Extended Data Fig. 10: Similarities and differences between ageing-induced and obesity-induced hair loss.

Chronological ageing and obesity induce or accelerate hair follicle miniaturization through stem cell depletion that is based on distinct molecular mechanisms. Age-associated repetition of hair cycles causes a sustained DNA damage response in HFSCs to reduce their expression of COL17A1; this results in hemidesmosomal instability, which causes the repetition of atypical stem cell divisions that induce the epidermal differentiation of HFSCs and eventually detach HFSCs from the basement membrane. By sharp contrast, short-term exposure of HFSCs to an HFD causes the accumulation of ROS, and long-term exposure causes lipid droplets in HFSCs, activates IL-1R signalling and inhibits SHH signalling, which induces epidermal and sebocyte differentiation and elimination of lipid-laden HFSCs upon hair cycle-coupled activation. In both cases, those aberrant fate changes occur in a small population of HFSCs upon their activation at early anagen, thereby diminishing the pool of HFSCs in those particular follicles and causing hair follicle miniaturization and hair thinning in a stepwise manner. Because the skin contains a densely arranged hair follicle bulge (niche) that contains abundant HFSC pools, and the expression of the hair thinning phenotype appears with a time delay because of the long duration of the hair cycle, HFSC depletion proceeds in a latent manner and manifests the hair thinning and loss phenotype only after several rounds of hair cycles.