Full geroprotection from brief rapamycin treatment by persistently increased intestinal autophagy

Abstract

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 levels of intestinal lysosomal alpha-mannosidase V (LManV), proteins involved in branched-chain amino acid metabolism and lysozyme levels, and by maintained structure and function of the ageing intestine. Brief elevation of autophagy in early adulthood 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 maintenance similar to that seen with chronic treatment, of lysozyme distribution, Man2B1 level in intestinal crypts, Paneth cell architecture and gut barrier function, even 6 months after rapamycin was withdrawn. The geroprotective effects of chronic rapamycin treatment can thus be obtained with a brief pulse of the drug in early adulthood.