| Summary: | Skin is the largest organ in human body, harboring a plethora of cell types and serving as the organismal barrier. Skin aging such as wrinkling and hair graying is graphically pronounced, and the molecular mechanisms behind these phenotypic manifestations are beginning to unfold. As in many other organs and tissues, epigenetic and metabolic deregulations have emerged as key aging drivers. Particularly in the context of the skin epithelium, the epigenome and metabolome coordinately shape lineage plasticity and orchestrate stem cell function during aging. Our review discusses recent studies that proposed molecular mechanisms that drive the degeneration of hair follicles, a major appendage of the skin. By focusing on skin while comparing it to model organisms and adult stem cells of other tissues, we summarize literature on genotoxic stress, nutritional sensing, metabolic rewiring, mitochondrial activity, and epigenetic regulations of stem cell plasticity. Finally, we speculate about the rejuvenation potential of rate-limiting upstream signals during aging and the dominant role of the tissue microenvironment in dictating aged epithelial stem cell function.
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