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Photoaging – ultraviolet radiation ages the skin

Luis Almeida Jan 03, 2021
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Cellular senescence is a double-edged sword. For one, the accumulation of senescent cells contributes to age-related complications. On the other hand, it is necessary to suppress the uncontrolled proliferation of cells at high-risk of neoplastic transformation, limiting the development of tumors. Senescence is broadly defined as a state of irreversible cell-cycle arrest. Once senescent, cells are unable to proliferate and are less prone to undergo apoptosis. They also tend to secrete several distinct proinflammatory cytokines that disrupt local homeostasis. The myriad of proteins secreted by senescent cells is known as the senescence-associated secretory phenotype (SASP). SASP factors can inhibit cell growth in neighboring cells and recruit leukocytes to maintain an anti-tumorigenic environment and to clear senescent cells.
Besides the natural aging process, certain environmental stresses can induce or accelerate senescence. For example, when the skin is exposed to excessive amounts of ultraviolet (UV) radiation, DNA damage tends to occur. UV radiation can damage DNA directly, or indirectly through the generation of reactive oxygen species. This radiation-induced cellular damage leads to the accumulation of senescent keratinocytes and fibroblasts. Senescent skin cells in the skin are problematic because they have the potential to change the function of nearby cells. Furthermore, senescent cells secrete matrix metalloproteinases, proteins that degrade collagen, an essential skin building block. While the removal of these secreted factors is not trivial, it could represent a method to prevent already established senescent cells from “causing havoc” in the surrounding tissues. Normally, senescence is an anti-tumorigenic process. Paradoxically, UV-induced senescent cells produce proinflammatory cytokines that can actually drive skin cancer; this is known as photoaging. This duality of outcomes has been observed before, with senescent cells promoting both pro-inflammatory (anti-tumorigenic) and anti-inflammatory (pro-tumorigenic) microenvironments, in a context-dependent fashion. The reason why the latter phenotype apparently predominates in UV-induced senescence is not understood. With that in mind, might the following options be able to prevent or delay photoaging? 1 – Could we somehow inhibit the effects of SASP, to prevent established senescent cells from exerting deleterious effects within the surrounding tissue and cells? 2 – Could we promote local immunity to restore a pro-inflammatory environment that allows the immune system to clear senescent cells?
3 – If the former option is scientifically feasible, how could we achieve that without achieving excessive inflammation in an economically viable fashion? 4 – Could the topical application of senolytic creams lead to the creation of a new “anti-skin aging” product? The last option is a particularly exciting novel avenue of treatments, with some very recent promising results. Two senolytic drugs named dasatinib and quercetin were recently shown to decrease p16INK4A- and p21CIP1-positive cells by 38% and 30% in the epidermal layer of the skin, respectively. Because p16INK4A- and p21CIP1 are usually indicators of senescent cells, these drugs could potentially be used for the aforementioned purpose.

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