Attenuation of intrinsic ageing of the skin via elimination of senescent dermal fibroblasts with senolytic drugs

Abstract

Background Skin ageing is caused by numerous factors that result in structural and functional changes in cutaneous components. Research has shown that senescent cells are known to accumulate in skin ageing, however, the role of senescent cells in skin ageing has not been defined. Objectives To elucidate the role of the senescent cell in skin ageing, we evaluated the effect of known senolytic drugs on senescent dermal fibroblasts. Methods Primary human dermal fibroblasts (HDFs) were induced to senescence by long‐term passaging, UV irradiation, and H2O2 treatment. Cell viability was measured after treatment of ABT‐263 and ABT‐737 on HDFs. Young and aged hairless mice were intradermally injected with drugs or vehicle on the dorsal skin for 10 days. Skin specimens were obtained and reverse‐transcription quantitative PCR, western blotting, and histological analysis were performed. Results We found that ABT‐263 and ABT‐737 induced selective clearance of senescent dermal fibroblasts, regardless of the method of senescence induction. Aged mouse skin treated with ABT‐263 or ABT‐737 showed increased collagen density, epidermal thickness, and proliferation of keratinocytes, as well as decreased senescence‐associated secretory phenotypes, such as MMP‐1 and IL‐6. Conclusions Taken together, our results indicate that selective clearance of senescent skin cells can attenuate and improve skin ageing phenotypes and that senolytic drugs may be of potential use as new therapeutic agents for treating ageing of the skin.

Human placental extract activates a wide array of gene expressions related to skin functions

“…Fibroblasts in the dermis layer of the skin has been shown to maintain the skin's strength, elasticity, and moisture by producing ECM proteins such as collagen fibrils and the elastic fibers 12,13 . It is worthy to note that senescent fibroblasts appear to accumulate in the skin with age 14,15 , and the elimination of senescent fibroblasts in the skin has recently been demonstrated to attenuate intrinsic skin aging 16 . The hallmarks of fibroblast aging include genome instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, cellular senescence, altered intercellular communication, and loss of proteostatis 17 .Strategies against skin aging have been developed since ancient times.…”

Cathepsin F is a potential marker for senescent human skin fibroblasts and keratinocytes associated with skin aging

“…Results of clinical studies conducted using topical application of rapamycin to the skin of elderly subjects showed reduction in the levels of p16INK4a-positive skin fibroblasts as well as the number of fine wrinkles and an increase in skin thickness and elasticity [ 36 ]. Furthermore, in a recent study, ABT-263 and ABT-737 induced selective clearance of aging dermal fibroblasts, regardless of the method of aging induction, and skin from aging mice treated with ABT-263 or ABT-737 showed increased collagen density, epidermal thickness, and keratinocyte proliferation and decreased senescence-associated secretory phenotype-associated factors such as MMP-1 and IL-6 [ 37 ]. Thus, removal of SASP-positive senescent cells from the skin by targeting CTSF could be applied for improving the properties of aging skin.…”

Skin-Aging Pigmentation: Who Is the Real Enemy?

“…Therefore, the elimination of senescent fibroblasts has the potential to improve photoaging-related skin pigmentation and re-lighten pigmented skin. The beneficial effects of senolytics in improving skin aging were recently demonstrated [ 129 , 130 ]. Topical rapamycin, an FDA-approved drug targeting the mTOR complex, reduces either the expression of the p16 INK4A protein consistent with a reduction in cellular senescence or the number of cells entering senescence with clinical improvements in aging skin [ 131 ].…”

“…Topical rapamycin, an FDA-approved drug targeting the mTOR complex, reduces either the expression of the p16 INK4A protein consistent with a reduction in cellular senescence or the number of cells entering senescence with clinical improvements in aging skin [ 131 ]. In addition, treatments with ABT-263 or ABT-737, well-known B-cell lymphoma 2 (BCL-2) inhibitors and senolytics, induced the selective clearance of senescent dermal fibroblasts [ 129 ]. The aged mouse skin treated with ABT-263 or ABT-737 showed increased collagen density, epidermal thickness, and the proliferation of keratinocytes, as well as decreased levels of senescence-associated secretory phenotypes, such as MMP-1 and IL-6.…”