Hydrogen sulfide may contribute to longevity: Results from a preclinical study on C. elegans

Research on aging revealed that the lifespan could be extended by inhibiting mechanisms that promote growth and proliferation. An example of the latter is the serine/threonine kinase complex mTORC1 (mechanistic target of rapamycin complex), which regulates the growth process through growth factors and nutritional elements. Several approaches have been suggested to influence (reduce) the activity of mTORC1. Examples include dietary restriction, pharmacological options like rapamycin (a medication used as an immunosuppressant), and genetic pertubations (changes in function in response to stimuli).

mTORC1 is involved in the synthesis of proteins through exerting influence on messenger RNA. Studies on model organisms like nematodes C. elegans and fruit flies have revealed that lifespan extension mediated by mTORC1 inhibition is due to an overall decrease in the translation process, leading to reduced protein production. In addition, suppressing mTORC1 in C. elegans resulted in improved stress resistance. Suppression of new protein synthesis is one of the mechanisms by which cells protect themselves from stressful conditions like nutrient deprivation.

The aforementioned suppression in protein synthesis leads to translation of activating transcription factor 4 (ATF-4). The outcome of this process is the reestablishment of homeostasis through activating stress defense mechanisms. Results from the literature have highlighted that genetic or pharmacological options that impair stress response in C. elegans promote their longevity. To better understand the effect of ATF-4 on the lifespan of C. elegans, Statzer et al. initiated a study.

Results of their experiments revealed that ATF-4 influences longevity through hydrogen sulfide (H2S) production and not by regulating amino acid (AA) synthesis. This is because the levels of AA expression were similar between wild type and ATF-4-overexpressing animals, while the levels of H2S production increased with ATF-4 overexpression by the influence of CTH-2 (cystathionine gamma-lyase, an enzyme that plays a role in the production of H2S). Using a fluorescent H2S probe, the investigators found that mutations in genes of ATF4 or CTH-2 reduced H2S levels. Additionally, the researchers highlighted that genetic inhibition of mTORC1 or mTORC2 led to increased H2S production capacity. Their results suggested that knockdown of CTH-2 prevented mTORC1 inhibition from enhancing stress resistance, affecting longevity. Taken together, the results of their experiment reveal that a reduction in mTORC1 signaling leads to preferential translation of ATF-4, which acts through CTH-2 to increase H2S production, thus promoting stress resistance and healthy aging.

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