Nfatc1 orchestrates aging in hair follicle stem cells

Significance Signs of aging often first appear in our skin and hair. As animals age, hair follicles spend more time resting instead of generating hair. Here we show that this decline is rooted in age-related changes in systemic, local, and intrinsic factors, which collaborate to reduce hair follicle stem cell (HFSC) activity. We uncover a unique and hitherto-undescribed age-related role for bone morphogenic protein signaling and a downstream effector, nuclear factor of activated T-cell c1 (NFATc1). In young stem cells, NFATc1 is on when they are quiescent and wanes when they make hair. In aging follicles, NFATc1 and its target genes remain high too long. Importantly, NFATc1 inhibitors restore youthful behavior to aging HFSCs, providing unique insights into age-related changes in skin physiology.