Hydrogen Indirectly Suppresses Increases in Hydrogen Peroxide in Cytoplasmic Hydroxyl Radical-Induced Cells and Suppresses Cellular Senescence

Bacteria inhabiting the human gut metabolize microbiota-accessible carbohydrates (MAC) contained in plant fibers and subsequently release metabolic products. Gut bacteria produce hydrogen (H-2), which scavenges the hydroxyl radical (center dot OH). Because H-2 diffuses within the cell, it is hypothesized that H-2 scavenges cytoplasmic center dot OH (cyto center dot OH) and suppresses cellular senescence. However, the mechanisms of cyto center dot OH-induced cellular senescence and the physiological role of gut bacteria-secreted H-2 have not been elucidated. Based on the pyocyanin-stimulated cyto center dot OH-induced cellular senescence model, the mechanism by which cyto center dot OH causes cellular senescence was investigated by adding a supersaturated concentration of H-2 into the cell culture medium. Cyto center dot OH-generated lipid peroxide caused glutathione (GSH) and heme shortage, increased hydrogen peroxide (H2O2), and induced cellular senescence via the phosphorylation of ataxia telangiectasia mutated kinase serine 1981 (p-ATM(ser1981))/p53 serine 15 (p-p53(ser15))/p21 and phosphorylation of heme-regulated inhibitor (p-HRI)/phospho-eukaryotic translation initiation factor 2 subunit alpha serine 51 (p-eIF2)/activating transcription factor 4 (ATF4)/p16 pathways. Further, H-2 suppressed increased H2O2 by suppressing cyto center dot OH-mediated lipid peroxide formation and cellular senescence induction via two pathways. H-2 produced by gut bacteria diffuses throughout the body to scavenge cyto center dot OH in cells. Therefore, it is highly likely that gut bacteria-produced H-2 is involved in intracellular maintenance of the redox state, thereby suppressing cellular senescence and individual aging. Hence, H-2 produced by intestinal bacteria may be involved in the suppression of aging.