Long-lasting geroprotection from brief rapamycin treatment in early adulthood 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. Here we show that geroprotective effects of chronic rapamycin treatment can be obtained with a brief pulse of the drug in early adulthood in female Drosophila and mice. In Drosophila, a brief, early rapamycin treatment of adults extended lifespan and attenuated age-related decline in the intestine to the same degree as lifelong dosing. Lasting memory of earlier treatment was mediated by elevated autophagy in intestinal enterocytes, accompanied by increased levels of intestinal LManV and lysozyme. Brief elevation of autophagy in early adulthood itself induced a long-term increase in autophagy. In mice, a 3-month, early treatment also induced a memory effect, with maintenance similar to chronic treatment, of lysozyme distribution, Man2B1 level in intestinal crypts, Paneth cell architecture and gut barrier function, even 6 months after rapamycin was withdrawn.

Rapamycin treatment early in life reprograms aging: hyperfunction theory and clinical practice

“…What is remarkable though is that lifelong treatment with rapamycin was safe (no increase in mortality) and effective (an increase in longevity) in mice [2] and Drosophila [1,2]. The results of these studies agree with the predictions of hyperfunction theory of mTOR-driven quasi-program of aging.…”

“…In young adult mice, a 3-month treatment with rapamycin produced a long-lasting effect on the deceleration of intestinal pathology. The effect of rapamycin on lifespan in mice was not measured in this study [1].…”

“…This seems exciting on the surface. However, according to these well-executed studies in mice and flies, rapamycin treatment should be started at birth (or shortly after birth) to be most effective [1][2][3]. So, it's definitely too late for anyone capable of reading this article.…”

“…Rapamycin treatment (for a duration of 30 days and 15 days) started at day 3 after eclosion (the emergence of an adult fly from its pupal case) and increased lifespan as much as lifelong treatment did in Drosophila [1]. (Note: Given the short lifespan of Drosophila, this can be compared to treatment in humans for 15 years).…”

Rapamycin not Dietary Restriction improves resilience against pathogens: a meta-analysis

“…Timing and scheduling of rapamycin treatment can have unpredictable effects and could depend on age. Transient rapamycin treatment (Juricic et al, 2022) and mTor knockdown (Simons et al, 2019) in early adult life extend lifespan in flies. Similarly, rapamycin during development (Shindyapina et al, 2022) and a short bout of treatment at middle-age (Bitto et al, 2016) extend lifespan in mice.…”