Molecular Mechanisms Of The Super Longevity Produced By Inhibiting Both IGF-1 And TOR Pathways In C.elegans

Aging can be modulated by highly conserved pathways,such as insulin/insulin-like growth factor-1(IGF-1)and TOR(target of rapamycin)signaling pathways.We previously reported that double mutations in DAF-2(IGF-1 receptor)and RSKS-1(S6K),which block both the IGF-1 and TOR pathways,led to 5-fold,synergistic lifespan extension in C.elegans.Further studies demonstrated that AMPK-mediated positive feedback regulation of the DAF-16(FOXO)transcription factor is required for the synergistic lifespan extension by the daf-2 rsks-1 mutant,and the germline tissue plays an important role in modulating the synergistic longevity through cell non-autonomous regulation of DAF-16.S6K plays important roles in protein synthesis at the mRNA translation level.Studies provided evidence that inhibition of mRNA translation strongly increases lifespan in different species,however,the potential mechanisms are still elusive.In order to gain better understanding of the molecular mechanisms of the significantly prolonged longevity by daf-2 rsks-1,we performed polysomal profiling and RNA-Seq to identify genes that are differentially translated in the daf-2 rsks-1 mutant compared with wild-type animals,and subsequently analyzed their functions in aging as well as the translational regulation.These lifespan determinant genes are enriched with essential genes that encode various ribosomal subunits,whereas the most significant lifespan extension phenotype was produced by inhibiting CYC-2.1,the highly conserved cytochrome c orthologous in C.elegans.cyc-2.1 knockdown significantly extends lifespan via activating the intestinal mitochondrial unfolded protein response(UPRmt),mitochondrial fission and AMP-activated kinase(AMPK).The germline serves as the key tissue for cyc-2.1 to regulate lifespan,and germline-specific cyc-2.1 knockdown non-autonomously activates intestinal UPRmt and AMPK.Furthermore,CYC-2.1 is translationally down-regulated in the germline of daf-2 rsks-1.Consistently,the daf-2 rsks-1 mutant showed UPRmt activation in the intestine,and inhibition of UPRmt significantly suppressed the super longevity of daf-2 rsks-1.Bioinformatic analysis helped to identify the RNA binding protein GLD-1,which is translationally up-regulated in the germline of daf-2 rsks-1,as a promising translational repressor of cyc-2.1.Inhibition of GLD-1 in the daf-2 rsks-1 significantly relieves the CYC-2.1 translational repression in the germline,which subsequently suppresses the intestinal UPRmt activation and shortens the lifespan of daf-2 rsks-1.Collectively,these findings unveiled the new molecular mechanism how mRNA translation regulates aging,which helps elucidate the network of translational control downstream of the insulin/IGF-1 and TOR pathways.We also find that mitochondrial stress response could be initiated by the germline-to-intestine cell non-autonomous signals,identification of these signals would further characterize how organism balances reproduction and metabolism.Most importantly,some key genes identified in this research are highly conserved across species,providing the hints that there exists similar mechanism in higher organism,discussion of these issues will help us understand the nature of aging and provide new targets and ideas for the treatment of age-related diseases.