Prevention of cell senescence is a potential means to extend healthspan and perhaps lifespan. Agents that increase NAD+ levels, which are diminished with age, may be senopreventive through restoration of SIRT1 and normal mitochondrial activity. The ketone body [Formula: see text]-hydroxybutyrate ([Formula: see text]-HB) prevents senescence by inducing quiescence in endothelial cells. [Formula: see text]-HB activates hnRNP A1, which then binds and stabilizes Oct4 mRNA. In turn, expression of Oct4 in endothelial cells induces quiescence, which protects cells from DNA-damage-induced and replicative senescence, but not p53-mediated senescence. [Formula: see text]-HB, which increases in fasting, caloric restriction, and exercise, may synergize with agents that increase NAD+ levels in middle-aged and old animals and people to reduce the rate at which senescent cells form and alter metabolism. Moreover, observed induction of Oct4 by [Formula: see text]-HB in the brain as well suggests a possible nexus with reprogramming pathways in neural stem cells should be explored. The development of and potential combined efficacy of senolytic, senomodulatory, and senopreventive therapeutics may have significant benefits for maintaining healthspan and increasing lifespan.
Keywords: Oct4; beta-hydroxybutyrate; ketone bodies; quiescence; senescence.