September 17, 2008
Listening to Resveratrol
By Kent, David M
IN MY CAMBRIDGE, Massachusetts, neighborhood, competing restaurants have promoted opposing gastronomic and life strategies. The motto at Jae's, a "nouvelle" Pan-Asian cafe specializing in presenting small, stylized foods on oversized white plates, was "Eat at Jae's. Live forever!" The sign next door at Jake and Earl's take- out grill read "Eat BBQ. Die Happy!" Although neither establishment survived long, the stark choice that together they presented- between a savory, greasy gluttony and a long life-conforms to some deeply rooted and more enduring puritanical logic. Indeed, until recently the only approach researchers had found to effectively extend lifespan-whether in a single-celled organism or a mammal-was through severe caloric restriction. Countless people have accordingly taken up caloric-restriction diets in the hope that it will work in humans too. Though this tactic is unproven, my friends who have tried it assure me that, at the very least, their lives will certainly seem longer. Biotechnology, however, presently promises to offer us a more palatable means of attaining a longer life than perpetual semi-starvation.Calorie deprivation appears to slow aging through the activation of members of a family of enzymes called sirtuins, which belong to a larger group called deacetylases. These enzymes appear to reduce cell death by protecting cells against reactive oxygen species and DNA damage. Perhaps the most seminal work in this area came from David A. Sinclair's laboratory at Harvard, which described a group of compounds, including resveratrol (famously in red wine), that stimulate the activity of sirtuins across a variety of species. Resveratrol also has been found to increase lifespan in a variety of laboratory animals, including simple worms, fruit flies and short- lived fish. More recently, Sinclair and his colleagues reported that resveratrol can improve health and survival in mice fed a high- calorie diet (perhaps of Jake and Earl's BBQ).
Not surprisingly, these findings led to a spike in the sale of red wine (which apparently has such small amounts of active resveratrol as to be biologically inert at drinkable doses) as well as over-the-counter nonalcoholic wine-derived dietary supplements (of variable activity). In order to develop and bring to market more potent-and patentable-alternatives, Sinclair helped to create a company, called Sirtris. In June of this year, only four years after it was founded, Sirtris was bought by the pharmaceutical giant GlaxoSmithKline for a tidy $720 million. Who can doubt that commercially available life-extending compounds are around the corner? Even if the effects in humans are less dramatic than those of resveratrol in yeast (60 percent increase in replicative lifespan) or than in the overfed mouse (15 percent increase in lifespan), it seems that we are on the cusp of a dramatic shift in medicine, one for which we may not be fully prepared.
Life's Natural Limits
In the July 1980 issue of the New England Journal of Medicine, James F. Fries proposed an influential model of health and illness based on the observation that there appear to be, even in the absence of disease, natural limits to the human lifespan. According to this view, aging is a natural and inevitable part of life. It is marked by a decline in organ function that begins in our 30s and eventually reaches a critical state in which even small perturbations in homeostasis cannot be tolerated. The benefits of modern medicine, it follows, would be confined to preventing premature death and compressing sickness toward the end of life, not fundamentally prolonging our natural lifespan.
Fries supported his model with a set of curves that plot survival against age over the 20th century (see the graph on page 360). As the curves show, improvements in medicine and public health have increased average life expectancy at birth enormously (close to 30 years), whereas the life expectancy of an 80-year-old has hardly increased at all (about two years). This "rectangularization" of the life expectancy function lends support to Fries's concept of fundamental limits on the human lifespan, and suggests that-at least for richer segments of the population-life expectancy is approaching those limits. Therefore, according to Fries, in the future we should expect diminishing returns in mortality gains for new treatments of infectious diseases, cardiovascular diseases, cancer and the like. Medical innovation, he argued, should concentrate instead on living better, by "compressing" morbidity to the very end of life, not on living longer.
However, discoveries in more basic sciences, such as our developing understanding of sirtuin activators, suggest that this model may be at least half wrong. There may be natural limits to the mortality gains we should expect from disease-specific therapies, as Fries suggested. But by influencing the basic mechanisms underlying aging, medical innovations of the 21st century may yet increase the human lifespan in ways he did not foresee. Indeed, since the remaining frontier for mortality reduction is largely at the end of life, aging itself will have to be addressed and the shape of progress must be altered if there are to be any mortality gains from our huge investment in medical science and technology. Thus, a new set of curves, extending life expectancy beyond the frontier at the far right of the survival function, could well describe gains in life expectancy in the coming 100 years.
We may be on the brink of an important and unrecognized change in medical technology development, one that raises important questions about the future of medicine and human health.
How will we test the efficacy and safety of new life-prolonging technologies?
Currently our drug development and approval systems aim at disease-specific treatments. Indeed, the Food and Drug Administration approves medications only for specific indications, and "mortality," a universal condition, would seem unlikely to qualify under the current system. Further, if senescence begins in one's 30s but the outcome (that is, death) can be measured only in one's 70s or 80s, how will researchers be able to perform timely clinical trials in humans? Sinclair and others hoping to commercialize anti-aging elixirs have devised a strategy of testing agents for the treatment of age-related diseases, such as specific forms of cancer, Alzheimer's disease and heart disease. Yet Sinclair also reports that he started taking resveratrol in his 30s-a reasonable course for an anti-aging agent-but such use will remain "off-label" unless we create a new system, including reliable surrogate outcomes, to test and approve such compounds for this purpose.
How much will life-prolonging therapies cost-and who will pay?
Health insurance is based on the principle of risk pooling. Because nobody can be certain that they will remain healthy, the disease-free are willing to share the cost burden with the sick, who often are unable to handle the expense of their own care. This approach works with disease-oriented treatments in which risks are pooled across those people who could and those who actually do develop an illness. But if resveratrol-like drugs are recommended for everybody over 30 at risk for mortality (a universal condition), there would be no risk pooling; insurance premiums for everybody would just go up by the drugs' cost (plus an administrative fee).
Although drug pricing strategies remain a deeply held trade secret among pharmaceutical companies, there is little doubt that there will be consumers willing to pay very high prices for life- prolonging elixirs, even for drugs with a relatively small incremental benefit. The optimal pricing strategy for such agents might put them well out of reach of the poor and possibly also some of the middle class. Since multiple cellular pathways are probably involved in aging, there are sure to be multiple medicines in our antiaging cocktail. The rich have always lived longer and healthier lives than the poor, and new lifespan-extending technologies could widen this gap.
Should access to resveratrol and other such agents be an entitlement? Many societies see access to health care to cure diseases and rescue patients from premature death as a matter of equity. What ethical attitude will we take toward 21st-century medical technologies aimed at challenging the limits of our natural lifespan?
How will lifespan-prolonging therapies affect population growth and demographic structure, and what will be the consequences?
In the past century, disease-specific medicine reduced mortality at all ages, including the economically productive years between one's 20s and 60s. But the rectangularization of the mortality curve implies that life-prolonging therapies will add years only at the end of life. Unless there is a shift in the retirement age, 21st- century medical innovation will have an even more dramatic effect on the dependency ratio (a measure of the portion of a population composed of those either too old or too young to work). Maintaining retirement as a widespread option at around 65, already an economic stretch, undoubtedly will become untenable. The price of longer life will almost certainly be a longer work life. Society's Demands
There are many who would argue that significant extension of the human lifespan remains a pipe dream. Aging, they argue, is an over- determined process of cellular entropy, a ubiquitous force with so much empirical evidence that it has its own law of thermodynamics. There are too many cellular pathways that would have to be halted or reversed in order to alter aging. But if we were mice, this inevitable process would culminate in two years, not 85 years; if we were dogs in about 12 years. The extreme elasticity of aging is evident in the range of lifespans among our mammalian cousins.
Indeed, the plasticity of lifespan across species is not mere accident, but a consequence of one of the central levers of evolution. In his 1977 book Ontogeny and Phylogeny, Steven J. Gould provides a persuasive account of how changes in the timing of developmental events have manifold consequences on size, form and life history, such that small alterations in the regulatory genes governing these processes may be a central mechanism of evolution. seen in this way, lifespan is a fundamental part of the identity of an organism. It is a well-accepted rule that natural selection among complexly social animals favors delayed development; this delay permits the expansion of the central nervous system necessary for complex social life and a prolonged apprenticeship before sexual maturation. Such trends among social animals have reached an extreme in humans: we exhibit delayed sexual maturation, long gestation, reduced number of offspring and long and intense parental support.
As social complexity has increased through cultural evolution, our need for increased differentiation and specialization has outstripped even our extreme biological adaptations. In my own field of medicine, it is typical for training and apprenticeship to extend well into the fourth decade of life. Recently, in vitro fertilization has been enthusiastically adopted into our culture to allow women to defer childbearing beyond their natural period of fertility, permitting women to more fully participate and compete in the workplace. Among most people I know, technology-assisted pregnancy in one's fifth decade is seen as more normal than pregnancy in one's late teens, a time where natural fertility is near its peak. Given their early, yet unmistakable, signs of talent and ambition, and the ever-increasing complexity of the global society and market in which they'll need to find their place, my own daughters (ages two and six) might well opt to defer childbearing until well after they are 40. Indeed, should they choose to do so, I am certain that they will have the technology to enable this choice, and perhaps also anti-aging agents that would still permit them to dance at their own grandchildren's weddings.
In this way, resveratrol-like agents may truly be medicines for the 21st century, permitting humans to tinker with the clock of our own development. Through such means we may be able to adjust our life history to meet the demands of an emerging society that changes in ways that seem beyond our control. Judging from our past behavior, it is hard to imagine that science or the marketplace will pause very long to consider the important questions raised by the possibility of life-prolonging pharmaceuticals. It seems hardly a fair fight when the potential and uncertain consequences to society are pitted against the urgent, deeply rooted, biologically programmed desires and demands of the individuals of which it is composed.
Could the famous ingredient of red wine herald a new era in medicine?
Fries, J. F. 1983. The compression of morbidity. The Millbank Memorial Fund Quarterly 61:397-419.
Fries, J. F. 1980. Aging, natural death and the compression of morbidity. The New England Journal of Medicine 303:130-135.
Wood, J., et al 2004. Sirtuin activators mimic calorie restriction and delay aging in metazoans. Nature 430:686-689.
David M. Kent is an associate professor of medicine at Tufts Medical Center and an associate professor of clinical research at the Sackler School for Graduate Biomedical Sciences of Tufts University. Address: Tufts Medical Center, 800 Washington St #63, Boston MA 02111. Internet: [email protected]
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