The Mechanism Of Lifespan Extension Induced By Exercise In C.elegans

Regular exercise has a multi-system anti-ageing effect among different species,including worms,flies,mice,and primates.It is an effective therapeutic measure for chronic diseases such as obesity,neurodegeneration,type 2 diabetes,osteoporosis and sarcopenia.Exercise can delay the ageing of the cardiovascular system,the immune system,and skeletal muscle.Although numerous hypotheses have been proposed to explain the benefits of exercise on organism,most of the studies focus on the tissues or organs.Recent evidence suggests that exercise extends the lifespan of Caenorhabditis.elegans,but the specific molecular mechanisms are still poorly characterized.Studies have shown that adiponectin levels are significantly increased in the exercised wild-type mice.Meanwhile,autophagy serves as an evolutionally conserved mechanism for longevity,which is also induced by exercise,but the adiponectin levels are not up-regulated by exercise in the Bcl-2 mutant mice.It is suggested that adiponectin receptor signaling is related to the exercise-induced autophagy,however,it is unclear whether the adiponectin receptor signaling regulates exercise-induced longevity.C.elegans is one of the principle models used to study ageing because of its excellent genetics and short lifespan,in addition,60-80% of human genes have an ortholog in the C.elegans genome.Here,we show that exercise induces autophagy in the hypodermal seam cells,intestine and neurons of worms.Knockdown of the autophagy-related genes by RNAi significantly inhibits the lifespan extension by exercise,which suggests autophagy could regulate exercise-induced longevity.Transcription factor DAF-16/FOXO which is activated by exercise,then regulates autophagy.The adiponectin receptor PAQR-1 signaling pathway(PAQR-1-AMPK-SIR-2.1)acts as an upstream effector of DAF-16/FOXO and plays an important role in exercise-induced autophagy and longevity.Interestingly,PAQR-1-AMPK-SIR-2.1 signaling does not affect the nuclear translocation of DAF-16/FOXO,but regulates the transcription activity of DAF-16.In addition,at the organelle level,we find that lifespan extension indcued by exercise is dependent on mitochondrial function.Knockdown of mev-1(mitochondrial succinate dehydrogenase complex subunit C,SDHC)by RNAi causes an insult in mitochondrial function,leading to the suppress of lifespan extention by exercise.Konckdown of fzo-1(mediates outer mitochondrial membrane fusion),or eat-3(mediates inner mitochondrial membrane fusion)by RNAi,abolishes the exercise-induced lifespan extension.DRP-1 is a conserved GTPase that catalyzes mitochondrial,which mediates fusion of mitochondrial,knockdown of drp-1 by RNAi also inhibits exercise-induced lifespan extension,which suggests both fusion and fission are required for exercise-induced longevity.Co-knockdown of fusion and fission machinery components fzo-1 and drp-1 by RNAi significantly abolishes the exercise-indced longevity,demonstrating that mitochondrial network plasticity is required for exercise-mediated longevity.We also find that mitophagy is specifically activated by exercise via AMPK-DAF-16 signaling,and regulates the content of mitochondria.Meanwhile,mitophagy is also required for exercise-induced longevity in C.elegans.Taken together,we report that autophagy induced by exercise serves as a molecular mechanism for longevity.The PAQR-1-AMPK-SIR-2.1 signaling together with transcription factor DAF-16/FOXO act as a regulator of autophagy to extend lifespan in C.elegans.In addition,mitochondrial network homeostasis and mitophagy are sufficient to extend the lifespan,and such mechanisms may be evolutionally conserved among diverse species.