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

Area of Science:

• Evolutionary biology
• Genomics
• Biochemistry

Background:

• Hydrogen sulfide (H2S) is vital for physiological processes and influences aging via oxidative stress.
• Endogenous H2S production involves key enzymes: cystathionine-β-synthase (CBS), cystathionine-ƴ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST).
• Long-lived mammals may possess unique genetic adaptations related to H2S metabolism and longevity.

Purpose of the Study:

• To investigate the evolutionary dynamics of CBS, CSE, and 3-MST genes in long-lived mammals.
• To determine if these genes show signs of positive selection associated with extended lifespan.
• To explore the role of CSE gene evolution in the naked mole-rat's remarkable longevity.

Main Methods:

• Comparative genomic analysis of CBS, CSE, and 3-MST genes across 114 mammalian species.
• Application of codon-based evolutionary models to detect selection pressures.
• Focus on the naked mole-rat (Heterocephalus glaber) as a model for long-lived mammals.

Main Results:

• A relaxation of purifying selection, not positive selection, was observed in the CSE gene of long-lived mammals, suggesting adaptive mutations.
• CBS and 3-MST genes did not show significant selection patterns related to longevity.
• The naked mole-rat's CSE gene displayed clear positive selection, with specific mutations (G116A, T118V) enhancing protein stability and cofactor binding.

Conclusions:

• The CSE gene, but not CBS or 3-MST, shows a potential correlation with longevity in mammals.
• Specific CSE mutations in the naked mole-rat may improve H2S production, contributing to its extended lifespan and adaptations.
• This study offers insights into the molecular basis of longevity and the adaptive significance of H2S biogenesis.