Cellular Senescence in Aging Skin

In one sense, the accumulation of senescent cells with age is the same story in every tissue. These cells secrete pro-inflammatory, disruptive signaling that actively degrades tissue structure and function. The targeted destruction of lingering senescent cells produces aspects of rapid rejuvenation in aged mice. In another sense, every tissue is different and senescence in that tissue likely worthy of at least some degree of distinct study, perhaps leading to optimized therapies for clearance of senescent cells on a tissue by tissue basis, for example. Here, find a review that looks at cellular senescence in the context of skin and the known aspects of aging observed in skin tissue.

Despite the growing interest by researchers into cellular senescence, a hallmark of aging, its role in human skin remains equivocal. The skin is the largest and most accessible human organ, reacting to the external and internal environment. Hence, it is an organ of choice to investigate cellular senescence and to target root-cause aging processes using senolytic and senomorphic agents. This review presents different aspects of skin cellular senescence, from physiology to pathology and signaling pathways. Premature cellular senescence can underlie pathological skin conditions. However, its role is ambiguous, and it seems that a distinction needs to be made between acute and chronic senescence. It appears that the chronic accumulation of senescent cells can have a detrimental effect on skin function, health, and aging, while acute stimulation of transient senescent cells plays an important role in wound healing.

In contrast to acute wound healing, chronic, nonhealing ulcers (e.g., murine model of diabetes, venous ulcers, radiation ulcers) are characterized by higher levels of senescence. Clearance of senescent cells with senolytics (i.e., dasatinib plus quercetin) has been shown to mitigate radiation ulcers. Additionally, it is well known that the regenerative capacity of the skin declines with age in conjunction with increased accumulation of senescent cells. Delayed wound healing was reported in young 8-week-old mice after the subcutaneous transfer of irradiated fibroblasts. In this case, the kinetics of wound healing were similar to those observed in naturally aging 2-year-old mice.

On the other hand, researchers have reported different senescent responses in younger (30.2 ± 1.3 years) vs. older (75.6 ± 1.8 years) healthy subjects in punch biopsy wounds. The second biopsy, taken for analysis, was performed several days after the first one. Induction of p21 and p53 was observed during healing in younger but not older skin. Therefore, transient appearance of senescent cells may be needed for proper healing of acute wounds, but their chronic presence delays healing. Moreover, senescent fibroblasts have also been found in keloid scars - lesions that result from abnormal wound healing and can be classified as benign skin tumors. It is believed that the appearance of aging is a desirable phenomenon in keloids as a mechanism potentially responsible for stopping the proliferation of fibroblasts and the progression of lesions.

Hair disorders can also be affected by senescent pathways. In an experimental model of age-related hair loss, hair follicle dermal stem cells exhibited features of senescent cells (overexpression of p16INK4a and SA-β-Gal). Additionally, increased senescence-associated secretory phenotype (SASP) components were detected in the mesenchymal niche of the hair follicle. Moreover, clearing senescent cells by a possible senolytic, FOXO4-DRI, reduced hair loss in progeroid aging mice. Additionally, hair follicle dermal papillary cells from the male balding scalp showed the loss of proliferative capacity. This phenomenon was associated with increased SA-β-Gal and p16INK4a/pRb expression. Moreover, knocking out p16INK4a promoted faster growth of hair follicle dermal papillary cells.

Link: https://doi.org/10.1111/acel.13845

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