Age-dependent effects of reduced mTor signalling on life expectancy through distinct physiology

Abstract

Research on the mechanisms of ageing has identified ways via which lifespan can be extended in model organisms, increasing the potential for translation of these findings to our own species. However, the large majority of research on animal models involves dietary, genetic or pharmacological treatments throughout life - limiting translational potential and ignoring age-dependent effects. Previously, we have suggested using demographic meta-analysis that reduced mTor signalling has the potential to instantly rejuvenate. We have now tested this prediction experimentally using large-scale demographic data (N > 10,000) combined with conditional knockdown of mTor in Drosophila melanogaster. Indeed, reduced mTor decreased mortality rate when applied during old age. Interestingly, we found that transient treatment during early adult life had long-lasting benefits. Age-dependent deep-RNAseq indicated that these effects arose from distinct physiology and implicate alternative splicing as a potential mechanism for the long-lasting benefits of transient mTor reduction. These findings suggest that reducing mTor short term or during old age could be used to combat ageing. In addition, our findings suggest that the results from experimental research on mTor signalling, and potentially other mechanisms of ageing, that employ life-long interventions are likely to be a complex composite of age-dependent effects that counteract or enhance each other.