The Achilles’ Heel of Aging

The Big Idea / by David Sinclair /

Understanding the biological basis of senescence may allow us to delay or prevent the degenerative declines long accepted as an inevitable part of getting older.

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The next step was testing this in mammals. In 2004 my lab teamed up with Dr. Rafael de Cabo at the National Institutes of Health to see if resveratrol could improve the health and extend the lifespan of mice. When middle-aged mice were fed a low-fat diet, resveratrol delayed diseases of aging but did not extend lifespan. When fed a high-fat diet, mice on resveratrol got chubby but stayed healthy — they were less susceptible to diseases we associate with obesity, like type II diabetes. And with a sufficiently high resveratrol dose, they burned enough fat to stay lean. What’s more, the resveratrol mice on the high-fat diet ran twice as far on a treadmill as their unmedicated counterparts, and their remaining lifespan after treatment began increasing by an average of 25 percent compared with the high-fat controls. Notably, in both the obese and the lean mice on resveratrol, there was the clear physiological signature of calorie restriction.

The trouble is, while resveratrol is found in many foods, it is present only in very low concentrations. Someone wanting to get a resveratrol dose equivalent to what we used in our mice studies would need to consume hundreds of bottles of red wine each day. Resveratrol has served its purpose, proving the possibility of inducing the physiology of dieting and exercise with a small molecule. Now pharmaceutical companies are working on synthetic molecules that are thousands of times as potent as resveratrol: The race to develop a drug that targets sirtuins is on, though the longterm effect of activating sirtuins in humans requires further research. If the mice studies are anything to go by, the side effects of these drugs could include protection from multiple illnesses, including heart disease, osteoporosis, cataracts, and Alzheimer’s.

Paradoxically, the prospect of powerful drugs to combat aging elicits very negative feelings in many people, who presumably see age-related decline as “natural” and therefore preferable. This strikes me as misguided. In the early 16th century, Francis Bacon wrote in The Advancement of Learning that “there is no nobler cause than the prolongation of life.” And this, along with reducing suffering, is the role of doctors and medical researchers in our society.

During the Victorian era, children commonly died of illnesses like measles, mumps, and whooping cough; surely, no one would suggest today that we eliminate prenatal care, vaccines, or water purification in order to return to a more “natural” state. Now that we have the technology to eliminate the scourge of infant mortality, it would be immoral to not use it. In truth, we’re fighting aging and extending lifespan every time a doctor prescribes a statin drug or recommends a healthier diet to a patient. And the fact remains that science has not yet discovered an indisputable biological “expiration date” for a human life, nor is there good evidence that one exists.

In time, the idea of an inevitable, debilitating decline starting at age 50 will seem as horrifying and primitive as it does for us, in the age of potent antibiotic cocktails, to imagine a young person in the 19th century dying from an infection caused by a splinter. As a society, we should not accept a terrible period of suffering, dependence, sickness, and frailty if we don’t have to. There’s nothing more natural than marshalling the body’s own defenses to treat and heal itself, and that is precisely what longevity genes like SIRT1 do.

Of course, we must really consider what the world could be like if it’s routine to live in good health until the age of 90 or 100. Some predict overpopulation and financial ruin, but we have adapted to similar changes in health and lifespan before. People used to raise seven or eight children as a matter of course; now that so many more children live to adulthood in the developed world, we have fewer of them. As we have seen any number of times — most recently with the lifespan increase afforded by the advent of antibiotics — institutions like marriage, family, and work evolve along with changes in lifespan. We should have time to adjust to a new surge in longevity.

In fact, economic forecasters are already predicting a “longevity dividend.” The costs of treating a chronically sick population like today’s elderly are ruinous, and the graying of the boomer generation threatens to overwhelm an already overburdened health care system. Pushing the occurrence of diabetes, heart disease, and cancer to the outermost limits of our lifespan represents an astronomical savings, both in direct medical costs and otherwise lost productivity. For instance, a joint study from the University of Chicago and National Bureau of Economic Research concluded that a 1 percent reduction in cancer mortality alone would save $500 billion — and that’s just one disease. By comparison, a pill that could eventually emerge from this research would likely cost about as much as the average cholesterol drug does: around a dollar a day. Given these numbers, it may come as a surprise that research on longevity genes is conducted by only a handful of devoted scientists who receive a small fraction — 0.6 percent, to be exact — of the National Institutes of Health’s annual budget.

It is premature to call these drugs a sure thing, but we already have come much further than I expected to witness in my lifetime. Each morning, I awaken excited to see what new discovery the day may bring, for soon we’ll know whether ours will be the last generation in human history to merely dream of a healthy, vibrant life beyond 90 — or become the very first generation to experience it.  — David Sinclair is a professor of pathology at Harvard Medical School. He is also a consultant to Sirtris, a GlaxoSmithKline company developing sirtuin-based drugs, and to the vaccine company Genocea.

Originally published April 20, 2009

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