Trending toward gero-electroceuticals that target membrane potential for reprogramming aging and lifespan

Ion gradients across cell membranes generate voltage potentials that are involved in a wide range of biological processes. According to the membrane hypothesis of aging, aging is inextricably linked to a decrease in resting membrane potential (V_mem). Alterations in ion channel activity and membrane fluidity caused by aging disrupt bioelectric homeostasis, increase intracellular calcium and potassium concentrations, induce abnormal mechanistic target of rapamycin (MTOR)- and AMPK-regulated metabolism and energy dissipation, and decrease proliferation and regeneration. Failure to maintain ion channel activity and membrane potential leads to cell senescence or death. There is evidence that by manipulating ion channel activities, a cryptic memory can be recalled to restore lost proliferative or regenerative abilities. Reversal or prevention of senescence, aging phenotypes, and longevity may be achieved by fine-tuning mitochondrial membrane polarization. Therefore, there is optimism that deciphering the bioelectric codes that govern cell functions will lead to the development of new gero-electroceuticals that restore cell function and prevent tissue loss during aging.