Stimulation of Hair Growth by Small Molecules that Activate Autophagy

Summary: Hair plays important roles, ranging from the conservation of body heat to the preservation of psychological well-being. Hair loss or alopecia affects millions worldwide, but methods that can be used to regrow hair are lacking. We report that quiescent (telogen) hair follicles can be stimulated to initiate anagen and hair growth by small molecules that activate autophagy, including the metabolites α-ketoglutarate (α-KG) and α-ketobutyrate (α-KB), and the prescription drugs rapamycin and metformin, which impinge on mTOR and AMPK signaling. Stimulation of hair growth by these agents is blocked by specific autophagy inhibitors, suggesting a mechanistic link between autophagy and hair regeneration. Consistently, increased autophagy is detected upon anagen entry during the natural hair follicle cycle, and oral α-KB prevents hair loss in aged mice. Our finding that anagen can be pharmacologically activated in telogen skin when natural anagen-inducing signal(s) are absent has implications for the treatment of hair loss patients. : Hair regeneration requires reactivating dormant hair follicle stem cells. Chai et al. discover that pharmacological induction of autophagy is sufficient to activate quiescent telogen hair follicles, initiating new anagen hair growth. Hair loss resulting from shortened anagen, lengthened telogen, and/or impeded anagen induction may thereby be rescued by activating autophagy. Keywords: autophagy, metabolite, hair loss, hair regeneration, α-ketoglutarate, α-ketobutyrate, rapamycin, metformin, mTOR, AMPK