescent "throt— tles"—such as bone and muscle mass, DNA repair, cardiovascular physiology and so on—in ways that prolong youth and postpone death. A cautionary note is warranted. Our society is experiencing unprecedented rates of survival into older ages, but this success has also been accompanied by a rise in frailty and disability in the general population This is a conse- quence that neither the medical com- munity nor society was prepared for, as evidenced by the ongoing national concern over crises in the Social Securi- ty program, Medicare, Medicaid and health-care costs. Conclusion Survival time has already been manu- factured by medical and biomedical in- terventions that have, for example, ex- tended the lives of people suffering from kidney failure, diabetes and certain forms of cancer (particularly cancers ex— pressed early in life). Surgical proce- dures now considered simple (remov- ing the gall bladder or appendix) as well as more complex procedures (such as coronary bypass, cancer surgery and or- gan transplants) are manufacturing sur- vival time for individuals who would otherwise have died within a short time without the intervention. Biomedical ad- vances have already been made in tech- niques of gene therapy that extend life (introducing normal gene products, pre- venting the production of abnormal gene products, and even replacing de- fective genes themselves). There is no doubt that these advances have already had a major impact on the extension of life for some people, and there is reason to be optimistic that further gains are forthcoming. The extent and limit to which these advances can impact the av— erage life expectancy of a genetically heterogeneous population has yet to be determined Our optimism that survival time will continue to be manufactured must be tempered by the realization that many if not most of the ailments that afflict peo- ple as they age have a genetic basis. The biology of senescence ensures that there are mortality hazards lurking in the old- er regions of the lifespan our society is now exploring. It is possible that new or infrequently observed diseases and disorders could appear among future cohorts of older people as manufac- tured time permits the expression of genes that would have been precluded by death in earlier times. The amount of manufactured time required to achieve dramatic gains in life expectan- cy (above age 85) may very well require tinkering with the genetic blueprint that defines who we are as individuals and the composition of our populations—a technological advance that by its very nature precedes our ability to under- stand or cope with its consequences. Further, the re-emergence of infectious and parasitic diseases that we thought were eradicated suggests that our species has far less control over the environment than we would like to think. In fact, our efforts to control the environment, as with the introduction of antibiotics in the 19405, may have actually accelerated the evolution of more—virulent strains of mi— croorganisms that prey on our species Perhaps our greatest reason for opti- mism should lie in the recognition that the remarkable progress already made in extending survival has been accom- plished with surprisingly little knowl— edge about the biological processes that govern senescence. We have made the argument that senescence and patterns of intrinsic mortality are consequences of the evo- lution of organisms designed for repro- duction. As human beings continue to extend survival time further beyond the age of reproduction, it is possible that the diseases and disorders ex- pressed at later ages will be more debil- itating than the ones expressed at earli- er ages. lf, as we argue, the expression of senescence is inherently modifiable, increasing longevity without sacrificing health or adversely influencing the del» icate social fabric of life will be an im- portant and difficult challenge in the 21 st century. What is certain is that con— frontations between technology and medical ethics will escalate as our species continues its relentless pursuit of manufacturing more survival time. Acknowledgments Funding for this work was provided by the Department of Energy Office off-[colt]: and Environmental Research (contract No. W—31—109—ENG—38), the Social Security Administration (Grant IO—P-—98347—5-01) and the National Institute on Aging (NIH/NM Grant No. AG—0057 7—01). Bibliography Carnes, B. A., and S. I. 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The aging of the human species. Scientific American (April) 268246-52. Olshansky, S. J,, B. A. Carnes and C. Cassel. 1990. hi search of Methuselah: Estimating the upper limits to human longevity Science 250:634—640. Pearl, R., and J. R. Miner. 1935. Experimental studies on the duration of life. XlV. The com- parative mortality of certain lower organ- isms. Qimrtcrti/ Review of Biology 10:60—79. Pearson, K. 1897. The Chances of Death and Other Studies in Evolution. London: Edward Arnold. Rose, M. R. 1991. Evolutionary Biology of Aging. Oxford: Oxford University Press. Strehler, B. L., and A. S. Mildvan. 1960. General theory of mortality and aging (A stochastic model relates observations on aging, physios logic decline, mortality, and radiation). Sci~ once 132:14—19. Weismann, A. 1891. Essays Upon Heredity and Kindred Biological Pioblcins. Oxford: Claren- don Press. Williams, G. C. 1957. Pleiotropy, natural selec— tion, and the evolution of senescence. Evolu- tion 11 :298—31 1. 1998 January-February 6l ...
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