Downregulation of senescence-associated secretory phenotype by knockdown of secreted frizzled-related protein 4 contributes to the prevention of skin aging

Abstract

There is growing evidence that the appearance and texture of the skin that is altered during the aging process are considerably enhanced by the accumulation of senescent dermal fibroblasts. These senescent cells magnify aging via an inflammatory, histolytic, and senescence-associated secretory phenotype (SASP). Secreted frizzledrelated protein 4 (SFRP4) was previously determined to be expressed in dermal fibroblasts of aging skin, and its increased expression has been shown to promote cellular senescence. However, its role in the SASP remains unknown. We found that SFRP4 was significantly expressed in p16ink4a-positive human skin fibroblasts and that treatment with recombinant SFRP4 promoted SASP and senescence, whereas siRNA knockdown of SFRP4 suppressed SASP. Furthermore, we found that knockdown of SFRP4 in mouse skin ameliorates age-related reduction of subcutaneous adipose tissue, panniculus carnosus muscle layer, and thinning and dispersion of collagen fibers. These findings suggest a potential candidate for the development of new skin rejuvenation therapies that suppress SASP.

Ageing-related defects in macrophage function are driven byMYCandUSF1transcriptional programmes

“…ATP8B1 is associated with macrophage efferocytosis and resolution of inflammation and may be a potential therapeutic target in chronic pancreatitis (78). SFRP4 is involved in Wnt signalling and has been implicated in skin ageing through promoting SASP, while its knockdown suppressed SASP (79). SFRP4 is upregulated in ageing, correlating with our data, suggesting a role in macrophage chronic inflammation and ageing.…”

Lipid and glucose metabolism in senescence

“…SRSPs can have both beneficial and detrimental effects on the organism, depending on the expression context and duration. While SRSPs can promote wound healing, tissue repair, and immune surveillance by stimulating cell proliferation, angiogenesis, and immune cell recruitment ( 170 ), they can also induce cellular senescence in neighboring cells, disrupt tissue homeostasis and function, and facilitate the development and progression of age-related diseases such as cancer, neurodegeneration, cardiovascular disease, diabetes, and osteoporosis ( 171 , 172 ).…”

“…SRSPs describe the diverse array of proinflammatory and profibrotic factors secreted by senescent cells (169). SRSPs include (171,172).…”