You may, or may not, have heard of sirtuins, a family of enzymes that influence the way our genes do their job of making the proteins that run our bodies. But I’d be willing to bet that most of my readers are familiar with resveratrol, the compound found in red wine. That’s because, about twenty years ago, the resveratrol/sirtuin story was front-page news. Since then, the excitement over resveratrol has cooled off somewhat. But, what’s taken its place is a more sophisticated conception of human aging, one that’s mediated by the balance between growth – new proteins, new tissues -- and cellular maintenance and repair. Within this new framework, sirtuins still play a crucial role, not as solo superstars but as ensemble players which interact with other metabolic pathways like mTOR, AMPK and NAD+ to regulate the pace at which we all, in our different ways, grow older. Here’s the topline on what you need to know about this key metabolic player and how to make it work for your health and longevity: 

Ripped from the headlines – the sirtuin story.

In the early ‘90s, researchers at MIT discovered a particular protein in yeast, a member of the sirtuin family. When you boosted its activity, the yeast lived longer. That may not sound like a big deal but then it was the most persuasive evidence we had that aging wasn’t the inevitable result of metabolic wear and tear but rather a process that could be modified. 

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About a decade later, a Harvard lab reported extending the lifespan of worms and fruit flies by enhancing sirtuin activity, feeding them resveratrol, a natural antioxidant (in the polyphenol family) found in fruits like grapes and berries. Then this same lab fed resveratrol to overweight lab mice and saw metabolic improvements, and a modest increase in lifespan, compared to animals who were similarly fat, but not dosed with the compound. That’s when the media frenzy kicked in.

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Because resveratrol was found in even higher concentrations in red wine than in grapes, headlines popped up suggesting you could drink yourself to a ripe old age. Of course, you’d die of alcohol poisoning long before you had a prayer of extending your life, but resveratrol was readily available in supplement form, derived from the Japanese knotweed plant. And the experimental evidence seemed to suggest that this more concentrated resveratrol mimicked the effects of caloric restriction – cutting normal caloric consumption by 15 or 20% -- which was the one intervention that had been proven to sharpen metabolism, prolong youthfulness and extend lifespan. In lab rodents. 

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Imagining that it would have a similar effect in humans was hardly a sure thing, but no matter. Sirtuins became thought of as “longevity genes” and boosting their impact on longevity with resveratrol became all the rage. 

The bloom comes off the resveratrol rose.

The past fifteen or so years have not been kind to resveratrol as a longevity pill. Much of the original Harvard mouse research could not be replicated and it became increasingly obvious that the compound had never been found to extend lifespan in healthy mice, much less people. But scientific interest in longevity-enhancing or “geroscience” compounds didn’t disappear, it shifted, for one, to rapamycin, an immune-suppressing medication taken by organ-transplant patients. 

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Rapamycin, it was discovered, tamped down the body’s metabolic pathway that was responsible for promoting growth, thereby shifting resources to cellular maintenance. (Rapamycin even lent its name to the pathway – “mechanistic target of rapamycin” or mTOR.) And the drug really did make mice live longer. No one’s yet figured how to measure possible longevity gains in the long-lived human species but some studies have shown improved markers of immune and metabolic function that suggested lifespan or, at any rate, healthspan, gains might be possible, at the cost of some not inconsequential side effects. 

This year’s (aging) model.

Over the past decade or so, research driven by the initial excitement over resveratrol and rapamycin has yielded, not a revolutionary anti-aging drug, but a whole new way of looking at aging. Researchers now see the aging process as being profoundly influenced by the body’s balance between growth and maintenance. 

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When the food supply is abundant, the body directs most of the calories you consume to muscle building or fat storage – growth mode. When calories are relatively scarce, the body gets more conservative, and burns them for energy as efficiently as possible, with some of that energy being devoted to cellular maintenance, for instance getting rid of old or “senescent” cells or stripping them for parts to make new cells (“autophagy”). The body’s mTOR pathway is the pro-growth mode; the AMPK pathway, pro-maintenance. After we’ve reached adulthood and adult size, we want as much as possible to tilt the balance towards maintenance, to keep metabolism humming, not gummed up with waste, for as long as humanly possible. 

What about the sirtuins? 

I haven’t forgotten about them. When we are running a lean, clean machine, with AMPK calling the shots, a couple of things happen. Levels of a particular energy molecule, NAD+, increase, to make energy burning more efficient. That in turn activates the sirtuin system which helps with that clean burn and rolls up it sleeves to work on a slew of important metabolic fixes. They help coordinate DNA repair; they help the cells’ power plants, the mitochondria, resist damage; they push back against the pro-aging forces of oxidative stress and inflammation. 

Boosting the sirtuins – the exercise Rx.

Most anything you can do to enhance your body’s resilience will boost the sirtuins, as part of an integrated repair system. And first on your list should be movement, whether that’s brisk everyday physical activity or a dedicated exercise program. A body in motion burns more calories and that boosts NAD+ which then boosts the sirtuins. If you’re going for more bang for the buck, the research suggests that high-intensity interval training (HIIT) and resistance training have the biggest impact on the body’s repair machinery – a short-term healthy or “hormetic” stress that toughens up the system. (But don’t overdo it and cross the line into stress that breaks the body down.) Also, brief exposure to temperature extremes, either hot (saunas, including infra-red saunas) or cold (ice baths, cryotherapy), can provide an extra hormesis lift. 

Fasting for your metabolism.

Modern longevity research came into being back in the 1930s when it was discovered that restricting the calories consumed by lab rats extended their lifespans. We still don’t have any evidence that it will do the same thing for us – and who really wants to go hungry all the time? But with techniques like occasional fasting or any of the various forms of intermittent fasting or time-restricted eating, we can get some of the proven metabolic benefits of running on (near-) empty. Sirtuins are part of that story. 

Sleeping for your sirtuins.

It stands to reason that good sleep practices, which deliver as much time in the restorative deep sleep phase as possible, will loop in the sirtuins as part of the anti-inflammatory, healthspan-enhancing package. And sure enough, research is building a picture of how the sirtuin family helps regulate the genes that are responsible for making our circadian rhythm clocks work. 

Supplementing your sirtuins.

Yes, resveratrol is still on the market and some of my patients say that they feel it’s doing something positive for them. But a more scientifically-grounded supplement strategy might be to lean on several other compounds, sold in supplement form, which are precursors to NAD+. That would be NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide). In theory, increasing levels of NAD+ with these supplements should lift sirtuin activity. So far, some human studies have shown real if modest, metabolic benefit.