Intermittent fasting triggers interorgan communication to suppress hair follicle regeneration
Intermittent fasting has gained increasing popularity globally for its potential benefits for improving health and managing weight, but how it impacts the homeostasis and regeneration of peripheral tissues remains elusive. Here we report that in mice, commonly used intermittent fasting regimens negatively affect hair regeneration by selectively inducing apoptosis in activated hair follicle stem cells (HFSCs). Through manipulating animals' daily feeding schedules and caloric intake, we have found that the impaired hair regeneration is primarily caused by the extended fasting periods within these regimens, rather than a reduction in total caloric intake or alterations in circadian rhythm. As the fasting period lengthens, the severity of the defects worsens. Mechanistically, extended periods of fasting activate the hypothalamic-pituitary-adrenal axis, prompting the release of lipolytic hormones from the adrenal glands into circulation. This triggers rapid lipolysis in dermal adipocytes, elevating levels of free fatty acids within the skin. Consequently, fatty acid oxidation is activated in HFSCs, causing increased cellular oxidative stress and apoptosis. Surgical removal of adrenal glands, genetic inhibition of fatty acid oxidation in HFSCs, or enhancement of HFSCs' antioxidant capability genetically or pharmaceutically prevents fasting-induced stem cell death. Our study reveals a detrimental effect of intermittent fasting on somatic stem cells and peripheral tissue regeneration, and identifies a close crosstalk between an ancient neuroendocrine mechanism and a critical niche component that functions as a “brake” to halt tissue regeneration when the supply of nutrients becomes unstable. Overall design: Cell type: FACS purified hair follicle stem cells (HFSCs) and epidermal stem cells (EpiSCs) from mouse skin; 3 conditions: Ad libitum, Fasting for 24 hours, and Fasting for 48 hours; 2 replicates for EpiSCs, and 3 replicates for HFSCs each condition. Cell type: FACS purified hair follicle stem cells (HFSCs) from mouse skin; 2 conditions: 6 months of Ad libitum and 6 months of Alternative day fasting (sampled at the day after fasting); 2 replicates for HFSCs each condition. Cell type: FACS purified hair follicle stem cells (HFSCs) from mouse skin; 2 replicates for HFSCs at 2nd telogen.