The Achilles’ Heel of Aging

The Big Idea by David Sinclair / April 20, 2009

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.

Illustration: Dextro

The chief causes of natural death among the elderly form a concise set: Heart disease and cancer are the big killers, with strokes, Alzheimer’s, diabetes, or opportunistic infections claiming most of the rest. Until recently, we’ve focused on attacking each of these diseases separately, but we’ve made little progress; despite developed countries’ collectively spending untold billions of dollars pursuing this elusive goal, eventually something from the same old rogue’s gallery seems to arrive for everyone.

This could all soon change, thanks to a recent, astonishing discovery of genetic pathways that defend against aging. This has opened up, for the first time, the possibility that we can develop medicines that will not only help us live longer but also reach the ends of our lives more gracefully, free from the pernicious diseases that would otherwise plague us. In other words, with the help of drugs already in human trials, there is now a chance that you will be able to dance at your great-granddaughter’s wedding just as you did at your own.

In a way, this isn’t terribly new, because a proven method to extend life already exists; scientists have known about it since the 1930s. It’s called calorie restriction, or CR. Feed a mouse a nutritious diet that has 30 percent fewer calories, and she lives 30 percent longer than the one in the next cage. Nor is she condemned to an extended, prolonged period of senescence; on less food, she lives longer and better, resistant to age-related diseases.

Although we’ve been able to reliably slow aging in lab animals since the Jazz Age, for most of us — myself included — eating 30 percent less simply isn’t a realistic way to dodge the aging bullet, and it’s certainly not an option for the very sick or the elderly. So, for 80 years, scientists have chased the dream of a CR mimetic, something that can do for the body what CR does without requiring us to forgo dinner.

Twenty years ago, if you’d suggested to a parlor full of erudite doctors and professors that something as complicated as aging might be controlled by a small set of genes, you would have been laughed out of the room. But that was precisely what Drs. Cynthia Kenyon, Tom Johnson, and Gary Ruvkun demonstrated in their landmark studies of the roundworm C. elegans in the 1990s. Now, thanks to those trailblazers and my mentor, Dr. Lenny Guarente, we have isolated those genes and discovered ways to tweak them to our advantage.

I began my career in aging research studying baker’s yeast in Guarente’s lab at MIT in the mid-1990s. It’s quite understandable that many scientists at the time were skeptical that any knowledge of relevance to humans would come out of these single-celled organisms, a pile of which would barely cover the period at the end of this sentence. But two discoveries of great interest came from those studies: We learned that yeast cells age because their DNA breaks and gets tangled, and that an enzyme called sir2 slows this process down, extending lifespan by 20 to 30 percent as a result.

This might have been the end of the story, but it turned out that sir2 belongs to a regulatory protein family called the sirtuins, which appear in many organisms, from plants to fruit flies to humans. In humans sirtuin is coded for by a gene called SIRT1. Sirtuins have been conserved by natural selection for a very long time, more than a billion years, because they do something very important. When they’re switched on in an organism, they promote an ultra-protective “maintenance mode,” one that shields against the biochemical deterioration that increases the chance of disease over time. So it’s no accident that they play a role in controlling energy metabolism, endurance, and even the ability to resist cancer. And environmental stress, like calorie restriction, is what sends sirtuins into overdrive.

But this raises a crucial question: With sirtuins on board, why do we age at all? Part of the answer is that there are many processes that cause aging, including some we probably don’t yet know about. My colleagues and I recently published a paper in Cell identifying a previously unrecognized potential cause. We’ve all had days where we find ourselves pulled in too many directions, doing too many things, and none of them particularly well. Aging could be what happens when sirtuins find themselves in the same bind. This is because in yeast and mammals they serve a dual function. Their primary task is to ensure that only the appropriate genes get expressed in any given cell, but their other role is to repair broken DNA in the cell. We propose that when we’re young, SIRT1 juggles both responsibilities fairly easily. But the older we get, the more DNA damage we accrue. As the sirtuins leave their primary posts to address the DNA problem, the ability of our cells to properly control which genes are expressed suffers proportionately, which raises the risk of diseases like cancer and Alzheimer’s. But boosting levels of SIRT1 appears to solve the labor problem — there’s enough to tackle DNA damage while still ensuring that gene expression occurs appropriately in old age.

Even before we knew why, we knew that having more SIRT1 was better for organisms, but we didn’t seriously expect to find a molecule to increase SIRT1’s efficiency; that would be akin to finding a wrench that makes a Ferrari go twice as fast. But in 2003, Dr. Konrad Howitz and Dr. Robert Zipkin of Biomol Labs notified me about some molecules that seemed to activate SIRT1, and we teamed up to test them further. One of the molecules was resveratrol, a protective compound that many plants produce when they are besieged by bacterial or fungal infection. Due to its presence in the skins of red grapes, resveratrol is found in red wine (this may help explain how the French eat high-fat diets with what appear to be few adverse health effects). Our research paper proposing that resveratrol activates SIRT1 and thereby extends the lifespan of yeast cells was published at the end of 2003 in the journal Nature. Since then, I’ve been lucky to work with prominent scientists, including Steve Helfand and Marc Tatar, to show that resveratrol extends the lifespan of nematode worms and fruit flies as well.

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.