SIRT1 Activator Resveratrol Attenuates Age-Related Skin Thinning in Mice

Aging is associated with thinning of the epidermis and dermis, leading to wrinkles, dryness, and impaired skin barrier function. Sirtuin-1 (SIRT1) is an NAD⁺-dependent protein deacetylase that suppresses cellular senescence and matrix metalloproteinase (MMP) expression, both of which contribute to skin thinning. Here, we investigated whether dietary resveratrol (RSV), a SIRT1 activator, mitigates age-related skin thinning in mice. Epidermal and dermal thicknesses were significantly reduced in 60-week-old (wo) mice compared with 20-wo mice, and these changes were attenuated by RSV administration (0.4 g/kg diet) from 28 weeks of age for 32 weeks. In the epidermis, the number of Ki67-positive cells decreased in aged mice but was restored by RSV treatment. Although RSV did not alter the number of SIRT1-positive cells, it significantly reduced the number of acetyl-lysine-positive cells, indicating enhanced SIRT1 activity. In the dermis, the immunopositive areas of MMP-9 and MMP-13 increased in aged mice, and these age-associated increases were not observed in RSV-treated aged mice. Phosphorylated SMAD2 levels decreased with age but were not affected by RSV. Furthermore, SIRT1 knockdown in human HaCaT keratinocytes increased p21 expression and senescence-associated β-galactosidase activity. Taken together, these findings suggest that the SIRT1 activator RSV ameliorates age-related skin thinning by suppressing cellular senescence in the epidermis and inhibiting dermal collagen degradation.