Researchers have investigated the favorable effects of hydrogen sulfide (H2S) on cell metabolism in the context of aging. An increased presence of H2S appears to modestly improve mitochondrial function and autophagy to some degree, thereby reducing oxidative stress and inflammation characteristic of aging. This functions via post-translational modification of important proteins via S-sulfhydration, changing their function. Like most approaches to metabolic manipulation, the effect size is not as large as we might like it to be, and the underlying biochemistry may overlap to some degree with responses to exercise and calorie restriction.
Hydrogen sulfide (H2S) and hydrogen polysulfide-induced S-sulfhydration are critical posttranslational modifications that specifically target cysteine residues within proteins. Degenerative diseases are often characterized by oxidative stress and inflammaging, ultimately leading to progressive organ dysfunction. Emerging evidence underscores the essential role of S-sulfhydration in modulating mitochondrial biosynthesis, energy metabolism, and cellular homeostasis during aging. However, the intricate pathways and molecular regulators that connect S-sulfhydration to degenerative pathologies remain insufficiently elucidated.
The age-related decrease in endogenous H2S synthase leads to a decline in the level of S-sulfhydration modification of cysteine residues in target proteins, which ultimately promotes the accumulation of reactive oxygen species (ROS) in an age-dependent manner, thereby triggering DNA damage. Moreover, the reduction in intracellular protein S-sulfhydration is correlated with an age-related secretory phenotype, characterized by heightened secretion of inflammatory factors and chemokines, as well as impairment of the autophagy-lysosomal pathway. This leads to the onset of systemic chronic inflammation and ultimately contributes to inflammaging.
To date, numerous studies have emphasized the potential role of protein S-sulfhydration in addressing age and stress-related inflammatory disorders. In disease models such as arthritis and myocardial ischemia reperfusion injury (IRI), supplementation with exogenous H2S donors can effectively counteract cell senescence by promoting the nuclear entry of KEAP1/NRF2, reducing the membrane stability of the receptor RAGE, inhibiting the S-sulfhydration of the NF-κB p65 subunit, and decreasing oxidative stress along with the release of inflammatory factors. Nevertheless, there is a paucity of effective therapeutic interventions targeting age-related pathways. In this review, we offer a comprehensive overview of the current understanding of S-sulfhydration and its role in combating oxidative-inflammatory stress and cellular aging.
Link: https://doi.org/10.1...are.2025.06.038
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