Leonard Guarente Ph.D.

The New Old Age

Can We Stop the Effects of Aging With a Pill?

The science of calorie restriction mimetics makes this future not so far off.

Posted Aug 20, 2019

Zak Bickel for Elysium Health, Used with permission
The arrival of drugs or supplements that deliver many of the anti-aging benefits of calorie restriction without side effects.
Source: Zak Bickel for Elysium Health, Used with permission

Every so often, a wise older person makes the news for passing their 100-year mark. In 2013, a then 105-year-old great grandmother Pearl Cantrell made headlines when she said the secret to her long life was a daily serving of bacon. More recently, 107-year-old Louise Signore told USA Today her advice: Never get married.

Cantrell and Signore, whose contrarian quips both went viral, are of course just two extraordinary people sharing anecdotal advice. No scientist or medical expert would tell you to eat bacon or skip marriage for your health. Nonetheless, both of these stories contain a kernel of truth: What’s the use in living long if you’re not going to enjoy your life?

Last month, we went over the fascinating science of calorie restriction (CR) for delaying disease and increasing longevity. For decades, scientists have known that reducing food intake to just enough to meet nutrient needs can extend lifespan. More recent scientific advances found that CR slows aging by activating specific genes and pathways.

But anyone who’s been on any kind of restricted diet knows that’s no way to live, and it’s nearly impossible to keep up with a strict CR regimen over the long term. That’s where CR mimetics—drugs or supplements that elicit the slow-aging mechanisms of CR—come in. The promise is that mimetics could deliver the benefits of calorie restriction without any of the negative side effects. 

Best of all, CR mimetics might not be as far off as you might think. Currently, there are three very promising potential strategies in the pipeline, all of which have been proven to extend the lifespan of animals in preclinical studies. 

The first is supplementation with what scientists call “sirtuin activators,” a number of which are currently on the market. Sirtuins are a group of related proteins in your cells that are involved in a variety of important processes, like DNA repair, epigenetics, and mitochondrial function. Numerous studies have shown that sirtuins are activated by CR, and, conversely, when their activities are blocked, the benefits of CR are prevented. Therefore, sirtuin activation is likely one mechanism by which CR works. Given the potential benefits of activating sirtuins via CR, scientists have searched for natural compounds that mimic its effects and yielded a number of promising leads. 

For example, resveratrol, a compound famously found in red wine and certain berries, is among the most potent. In mice, resveratrol supplementation has been shown to improve metabolic health and slow down the effects of aging. In monkeys, resveratrol supplementation was shown to prevent hardening of the arteries. In humans, however, studies have given mixed results, at best, leading to a search for analogs that work better. One of these is pterostilbene, another natural compound which is found in blueberries.

A second way to activate sirtuins rests on the fact that their activities are dependent on a coenzyme synthesized in cells called NAD+. NAD+ levels decline naturally with age, so replenishing it with supplementation may keep sirtuins active for longer. NAD+ precursors like nicotinamide riboside (NR) boost NAD+ levels in cells and, like resveratrol, confer many health benefits in mice. A novel strategy is to combine an NAD+ booster with a resveratrol analog to hit sirtuins with a one-two punch for maximal effect. This is the strategy underlying the ingredients in Basis, a cellular health supplement based on my research and brought to market by Elysium Health, of which I am a co-founder.  

A different approach employs a compound called rapamycin, which was discovered in a long-forgotten soil sample taken from Easter Island. In the 1970s, it was found to be a powerful immunosuppressant and in 1999, it was approved by the FDA for use in transplant patients. 

Rapamycin works by inhibiting a protein called mTOR, which is important for cell metabolism and has been shown to play a role in longevity. By inhibiting mTOR, rapamycin slows down protein synthesis and activates autophagy, a process by which cells recycle their components and which also happens under CR. Mouse studies have shown that rapamycin increases lifespan; on average mice fed rapamycin will live 25 percent longer. We can’t forget, however, that rapamycin has the disadvantage of suppressing the immune system, although this might possibly be mitigated by careful dosing.

Finally, there’s the prescription drug metformin, which has been used to treat diabetes for many years and is still the front-line therapy for this disease. Interest in metformin as an anti-aging drug has grown because mouse studies show that low-doses of metformin can increase lifespan. At a molecular level, it is thought that metformin works by targeting another protein called AMP-kinase, which is normally upregulated by an energy deficit in cells. 

For all three of the potential mimetics discussed here, the pre-clinical data is very promising. Under normal CR, it's likely that all three of these processes are happening: sirtuins and AMP-kinase are up-regulated, and mTOR is down-regulated. And because lifespan is indeed extended by all three, it’s probable that there is cross-talk—such that if you target one with a mimetic, a chain reaction occurs that activates all of them. 

Supplementation with sirtuin activators is actionable right now because these compounds are already available and are unlikely to lead to negative side effects. Likewise, because of metformin’s long-term use, we can assume that it’s a relatively safe drug, but its off-label use to combat the effects of aging will require further study. So, there is great excitement that the next few years will reveal the true potential of CR mimetics to maintain robust health and forestall major diseases of aging.