Skin senescence: mechanisms and impact on whole-body aging

With age, senescent cells accumulate in the skin and spread the aging phenotype to neighboring cells, resulting in decreased thickness, regenerative capacity, and a barrier effect in the skin. Aging and cellular senescence phenotypes in the skin were found to correlate with immunosenescence, longevity, or cardiovascular disease risk. Skin aging, induced by ultraviolet radiation, has an impact in the brain, by decreasing hippocampal neurogenesis and activating the central hypothalamic–pituitary–adrenal axis. Senolytics, such as dasatinib and fisetin, are drugs that selectively eliminate senescent cells and are already topically administered to the skin, showing potential antiaging effects. The skin is the largest organ and has a key protective role. Similar to any other tissue, the skin is influenced not only by intrinsic/chronological aging, but also by extrinsic aging, triggered by environmental factors that contribute to accelerating the skin aging process. Aged skin shows structural, cellular, and molecular changes and accumulation of senescent cells. These senescent cells can induce or accelerate the age-related dysfunction of other nearby cells from the skin, or from different origins. However, the extent and underlying mechanisms remain unknown. In this opinion, we discuss the possible relevant role of skin senescence in the induction of aging phenotypes to other organs/tissues, contributing to whole-body aging. Moreover, we suggest that topical administration of senolytics/senotherapeutics could counteract the overall whole-body aging phenotype. The skin is the largest organ and has a key protective role. Similar to any other tissue, the skin is influenced not only by intrinsic/chronological aging, but also by extrinsic aging, triggered by environmental factors that contribute to accelerating the skin aging process. Aged skin shows structural, cellular, and molecular changes and accumulation of senescent cells. These senescent cells can induce or accelerate the age-related dysfunction of other nearby cells from the skin, or from different origins. However, the extent and underlying mechanisms remain unknown. In this opinion, we discuss the possible relevant role of skin senescence in the induction of aging phenotypes to other organs/tissues, contributing to whole-body aging. Moreover, we suggest that topical administration of senolytics/senotherapeutics could counteract the overall whole-body aging phenotype. small lipid bilayer structures, deliberately secreted by cells into the extracellular space, that can enclose nucleic acids, proteins, or lipids. EVs can be taken up by recipient cells, with various effects on that target cell. type of skin aging caused by exposure to hazardous environmental factors and lifestyle. a neuroendocrine unit comprising the hypothalamus, pituitary gland, and adrenal glands, which, by integrating physiological and endocrine signals, has a central role in body homeostasis and response to stress. progressive dysfunction and decline in immune function, generally associated with aging or age-related diseases. state of chronic low-grade inflammation associated with progressive age. type of genetically programmed aging, caused by the natural passage of time; also known as chronological aging. process of the generation of new neurons in the brain through differentiation from stem cells. cellular senescence caused by the secretome of primary senescent cells. type of extrinsic skin aging caused by exposure to UVR from sunlight. entire set of proteins secreted by a given cell. set of proinflammatory, proangiogenic, and growth stimulatory molecular agents secreted by senescent cells, which influences the microenvironment and surrounding cells. class of drugs that selectively eliminate senescent cells, therefore targeting the deleterious effects of senescent cells within tissues.