Of all of the pharmaceutical approaches to slowing aging, rapamycin has the best, most robust, largest body of evidence from animal studies. Rapamycin is an mTOR inhibitor, mimicking some of the beneficial effects of calorie restriction on metabolism, long-term health, and life span. The most important outcome is thought to be improved autophagy, the cell maintenance process responsible for recycling unwanted proteins and structures in the cell. While rapamycin has been widely used for a long time at relatively high doses, there remains comparatively little human data at lower, anti-aging doses. Still, what data there is paints the picture of a safe drug with few to no side-effects.
Dietary restriction (DR) robustly increases lifespan across taxa. However, in humans, long-term DR is difficult to maintain, leading to the search for compounds that regulate metabolism and increase lifespan without reducing caloric intake. The magnitude of lifespan extension from two such compounds, rapamycin and metformin, remains inconclusive, particularly in vertebrates. Here, we conducted a meta-analysis comparing lifespan extension conferred by rapamycin and metformin to DR-mediated lifespan extension across vertebrates. We assessed whether these effects were sex- and, when considering DR, treatment-specific.
In total, we analysed 911 effect sizes from 167 papers covering eight different vertebrate species. We find that DR robustly extends lifespan and, importantly, rapamycin - but not metformin - produced a significant lifespan extension. We also observed no consistent effect of sex across all treatments and log-response measures. Furthermore, we found that the effect of DR was robust to differences in the type of DR methodology used. However, high heterogeneity and significant publication bias influenced results across all treatments. Additionally, results were sensitive to how lifespan was reported, although some consistent patterns still emerged. Overall, this study suggests that rapamycin and DR confer comparable lifespan extension across a broad range of vertebrates.
Link: https://doi.org/10.1111/acel.70131
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