<p>[Background] Skin thinning associated with aging leads to various health disadvantages such as decubitus. Cellular senescence has been implicated in skin thinning, and previous in vitro studies have demonstrated that SIRT1, an NAD⁺-dependent protein deacetylase, suppresses cellular senescence in keratinocytes and dermal fibroblasts. This study aimed to elucidate whether activation of SIRT1 attenuates age-related skin thinning in mice. </p><p>[Method and Results] DDY mice were fed a normal diet or a diet containing a SIRT1 activator resveratrol (RSV, 0.4 g/kg diet) for 37 weeks starting at 23 weeks of age. Back and ventral skin samples were obtained from 60-week-old mice (Old), resveratrol-fed 60-week-old mice (Old+RSV), and 20-week-old mice (Young). Skin thickness was examined histologically in Hematoxylin-Eosin staining. Epidermal cell proliferation was evaluated by immunohistochemistry using an anti-Ki67 antibody. In the back skin, dermal and epidermal thicknesses were significantly decreased in Old compared to Young, but these aging-related changes was attenuated in Old+RSV. In ventral skin, fat layer thickness was significantly thinner in Old than those in Young. Fat layer thickness was also maintained in Old+RSV. The percentage of Ki67-positive cells in epidermis was significantly decreased in Old compared to Young, but this was preserved in Old+RSV.</p><p>[Conclusion] These findings suggest that activation of SIRT1 by administration of resveratrol attenuates skin thinning with aging partly via maintaining epidermal cell proliferation.</p>