Stimulation of Hair Growth by Small Molecules that Activate Autophagy

Highlights•mTOR and AMPK modulation by rapamycin, metformin, and α-KG induces anagen hair growth•Autophagy induction is necessary and sufficient for anagen entry and hair growth•Autophagy is increased during anagen phase of the natural hair follicle cycle•Aged mice fed the autophagy-inducing metabolite α-KB are protected from hair lossSummaryHair 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.Graphical abstract