Replicative Senescence in Human Fibroblasts Is Delayed by Hydrogen Sulfide in a NAMPT/SIRT1 Dependent Manner

Recent evidence suggests that hydrogen sulfide (H(2)S) has cytoprotective and anti-aging effects. However, the mechanisms for such properties are not fully understood. Here, we show that the expression of the main H(2)S producing enzyme, CBS, and production of H(2)S are coordinately diminished in replicative senescent adult human dermal fibroblasts. The reduced production of H(2)S falls within the same time-frame that the hallmarks of replicative senescence appear including accumulation of SA–β-Gal, enhanced expression of p16, p21, and RRM2B while the expression of RRM2, hTERT, SIRT1, NAMPT, and NAD/NADH ratio all fall. Exogenous H(2)S increases the expression of hTERT, NAMPT, SIRT1 and NAD/NADH ratio in treated cells. Moreover, H(2)S safeguards the expression of hTERT in a NAMPT and SIRT1 dependent manner and delays the onset of replicative senescence as evidenced by reduced accumulation of age associated SA–β-Gal and cessation of proliferation. Postponement of loss of cell proliferative capacity without risk of mutagenesis shows implications for use of H(2)S in delaying the adverse effects of senescence in organisms.