Staff Background Paper

Many of the oldest human stories are myths of long lives: of ancients who lived for hundreds of years, of far-away places where even now the barriers of age are broken, or of magical formulas, concoctions or fountains of youth. Human beings have never been simply at ease with the common fate that hangs over our heads: that we are to age (if we are lucky), and then to die. There has always been some dispute about whether this destiny is a blessing or a curse, but there have also always been efforts to slow or reverse the process of aging, if not to beat back death itself.

In the last hundred years, this project appears at first glance to have been more successful than ever. At the turn of the twentieth century, life expectancy in the United States was, on average, about 45 years. At the turn of the twenty-first century, it was 78 years. This is an astonishing increase, likely unequalled in human history. But these figures are not exactly what they seem. More than a conquest of the limits of old age, they represent an overcoming of the risks of dying young, and especially the dangers of infancy. In 1900, nearly 15 percent of American infants died before their first birthday. Today, less than 1 percent of children do. This, much more than the improved health of the elderly, has caused the dramatic rise in life expectancy. So while the average human lifespan has increased, the maximum has not. More and more people live into their 80s and 90s, but no one lives longer than the longest-lived humans did in times gone by.

The attenuation of infant mortality and childhood diseases (accomplished mostly through improvements in basic public health, sanitation and immunization, rather than high-tech intervention) 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 fact, even if, starting today, no one in the United States died before the age of 50, average life expectancy would increase by only about 3.5 years. The increasing lifespans of the 20th century were an extraordinary achievement, but further significant gains in life expectancy would require a much greater feat: extending the lives of older people. This very different project presents us with a different set of challenges, both scientific and ethical.

The purpose of medicine has always been to heal disease and ease suffering. This has generally meant staving off premature death by combating the causes and effects of sicknesses and injuries. This is still the way in which most research into life-extending medicine now works, addressing not aging as such, but rather some specific diseases of the aged, including Alzheimer's, Parkinson's, cardiovascular diseases, and many others. This approach 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 work of art, and modern medicine seems likely to make it more so and to bring further modest increases in average lifespan. But this approach does not get at the more general physical and mental deterioration that often comes with old age, and which we more generally think of as "aging." It therefore allows individuals to live longer, but often thereby exposes 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. Extensions of life that do not address this general degeneration consign their beneficiaries to the fate of Tithonus or the Struldbruggs in Swift's Gulliver's Travels: degeneration without end.

For this reason, many in the field of aging research have turned to examining the causes of this more general age-related degeneration of body and mind, in the hope of offering ways to preserve not only life but full and healthy life. This broader approach to aging is being attempted on several fronts, including, among others:

1. Free radicals and mitochondrial dysfunction. Some of the "symptoms" of aging may be caused by what are termed "free radicals": molecules that have at least one unpaired electron, and which are therefore very chemically active. These can disrupt the mechanisms of protein synthesis and repair (especially in mitochondria), and can cause minor errors in DNA replication that accumulate over time. Researchers hope to impede this process, thereby possibly slowing the process of degeneration.
   
   
2. Caloric restriction. A drastic restriction of the caloric intake of worms, mice, and rats has been shown to dramatically extend their lifespans. This phenomenon is being investigated to see what it might reveal about the processes involved in aging, and their relation to calorie consumption, with the aim of reproducing the effect in humans without drastic restrictions in caloric intake.
   
   
3. The genetics of aging. Researchers are also seeking the genetic components of the aging process, including both genes involved in the most common diseases of old age, and genes related to extreme longevity. In addition, research into telomeres has shown promise in extending the life of cells, and potentially answering some key questions about aging.
   
   
4. Regenerative medicine. The field of regenerative medicine seeks to develop therapies that reestablish tissue and organ function impaired by disease, trauma or congenital abnormalities.
   
   
5. Hormone treatments. A number of hormone treatments, including Dehydroepiandrosterone (or DHEA), Testosterone, Estrogen, and especially human Growth Hormone, may slow or reverse some age-related physical degeneration, most notably loss of muscle mass.
   
   

This work has yielded some remarkable findings (for instance regarding the effect of caloric restriction on the lifespan of rodents, or a single-gene mutation in fruit flies that can lead to a 50 percent increase in lifespan). The aims, in the long run, are greater vigor in people's later years, and real increases in life expectancy achieved by a dramatic increase in the maximum human lifespan. More than preventing early deaths, this would change the definition of early, extend the vitality of the body over time, and retard the process of aging.

Such research is still in its early stages and, as a group of 51 experts warned in the June, 2002 issue of Scientific American, we must take claims of success with a healthy dose of salt. But although none have yet been developed, it is clear that such techniques are very much desired and are actively being sought. It is therefore not too early to begin to consider the implications of such technologies. The prospect they present-of moving beyond affording more and more people the opportunity to reach the natural limits of life, to begin to seriously push back those limits-must force us to confront some difficult social, political and ethical questions. Among these are:

1. Questions regarding the effect of extended lifespans on society. Many social institutions are based on "age-graded" hierarchies that depend on older individuals at the top making way for younger individuals, and allowing everyone to rise. How might dramatic extensions of healthy active life affect the generational succession that allows these sorts of hierarchies to function? Since such succession is an important stimulus to change, will slower succession mean less adaptive institutions? In addition, the evidence of the past century suggests that increased lifespans tend to be accompanied by decreased birthrates. Will vastly longer lives mean fewer children, and if so how might such aging societies function? What will their priorities and outlooks be? How will families work in such circumstances? How will social and political institutions-like the education system, the retirement system, the healthcare and insurance systems-deal with such changes?
   
   
2. Questions regarding effects of the extension of life on the course of life. Would substantially longer lives alter the rate at which we experience the life-cycle: the length of time spent growing up, in adolescence, at our peak, in decline? How might it affect our ideas concerning time, change, and especially mortality? How could our ability to control the length of life affect our thinking about the breadth and depth of life? Will the fear of death fade, or will it (and especially the fear of sudden or violent death) grow more acute? Would the fact that we might die at any time sting more if we were less attuned to the fact that we must die at some time?
   
   
3. Questions regarding the implications of these technologies for our understanding of medicine. The goals of anti-aging technologies appear in most respects to be continuous with those of medicine more generally: better health and longer life. But the prospect of substantial extensions of life may force us to confront more directly than ever the question of whether all death is premature death, and the assumptions that sit at the heart of modern medicine. Should we in general do everything possible to extend life as far as possible? In principle, is the guiding (if unachievable) goal of medicine to allow us to live vigorously indefinitely? Or is it rather, as the great medieval Muslim scholar Avicenna put it centuries ago, that "the art of maintaining health is not the art of averting death.[it] is the art of guiding the body through its natural span of life"? Our advancing technical powers may soon force us to decide.
   
   
4. Questions regarding the significance and character of aging. Is aging a disease? Is our degeneration and mortality a scourge to be pushed back as far as possible? Or is there some edifying facet to the life cycle, which might be undermined if the cycle was stretched out of shape? Why does the psalmist ask God to "teach us to number our days, that we may apply our hearts unto wisdom," and what did Thomas Jefferson have in mind when he wrote: "my only fear is that I may live too long"?

We all age, and we all live with the knowledge of our mortality. The modern science of aging therefore speaks to us all, and offers the hope of what human beings have always wanted and what medicine has long sought to provide: longer, healthier lives. In this arena, as in so many others, the challenge that confronts us is to understand the meanings and the consequences-good and ill-of our growing power to satisfy our deepest desires.