Toward Elucidating Epigenetic and Metabolic Regulation of Stem Cell Lineage Plasticity in Skin Aging

Abstract

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.

Irradiation-induced hair graying in mice: an experimental model to evaluate the effectiveness of interventions targeting oxidative stress, DNA damage prevention, and cellular senescence

“…Genetic factors play a significant role in determining hair pigmentation, including the process of hair graying [56]. Several genes involved in melanin synthesis, regulation, and distribution have been identified as key contributors to hair graying [54,[56][57][58][59][60][61][62][63]. Genes associated with melanogenesis, such as the melanocortin 1 receptor (MC1R), tyrosinase-related protein 1 (TYRP1), and tyrosinase (TYR ), have been found to influence hair pigmentation [39,44,[64][65][66].…”

Autophagy Dysfunction: The Kernel of Hair Loss?

“…Melanocytes, HF mesenchymal cells, and immune cells were adversely affected by significant mitochondrial dysfunction following the epithelium-specific deletion of mitochondrial transcription factor A (TFAM) in mice. 121,122 This led to increased apoptosis, reduced proliferation, and premature progression to the catagen phase of the HFs on the mice's dorsal. 121 A mitochondrial-associated protein named Crif1 regulates transcription and translation.…”

Skin Cancer Microenvironment: What We Can Learn from Skin Aging?

“…Skin aging is characterized by various changes in both epidermal and dermal layers, including alterations in the ECM composition, cellular senescence, and chronic inflammation [ 10 ]. All these changes have been linked to an increased susceptibility to skin cancer [ 16 , 17 , 18 ]. During aging, the gradual loss of tissue functions and reparative capacity leads to the accumulation of cellular damage and dysfunction [ 19 , 20 ].…”