Late-Onset exposure to the epigenetic drug valproic acid extends lifespan in the vertebrate model Nothobranchius furzeri

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 initiated at middle age produced a highly significant life-extending effect. Specifically, median and maximum survival was increased by 30% and 28,5%, respectively. With regard to in vivo reaction kinetics indicating epigenetic modifications, administration of the geroprotective concentration of 0.25mM VPA via the system water induced histone hyperacetylation within the first 24 hours indicative of a rapidly responding transcriptome. Next, to identify longevity-associated gene expression signatures and to distinguish immediate from long-term manifestation effects upon VPA treatment we performed a transcriptomic profiling experiment employing a late-onset VPA administration protocol of biological samples spanning the second half of the killifish lifespan including initial sampling time points week 10, 24 hours post drug administration and week 14, corresponding to continuous treatment. 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.