PCBE: Beyond Therapy: Biotechnology and the Pursuit of Happiness (Ageless Bodies)

The President's Council on Bioethics
Washington, D.C.
October 2003
www.bioethics.gov

Ageless Bodies

To elucidate these hopes, and to introduce these questions, we will examine some of the potential techniques for the extension of longevity and youthfulness, and some of their imaginable consequences. Our aim here, as throughout this report, is not primarily to analyze the details of the scientific prospects, or to predict which techniques might prove most effective in retarding aging. Rather we consider a range of reasonably plausible possibilities in order to discern their potential human and ethical implications.ⁱ But before we can begin to examine such possibilities, we must inquire about the underlying desire. What do we wish for when we yearn for "ageless bodies"?

I. THE MEANING OF "AGELESS BODIES"

It may at first seem strange to suggest that we yearn for an "ageless body," not a term commonly heard and certainly not the conscious and explicit longing of very many people. Still, when properly examined, something like a desire for an "ageless body" seems in fact to be commonplace and deeply held; and should our capacities to retard the senescence of our bodies increase, that desire may well become more explicit and strong.

We all know at least something of what it is to age, but perhaps we have not often enough given thought to the full place of aging in human experience, and to the significance of the nearly universal desire to defy or to stop it. We measure our age in terms of years we have lived, and in that sense there is no stopping aging. Time marches on incessantly, and we are ever dragged along right with it. But we experience aging not just as the passage of time, but rather also as the effect of that passage on us: on our bodies, our minds, our souls, and our lives. In this respect, aging has two contradictory faces. Generally speaking, our physical and mental faculties degrade as we age, but often our understanding and judgment can improve. Our bodies grow frail under the weight of the years, but our wisdom-we hope-may grow greater as our store of experience swells.

It is only the former of these facets of aging that we rebel against and seek to push away. We want still to grow wiser or at least less foolish with age, but we wish we could do it without growing weaker. We mean not so much to slow the passing of the years as merely to shield our bodies from brutal bombardment by the silent artillery of time (in Abraham Lincoln's memorable phrase). That way, we might be in a position to make more practical use of our hard-earned wisdom, and youth would not be so carelessly wasted on the young. As C.S. Lewis put it: "I envy youth its stomach, not its heart."

In this sense, it is fundamentally the aging of the body we wish to stop. Indeed, we experience bodily decline as in many respects a kind of betrayal, as our body, once youthful and vibrant, seems somehow less responsive to our will, and less capable of executing some once routine demands of daily life. We wonder, together with Shakespeare, "is it not strange that desire should so many years outlive performance?"² And this betrayal grows worse with time, and step by step we find ourselves less able and competent in many of life's activities. We feel keenly what we have irreversibly lost, and worse yet, we know that much of the strength that remains will also be lost over time.

But it is more than the dread of decline that motivates us to seek ageless bodies. The corruption of the body brought on by aging points necessarily in the direction of eventual death, and unexpected encounters with new and unfamiliar weaknesses give us glimpses of mortality we would rather avoid. The fear of death, that ultimate and universal fear, surely has a hand (even if only implicitly) in motivating the search for ways to slow the clock. Death is nature's deepest and greatest barrier to total human self-mastery. However much power and control we may come to exercise over our lives and our environments, the time in which we may exercise that power and control is finite, and awareness of that finitude must always make the power feel somehow lacking. Different human societies have had very different conceptions of the divine, but one attribute has almost universally been attached to the gods: immortality. Our subjection to death-and our awareness of this fact-is central to what makes us human ("mortals") rather than divine, and it makes us fearful and weak and constrained.

The scientific quest to slow the aging process is not explicitly aimed at conquering death. But in taking the aging of the body as itself a kind of disorder to be corrected, it treats man's mortal condition as a target for medicine, as if death were indeed rather like one of the specific (fatal) diseases. There is no obvious end-point to the quest for ageless bodies: after all, why should any lifespan, however long, be long enough? In principle, the quest for any age-retardation suggests no inherent stopping point, and therefore, in the extreme case, it is difficult to distinguish it from a quest for endless life. It seeks to overcome the ephemeral nature of the human body, and to replace it with permanent facility and endless youth.ⁱⁱ

The finitude of our power, and of our time, is part and parcel of our being embodied living creatures. An ageless body is almost a contradiction in terms, since all physical things necessarily decay over time, and so experience the passing of time in a most immediate way. To escape from time and age would be to escape from our bodily self-and the wish for this escape, too, inheres deeply in at least some forms of the desire for agelessness.

In these fundamental terms, the wish for ageless bodies and its potential fulfillment by biotechnology may be the most radical of the subjects we address in this report. It is not only an aspiration that can carry us past its usual and reasonable bounds by means of new technical powers; and it is more than a desire to be always what we are only sometimes. It is, at its core, a desire to overcome the most fundamental bounds of our humanity, and to redefine our bodily relationship with time and with the physical world.

And yet, although supremely radical, it is at the same time a perfectly routine desire, one which absolutely every one of us has often felt: watching helplessly as a loved one weakens and declines; contemplating the limits of our time here on earth; or just hearing an unfamiliar "snap" in our back as we reach up for a rebound on the basketball court or bend over to lift up a grandchild. The possibility that biotechnology might be able to significantly slow the process of aging invites us to consider carefully the meaning of this routine but radical desire.

The retardation of aging is among the most complex-both scientifically and ethically-of the potential "nontherapeutic" or "extra-therapeutic" uses of biotechnology, involving several different scientific avenues and raising deeply complicated questions for individuals and society. The moral case for living longer is very strong, and the desire to live longer speaks powerfully to each and every one of us. But the full consequences of doing so may not be quite so obvious.

II. BASIC TERMS AND CONCEPTS

Though everybody more or less knows what aging means, offering a concrete definition is no simple task. In one sense, aging just refers to the passage of time in relation to us or, put another way, it describes our passage through time. The more years we have lived, the greater our age (and with it our cumulative experience of life). In this sense, of course, it is absurd to speak of age-retardation, for by definition, only death could put a stop to our increasing years. But we mean more than this by "aging." It encompasses not only the passage of time but also (and more so) the biological processes of senescence that accompany that passage, and especially the progressive degeneration that affects the body and mind, beginning in adulthood. To clarify the discussion that follows, we offer some basic definitions for aging and related terms:

Aging: In this chapter we shall use "aging" synonymously with "senescence," rather than merely to describe the increase in the number of years a person has been alive. Aging therefore denotes the gradual and progressive loss of various functions over time, beginning in early adulthood, leading to decreasing health, vigor, and well-being, increasing vulnerability to disease, and increased likelihood of death.ⁱⁱⁱ

Life-Extension: An increase in the number of years that a person remains alive. It may be accomplished by a variety of means, including reducing causes of death among the young, combating the diseases of the aged, or the slowing down of aging. It may involve pushing back senescence or merely allowing an individual to survive into longer and deeper senescence.

Age-Retardation: The slowing down of the biological processes involved in aging, resulting in delayed decline and degeneration and perhaps also a longer life. It is one possible route to life-extension.

Lifespan: The verified age at death of an individual, and therefore the strictly chronological duration of life.

Maximum Lifespan: The longest lifespan ever recorded for a species-in humans today it is 122.5 years.

Life Expectancy: The average number of years of life remaining for individuals at a given age, assuming that age-specific mortality risks remain unchanged.

Life Cycle: The series of "stages" through which one passes in the course of life-including, among others, infancy, childhood, adolescence, adulthood, and old age; and the overall form given to the experience of life by the relations of these "stages" and the transitions between them.^iv

The desire for ageless bodies involves the pursuit not only of longer lives, but also of lives that remain vigorous longer. It seeks not only to add years to life, but also to add life to years. This double purpose is therefore likely to be better served by certain approaches to life-extension than by others. Life-extension may take three broad approaches: (1) efforts to allow more individuals to live to old age by combating the causes of death among the young and middle-aged; (2) efforts to further extend the lives of those who already live to advanced ages by reducing the incidence and severity of diseases and impairments of the elderly (including muscle and memory loss) or by replacing cells, tissues, and organs damaged over time; and (3) efforts to mitigate or retard the effects of senescence more generally by affecting the general process (or processes) of aging, potentially increasing not only the average but also the maximum human lifespan.

The first, particularly in the form of combating infant mortality (mostly through improvements in basic public health, sanitation, and immunization), is largely responsible for the great increase in lifespans in the twentieth century, from an average life expectancy at birth of about 48 years in 1900 to an average of about 78 years in 1999 in the United States (and even higher in some other developed nations-for instance, over 80 years in Japan). But this approach has been so successful that almost no further gains in average lifespan can be expected from efforts to improve the health of the young in the developed world.^v In fact, even if, starting today, no one in the United States died before the age of 50, average life expectancy at birth would increase by only about 3.5 years (from just over 78 to 82 years). The increasing lifespans of the twentieth century were an extraordinary achievement, but further significant gains in life expectancy would require a much greater feat: extending the lives of people who already make it to old age, and eventually extending the maximum lifespan.

The second approach, extending the life of the elderly by combating particular causes of death or reversing damage done by senescence, has been most actively pursued over the past several decades. In some forms, it has already contributed to the improved health of the elderly and to moderate extensions of life. Extreme old age already is, in many respects, a gift or product of human artifice, and modern medicine seems likely to make it more so and to bring further modest increases in average lifespan. But in most of its forms this approach, too, promises relatively moderate (though surely meaningful and much-desired) life-extension, even if it succeeds far beyond the most optimistic of present expectations.

For instance, if diabetes, all cardiovascular diseases, and all forms of cancer were eliminated today, life expectancy at birth in the United States would rise to about 90 years, from the present 78. This would certainly be a significant increase, but not one so great as to bring about many of the social and moral consequences that might be anticipated with significant age-retardation. It would be a much smaller increase than that achieved in the last century. Also, it would likely not have a serious impact on the maximum lifespan, with few if any people living longer than the current human maximum of 122 years.

The piecemeal character of this disease-by-disease approach contributes to what might be its most important limitation. If (on hypothesis) it would not get at the more general physical and mental deterioration that often comes with old age,^vi and which we more generally think of as "aging," it would allow individuals to live longer, but often thereby expose them further and for a longer time to the other ravages of the general process of progressive degeneration, including loss of strength, hampered mobility, memory problems, impairments of the senses, and declining mental functions and any other particular age-related declines not specifically addressed by the methods employed. Extensions of life that do not address this general degeneration consign their beneficiaries to the fate of the mythical Tithonus or the Struldbruggs in Swift's Gulliver's Travels: degeneration without end. A number of the most promising avenues of cutting-edge aging research-including those involving stem-cell research, tissue and organ replacement, and, potentially some day, nanotechnology-would likely fall into this category, as do current efforts to find treatments for cancers, heart disease, Alzheimer disease, and other ailments. Promising though these may be, their currently foreseeable applications do not seem likely to significantly extend the maximum human lifespan or to fundamentally alter the shape of the human life cycle.

Since aging is itself a major risk-factor for many of these human diseases, if aging could be slowed, the onset of these diseases might be greatly delayed or mitigated. For this reason, among others, it is the third approach-direct and general age-retardation, now being actively pursued on several paths-that, if successful, would have the most significant physical, social, and moral consequences. If successful, age-retardation could not only extend the average lifespan or slow down generalized senescence; it could extend the maximum lifespan, perhaps quite significantly. Should it succeed in doing so, it may involve heretofore-unknown changes throughout the human life cycle. Our discussion will briefly touch on two sorts of piecemeal approaches to combating senescence (muscle enhancement and memory improvement), but will then focus largely on the more generalized approach to the retardation of aging as a whole.

III. SCIENTIFIC BACKGROUND

Two piecemeal approaches to opposing or slowing two specific debilities of old age illustrate the potential of targeted techniques of combating the aging of the body, and display their differences from the more holistic efforts to retard bodily aging altogether.

A loss of strength and muscle mass is one of the most noticeable and significant signs of bodily senescence. With aging, we become more sedentary and use our muscles less, and the production of growth hormone and circulating insulin-like growth factor (IGF-1, discussed in the previous chapter) also decreases. There is thus less IGF-1 available to keep the muscles large, and they become smaller, weaker, and less easily repaired when injured. In addition, aged muscle cells are apparently less responsive to the action of IGF-1 and mIGF-1 (muscle IGF-1) so that the impact of even vigorous exercise on muscle size and strength diminishes with age.³ This age-related muscle diminution has been given a medical-sounding name: sarcopenia.

As we age, several things change that predispose us to the development of sarcopenia. We either reduce the output of, and/or become more resistant to, anabolic stimuli to muscle, such as central nervous system input, growth hormone, estrogen, testosterone, dietary protein, physical activity, and insulin action. The loss of alpha-motor neuron input to muscle that occurs with age⁴ is believed to be a critical factor⁵ since nerve-cell-to-muscle-cell connections are critical to maintaining muscle mass and strength.

A loss of muscle size and strength is a significant problem for older persons. In addition to slowing movement and hampering some activities, sarcopenia is associated with an increased tendency to fall and break bones, and such falls are major causes of morbidity among the elderly. The techniques of muscle enhancement described in the previous chapter (including the introduction of IGF-1 genes, the use of human growth hormone, and other approaches) seem likely (and in a number of cases have been shown in animals) to significantly reduce age-related loss of strength and of muscle mass.

Memory loss is another particularly agonizing consequence of senescence, disjointing the individual from his or her past, and bringing about not only a loss of function but a loss of faith in one's own senses of self and the world. Researchers have been making meaningful strides toward an understanding of memory loss-as a discrete and specific consequence of aging. Much of this work has been a by-product of the effort to understand and to treat Alzheimer disease, which first expresses itself in memory loss.

For example, researchers have discovered that cholinergic cells are "among the first to die in Alzheimer patients and that cholinergic mechanisms may be involved in memory formation."⁶ This has led to therapeutic interventions with a class of drugs called acetylcholinesterase inhibitors. These agents block the enzyme that destroys acetylcholine (a neurotransmitter that scientists believe is crucial to forming memories), with the result that acetylcholine, once released, remains in the synapse for a longer period of time. These drugs have had a real but limited effect on improving memory in some Alzheimer patients; they can slow down or moderate the effects of the disease, but they do not reverse the progressive destruction of the brain.

Memory loss is not confined to patients with Alzheimer disease, or even to the elderly. And we should not simply assume that biotechnical interventions that address or counteract the biological causes of specific memory diseases like Alzheimer would have a similar effect on other elderly individuals, or would improve memory in general. As Stephen Rose explains: "The deficits in Alzheimer Disease and other conditions relate to specific biochemical or physiological lesions, and there is no a priori reason, irrespective of any ethical or other arguments, to suppose that, in the absence of pathology, pharmacological enhancement of such processes will necessarily enhance memory or cognition, which may already be 'set' at psychologically optimal levels."⁷

Nonetheless, some evidence suggests that at least some portion of the discoveries made in research on Alzheimer disease could well prove to enhance memory in general. For instance, a recent study tested the effect of donepezil, one of the major acetylcholinesterase inhibitors, on the performance of middle-aged pilots. Pilots conducted seven practice flights on a flight simulator to train them to perform a complex series of instructions. Then half of them took the drug donepezil for thirty days, while the other half took a placebo. When the simulator test was then repeated, the pilots who had taken the drug retained the training better than those who had taken the placebo.⁸ There is also a large body of research, mostly in animals, demonstrating that "opiate receptor antagonists" may improve memory formation by stimulating the hormones that are typically released in response to emotionally arousing experiences.⁹

The remarkable complexity of the human body as a whole and the brain in particular makes it very difficult to isolate the functions of memory from other neuro-physiological processes (perception, attention, arousal, etc.) with which it is interconnected. Many "non-memory drugs" or stimulants therefore have a significant effect on memory; and many "memory drugs" have a significant effect on other bodily functions. So, for example, amphetamines, Ritalin, and dunking one's hand in freezing water have a "positive effect" on the capacity to remember new information, at least over the short term. But these drugs or experiences work on memory only indirectly, affecting not the specific memory systems but the other systems of the body that influence how the different memory systems function.^vii

Recent research in animals has also improved our understanding of certain molecular and genetic "switches" that control memory. For example, in 1990, Eric Kandel discovered that blocking the molecule CREB (c-AMP [cyclic adenosine monophosphate] Response Element Binding protein) in sea slug nerve cells blocked new long-term memory without affecting short-term memory.¹⁰ A few years later, Tim Tully and Jerry Yin genetically engineered fruit flies with the CREB molecule turned "on"; the resulting flies learned basic tasks in one try, where for normal flies it often took ten tries or more. The hypothesis is that "CREB helps turn on the genes needed to produce new proteins that etch permanent connections between nerve cells," and that it is "in these links that long-term memories are stored."¹¹ These exciting discoveries have already launched several new pharmaceutical companies formed specifically to develop potential drugs based on this research. In 1999, another group of researchers succeeded in genetically engineering mice that learn tasks much more readily. They inserted into a mouse embryo a gene that caused over-expression of a specific receptor in the outer surface of certain brain cells, "long suspected to be one of the basic mechanisms of memory formation" because it allows the "brain to make an association between two events."^viii ¹²

Though exciting, all of this work is very preliminary; and its significance for producing biotechnologies that might preserve or enhance human memory remains to be determined. So far, there seems to be no efficacious "silver pill" or "golden gene" for producing better memories, never mind one without any countervailing biological costs. But the work continues, and its potential ought not be dismissed.

Piecemeal interventions to combat sarcopenia, memory loss, or any other specific aspect or consequence of aging and senescence may of course have profound implications for the way human beings age. But inasmuch as they mitigate one element of aging while further exposing the individual to others, their overall result may not be simply attractive: Longer life with improved muscles but with unimproved or ever-weaker memories might well be undesirable. In any case, the contribution of these piecemeal interventions to longer, more vigorous life is unlikely to be as profound as that of some potential approaches to the systematic (body-wide) retardation of aging.

An even more significant potential route to nearly ageless bodies involves the body-wide retardation of the aging process, now being pursued by some researchers. The concept of general age-retardation presumes the existence of a general organism-wide process of aging, as opposed to a series of unconnected processes of degeneration that would have to be treated separately. For aging as a whole to be slowed, there must be such a thing as "aging as a whole." Its existence has been debated by biologists for many years, but over the last two decades experimental evidence has increasingly suggested that a unified process of senescence does indeed exist. There is still no clear empirically supported theoretical concept of just how aging works, but evidence has shown that a number of techniques appear to affect the aging of a wide variety, if not indeed all, of the body's organs and systems. Sharp decreases in caloric intake and a number of genetic interventions in animals (both of which will be discussed in greater detail below) have been shown to have dramatic effects not only on longevity, but on practically every measurable expression of the rate of aging, including the rates of memory loss, muscle loss, declining activity, immune-system response, and a broad range of bodily processes that might not otherwise be conceived of as synchronized.

Even if the way in which these techniques of age-retardation work is not fully understood, it seems increasingly plausible that there just might be a single process (or a small number of processes) of aging on which they do their work. The multiple effects suggest that most, if not all, of the various phenomena of aging are deeply connected and, in principle, could be jointly influenced by the right sorts of interventions. It seems increasingly likely, therefore, that something like age-retardation is in fact possible.

The most prominent techniques of age-retardation currently under investigation fall into the following four general categories: caloric restriction, genetic manipulations, prevention of oxidative damage, and methods of treating the ailments of the aged that might affect age-retardation.

It has been known since the mid-1930s that substantial reductions in the food intake of many animals (combined with nutritional supplements to avoid malnutrition) can have a dramatic effect on lifespan. With nearly seven decades of laboratory research, this is by far the most studied and best-described avenue of age-retardation, though scientists still lack a clear understanding of how it works. What is clear, however, from numerous studies in both invertebrates and vertebrates (including mammals), is that a reduction of food intake to about 60 percent of normal has a significant impact not only on lifespan but also on the rate of decline of the animal's neurological activity, muscle functions, immune response, and nearly every other measurable marker of aging. Moreover, it is now clear that the effect is not a product of a diminished metabolism, as was long believed. Calorically restricted animals do become physically smaller, but they process energy at the same levels as members of their species on a normal diet. In fact, studies in mice and rats suggest that caloric restriction appears to result in significantly increased rates of spontaneous activity, including the ability to run greater distances and to maintain a "youthful" level of activity at an age well beyond that of non-restricted animals of the same species. (Importantly, however, caloric restriction in animals also often results in sterility, or reduced fertility.)

The degree of life-extension (and likely age-retardation) achieved through caloric restriction is quite remarkable. In mice and rats, researchers have regularly found lifespan extended by more than 30 percent, and in some studies by more than 50 percent.¹³ Studies have also found significant extensions of life and signs of retarded aging in a number of other mammalian species, including, recently, a 16-percent increase in the lifespan of dogs.¹⁴

Studies of caloric restriction in monkeys, conducted since the late 1980s at the National Institute on Aging, the University of Maryland, and the University of Wisconsin, have shown comparable effects even on some of our nearest evolutionary cousins.¹⁵ Calorically restricted monkeys retain youthful levels of several vital hormones well into late adulthood, have lower blood pressure, and, over a fifteen-year period, suffer substantially less chronic illness than members of their species on normal diets. The effect on lifespan is as yet not known. Monkeys generally live several decades, so it will be years before it is apparent whether calorically restricted monkeys live significantly longer than others.

The biological basis for the dramatic anti-aging effects of caloric restriction is not now well understood, in large part because of the sheer number of changes wrought by a simple reduction in food intake. Hundreds of discretely measurable physiological changes occur in mice and rats on reduced diets, making cause and effect difficult to disentangle and the processes from which age-retardation results difficult to identify. However, researchers in the field believe that a number of new tools and techniques available only in the last decade or so (including DNA microarrays, new types of genetically engineered mice, and others) promise to facilitate a greater understanding of this process, and they believe that, in the foreseeable future, the mechanisms by which it operates might be understood, and techniques for achieving the same ends without a diet of near-starvation may be developed.^ix

Some of the most startling and extraordinary discoveries in age-retardation research have involved genetic mutations that have significant impact on lifespan and on the rate of senescence. Over the past few decades, researchers have identified single gene alterations that, in a number of species, dramatically extend life. For example, in nematode worms, it appears that changes in any one of at least 50 and potentially as many as 200 genes can significantly extend life.^x Study of these mutations is enabling scientists to trace with some precision the biochemical pathways responsible for changes in the aging rate; knowledge of these pathways will then provide specific targets for possible age-retarding interventions. In recent years, a few such pathways have been identified in worms, fruit flies, and yeast, with the numerous mutant genes having their effect on one or another of these pathways.^xi More remarkably, a number of life-extending genetic mutations have been identified in mice, whose genetics and physiology are far more complex than those of worms.

As long as life-extending single-gene mutations were known only in worms and fruit flies, there was little reason to expect that they might also occur in humans. But findings that similar biochemical pathways are responsible for this phenomenon in both worms and mice suggest the potential for a similar possibility in humans. For instance, in worms, flies, and mice, an alteration in a receptor for an insulin-like growth factor (present also in humans) has resulted in substantial increases in lifespan. It now seems possible that the rate of aging may be governed by highly conserved general mechanisms across many species, and that single-gene alterations that extend life may ultimately be discovered in humans.

Most remarkable is the magnitude of life-extension that these mutations confer. In worms, where the effect has been most dramatic, a single-gene alteration has been shown to double lifespan, and an alteration in two genes has nearly tripled it. In the most extreme cases, involving particular single-gene mutations in male worms, researchers have observed a six-fold increase in lifespan. There are, of course, enormous physiological differences between humans and worms. Most notably, the cells of nematode worms stop dividing in adulthood, a fact that of course has great significance for aging. In mammals, most notably mice, the effects have been less pronounced, but still quite significant. Increases in the normal two-year lifespan of laboratory mice by 25 percent to even 50 percent have been reported, and single-gene mutations combined with caloric restriction have been shown to result in a nearly 75-percent increase in lifespan (or up to nearly three-and-a-half years). That 75-percent extension is, to date, the greatest increased lifespan achieved in mammals.¹⁶

Some single-gene mutations do, however, have serious side effects, including, most commonly, sterility or reduced fertility-problems also observed with other techniques of age-retardation-though, on the other hand, some recent research suggests that, at least in some organisms, it may be possible to decouple the age-retarding effects of certain mutations from the observed diminution of fertility and reproductive fitness.¹⁷ Some single-gene differences have also been shown to decrease longevity in one sex of a species (most notably in fruit flies) while increasing it in the other. In addition, some of these mutations result in reduced body size and increased susceptibility to cold.

The effects of induced age retardation on fertility and reproductive fitness invite interesting speculation on the possible connection between longevity and reproduction: prolongation of life for the individual may be in tension with renewal of life through generation; conversely, fitness for reproduction is correlated with the process of decline leading to death. The possibility that hormonal events triggering puberty might also be involved in accelerating senescence has also been discussed by researchers on aging.

A different approach to the genetics of age-retardation, this one in humans, begins with knowledge gained from the study of progeria, a very rare genetic condition that leads not to delayed but to precocious senescence. One form of this progressive, fatal disorder, which afflicts approximately one in eight million newborns, is now believed to result from a single DNA base substitution in a gene on chromosome 1. This mutation leads to abnormal formation of the protein lamin A (LMNA), a key component of the membrane surrounding the nucleus of cells. Many victims of progeria carry the defective LMNA gene; others carry a mutation in a gene encoding a protein that repairs DNA damage. These findings will likely lead not only to genetic tests and therapeutic approaches to the treatment of progeria but also, perhaps, to new insights into the normal aging process itself. According to Dr. Francis Collins, director of the National Human Genome Research Institute (NHGRI) and the leader of the research team that found the LMNA gene defect, "Our hypothesis is that LMNA may help us solve some of the great mysteries of aging." Conceivably, future therapies developed to alleviate symptoms of premature aging in progeria patients may prove effective in delaying the aging process in unafflicted human beings as well.¹⁸

Single-gene differences that affect lifespan have not been studied for as long as caloric restriction. It is not yet clear, in this case, whether what is involved is true age-retardation or a form of more general extension of life. The evidence that does exist, however, suggests a retardation of aging, and a slowing of the loss of function and of the deterioration of tissues and cells.

For many years, there has been ample (if indirect) evidence that oxygen free radicals-oxygen molecules that have one unpaired electron, and that are therefore chemically very active-produced as inevitable by-products of the body's various functions, cause gradual deterioration of many of the body's cells and tissues. These oxygen free radicals perform some important metabolic functions, but they can also disrupt protein synthesis and repair (especially in mitochondria) and can cause minor errors in DNA replication that accumulate over time. Our body produces, or obtains through our diet, a number of antioxidants (such as superoxide dismutase [SOD], catalase [CAT], vitamin E, vitamin C, coenzyme Q10, and alpha-lipoic acid) that destroy many, but not all, of these oxygen free radicals. The balance of oxygen free radicals and antioxidants seems to be connected to the rate of degeneration of cells and tissues in the body. In fact, antioxidants may be deeply involved in the operation of the other successful age-retardation techniques in animals. For instance, the balance between free-radical production and antioxidant activity may modulate the impact of caloric restriction; and one specific antioxidant seems to play a critical role in the operation of nearly all the single-gene life-extending mutations in nematode worms. In addition, a recent study has shown that a synthetic antioxidant can significantly extend the lifespan of mice, and the life-extending effect of antioxidant activity in fruit flies has also been well documented. Researchers are exploring the potential for employing both naturally occurring and synthetic antioxidants in humans, to retard the degeneration of cells, reduce and slow the accumulation of errors in DNA replication, and thereby extend the human lifespan, perhaps significantly. The study of free-radical activity will also likely inform our understanding of the operation of other age-retardation techniques.

4. Methods of Treating the Ailments of the Aged That Might Affect Age-Retardation.

A number of techniques that do not themselves fall squarely under the heading of age-retardation may nonetheless offer vital clues to the nature of the aging process, and may have a significant role to play in the operation of age-retardation techniques. These include:

These different avenues of age-retardation research are not as clearly distinguished from one another as this classification suggests. In almost all cases, the employment of one technique offers results that are relevant for the understanding of the others. Caloric restriction seems to affect antioxidant production; genetic alterations can affect telo-mere length. Several of these methods have also been shown to work in tandem. Also, recent developments and advances in the tools of cellular and molecular biology have begun to fuse together these disparate fields. The techniques used for one are often also used in the others.

None of these techniques has been demonstrated to increase human lifespans or to slow the process of aging in humans. Such a demonstration would be quite difficult to undertake, since the human lifespan is on average between seven and eight decades. Experiments seeking to alter it would require a great deal of time and more than one generation of researchers (as the subjects outlived the researchers). Moreover, there are reasons to be cautious about extrapolating from animal models to human beings, for we are not simply more complicated versions of worms, flies, or mice.^xii Nevertheless, there is much to be learned from animal experiments, and from planned observational studies of human populations, and the results of such work, combined with the existence of analogous systems and processes in humans, suggest that scientists may indeed in the future be able to retard the human aging process and extend both the maximum and average human lifespan. Even if the prospect is not imminent, it may not be too early to begin considering its potential implications.

IV. ETHICAL ISSUES

That this prospect will be welcomed seems almost self-evident. Who among us would not want more healthy years added to his or her life? No one truly relishes the thought of bodily degeneration or decline, and of one's final years marked, as Shakespeare put it, by "a moist eye, a dry hand, a yellow cheek, a white beard, a decreasing leg, an increasing belly . . . your voice broken, your wind short, your chin double, your wit single, and every part about you blasted with antiquity."²³ We would probably all want to save ourselves, and even more so our loved ones, from the fate we have seen some of our elders endure.

The desire to live longer is also clearly echoed in some ethical ideals. It is surely one form of the true love of life and is driven by a deep commitment to the activities and engagements to which our lives are dedicated. Life's end nearly always finds human beings in the midst of projects still uncompleted, painfully aware that the world is full of wisdom they have yet to gain and experiences they have yet to enjoy. Much that is good about life is the result not of our finitude but of our longevity. Although some of us may live best when we live each day as if it were our last, many of us thrive because we live looking ahead to many days to come-making plans, laying foundations, building our lives with the future in mind. More time to plan, more healthy years in which to build and to enjoy what we have built, and in which to contribute to the lives of others, would surely be a great blessing. Not only individuals but society too might benefit, gaining much from the added experience and wisdom of its older members. The case for living longer is, in part, a moral case, and a strong one. Indeed, it may well be strong enough to overwhelm any possible objections or worries.

But to know if it would overwhelm such worries, we must identify those worries and examine them with care. Because the case for longer-even greatly longer-life seems so strong, the worries may at first escape our notice. Finding and pondering them leads us to suggest that any major alteration of the human life cycle is likely to have serious consequences beyond the mere extension of life, and to raise difficult ethical and practical questions, both for individuals and especially for society.

In suggesting some of these questions (and for the sake of discussion), we make several assumptions, both about the availability of age-retarding technology and its likely effects. We assume, first, that technology will be available to significantly retard the process of aging, of both body and mind, and second, that this technology will be widely available and widely used. If the first is correct, the second almost certainly will be. Which consequences of age-retardation are most likely will depend upon the particular techniques that become available and the effect they have on the shape of a life. Different techniques might alter the aging process differently and have different effects on the life cycle. Three general possibilities might be considered: (1) the life cycle would be stretched out like a rubber band, so that aging is slowed more or less equally at all stages of life, and maturation, middle age, and decline extend over a greater period; (2) a holding back of bodily decline, so that both the process of maturation and the process of decline occur roughly in the way they do now, but the period between them-that is, the healthy years of the prime of life-are greatly extended; and (3) a change in the form of decline, so that, for instance, rather than a slow and gradual loss of faculties, bodily degradation comes very quickly, and death comes suddenly following long years of health and vigor. We shall seek to take account of all of these possibilities, pointing to their potentially different ethical implications where they arise.

In listing the three alternatives, we have taken the optimist's view, confining our attention to life-extending outcomes that many people might find attractive. We have done this deliberately, for two reasons. First, only such attractive outcomes are likely to be widely embraced. Second, we wish to stipulate that people will get what they wish for, so that we may then examine whether what they get is likely to turn out in fact to be what they wanted (the Midas problem). Yet before proceeding to the ethical discussion, we should insert some notes of caution. It is possible that age-retarding techniques, like many medical interventions, will have uneven effects: they might work well for some, not well for others, and cause serious side effects in yet others. For example, for some recipients of greater longevity, the result might include a much longer period of decline and debility. Indeed, the period of debility could be lengthened not only absolutely (as it would be on the model of a rubber band being stretched) but also relative to the whole lifespan, and, in either case, virtually everyone who survives past eighty or ninety might come to expect ten to fifteen years of severely diminished capacity. All the scenarios for happy life-extension depend on technologies that will keep all the body's systems going for roughly the same duration, after which time they will shut down more or less simultaneously. But what if it should turn out that many people experience instead partial or uncoordinated increases in vigor (stronger joints but weaker memory, more ardent desire but diminished potency)? Given that age-retardation sets out to alter not just this organ or that tissue but the entire (putative) coordinated biological clock of a most complex organism, caution and modest expectations are proper leavens for zeal, especially as the love of longer life needs little encouragement to embrace false hopes of greater time on earth.

We divide our discussion of the ethical questions into two sections, dealing with the effects on individuals and the effects on society and its institutions. As will become evident, however, the distinction between them is not always sharp.

The question of the effect of age-retardation on our individual lives must begin with a sense of what aging means in those lives.

First we must remember that aging is not just about old age. It is a crucial part of the (nearly) lifelong process by which we reach old age and the end of our lives. Accordingly, its product is not so much old age and death as the life cycle itself: the form and contour of our life experienced in time. Strange as it may seem, from the perspective of personal experience aging defines youth almost as much as it does old age, because each stage of our life is defined relative to the others and to the whole of life. Age-retardation would therefore affect not only our later years, but all of our years, in both immediate and mediated ways. For one thing, if administered early in life, it might quite directly prolong our youthful years by slowing down the processes of maturation. Some of the evidence from animal studies, cited above, suggests that some of the methods that rely upon an alteration at the outset-including genetic alteration or the mimetics of lifelong caloric restriction-might retard aging in the young just as in the old. This might imply an overall "stretching out" of the entire life cycle, as one stretches a rubber band, extending the period we spend in infancy, childhood, adolescence, in our prime and in decline, and profoundly altering our sense of the relation between years lived and stages of life. Slower biological aging (particularly in a culture of faster "social aging" like ours, in which children are increasingly exposed to things that might not so long ago have been deemed exclusively appropriate for adult life) may cause an increasing disjunction between the maturity of the body and mind and the expectations and requirements of life.

Even if the age-retarding technology produces no direct bodily effects during youth, an increased maximum lifespan or even only greatly diminished senescence in the old could very likely affect the attitudes of the young along with those of the old. Indeed, age-retardation could affect the young even more than the old, insofar as the attitudes of the young are shaped by a sense of what is to come and what is to be expected of life. The great changes in average life expectancy over the twentieth century may have already influenced ways in which people perceive their own future, though it is a difficult matter after the fact to determine exactly how and why. Yet the changes resulting from those recent increases in average life expectancy may not provide precedent for human expectations in an unprecedented world, in which the maximum lifespan has increased significantly and many people are living longer than anyone has ever lived before.^xiii

How might such expectations be different? It is not easy to say, and different people will no doubt react differently. But some general observations are in order. The first concerns the "shape" of the life cycle as a whole. Some proponents of age-retardation research use language that suggests an image of life as a "time line," uniform and homogeneous, rather than as a forward-moving drama, composing different acts or stages-infancy, childhood, adolescence, coming-of-age, adulthood, parenthood, ripeness, decline. This would imply an understanding of life as composed of interchangeable and essentially identical units of time, rather than composing a whole with a meaningful form of its own, its meaning derived in part from the stages of the life cycle and the fact that we live as links in the chain of generations. Viewed through the prism of this chronological atomism, the prospect of adding more years to our lives means simply having more time, more of the same. And since life is good, more life is better. But life as lived and experienced does not present itself homogeneously and in discrete uniform bits, and the "time of our lives," informed by experience past and bent toward the future, is not the homogeneous and featureless "dimension" that is the time of physicists. Life as lived in time may be more akin to a symphony, in which a certain temporal order-pacing and procession, meter and momentum-governs the relationship between the parts and the whole and, more important, gives a dynamic process its directed character. Lived time is also shaped by memories of those who came before, and of who we ourselves have been; it is informed by imagined future possibilities, created by our hopes and plans for what we might yet become. The animated shape of a whole life affects how we live every portion, and altering the shape of that whole might therefore have far greater consequences than merely giving us more time.

A second observation concerns the relation between aging and death, and between age-retardation and our attitudes about mortality. Moving the midnight hour of a human lifespan could alter human attitudes and dispositions toward mortality and toward the whole of life. Life-extension does not mean immortality, to be sure-if for no other reason than that the attainment of immortality is scientifically implausible. But the impulse to extend our lives in general, rather than to combat particular diseases or ailments that shorten our lives, is a declaration of opposition to death as such. In addressing aging as a disease to be cured, we are, in principle, and at least tacitly, expressing a desire never to grow old and die, or, in a word, a desire to live forever. There is no reason to suspect that life-extension research would stop were we to achieve some mildly extended human lifespan, say, to 140, or 160, or 180 years. Why would it? Having declared that our present term of life is inadequate, why should we settle for another? A life lived from the start under the influence of age-retarding techniques is a life lived in express opposition to the constraints of mortality. Taken to its extreme, the underlying impulse driving age-retardation research is, at least implicitly, limitless, the equivalent of a desire for immortality.

These two observations are, of course, closely tied, since the boundaries and shape of the life cycle give form and possible meaning to a mortal life. Its virtue consists not so much in that it leads us to death, but in that it reminds us, by its very nature, that we will someday die, and that we must live in a way that takes heed of that reality. If we remained at our prime, in full swing, for decade after decade, and perhaps even for a couple of centuries, the character of our attitudes and our activities might well change significantly. These changes could take at least six principal forms:

First is a potentially positive consequence. A significantly greater lifespan would open up new possibilities and freedoms. Quite simply, longer-lived individuals would have more time in the course of their lives to explore new things and enjoy familiar ones, to gain more and deeper experiences, to complete more projects, to engage in more activities, to start a new course or a new career having gained much valuable experience in earlier ones, to have a second or third or fourth chance at something they deem important. If life is good, more life is in many ways better. Moreover, if the prospect of dying is well out of sight, the fear of death might diminish as well, alleviating many of the distortions this fear can produce in our lives.

On the other hand, the remoteness of the midnight hour might influence negatively how we spend our days. For although the gift of extra time is a boon, the perception of time ahead as less limited or as indefinite may not be. All our activities are, in one way or another, informed by the knowledge that our time is limited, and ultimately that we have only a certain portion of years to use up. The more keenly we are aware of that fact, the more likely we are to aspire to spend our lives in the ways we deem most important and vital. The notion of spending a life suggests a finite quantity of available devotion, and as economists are fond of telling us, the scarcity of a commodity contributes to its value. The very experience of spending a life, and of becoming spent in doing so-that is, the very experience of aging-contributes to our sense of accomplishment and commitment, and to our sense of the meaningfulness of time's passage, and of our passage through it. Being "used up" by our activities reinforces our sense of fully living in the world. Our dedication to our activities, our engagement with life's callings, and our continuing interest in our projects all rely to some degree upon a sense that we are giving of ourselves, in a process destined to result in our complete expenditure. A life lived devoid of that sense, or so thoroughly removed from it as to be in practice devoid of it, might well be a life of lesser engagements and weakened commitments-a life other than the one that we have come to understand as fully human. This is not to say it will be worse-but it will very likely be quite different.

Very much related to our sense of being used up in the course of our lives is the sense of urgency given to life by the prospect of foreseeable death. This may be what the Psalmist means in asking God to "teach us to number our days, that we may get a heart of wisdom." Many of our greatest accomplishments are pushed along, if only subtly and implicitly, by the spur of our finitude and the sense of having only a limited time. A far more distant horizon, a sense of essentially limitless time, might leave us less inclined to act with urgency. Why not leave for tomorrow what you might do today, if there are endless tomorrows before you? Our sense of the size and shape of our future-our "life expectancy"-is a major factor affecting how we act and think in the present.

Perhaps most significant, and most intriguing, is the deep connection between death and new birth. The link between longevity and fertility is a nexus of profound and mysterious human significance. The link appears again and again, in different forms and different arenas, both in empirical scientific investigation and in any effort at moral analysis. Most of the age-retardation techniques tested in animals to this point appear to result in very significant decreases in fertility (though, as noted earlier, in some cases the effects can be uncoupled). Various theories have been proffered to explain this link, mostly having to do with a relationship between the mechanisms that enable fertility and those that result in degeneration and death. Some have even suggested that the changes connected to puberty may well be linked to those that trigger decline. Fertility and aging may be biologically linked. Moreover, they seem to be linked in terms of human behavior and experience.

Throughout the twentieth century, increases in life expectancy have been accompanied by decreases in the birth rate.^xiv Of course, increased longevity alone does not explain declining birth rates. Increased income and economic opportunity as well as improved methods of contraception surely play a role. But increased longevity and improved health are surely elements of the broader cultural transformation that does explain declining birth rates. Perhaps for the first time in human history, vast numbers of young adults, blessed with an expectation of a long disease-free and war-free future, are living childlessly through their most fertile years, pursuing their own fulfillment now, but with the (often mistaken) expectation that there will always be time enough later to start a family.

One important reason for the apparent experiential link between longevity and childbearing seems readily intelligible: without some presentiment of our mortality, there might be less desire for renewal. And so a world of men and women who do not hear the biological clock ticking or do not feel the approach of their own decline might have far less interest in bearing-and, more important, caring for-children. Children are one answer to mortality. But people in search of other more direct and immediate answers, or, more to the point, people whose longer lease on life leaves them relatively heedless of its finitude, might very well be far less welcoming of children, and far less interested in making the sacrifices needed to promote human renewal through the coming of new generations. Whether this would in fact occur is an empirical question, and not all Council Members are convinced of this connection between awareness of finitude and devotion to perpetuation. But we all believe these are possibilities well worth contemplating.

Related to the subject of the effects of longevity on procreation is the subject of the effects of longevity on marriage and the resulting family connections. These topics are too large-and perhaps too speculative-to explore here. Yet two questions may suffice to point to what may be at stake. Would people in a world affected by age-retardation be more or less inclined to swear lifelong fidelity "until death do us part," if their life expectancy at the time of marriage were eighty or a hundred more years, rather than, as today, fifty? And would intergenerational family ties be stronger or weaker if there were five or more generations alive at any one time?

How a greatly increased lifespan lived in good health would affect attitudes toward death is another important matter. Certainly, the removal of the numerous causes of premature death has diminished through much of life the fear of untimely death, though its overall effects on our views of mortality are less easy to discern. Yet it is possible that an individual committed to the technological struggle against aging and decline would be less prepared for and less accepting of death, and the least willing to acknowledge its inevitability. Given that these technologies would not in fact achieve immortality, but only lengthen life, they could in effect make death even less bearable, and make their beneficiaries even more terrified of it and obsessed with it. The fact that we might die at any time could sting more if we were less attuned to the fact that we must die at some (more-or-less known) time. In an era of age-retardation, we might in practice therefore live under an even more powerful preoccupation with death, but one that leads us not to commitment, engagement, urgency, and renewal, but rather to anxiety, self-absorption, and preoccupation with any bodily mishap or every new anti-senescence measure.

Much may depend on how people actually grow old and die in a new world of increased longevity. Should the end come swiftly, with little premonitory illness (the third of the possibilities discussed above), death might always be regarded as untimely, unprepared for, shocking, and anxiety about accidents or other health hazards might rise.^xv But what if, in the "stretched rubber band" sort of life cycle, the period of debility became even more protracted and difficult than it now is? We have already seen how, thanks to antibiotics, techniques of life-support, and medicine's general success in preventing quick deaths from infectious diseases, heart attacks, and strokes, many more people are now spending prolonged periods in decay, or subject to Alzheimer disease and other age-related degenerative disorders. One of the costs we are already paying for the gift of longevity is the placement of elderly citizens and their families in degrading and difficult situations that simply were not possible in earlier times. Even a cure for Alzheimer disease, welcome as it most surely would be, would very likely leave some other chronic debilitating illness in command of those declining years. Under such circumstances, death might come to seem a blessing. And in the absence of fatal illnesses to end the misery, pressures for euthanasia and assisted suicide might mount.

There is also more to the question of aging than the place of death and mortality in our lives. Not just the specter of mortality, but also the process of aging itself affects our lives in profound ways. Aging, after all, is a process that mediates our passage through life, and that gives shape to our sense of the passage of time and our own maturity and relations with others. Age-retardation technologies make aging both more manipulable and more controllable as explicitly a human project, and partially sever age from the moorings of nature, time, and maturity. They put it in our hands, but make it a less intelligible component of our full human life. Having many long, productive years, with the knowledge of many more to come, would surely bring joy to many of us. But in the end, these techniques could also leave the individual somewhat unhinged from the life cycle. Without the guidance of our biological life cycle, we would be hard-pressed to give form to our experiential life cycle, and to make sense of what time, age, and change should mean to us.

Any of the foregoing effects of course would most likely be subtle, and it would be exceedingly difficult to hold them up against the promise of longer and longer life and to expect any of us simply to reject the offer. But in considering the offer, we must take into account the value inherent in the human life cycle, in the process of aging, and in the knowledge we have of our mortality as we experience it. We should recognize that age-retardation may irreparably distort these and leave us living lives that, whatever else they might become, are in fundamental ways different from-and perhaps less serious or rich than-what we have to this point understood to be truly human.

Powerful as some of these concerns are, however, from the point of view of the individual considered in isolation, the advantages of age-retardation may well be deemed to outweigh the dangers. But individuals should not be considered in isolation, and the full potential meaning of age-retardation cannot come into view until we take in the possible consequences for society as a whole. When we do so, some of these individual concerns become far more stark and apparent, and new concerns emerge as well.

To begin to grasp the full implications of significant age-retardation, we must imagine what our world would look like if the use of such techniques became the norm. This is both a reasonable expectation and a useful premise for analysis. If effective age-retardation technologies became available and relatively painless and inexpensive,^xvi the vast majority of us would surely opt to use them, and they would quickly become popular and widely employed. Moreover, viewing the effects of these technologies in the aggregate both highlights the consequences they would have for individuals by drawing them out and showing what they would mean on a large scale, and allows us to see certain consequences that affect the society and its institutions directly, and that are not just individual effects writ large. Individual changes in attitude and outlook toward children or mortality would have far more profound effects if they were widely shared throughout society. And at the same time, some changes, like age distributions in the population, only become apparent at all when we take in a view of entire communities or societies all at once.

The full social effects of age-retardation probably would not be evident until the first cohort to benefit from treatment began to cross the barrier of the present maximum lifespan, but lesser consequences would become evident much sooner, as more and more of the population survived to older ages, and lived with the plausible expectation of doing so.

Consequences will likely be apparent at every level of society, and in almost every institution. Among the more obvious may be effects on work opportunities, new hires, promotions and retirement plans; housing patterns; social and cultural attitudes and beliefs; the status of traditions; the rate and acceptability of social change; the structure of family life and relations between the generations; and political priorities and choices, and the locus of rule and authority in government. The experiences of the past century offer us some clues in this regard, though the effects of significant increases in lifespan would likely be more radical than those we have seen as a result of twentieth-century advances.

To paint a fuller picture, we consider the potential social implications of age-retardation in three areas: generations and families; innovation, change, and renewal; and the aging of society.

Family life and the relations between the generations are, quite obviously, built around the shape of the life cycle. A new generation enters the world when its parents are in their prime. With time, as parents pass the peak of their years and begin to make way and assist their children in taking on new responsibilities and powers, the children begin to enter their own age of maturity, slowly taking over and learning the ropes. In their own season, the children bring yet another generation into the world, and stand between their parents and their children, helped by the former in helping the latter. The cycle of succession proceeds, and the world is made fresh with a new generation, but is kept firmly rooted by the experience and hard-earned wisdom of the old. The neediness of the very young and the very old puts roughly one generation at a time at the helm, and charges it with caring for those who are coming and those who are going. They are given the power to command the institutions of society, but with it the responsibility for the health and continuity of those institutions.

A society reshaped by age-retardation could certainly benefit from the wisdom and experience of more generations of older people, and from the peace, patience, and crucial encouragement that is often a wonderful gift of those who are no longer forging their identity or caught up in economic or social competition. But at the same time, generation after generation would reach and remain in their prime for many decades.^xvii Sons might no longer surpass their fathers in vigor just as they prepared to become fathers themselves. The mature generation would have no obvious reason to make way for the next as the years passed, if its peak became a plateau. The succession of generations could be obstructed by a glut of the able. The old might think less of preparing their replacements, and the young could see before them only layers of their elders blocking the path, and no great reason to hurry in building families or careers-remaining functionally immature "young adults" for decades, neither willing nor able to step into the shoes of their mothers and fathers. Families and generational institutions would surely reshape themselves to suit the new demographic form of society, but would that new shape be good for the young, the old, the familial ties that bind them, the society as a whole, or the cause of well-lived human lives?

The same glut might also affect other institutions, private and public. From the small business to the city council, from the military to the Fortune 500 corporation, generational succession might be disrupted, as the rationale for retirement diminished. Again, these institutions would benefit from greater experience at the top, but they might find it far more difficult to adjust to change. With the slowing of the cycles of succession might also come the slowing of the cycles of innovation and adaptation in these institutions.

Cultural time is not chronological time. Beliefs and attitudes tend to be formed early in life, and few of us can really change our fundamental outlook once we have reached our intellectual maturity. Serious innovation, and even just successful adaptation to change, is therefore often the function of a new generation of leaders, with new ideas to try and a different sense of the institution's mission and environment. Waiting decades for upper management to retire would surely stifle this renewing energy and slow the pace of innovation-with costs for the institutions in question and society as a whole.

A society's openness and freshness might be diminished not only because large layers of elders block paths to youthful advancement. They might also be jeopardized more fundamentally by the psychological and existential changes that the mere passing of time and "learning how things are" bring to many, perhaps most, people. After a while, no matter how healthy we are or how well placed we are socially, most of us cease to look upon the world with fresh eyes. Familiarity and routine blunt awareness. Fewer things shock or surprise. Disappointed hopes and broken dreams, accumulated mistakes and misfortunes, and the struggle to meet the economic and emotional demands of daily life can take their toll in diminished ambition, insensitivity, fatigue, and cynicism-not in everyone, to be sure, but in many people growing older.^xviii As a general matter, a society's aspiration, hope, freshness, boldness, and openness depend for their continual renewal on the spirit of youth, of those to whom the world itself is new and full of promise.

Even as the ravages of aging on the lives of individuals were diminished, society as a whole would age. The average age of the population would, of course, increase, and, as we have seen, the birthrate and the inflow of the young would likely decrease. The consequences of these trends are very difficult to forecast, and would depend to a great extent on the character of the technique employed to retard aging. If the delay of senescence made it more acute when it did come, then the costs of caring for the aged would not be reduced but only put off, and perhaps increased. The trend we have already seen in our society, whereby a greater share of private and public resources goes to pay for the needs of the aged and a lesser share for the needs of the young, would continue and grow. But society's institutions could likely adapt themselves to this new dynamic (though of course the fact that we can adjust to something does not in itself settle the question of whether that something is good or bad). More important is the change in societal attitudes, and in the culture's view of itself. Even if age-retardation actually decreased the overall cost of caring for the old, which is not unimaginable, it would still increase the age of society, affecting its views and priorities. The nation might commit less of its intellectual energy and social resources to the cause of initiating the young, and more to the cause of accommodating the old.

A society is greatly strengthened by the constant task of introducing itself to new generations of members, and might perhaps be weakened by the relative attenuation of that mission. A world that truly belonged to the living-who expected to exercise their ownership into an ever-expanding future-would be a very different, and perhaps a much diminished, world, focused too narrowly on maintaining life and not sufficiently broadly on building a good life. If individuals did not age, if their functions did not decline and their horizons did not narrow, it might just be that societies would age far more acutely, and would experience their own sort of senescence-a hardening of the vital social pathways, a stiffening and loss of flexibility, a setting of the ways and views, a corroding of the muscles and the sinews. This sort of decline would be far less amenable to technological solutions.

A society reshaped in these and related ways would be a very different place to live than any we have known before. It could offer exciting new possibilities for personal fulfillment, and for the edifying accumulation of individual and societal experience and wisdom. But it might also be less accommodating of full human lives, less welcoming of new and uninitiated members, and less focused on the purposes that reach beyond survival. If so, retardation of aging-like sex selection, as discussed in an earlier chapter-might turn out to be a Tragedy of the Commons, in which the sought-for gains to individuals are undone or worse, owing to the social consequences of granting them to everyone. Contemplating these concerns in advance forces us to consider carefully the sort of world we wish to build, or to avert.

V. CONCLUSION

The prospect of effective and significant retardation of aging-a goal we are all at first strongly inclined to welcome-is rife with barely foreseeable consequences. We have tried to gesture toward some possible effects, both positive and negative, though no one can claim to know what a world remade by unprecedented longevity on a mass scale would really look like.

On its face, our effort to propose some possible concerns about such a world is open to the charge that we have taken the present to be "the best of all possible worlds." Indeed, simply by raising any doubts, some may accuse us-wrongly-of believing that the present is no longer the best of the worlds we have known. Some questions we have raised about the social implications of future increases in maximum lifespan might well have been raised a century ago, were someone then to have proposed-no one, of course, did-to increase the average life expectancy at birth by the amount in fact realized since 1900 (thirty years, from 48 to 78). Empirical studies of the consequences of that large increase are lacking, for obvious reasons, and it would be virtually impossible to try to assess now the full social costs of this widely welcomed change. Yet if there is merit in the suggestion that too long a life, with its end out of sight and mind, might diminish its worth, one might wonder whether we have already gone too far in increasing longevity. If so, one might further suggest that we should, if we could, roll back at least some of the increases made in the average human lifespan over the past century.

These remarks prompt some large questions: Is there an optimal human lifespan and an ideal contour of a human life? If so, does it resemble our historical lifespan (as framed and constrained by natural limits)?^xix Or does the optimal human lifespan lie in the future, to be achieved by some yet-to-be-developed life-extending technology? Whatever the answers to these intriguing and important questions, nothing in our inquiry ought to suggest that the present average lifespan is itself ideal. We do not take the present (or any specific time past) to be "the best of all possible worlds," and we would not favor rolling back the average lifespan even if it were doable. Although we suggest some possible problems with substantially longer lifespans, we have not expressed, and would not express, a wish for shorter lifespans than are now the norm. To the contrary, all of us surely want more people to be able to enjoy the increased longevity that the last century produced. Those previous efforts that have increased average lifespans have done so by reducing the risks and removing the causes of premature death, allowing many more people to live out their biblical three-score (today, four-score) and ten. Yet during that time, there has been relatively little increase in the maximum human lifespan, and not many people are living longer than the longest-lived people ever did. Although we may learn about the future by studying somewhat similar changes in the past, the effects of changes of the past are not an adequate guide for the radically new possibilities that age-retardation may bring into being. Thus, to be committed, as we are, to trying to help everyone make it through the natural human lifespan (surely a better world than the present) does not require our being committed to altering or increasing that lifespan. Conversely, to be concerned about the implications of departing from a three-to-four-generational lifespan does not necessitate a reactionary embrace of any putative virtues of premature death.

The past century's advances in average lifespan, now approaching eighty years for the majority of our fellow citizens, have come about through largely intelligible operations within a natural world shaped by human understanding and human powers. It is a conceptually manageable lifespan, with individuals living not only through childhood and parenthood but long enough to see their own grandchildren, and permitted a taste of each sort of relationship. It is a world in which one's direct family lineage is connected by both genetics and personal experience, not so attenuated by time that relatives feel unrelated. Generation and nurture, dependency and reciprocated generosity, are in some harmony of proportion, and there is a pace of journey, a coordinated coherence of meter and rhyme within the repeating cycles of birth, ascendancy, and decline-a balance and beauty of love and renewal giving answer to death that, however poignant, bespeaks the possibility of meaning and goodness in the human experience. All this might be overthrown or forgotten in the rush to fashion a technological project only along the gradient of our open-ended desires and ambitions.

Contemplating the speculative prospect of altering the human life cycle brings us to the crucial question: Is there a goodness and meaning in life so fundamental that it is too wide to be grasped by our scientific vision and too deep to be plumbed by the imperious exigencies of our natural desire? If we go with the grain of our desires and pursue indefinite prolongation and ageless bodies for ourselves, will we improve the parts and heighten the present, but only at the cost of losing the coherence of an ordered and integrated whole? Might we be cheating ourselves by departing from the contour and constraint of natural life (our frailty and finitude), which serve as a lens for a larger vision that might give all of life coherence and sustaining significance? Conversely, in affirming the unfolding of birth and growth, aging and death, might we not find access to something permanent, something beyond this "drama of time," something that at once transcends and gives purpose to the processes of the earth, lifting us to a dignity beyond all disorder, decay, and death? To raise these questions is not to answer them, but simply to indicate the enormous matters that are at stake.

Without some connection between change and permanence, time and the eternal, it is at best an open question whether life could be anything but a process without purpose, a circumscribed project of purely private significance. Our natural desires, focused on ourselves, would lead us either to attempt to extend time as far as technologically possible or to dissolve it in the involution of a ceaseless series of self-indulgent distractions. In Aldous Huxley's Brave New World, Bernard and Lenina are hovering in a helicopter over the city, wondering how to best spend their evening together. Lenina (typically jejune) suggests a game of electromagnetic golf. Bernard demurs and replies, "No, that would be a waste of time." Lenina answers back, "What's time for?" Only aging and death remind us that time is of the essence. They invite us to notice that the evolution of life on earth has produced souls with longings for the eternal and, if recognized, a chance to participate in matters of enduring significance that ultimately could transcend time itself.

The broader issue has to do with the meaning of certain elements of our human experience that medical science may now allow us to alter and manipulate. The ability to retard aging puts into question the meaning of aging in our lives, and the way we ought best to regard it: Is aging a disease? Is it a condition to be treated or cured? Does that mean that all the generations that have come before us have lived a life of suffering, either waiting for a cure that never came or foolishly convincing themselves that their curse was just a blessing in disguise? Is the finitude of human life, as our ancestors experienced it and as our faiths and our philosophies have taught us to understand it, really just a problem waiting to be solved? The anti-aging medicine of the not-so-distant future would treat what we have usually thought of as the whole, the healthy, human life as a condition to be healed. It therefore presents us with a questionable notion both of full humanity and of the proper ends of medicine.

The attempt to overcome aging puts in stark terms the question that defines much of our larger investigation of the uses of biotechnology that go beyond the treatment of the sick and wounded: Is the purpose of medicine to make us perfect, or to make us whole? And, medicine's purpose aside, would we really be better off as individuals (happier and more fulfilled) and as a society (more cultivated, more accomplished, more just) if we had more perfect and more ageless bodies? The human being in his or her natural wholeness is not a perfect being, and it is that very imperfection, that never fully satisfactory relation with the world, that gives rise to our deepest longings and our greatest accomplishments. It is what reminds us that we are more than mere chemical machines or collections of parts, and yet that we are less than flawless beings, seamlessly a part of and perfectly content in a world fully under our control and direction. It is the source of some of what we most appreciate about ourselves.

Some foreseeable biotechnologies, like those of effective age-retardation, hold out the prospect of perfecting some among our imperfections, and must lead us to ask just what sort of project this is that we have set upon. Is the purpose of medicine and biotechnology, in principle, to let us live endless, painless lives of perfect bliss? Or is their purpose rather to let us live out the humanly full span of life within the edifying limits and constraints of humanity's grasp and power? As that grasp expands, and that power increases, these fundamental questions of human purposes and ends become more and more important, and finding the proper ways to think about them becomes more vital but more difficult. The techniques themselves will not answer these questions for us, and ignoring the questions will not make them go away, even if we lived forever.

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FOOTNOTES

i. In doing so, we shall exploit the heuristic value of specific prospects and approaches (that may or may not pan out) because we believe they can most clearly teach us about the significance of any successful program for retarding human aging.

ii. Some commentators, including a few members of this Council, raise the legitimate question of whether an interest in retarding aging is, as implied here, an (at least tacit) interest in immortality. One could, after all, hope for a longer and hence more satisfying life or a less burdensome and decrepit old age without ever consciously formulating a wish to live forever. While the point is well taken, it does not refute the connection we have drawn between the open pursuit of ageless bodies and the secret longing to overcome death. Fear of death (however veiled and inchoate) and awareness of mortality (however dim and confused) have long wielded a pervasive influence on much if not all of human experience. And the founders of the modern scientific project brought that fear and that awareness very much into the foreground when they put forward the conquest of nature as mankind's utmost aim. Moreover, some contemporary scientists (though of course by no means all or most aging researchers) do express their aspirations in these terms. For instance, in marking the creation of the Society of Regenerative Medicine, William Hazeltine, head of Human Genome Sciences, declared that "the real goal is to keep people alive forever" (Science 290: 2249, 22 December 2000). We shall carry this suggestion-as well as the serious doubts raised-with us as we go forward.

iii. There is no clear consensus among scientists on a definition or even a particular physical description of aging. In offering the above "definition" we do not mean to imply a unitary phenomenon of aging, much less a unitary cause. This description is compatible both with the notion that senescence is due to some underlying process called "aging" and with the notion that "aging" is a descriptive term for observable senescence, from whatever cause.

iv. The trend has not been simply linear, and indeed a notable spike in total fertility rates occurred in the United States in the 1950s and early 60s, but on the whole, rates declined significantly from just over 80 births per thousand women of childbearing age in 1900 to just over 50 births per thousand women of childbearing age in 2000, while life expectancy increased throughout the period. In addition, the unusual size of the so-called “baby boom generation” in the United States has had to do not only with increased birthrates in the 1950s and early 60s, but also with substantially diminished infant mortality, that allowed more of those born to make it to adulthood.

v. Of course, this is very far from true in many less developed nations, where mortality among the young is still very high, andwhere the methods that served to improve health and increase lifespans in the United States in the twentieth century still stand to do a great deal of good.

vi. Until one knows the cause or causes of aging, one cannot be sure that piecemeal improvements would not significantly retard general deterioration and thereby extend lifespan. Consider just one possible explanation of aging that would suggest possible piecemeal interventions at numerous sites. If alpha motor neuron input into muscles declines (for whatever reason), this would lead to muscle weakness, which could lead to a more sedentary lifestyle, which would decrease aerobic exercise, which may cause generalized circulatory decline with a small but significant effect on tissue perfusion (perhaps only during stress or cold), which could result in periodic ischemia (inadequate oxygenation of tissues), which might result in cell damage that causes slight but progressive degeneration to specific organs (for example, kidneys, which influence blood pressure), which would add their own imbalance and deficiencies to overall body coordination of function and response with other "aging" effects (including maybe further decline in alpha motor neurons). Because the organism is a single interrelated unit, anything that adversely influences cell function can appear to be a "cause" of aging.

vii. The above description draws heavily on Steven Rose (Rose, S., "'Smart drugs': do they work, are they ethical, will they be legal?," Nature Reviews Neuroscience 3: 975-979, 2002). As Rose has said: "[M]emory formation requires, amongst other cerebral processes: perception, attention, arousal. All engage both peripheral (hormonal) and central mechanisms. Although the processes involved in recall are less well studied it may be assumed that it makes similar demands. Thus agents that affect any of these concomitant processes may also function to enhance (or inhibit) cognitive performance. Memory formation in simple learning tasks is affected by plasma steroid levels, by adrenaline and even by glucose. At least one agent claimed to function as a nootropic and once widely touted as a smart drug, piracetam, seems to act at least in part via modulation of peripheral steroid levels. Central processes too can affect performance by reducing anxiety, enhancing attention or increasing the salience of the experience to be learned and remembered. Amphetamines, methylphenidate (Ritalin), antidepressants, and anxiolytics probably act in this way. Other agents regularly cited as potential smart drugs, such as ACTH and vasopressin, may function similarly. Finally, there is evidence from animal studies that endogenous cerebral neuromodulators such as the neurosteroids (e.g., DHEA) and growth factors like BDNF will enhance long-term memory for weakly acquired stimuli." See original for complete list of citations.

viii. The difficulty of simple and direct improvement in complex neurological processes is underscored by the results of this experiment. Together with some improvements in memory the mice experienced other neurological changes, including hypersensitivity to inflammatory pain. See Pinker, S., "Human Nature and Its Future," presentation at the March 2003 meeting of the President's Council on Bioethics, Washington, D.C. Transcript available on the Council's website, www.bioethics.gov.

ix. To reduce food consumption to 60 percent of normal, the average active adult human being would have to lower his daily caloric intake from 2,500 calories a day to 1,500. By any standard, that is a severely restricted diet that few people would want to sustain for long periods. Accordingly, much research is being devoted to the search for pharmaceuticals (known as "caloric restriction mimetics") that might mimic the benefits of caloric restriction without actually forcing people to go hungry. See Lane, M., et al., "The Serious Search for an Anti-Aging Pill," Scientific American 287(2): 36-41, 2002.

x. See Austad, S., "Adding Years to Life: Current Knowledge and Future Prospects," presentation at the December 2002 meeting of the President's Council on Bioethics. Transcript available on the Council's website, www.bioethics.gov.

xi. A number of recent studies suggest that there may be three separate pathways affecting normal longevity: an insulin/IGF-1 pathway; a pathway that, during early development, sets the rate of mitochondrial respiration in ways that affect the rate of aging and behavior of the adult; and a poorly defined pathway affected by caloric restriction. Of course, all these pathways may converge at some "downstream" positions. See, for instance, Dillin, A., et al., "Rates of behavior and aging specified by mitochondrial function during development," Science 298 (5602): 2398-2401, 2002; and Murphy, C., et al., "Genes that act downstream of DAF-16 to influence the lifespan of Caenorhabditis elegans," Nature 424: 277-283, 2003.

xii. Fruit flies, roundworms, and mice are short-lived species subject to hazardous environments and seasonal exigencies. It may simply make sense biologically that their lifespan would be both constrained and flexibly regulated to coordinate survival and reproduction within favorable circumstances in a way quite different from the human lifespan. Also, they are less complex and more genetically determined than human beings; indeed, they are studied in part because their genetics are so predictable. Human beings have evolved to be much longer-lived and more versatile, and have a different overall biological strategy, one of open indeterminacy and consciously mediated flexibility and freedom, complemented by creativity, communication, and cultural continuity.

xiii. In this sense, life expectancy turns out to be a uniquely useful measure. Life expectancy is a measurement, based on statistical tables of mortality, of the number of additional years that people of some particular age may expect to live at a given time. This seems better suited for insurance purposes than for capturing a snapshot of longevity. And yet, life expectancy may be distinctly useful to moral reflection and analysis, because it is a measure of the number of years a person may expect to have yet ahead of him or her at any moment. It is therefore a measure of the view ahead, of the expected and anticipated years to come, which has much to do with our attitudes about aging and death and about how to regard and what to do with the time we have available. Many of the most significant consequences of age-retardation could result from an increase in the number of years that people can expect to live, and from the resulting changes in attitudes.

xiv. The great "baby boom" of the 1950s and 1960s in the United States was not, as one might imagine, a result of substantially increased birth rates. In 1900, the birth rate was just above 30 births per thousand population; in 1950 (roughly the beginning of the period called the "baby boom") it was 24.1, and in 1965 (the end of that period) it was 18.4. It is not increased rates of childbearing but rather extraordinary reductions in infant mortality (allowing many more children to live to adulthood) that explain the relative size of the generation born in those years. The birthrate has since continued to decline,reaching approximately 15 births per thousand population in 2001, bringing it closer to the death rate, and therefore bringing population growth roughly into line with figures from the early twentieth century.

xv. Montaigne puts it this way: "I notice that in proportion as I sink into sickness, I naturally enter into a certain disdain for life. I find that I have much more trouble digesting this resolution when I am in health than when I have a fever. Inasmuch as I no longer cling so hard to the good things of life when I begin to lose the use and pleasure of them, I come to view death with much less frightened eyes. This makes me hope that the farther I get from life and the nearer to death, the more easily I shall accept the exchange. . . . If we fell into such a change [decrepitude] suddenly, I don't think we could endure it. But when we are led by Nature's hand down a gentle and virtually imperceptible slope, bit by bit, one step at a time, she rolls us into this wretched state and makes us familiar with it; so that we find no shock when youth dies within us, which in essence and in truth is a harder death than the complete death of a languishing life or the death of old age; inasmuch as the leap is not so cruel from a painful life as from a sweet and flourishing life to a grievous and painful one." (Montaigne, M., "That to Philosophize Is to Learn to Die," The Complete Essays of Michel Montaigne, trans. Donald M. Frame, Stanford: Stanford University Press, 1965, p. 63.)

xvi. Other sorts of problems, involving aggravated social stratification based on the gift of lengthened life, might emerge if the lifespan-extending technologies were very expensive and available only to the privileged few, as they well might be, at least initially. Such difficulties, already anticipated in the current inequities in health care, could be much exacerbated even short of technologies to retard senescence. The projected opportunities for "regenerative medicine"-featuring stem-cell-based tissue transplantation or more extensive organ replacement-may turn out to be very expensive and available mainly to the wealthy.

xvii. Combined with patterns of decreasing family size in the West, this might create a peculiar reorienting of the generational makeup of families, with fewer children and far more and older adults, layered in succeeding generations-the opposite of a branching family tree. A lifespan of approximately 150 years could reasonably be expected to allow one to see his or her great-great-great-great-grandchild. But this child would have as many as 63 other such great-great-great-great-grandparents, along with 32 great-great-great-grandparents, 16 great-great-grandparents, eight great-grandparents, four grandparents and two parents-and, if certain demographic trends continue, few if any siblings, uncles and aunts, or cousins.

xviii. As Aristotle noted in his remarkable portrait of the old, the young, and those in their prime, the old often "aspire to nothing great and exalted and crave the mere necessities and comforts of existence." (Aristotle, Rhetoric, Book II, Ch. 13, 1389b22, trans. L. Cooper, Englewood Cliffs, N.J.: Prentice-Hall, 1960, p. 135.)

xix. The natural history of longevity might after all teach us something about the value of extended life. Lifespans have increased dramatically through evolution, and apparently to great advantage. Contemporary species are the products of evolutionary changes that have likely included something on the order of 1,000-fold increases of lifespan since the very short-lived earliest living forms. If increased longevity were inherently detrimental, we humans would not have evolved to have both great abilities and long lifespans. This result of natural and enormously gradual evolutionary change, however, cannot in itself be taken as a reassuring precedent for any humanly engineered change, especially if produced rapidly without the opportunity for evolutionary testing of the resulting changes in fitness.

Beyond Therapy: Biotechnology and the Pursuit of Happiness

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Ageless Bodies