Epigenetic Drug Valproic Acid in vertebrate Aging - Part I: Lifespan analyses

Aging is affected by both genetic and epigenetic factors. It has become increasingly clear that rather than being genetically predefined, our lifespan is largely epigenetically determined. Here, we show that exposure to the epigenetic compound valproic acid (VPA) significantly extended both average and maximum lifespan of the vertebrate research model Nothobranchius furzeri. First, to characterize the potentially effective range of VPA and to identify the optimal concentration inducing lifespan extension, we conducted a dose-response analysis in N. furzeri. We identified the concentration of 0.25mM VPA to be most effective in prolonging lifespan. As the incidence of age-related pathologies strikingly increases after having passed midlife, we implemented a late-onset protocol starting VPA administration at week 10 of adult killifish life, roughly corresponding to 90% survivorship of our killifish colony. In this study, VPA treatment (0.5mM and 0.25mM) initiated at middle age produced a highly significant life-extending effect. Specifically, exposure to 0.25mM VPA resulted in an increase  of median and maximum survival by 30% and 28,5%, respectively. With regard to in vivo reaction kinetics indicating epigenetic modifications, administration of the geroprotective compound VPA (0.5mM) via the system water induced histone hyperacetylation within the first 24 hours indicative of a rapidly responding transcriptome. Taken together, our study shows that epigenetic interventions initiated passed midlife hold the potential to slow down the aging process by “rejuvenating” the epigenome thereby extending the disease-free portion of life even at advanced age.