Epigenetic Regulation of Skin Cells in Natural Aging and Premature Aging Diseases

Abstract

Skin undergoes continuous renewal throughout an individual's lifetime relying on stem cell functionality. However, a decline of the skin regenerative potential occurs with age. The accumulation of senescent cells over time probably reduces tissue regeneration and contributes to skin aging. Keratinocytes and dermal fibroblasts undergo senescence in response to several intrinsic or extrinsic stresses, including telomere shortening, overproduction of reactive oxygen species, diet, and sunlight exposure. Epigenetic mechanisms directly regulate skin homeostasis and regeneration, but they also mark cell senescence and the natural and pathological aging processes. Progeroid syndromes represent a group of clinical and genetically heterogeneous pathologies characterized by the accelerated aging of various tissues and organs, including skin. Skin cells from progeroid patients display molecular hallmarks that mimic those associated with naturally occurring aging. Thus, investigations on progeroid syndromes strongly contribute to disclose the causal mechanisms that underlie the aging process. In the present review, we discuss the role of epigenetic pathways in skin cell regulation during physiologic and premature aging.

Keywords: aging; epigenetic mechanisms; premature aging syndromes; progeroid syndromes; skin; stem cells.

Figure 1

Morphological features of young, chronologically- and photo-aged skin. Schematic organization of the young, chronologically aged or photo-aged skin tissue. Human skin is constituted by three tissue layers: epidermis, dermis, and hypodermis. The epidermis is a stratified epithelium composed of keratinocytes organized into four major layers (basal, spinous, granular, and cornified layers) at progressive differentiation stages including melanocytes. The dermis is populated by fibroblasts embedded by the components of the extracellular matrix made of collagen, elastic fibers, glycoproteins, and proteoglycans. Fibroblasts are the main producers of the extracellular matrix components. The hypodermis is mainly populated by adipocytes. Morphological changes occurring with age are indicated in chronologically- and photo-aged skin.

Figure 2

De-regulation of epigenetic modifiers affecting senescent epidermal keratinocytes and senescent dermal fibroblasts in chronologically-, photo- and premature-aged skin. Senescent cells are characterized by alterations of several cellular processes (DNA damage response, inflammation, and cell-cycle exit). Senescent fibroblasts display a modified metabolism of collagen and elastic fibers (elastic fiber maturation, collagen synthesis, and collagen degradation). Epigenetic modifiers inhibiting the cellular processes are indicated in light red when down-regulated and in dark red when up-regulated (or not down-regulated). Epigenetic modifiers activating the cellular processes are indicated in light green when down-regulated and in dark green when up-regulated (or not down-regulated).