Abstract
Autophagy is a highly conserved mechanism for cellular repair that becomes progressively down-regulated during normal ageing. Hence, manipulations that activate autophagy could increase lifespan. Previous reports show that manipulations to the autophagy pathway can result in longevity extension in yeast, flies, worms and mammals. Under standard nutrition, autophagy is inhibited by the nutrient sensing kinase Target of Rapamycin (TOR). Therefore, manipulations of TOR that increase autophagy may offer a mechanism for extending lifespan. Ideally, such manipulations should be specific and minimise off-target effects, and it is important to discover additional methods for ‘clean’ lifespan manipulation. Here we report an initial study into the effect of up-regulating autophagy on lifespan and fertility in Drosophila melanogaster by dietary addition of Torin1. Activation of autophagy using this selective TOR inhibitor was associated with significantly increased lifespan in both sexes. Torin1 induced a dose-dependent increase in lifespan in once-mated females. There was no evidence of a trade-off between longevity and fecundity or fertility. Torin1-fed females exhibited significantly elevated fecundity, but also elevated egg infertility, resulting in no net change in overall fertility. This supports the idea that lifespan can be extended without trade-offs in fertility and suggest that Torin1 may be a useful tool with which to pursue anti-ageing research.
Highlights
Many diseases show a distinct increase in incidence or severity with age
Western blotting confirmed that the administration of Torin1 in the diet activated autophagy above control diet levels at all doses of Torin1 in the once-mated females from the first experiment (S1 Fig)
In once-mated and continually mated females, autophagy activation following 5 days on 1 μM Torin1 diets was higher than in individuals maintained on the control diets, but was not as high as for the starvation diet females maintained on agar only food
Summary
It is of paramount importance to understand the molecular and cellular mechanisms that regulate ageing in order to minimise health impacts in an ever-older human population. Research over the last two decades reveals that several linked and highly conserved repair, growth and nutrient sensing pathways (autophagy, ‘target of rapamycin’ (TOR) and insulin and insulin-like growth factor (IGF) signaling (IIS)) are intimately involved in determining length of life Lifespan extension in flies via dietary addition of Torin this study we focused on the links between TOR and autophagy in lifespan determination through specific manipulations of the TOR pathway. Down regulation of the protein kinase TOR is reported to increase lifespan [3,4]. TORC1 and 2 have distinct substrate specificities and are differentially sensitive to the TOR inhibitor rapamycin [8,9]. It’s role in proteins synthesis isn’t yet clear [10], though it plays roles in many cellular processes via the AGC kinases and is implicated in keratinocyte survival and cancer development [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
