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

Abstract

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.

Stable Expression of dmiR-283 in the Brain Promises Positive Effects in Endurance Exercise on Sleep–Wake Behavior in Aging Drosophila

“…Lifespan is considered to be a comprehensive indicator for detecting physiological health in Drosophila , and miRNAs have been demonstrated to be involved in regulating neuronal activity and lifespan [ 30 , 31 , 32 , 33 ]. Several studies have proven that disruption of the biological clock function, both in insects and rodents, has many detrimental effects on healthy lifespan, including oxidative damage, increased accumulation of protein glycosylation, disruption of metabolic homeostasis, premature aging, and age-related diseases [ 3 , 34 , 35 , 36 , 37 , 38 ].…”

Purification of exosome-enriched proteins produced in a Drosophila cell line by size exclusion chromatography

“…For the Western blot analysis of lysates, conditioned medium and exosome fractions for this protein, please refer to. 1 In addition to proteins, mRNAs and microRNAs are also loaded onto exosomes. For purification and characterization of miRNAs loaded into exosomes please refer to.…”

Noncoding RNA Regulation of Hormonal and Metabolic Systems in the Fruit Fly Drosophila

“…miR-125 and let-7 expression is elevated in response to dietary restriction, thus extending lifespan. miR-125 regulates the nutrient-dependent transcription factor Chinmo with dietary restriction and restrains the downstream genes of Chinmo from expressing to increase the lifespan in flies [ 68 ]. These findings confirm miRNA impacts on increased lifespan and the importance of dietary restrictions.…”