Highlights:

  • Dr. Attia categorizes widely touted longevity interventions based on their scientific backing, labeling them as proven, promising, fuzzy, noise, or nonsense. 
  • Dr. Attia classifies rapamycin as promising, metformin and fasting as fuzzy, and resveratrol as nonsense. 

In the 300th episode of The Drive podcast, hosted by Dr. Peter Attia, the popular physician and best-selling author shared his thoughts on several widely-touted health interventions, categorizing them as “proven, promising, fuzzy, noise, or nonsense.” As requested by his viewers, Dr. Attia sheds light on the science behind rapamycin, metformin, and resveratrol, clarifying their potential longevity benefits. Furthermore, Dr. Attia reflects on long-term fasting and caloric restriction, two aging interventions with strong scientific backing. 

Rapamycin

Dr. Attia kickstarts the conversation on geroprotective drugs by providing insight into one of the most talked about longevity-related drugs in existence, rapamycin. Originally used for its antifungal and immunosuppressive properties, rapamycin has repeatedly demonstrated its ability to extend lifespan across nearly all model organisms. 

Notably, the Interventions Testing Program (ITP), “a peer-reviewed program designed to identify agents that can extend lifespan and healthspan in mice,” confirms rapamycin’s potential to prolong lifespan. That being said, Dr. Attia points out that there is not enough human data to support rapamycin’s pro-longevity effects in humans. For this reason, he puts rapamycin in the “promising” category. 

“I think we still have a ways to go before we could say the following: Rapamycin is a geroprotective towards humans and taking rapamycin according to protocol X will add years to human life and presumably improve healthspan,” concludes Dr. Attia. 

Although the full effects of rapamycin remain unclear, its mechanism is understood fairly well. In fact, studies suggest that rapamycin’s mechanism mimics that of caloric restriction, another intervention shown to extend lifespan. Accordingly, rapamycin works by inhibiting mTOR – a key modulator of cellular growth and protein synthesis – and this inhibition is tied to increased autophagy.

Autophagy is the body’s process of clearing out damaged cells to repair and rejuvenate itself. Research has shown that enhancing autophagy not only mitigates neurodegenerative disease but also staves off oxidative stress, inflammation, and mitochondrial dysfunction, all of which are hallmarks of aging. 

Collectively, the current body of evidence suggests that rapamycin is indeed a geroprotective – a compound that aims to target the hallmarks of aging with the goal of prolonging lifespan and healthspan in organisms. 

Metformin

Following his discussion on rapamycin, Dr. Attia shifts the conversation to metformin, a popular FDA-approved type 2 diabetes drug that has been explored for its potential anti-aging benefits. Initially, Dr. Attia considered metformin as “promising” based on well-supported epidemiological studies suggesting that diabetics taking metformin have lower all-cause mortality than diabetics not taking metformin. 

However, his view has shifted and now puts metformin in the “fuzzy” category due to concerns over the methodological flaws in these studies and inconsistent results from animal models. To clarify, according to Dr. Attia, “fuzzy” means that while some data suggests potential health benefits, the evidence is inconsistent and unclear, thus warranting further investigation. Interestingly, scientists created the Targeting Aging with Metformin (TAME) trial to assess metformin’s impact on delaying age-related diseases in non-diabetic individuals, which will likely provide more clarity around metformin’s effect on lifespan and healthspan.  

Metformin’s cellular mechanisms are not fully understood, but research suggests that it activates an enzyme called AMPK, which has strong ties to several longevity-linked pathways. Once activated, AMPK enhances the metabolism of fats and sugars to increase energy levels, promotes autophagy, boosts antioxidant defenses, and reduces inflammation. Consequently, metformin is considered a leading candidate for anti-aging therapies. Still, Dr. Attia remains skeptical about metformin’s geroprotective effects. 

Resveratrol 

Following metformin’s analysis, Dr. Attia was asked about the potential geroprotective effects of resveratrol, a plant-based polyphenol found in grapes and peanuts. 

“I’m amazed people are still talking about resveratrol. This is absolute nonsense,” responded Dr. Attia. 

Dr. Attia believes resveratrol’s hype gained traction due to the fact it is found in wine. And while red wine contains small amounts of resveratrol, these concentrations pale in comparison to the doses commonly used in animal studies investigating resveratrol’s potential health benefits. Dr. Attia also mentions that the excitement around resveratrol stemmed from research showing it activates sirtuins, a family of guardian proteins involved in DNA repair and cellular survival processes.  

Despite resveratrol’s relationship with sirtuins, Dr. Attia asserts that there is just not enough evidence in animals or humans to suggest that resveratrol has any efficacy in prolonging lifespan or healthspan. Thus, he puts resveratrol in the “nonsense” category and states that it is likely not a geroprotective compound.

Long-Term Fasting  

Beyond geroprotective compounds, Dr. Attia dives into two science-backed dietary aging interventions shown to increase lifespan in several model organisms: long-term fasting and caloric restriction (CR) – limiting calories without malnourishment. Notably, CR has been shown to inhibit mTOR (similar to rapamycin) and increase AMPK activation (similar to metformin), further demonstrating that these two molecular pathways play crucial roles in regulating cellular aging and longevity. 

Dr. Attia states, “There’s clearly something magical about caloric restriction when it comes to elongating life. But the question is, can we extend that into humans? And perhaps the more important question is, what would the fasting protocol be? How long should you fast? To what extent should you fast? And how frequently should you repeat that fast?” 

Due to these complex variables, Dr. Attia believes it is too difficult to establish a universal fasting protocol and stresses that there is not enough data to answer these important questions. Moreover, he points out that it is unlikely humans will participate in a human trial where they have to stick to a fasting protocol for the entire duration of their lives. Because of this, Dr. Attia puts fasting and CR in the “fuzzy” category, stating that we need to come up with “better proxies and meaningful biomarkers of the hallmarks of aging.” 

Despite these uncertainties, Dr. Attia created his own fasting protocol, mentioning that he used to do a water-only fast for 7-10 days once a quarter and a 3 day water-only fast once a month. He stuck to this fasting protocol for 3 years, stating that it improved standard biological markers like glucose, insulin, and ketone levels. But he points out that he lost nearly 20 pounds of muscle and that the protocol eventually did not fit his lifestyle, which ultimately convinced him to switch to a regular caloric-restricted diet. 

Final Thoughts

Overall, Dr. Attia’s analysis provides critical insight into the complexities of geroprotective compounds and longevity interventions. Furthermore, his analysis highlights the importance of conducting robust human studies, urging caution against prematurely implementing interventions lacking scientific merit. Nevertheless, Dr. Attia acknowledges that new evidence can arise at any moment and states that his stance on these aging interventions could change in the future.