The licensed drug rapamycin has potential to be repurposed for geroprotection. A key challenge is to avoid adverse side-effects from continuous dosing regimes. Here we show a profound memory effect of brief, early rapamycin treatment of adults, which extended lifespan in Drosophila to the same degree as lifelong dosing. Lasting memory of earlier rapamycin treatment was mediated by elevated autophagy in enterocytes of the gut, accompanied by increased intestinal lysosomal alpha-mannosidase V (LManV) and lysozyme levels and improved structure and function of the ageing intestine. Brief elevation of autophagy itself induced a long-term increase in autophagy. In mice, a short-term, 3-month treatment in early adulthood also induced a memory effect, with enhanced autophagy in Paneth cells, improved Paneth cell architecture and gut barrier function at levels induced by chronic treatment, even 6 months after rapamycin was withdrawn. Past rapamycin treatment also enhanced the regenerative potential of aged intestine in intestinal organoids. Full geroprotective effects of chronic rapamycin treatment can thus be obtained with a brief pulse of the drug.
Can anyone make sense of this? We’re assuming that rapamycin is working via mTOR inhibition, but we have to keep dosing it, at least at some intervals. So we can achieve adequate inhibition with just some pulse dosing and then stop? Autophagy just needs a kick start? Geroconversion can be interrupted momentarily with long lasting effects? Or are humans different and we need lifelong dosing? Much we don’t yet understand.
Both drug treatments also caused substantial changes in the gut bacteria of the male and female mice, which could be related to effects of rapamycin on metabolism, immunity and health. More studies are needed to uncover precisely how such short-term treatments can yield long-term changes in the body, and how such changes are related to lifespan and healthy aging.
Here, we found that a short rapamycin treatment during early life can prolong lifespan in Mus musculus and Drosophila melanogaster. Notably, the same treatment at later time points has no evident effect on lifespan, suggesting that we found a crucial time-window involved in lifespan modulation
Fascinating discussion. The gut effects are substantial and , as we now know, very important to both health/ lifespan. Of course, we don’t know if short term pulsing would have the same long term benefits in every organ system. We also don’t know how to translate this into actual dosing for humans in a clinical setting. Your gut results are impressive.
The gut microbiome is an “organ” in of itself that affects the big players to a large degree - insulin sensitivity (hunger and craving regulation), atherosclerosis/CVD risk (TMAs), and the brain (ie gut brain axis) - just to name a few.
It literally can affect drugs/compounds/nutrient intake and produces a huge range of metabolites.
Puts a whole new dimension of “you are what you eat”