Effects of Creatine and Nicotinamide on Experimentally Induced Senescence in Dermal Fibroblasts

Dermal fibroblasts provide structural support by producing collagen and other structural/support proteins beneath the epidermis. Fibroblasts also produce Insulin-like growth factor-1 (IGF-1), which binds to the IGF-1 receptors (IGF-1Rs) on keratinocytes to activate signaling pathways that regulate cell proliferation and cellular responses to genotoxic stressors like ultraviolet B radiation found in sunlight. Our group has determined that the lack of IGF-1 expression due to fibroblast senescence in the dermis of geriatric individuals is correlated with an increased incidence of skin cancer in geriatric patients. The present studies were designed to test the hypothesis that pro-energetics like creatine monohydrate and nicotinamide can protect fibroblasts against senescence. To that end, we used an experimental model of senescence in which primary human fibroblasts are treated with hydrogen peroxide (H2O2) in vitro, with senescence measured by staining for beta-galactosidase activity (+beta-gal), p21 protein expression and senescence associated secretory phenotype (SASP) cytokine mRNA levels. We also determined the effect of H2O2 on IGF-1 mRNA and protein expression. Our studies indicate that pretreatment with creatine monohydrate or nicotinamide protects human fibroblasts from the H2O2-induced cell senescence. These studies suggest a potential strategy for protecting fibroblasts in geriatric skin from undergoing stress-induced senescence, which may maintain IGF-1 levels and therefore limit carcinogenesis in epidermal keratinocytes