A stress induced miR-31-CLOCK-ERK pathway is a key driver and therapeutic target for skin aging

Genotoxic effect is an important driver of skin aging under both physiological and pathological conditions, but the mechanism is not well understood. Here we report that HFSC aging is initiated by their intrinsic up-regulation of miR-31, a microRNA induced by physical or genotoxic damage. Using transgenic and conditional knockout mouse models plus lineage tracing technique, we demonstrated miR-31 as a key HFSC aging driver that can promote HFSC lineage infidelity and exhaustion. We identified a core circadian rhythm gene, Clock, as a novel miR-31 target, whose down-regulation by miR-31 activates MAPK/ERK pathway that drives HFSC lineage infidelity. Importantly, a short-term pharmaceutical inhibition of MAPK/ERK provided robust protection against IR induced premature skin aging without adverse effects, enlightening a promising avenue for treating skin aging and other conditions related to genotoxic effect.