For middle-aged mice, these are the best of times. Scientists now understand genetic factors that lead to the development of disease, disability, and death—in mice. Most importantly, researchers have found ways to improve the “healthspan,” the period of disease- and disability-free life before death—in mice. The question is whether the approaches they are developing will be applicable to people, and the ethical implications if they are.
The basic ideas are spelled out in a trio of “viewpoint” articles published in JAMA last week. S. Jay Olshansky, writing from an epidemiologic perspective, observes that over the past century, dramatic gains in life expectancy have been accomplished by reducing in mortality of children and young adults. But once these gains have been made, the only remaining way to lengthen life expectancy is by extending the lives of people at the other end of the age spectrum. Medical science has therefore concentrated on tackling the diseases of old age, one by one. Unfortunately, as Barzilai et al comment in their essay, “efforts focused on preventing individual diseases will have limited net effect on population health because one disease will be exchanged for another.” We’re already seeing this phenomenon: as fewer people die of heart disease, they develop and die of Alzheimer’s instead. Far better would be to tackle the aging process itself. Targeting the underlying driver of all the chronic diseases at once could, in principle, prevent or at least delay those disorders.
So, what do we know about turning off biological aging? We know there’s a gene in mice with the euphonious name rps6kb1 and if it’s “knocked out” (molecular genetics speak for “inactivated”), female mice live longer, healthier lives. We know there’s another gene called Sirt6 (short for Sirtuin 6), which is present in multiple mammalian species including humans, and if it is “overexpressed” (genetics speak for “turned on”) in male mice, they live longer. We also know that all creatures including people have “senescent cells,” cells that, old cells that start releasing all kinds of chemicals. When an individual has more than some threshold number of such cells, it develops chronic diseases, frailty, and is at high risk of dying. When the senescent cells of a mouse are destroyed, the mouse lives longer and without a long period of deterioration before death.
And what progress has been made in identifying drugs that achieve these goals in mice? And what about in people? Reportedly, the Interventions Testing Program, funded by the National Institute on Aging, has examined 26 “candidate drugs” for their effects on mice. They have identified 6, including the anti-inflammatory drug, aspirin, the anti-diabetes drug, acarbose, the immunosuppressive drug, rapamycin, and the estrogen, 17a-estradiol, as effective in some mice. Intervening in mice of an age equivalent to 70 human years has “extended life by more than 20 years and increase[d] health span even more substantially.” Other studies have found that the drug dasatinib (related to the anti-cancer drug, Tarceva) has a powerful effect in destroying senescent cells. In mice that are the equivalent of 80 human years, treatment with dasatinib combined with quercetin (a plant chemical found in green tea, red wine, apples, and other foods) increases survival 36 percent without increasing disability before death.
We don’t know whether any of these chemicals work in humans. And we have no idea at all whether they will produce side effects, though we do know that earlier attempts to interfere with cell lifespan were associated with the development of cancer. This is not entirely surprising, as the essence of cancer is uncontrolled cell proliferation. So even the very upbeat article by Tchkonia and Kirkland, the third of the triad, ends on a cautionary note: “…Patients should be advised not to self-medicate with senolytic agents or other drugs that target fundamental aging processes in the expectation that conditions alleviated in mice will be alleviated in people.”
If, years from now, human studies indicate the drugs or others like them are effective, we will have to deal with the ethical implications of extending the “healthspan.” What will they cost? Will everyone have access to such medications? Will we create greater inequality within society? Between countries? Banning such research on the grounds that a ballooning of the elderly population is unsustainable is almost certainly going to be impossible—the lure of more disease-free life will be irresistible. But we can begin to think about the consequences of our brave new world.
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