Cystathionine Gamma-Lyase: A Potential Longevity Gene Under Selection?

Hydrogen sulfide (H₂S) plays a crucial role in various physiological processes and has been implicated in modulating aging through its impacts on oxidative stress and cellular health. This study investigates the evolutionary dynamics of the cystathionine-β-synthase (CBS), the cystathionine-ƴ-lyase (CSE), and the 3-mercaptopyruvate sulfurtransferase (3-MST) genes, involved in endogenous H₂S production. We investigated CBS, CSE, and 3-MST in long-lived mammals, focusing on the naked mole-rat (Heterocephalus glaber). We hypothesized that these genes would exhibit signs of positive selection linked to extended lifespan. Codon-based evolutionary models were used to compare these genes across 114 mammalian species. Our results revealed a relaxation of purifying selection instead of positive selection in CSE, but not CBS and 3-MST, in long-lived mammals, suggesting an accumulation of mutations that enhance physiological functions related to longevity. In the naked mole-rat, CSE exhibited clear signs of positive selection, particularly in residues G116A and T118V, associated with increased protein stability and enhanced binding affinity to the cofactor pyridoxal-5'-phosphate (PLP). These mutations possibly improve CSE catalytic efficiency and potentially H₂S production, supporting the naked mole-rat's unique adaptations to its subterranean habitat and contributing to its remarkable lifespan. Our findings indicate a potential correlation between longevity and selection on the CSE gene, but not the CBS and 3-MST genes, highlighting the complex role of H₂S in aging and cellular health. The study provides new insights into the molecular mechanisms underlying lifespan extension in long-lived mammals and underscores the potential adaptive significance of H₂S biogenesis in the naked mole-rat.