Friday, October 01, 2004

Beyond Therapy: Biotechnology and the Pursuit of Happiness

A Report of the President’s Council on Bioethics

By: The President’s Council on Bioethics

In a chapter titled “Ageless Bodies,” the President’s council’s report considered the progress in research aimed at mitigating the normal changes and preventing the diseases associated with aging. This excerpt focuses on the research findings regarding the possibilities of retarding aging itself and the ethical implications for individuals and society of greatly increased longevity.

The brief of the President’s Council on Bioethics ranges wide. The council has issued reports on cloning, on stem cell research, and on reproduction, and even released a book of readings from classic literature, ancient and modern, bearing on ethical questions developing in the newest work in biomedicine. When the panel turned its attention to how people might wish to employ new drugs and technologies not to cure illness but to improve troubling features of ordinary life, the result was the report, Beyond Therapy: Biotechnology and the Pursuit of Happiness.

Everywhere in Beyond Therapy a reader encounters neuroscience and ethical questions arising from the research. The report deals with the idea of selecting babies for enhanced personal abilities, using psychotropic drugs in children, new drugs and techniques for sharpening mental performance, aging, and mood and memory manipulation.*

In a chapter titled “Ageless Bodies,” the council’s report considers the research aimed at overcoming the physical and mental declines associated with aging. The excerpts reprinted here focus on research—much of which is being done in neuroscience labs—that suggests the possibility of retarding aging itself and discuss the ethical implications of greatly increased longevity for individuals and society.

Excerpted from Beyond Therapy: Biotechnology and the Pursuit of Happiness— A Report of the President’s Council on Bioethics

© 2003. Published by Dana Press.

AGELESS BODIES

… (T)he 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. … 

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. 

…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. … 

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.

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. … 

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. 

1. Caloric Restriction.

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. … 

… 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.1 

2. Genetic Manipulations.

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. … 

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. 

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. 

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.2 Some single-gene differences have also been shown to actually 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. … 

3. Prevention of Oxidative Damage.

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. … 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. … 

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: 

a. Hormone treatments: It has long been known that endocrine factors are closely tied to a number of the most prominent elements of aging. The rates of production of certain hormones (particularly testosterone and estrogen) decline sharply in one’s later years, and these declines are closely related to the loss of muscle mass that accompanies aging and to a series of other age-related declines. In the past fifteen years, researchers have been investigating the possibility of slowing or, in certain instances, reversing these effects of aging by the replenishment of certain hormones to more youthful levels, with particular focus on human growth hormone, dehydroepiandrosterone (DHEA), testosterone, estrogen, pregnenolone, progesterone, and melatonin. One prominent study, conducted in 1990 and repeated several times since, showed that men between the ages of 60 and 80 who were injected with human growth hormone over a six-month period developed increased muscle mass, a loss of fat, improved skin elasticity, and decreased cholesterol levels.3 To this point, however, there has been no verifiable claim of changes in human lifespan as a result of hormone replacement, and some researchers have expressed doubts about the possibility of such changes.4 … 

There has been no verifiable claim of changes in human lifespan as a result of hormone replacement, and some researchers have expressed doubts about the possibility of such changes. 

b. Telomere research: Since the mid-1980s, researchers have known that telomeres— which form the tips of chromosomes—can shorten over time as cells divide, and that eventually this shortening causes cells to stop dividing and to die. Certain cells—germ cells, cancer cells, some stem cells, hair follicles, and others—are able to escape this process of degeneration with the help of an enzyme called telomerase, which slows the erosion and shortening of telomeres. Several studies in the 1990s suggested that telomere length correlates with cell aging, so that preventing the shortening of telomeres can slow the aging of cells, and, under certain conditions, might do so without increasing the risk of uncontrolled cell-growth and cancers.5 The links between cell aging and the general aging of organisms are, however, still quite unclear. … The promise of telomere manipulation appears greatest as a means of combating some afflictions of the aged, rather than retarding aging as such. … 

None of these techniques has been demonstrated to increase human lifespan 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.6 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. … 

Scientists may indeed in the future be able to retard the human aging process and extend both the maximum and average human lifespan.

Effects on the Individual

1. Greater Freedom from Constraints of Time.

… 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. … 

2. Commitment and Engagement.

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…. 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. 

3. Aspiration and Urgency.

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. 

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. 

4. Renewal and Children.

... 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.7 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. … 

5. Attitudes toward Death and Mortality.

… 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. … 

6. The Meaning of the Life Cycle.

… 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. … 

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. 

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. 

B. Effects on Society…

1. Generations and Families.

… 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.8 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? 

2. Innovation, Change, and Renewal.

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. … 

3. The Aging of Society.

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. … 

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.  

* (Authors in this issue of Cerebrum discuss many of these subjects; please see “Shall We Enhance,” “Seeking More Goodly Creatures,” “DARPA on Your Mind,” and “Pandora’s Hippocampus.”) 

References

  1. 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.
  2. Dillin, A., et al., “Timing requirements for insulin/IGF-1 signaling in C. elegans,” Science 298(5594): 830-834, 2002.
  3. Rudman, D., et al., “Effects of human growth hormone in men over sixty years old,” The New England Journal of Medicine 323:1-5, 1990.
  4. Olshansky, S., op. cit.
  5. An overview of the subject by Council Member Elizabeth Blackburn in the journal Nature from November 2000 sheds light on this controversial question (Blackburn, E., “Telomere states and cell fates,” Nature 408(6808): 53-56, 2000).
  6. 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.
  7. The great “baby boom” of the 1950s and ‘60s 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.
  8. 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-grand parents, four grandparents and two parents— and, if certain demographic trends continue, few if any siblings, uncles and aunts, or cousins.



About Cerebrum

Bill Glovin, editor
Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board
Joseph T. Coyle, M.D., Harvard Medical School
Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine
Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital
Robert Malenka, M.D., Ph.D., Stanford University School of Medicine
Bruce S. McEwen, Ph.D., The Rockefeller University
Donald Price, M.D., The Johns Hopkins University School of Medicine

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