Skin photoaging is mainly driven by chronic ultraviolet (UV) exposure and is closely associated with oxidative stress, DNA damage, cellular senescence, and extracellular matrix disruption. MDL800 is a selective allosteric activator of sirtuin 6 (SIRT6), but its role in UV-induced skin photoaging has not been investigated. Here, we examined the protective effects of MDL800 in UVA-treated human dermal fibroblasts (HDFs) and UV-irradiated BALB/c mouse dorsal skin. In HDFs, repeated UVA exposure induced marked photoaging-associated alterations accompanied by reduced SIRT6 expression. MDL800 partially reversed these changes, restored SIRT6 expression, reduced H3K9Ac and H3K56Ac levels, while lowering reactive oxygen species (ROS) and malondialdehyde (MDA) accumulation, comet tail formation, and γH2AX levels. MDL800 also improved Lamin B1 expression, superoxide dismutase (SOD) activity, NRF2-associated antioxidant molecules, and COL1A1 expression, and decreased MMP1 and MMP3 expression. To further examine the contribution of SIRT6, pharmacological inhibition experiments were performed using OSS-128167. Co-treatment with OSS-128167 increased H3K9 acetylation relative to MDL800 treatment alone and partially attenuated the MDL800-associated increase in HO-1 and Lamin B1 expression and decrease in SA-β-gal-positive cells. In UV-irradiated mouse skin, topical MDL800 improved gross photoaging-like changes, reduced epidermal thickening, preserved dermal collagen organization, and ameliorated associated molecular alterations. Overall, MDL800 exerted protective effects against UV-induced skin photoaging in both cellular and animal models. The partial attenuation of selected protective effects by OSS-128167 further supports the involvement of SIRT6 in MDL800-mediated protection.
