Targeting macro- and micro-nutrient regulation of H₂S signaling for the aging brain

Global growth in aged population demographics is a testament to medical and societal innovations over the past 100 years. However, with advanced age comes declines in various organs and tissues, thus limiting quality of life in one's later years. There are numerous hypotheses for what the driving and causative factors are for biological aging, with each proposing molecular targets and their therapeutic strategies. One such hypothesis is that dysfunctions in cellular and systemic redox homeostasis are to blame, in that aging-related increases in oxidative stress and diminished thiol-mediated protections and signaling activity drive macromolecular damage leading to tissue failure, particularly in the brain. Addressing redox dysfunction has been somewhat a challenge clinically, as antioxidant supplementation has not shown to be universally effective at slowing the aging process. Thus, geroscience interventions that can bolster our endogenous redox machinery may be more effective. In this review, we highlight hydrogen sulfide (H₂S) and its associated metabolism and gasotransmitter signaling as potent redox mechanisms that can be leveraged via macro- and/or micro-nutrient interventions. Specifically, dietary restriction (DR) and iron status greatly impact the enzymatic and non-enzymatic production, metabolism, and thiol modifications of H₂S. As both DR and iron status can have profound impacts on redox homeostasis and aging in the brain, we discuss how all these factors are intertwined in glioblastoma (GBM) and neurodegeneration, two of the most significant aging-related disorders of the brain that limit both lifespan and healthspan.