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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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.

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