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Dietary restriction (DR) extends healthy lifespan in diverse species. Age and nutrient-related changes in the abundance of microRNAs (miRNAs) and their processing factors have been linked to organismal longevity. However, the mechanisms by which they modulate lifespan and the tissue-specific role of miRNA-mediated networks in DR-dependent enhancement of lifespan remains largely unexplored. We show that two neuronally enriched and highly conserved microRNAs,  miR-125  and  let-7  mediate the DR response in  Drosophila melanogaster . Functional characterization of  miR-125  demonstrates its role in neurons while its target  chinmo  acts both in neurons and the fat body to modulate fat metabolism and longevity. Proteomic analysis revealed that Chinmo exerts its DR effects by regulating the expression of  FATP, CG2017, CG9577, CG17554, CG5009, CG8778, CG9527 , and  FASN1 . Our findings identify  miR-125  as a conserved effector of the DR pathway and open the avenue for this small RNA molecule and its downstream effectors to be considered as potential drug candidates for the treatment of late-onset diseases and biomarkers for healthy aging in humans.

miR-125-chinmo pathway regulates dietary restriction-dependent enhancement of lifespan in Drosophila