Caloric/dietary restriction (CR/DR) can promote longevity and protect against age-associated disease across species. The molecular mechanisms coordinating food intake with health-promoting metabolism are thus of significant medical interest. We report that conserved Caenorhabditis elegans microRNA-80 ( mir-80) is a major regulator of the DR state. mir-80 deletion confers system-wide healthy aging, including maintained cardiac-like and skeletal muscle-like function at advanced age, reduced accumulation of lipofuscin, and extended lifespan, coincident with induction of physiological features of DR. mir-80 expression is generally high under ad lib feeding and low under food limitation, with most striking food-sensitive expression changes in posterior intestine. The acetyltransferase transcription co-factor cbp-1 and interacting transcription factors daf-16/FOXO and heat shock factor-1 hsf-1 are essential for mir-80(Δ) benefits. Candidate miR-80 target sequences within the cbp-1 transcript may confer food-dependent regulation. Under food limitation, lowered miR-80 levels directly or indirectly increase CBP-1 protein levels to engage metabolic loops that promote DR.
Dietary restriction, limitation of calorie intake with maintained vitamin and mineral support, can extend lifespan and protect against diseases of age across many species. Elaboration of molecular mechanisms that control dietary restriction in simple animal models may therefore inform on strategies to activate health-promoting metabolism to help address clinical challenges associated with aging and age-associated disease. We characterize a single Caenorhabditis elegans microRNA gene that keeps dietary restriction programs off when food is abundant. A mir-80 deletion exhibits beneficial features of dietary restriction regardless of food availability, including extended maintenance of mobility and cardiac-like muscle function later into life as well as lifespan extension. We identify three key longevity genes that are required for these benefits. We hypothesize that miR-80 is a core regulator by which diverse and intersecting metabolic pathways are coordinately regulated to respond to nutrient availability.