Molecular Mechanism Underlying Pyruvate Regulates The Longevity Of Caenorhabditis Elegans

Aging is a natural and inevitable process of organisms as time goes on,which is manifested by the degenerative change of structure and the decline in function.Research in recent decades has found that a variety of small molecular substances are capable of prolonging life and resisting aging-related diseases.Caenorhabditis elegans,as an excellent model organism for studying lifespan mechanism.C.elegans and humans share many similar aspects and mechanisms of aging.Thus,C.elegans can provide a certain theoretical basis for the study of human lifespan.Pyruvate,an important metabolite in all organisms,has been shown to participate in the regulation of multiple physiological processes,but its role and molecular mechanism in longevity are still unclear.In this study,we selected Caenorhabditis elegans as a model to investigate the effect of pyruvate on the lifespan.Pyruvate treatment not only extended the lifespan,but also improved the physiological phenotypes,such as throat pumping,body bends and oxygen consumption in the wild-type worms.Further experiments found that pyruvate treatment could increase autophagy activity.Kncokdown of autophagy-related genes bec-1 and atg-16 by RNAi inhibited pyruvate-extended lifespan in worms,indicating that autophagy is involved in pyruvate-mediated longevity of C.elegans.Meanwhile,we found that pyruvate treatment promoted the nuclear translocation of the transcription factor DAF-16/FOXO and up-regulated the expression of DAF-16 target genes dod-3and hsp-16.2.Moreover,silencing of daf-16 inhibited the effect of pyruvate on the activation of autophagy and extension of lifespan,indicating that DAF-16 is involved in pyruvate-induced C.elegans longevity.Next we screened all the genes that are involved in DAF-16 nuclear translocation,and found that the deacetylase SIR-2.4 is involved in the regulation of pyruvate on DAF-16 and its target genes.In addition,we found that the mRNA levels of sir-2.4 were significantly increased after pyruvate treatment.In addition,silencing of sir-2.4 by RNAi suppressed pyruvate-induced autophagy and lifespan extension in worms.Finally,co-immunoprecipitation analysis revealed that pyruvate reduced the acetylation levels of DAF-16.In summary,our study demonstratethat pyruvate reduces the acetylation levels of DAF-16 by up-regulating the expression of SIR-2.4,leading to nuclear translocation of DAF-16.Activated DAF-16 further induces an increase in autophagy activity,thereby extending the lifespan of C.elegans.This study reveals the molecular mechanism underlying pyruvate regulates the longevity of Caenorhabditis elegans.