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Review
. 2022 May 19:10:903904.
doi: 10.3389/fcell.2022.903904. eCollection 2022.

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

Ying Lyu  1 , Yejing Ge  1
Affiliations
Review

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

Ying Lyu et al. Front Cell Dev Biol. .

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.

Keywords: epigenetics; inflammaging; metabolism; skin aging; stem cell lineage plasticity.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Molecular mechanisms underlying hair follicle miniaturization in aging (A) The hair follicle as a major skin appendage is maintained by hair follicle stem cells (HFSCs) residing in the bulge, an anatomic location beneath the sebaceous gland and isthmus of the pilosebaceous unit. HFSCs fuel the cyclic regeneration of hair follicles during homeostatic hair growth, whereas epidermal stem cells (EpdSC) and junctional zone stem cells (JzSCs) maintain the epidermis and junctional zone, respectively (B) HFSCs drive both follicular and epidermal regeneration during wound repair. Depending on the wounding depth, different populations of stem cells are induced to contribute to wound repair (C–E) Several cellular and molecular mechanisms have been recently proposed to explain the fate of aging HFSCs in murine models, including epidermal transdifferentiation (C), mechanical compression in situ (D), and escape into dermis (E).
FIGURE 2
FIGURE 2
The impact of genotoxic stress on skin aging. Numerous causes of genotoxic stresses including telomere attrition, DNA damage, circadian reprograming, and loss of quiescence could lead to stem cell functional decline in aging. The outcomes include increased oxidative stress, induction of P16 and cellular senescence, loss of cell adhesion, and activated innate immune pathways, among others.
FIGURE 3
FIGURE 3
Nutritional and metabolic regulation of skin aging (A) IIS (insulin/insulin-like growth factor) and AMPK/mTOR are two major pathways in regulating nutrients and metabolism that have been described in contributing to organismal aging (red circle) and longevity (green circle). Asterix indicates components of these pathways that have been demonstrated to contribute to skin aging (B) Mitochondrial biology is closely intertwined with aging biology. Highlighted in red are several key genes that have been shown to regulate skin stem cell aging in vivo. LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; MPC, mitochondrial pyruvate carrier; GLS, glutaminase; IDH, isocitrate dehydrogenase (converting isocitrate into alpha-ketoglutarate). Asterix indicates components of these pathways that have been demonstrated to contribute to skin aging.
FIGURE 4
FIGURE 4
Transcriptional and epigenetic noise in aging stem cells. Several proposed origins of the transcriptional and epigenetic noise in aged stem cells, including genome-wide hypomethylation and derepression of transposable elements, spurious transcription from the gene body, and deregulated transcription from ribosomal DNA (rDNA) at nucleoli. Global hypomethylation is accompanied by regional hypermethylation at gene promoters as well as formation of senescence-associated heterochromatin foci (SAHF). Some of the enzymes and post-translational histone modifications have been shown to regulate aging and longevity in a transgenerational fashion.
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