Rapamycin modulates tissue aging and lifespan independently of the gut microbiota in Drosophila

Joseph M Schinaman,David W Walker,Anil Rana,William W Ja,Rebecca I Clark

doi:10.1038/s41598-019-44106-5

Joseph M Schinaman, David W Walker + Show 3 more

Open Access

https://doi.org/10.1038/s41598-019-44106-5

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Abstract

The FDA approved drug rapamycin can prolong lifespan in diverse species and delay the onset of age-related disease in mammals. However, a number of fundamental questions remain unanswered regarding the mechanisms by which rapamycin modulates age-related pathophysiology and lifespan. Alterations in the gut microbiota can impact host physiology, metabolism and lifespan. While recent studies have shown that rapamycin treatment alters the gut microbiota in aged animals, the causal relationships between rapamycin treatment, microbiota dynamics and aging are not known. Here, using Drosophila as a model organism, we show that rapamycin-mediated alterations in microbiota dynamics in aged flies are associated with improved markers of intestinal and muscle aging. Critically, however, we show that the beneficial effects of rapamycin treatment on tissue aging and lifespan are not dependent upon the microbiota. Indeed, germ-free flies show delayed onset of intestinal barrier dysfunction, improved proteostasis in aged muscles and a significant lifespan extension upon rapamycin treatment. In contrast, genetic inhibition of autophagy impairs the ability of rapamycin to mediate improved gut health and proteostasis during aging. Our results indicate that rapamycin-mediated modulation of the microbiota in aged animals is not causally required to slow tissue and organismal aging.

Highlights

In recent years, there has been a growing appreciation of the potential impact of developing effective interventions to slow aging and prolong healthy lifespan[1,2]
Consistent with a previous report[32], we found that rapamycin treatment during adulthood delays the onset of intestinal barrier dysfunction (Figs 1B and S1B)
Rapamycin treatment led to a significant reduction in bacterial loads (Figs 1C and S1C), with these changes occurring before detectable intestinal barrier dysfunction

Summary

Introduction

There has been a growing appreciation of the potential impact of developing effective interventions to slow aging and prolong healthy lifespan[1,2]. Age-related alterations in microbiota composition have been reported in flies, fish, mice and humans[22,23,24,25,26,27]. Recent work has shown that microbial genetic composition and metabolites can positively impact host longevity[29,30]. Together, these findings raise the intriguing possibility that existing interventions that promote longevity do so via an interplay with the microbiota. These findings raise the intriguing possibility that existing interventions that promote longevity do so via an interplay with the microbiota Consistent with this idea, the lifespan-extending effects of metformin in C. elegans are eliminated when worms are cultured axenically (germ-free)[31]. Our findings demonstrate that rapamycin, provided in the food, can act directly on the host organism to maintain tissue homeostasis during aging in an autophagy-dependent fashion

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