The Mechanism Of MicroRNA Coordinating Autophagy Disruption Across Tissues With Aging

Aging happens with the disruption of material balance,including protein homeostasis.One of the crucial factors in maintaining protein homeostasis is macroautophagy(autophagy),which degrades damaged organelles and protein aggregates by engulfing them into autophagosomes and then fusing with lysosomes.Several lines of evidences suggest that autophagy level is decreased with aging,and the autophagy activity contributes to the regulation of lifespan and many age-related diseases.Moreover,the decrease speed of autophagy is diverse among tissues,but the mechanism of systemic autophagy disruption during aging is poorly explored.So we aim to identify the messenger transporting aging signal across tissues and reveal the mechanism of systemic autophagy disruption.In this study,we find mir-83/miR-29,a conserved microRNA,is increased with aging in Caenorhabditis elegans.mir-83 is enriched in the neuron and intestine,but only induced in the intestine during aging.We further show that HSF-1/HSF1,a transcription factor controlling stress response,promotes mir-83 in the aged intestine.We also identify CUP-5/MCOLN,a calcium channel localized in lysosomal membrane,as the target of mir-83,playing crucial roles in lysosome genesis and autophagy regulation.mir-83 mutation elevates lysosomal number and autophagy level in the intestine through increasing intestinal CUP-5 cell-autonomously.More intriguingly,we find intestinal mir-83 inhibits autophagy in the body wall muscle cell-nonautonomously,where mir-83 is not expressed,and it functions in a muscular CUP-5 dependent manner.We observe that intestinal mir-83 can be transported into body wall muscle.mir-83 is also detected in the coelomocytes and the extracellular vesicles secreted by worms,suggesting mir-83 may be packaged into the extracellular vesicles by intestine cell and transported into the body wall muscle through pseudocoelom.Moreover,mir-83 mutation also improves protein homeostasis in aged worms and promotes longevity through increasing CUP-5.Collectively,we identify a conserved microRNA as the messenger of aging signal,which is induced only in the intestine,but controls autophagy in multiple tissues cellnonautonomously and regulates proteostasis and lifespan in Caenorhabditis elegans.Our study reveals a mechanism of systemic autophagy disruption across tissues during aging preliminarily.