SIRT1 regulates dermal fibroblast senescence via impaired deacetylase function and mitochondrial dysfunction during skin aging induced by chronic oral cadmium exposure.

Abstract

Skin aging is a complex, multifactorial biological process that can be significantly accelerated by environmental toxicants such as cadmium (Cd), a highly toxic and ubiquitous heavy metal. Although the broad cytotoxic impacts of Cd have been extensively reported, a comprehensive understanding of the precise molecular pathways underlying Cd-induced skin senescence is still lacking. In this study, we investigated the protective role of Sirtuin 1 (SIRT1), a highly conserved nicotinamide adenine dinucleotide (NAD + )-dependent deacetylase that functions as a master regulator of mitochondrial homeostasis and cellular defense mechanisms. To delineate the influence of SIRT1 on dermal aging, we established an in vitro model using primary rat dermal fibroblasts and C3H/10 T1/2 cells, where SIRT1 levels were modulated via lentiviral-mediated overexpression. Concurrently, an in vivo model was developed using Sprague-Dawley rats subjected to chronic Cd exposure via drinking water (50 mg/L) for 6 months, complemented by skin-targeted SIRT1 upregulation through the local injection of AAV-r-SIRT1. Our results demonstrate that Cd exposure elevates reactive oxygen species (ROS), disrupts mitochondrial integrity, and activates DNA damage responses, collectively driving cellular senescence. SIRT1 was shown to exert protective effects through the deacetylation of key substrates such as P53 and SOD2, thereby restoring redox balance and promoting DNA repair. The elevation of SIRT1 expression markedly mitigated mitochondrial impairments, senescent phenotypes, and apoptotic features triggered by Cd exposure. Our findings position SIRT1 as a crucial regulator of Cd-induced skin aging and suggest that targeting this deacetylase may provide a viable strategy to counteract skin degeneration caused by environmental insults.