D-beta-hydroxybutyrate extends lifespan in C. elegans

The ketone body beta-hydroxybutyrate (beta HB) is a histone deacetylase (HDAC) inhibitor and has been shown to be protective in many disease models, but its effects on aging are not well studied. Therefore we determined the effect of beta HB supplementation on the lifespan of C. elegans nematodes. beta HB supplementation extended mean lifespan by approximately 20%. RNAi knockdown of HDACs hda-2 or hda-3 also increased lifespan and further prevented beta HB-mediated lifespan extension. beta HB-mediated lifespan extension required the DAF-16/FOXO and SKN-1/Nrf longevity pathways, the sirtuin SIR-2.1, and the AMP kinase subunit AAK-2. beta HB did not extend lifespan in a genetic model of dietary restriction indicating that beta HB is likely functioning through a similar mechanism. beta HB addition also upregulated BHB dehydrogenase activity and increased oxygen consumption in the worms. RNAi knockdown of F55E10.6, a short chain dehydrogenase and SKN-1 target gene, prevented the increased lifespan and beta HB dehydrogenase activity induced by beta HB addition, suggesting that F55E10.6 functions as an inducible beta HB dehydrogenase. Furthermore, beta HB supplementation increased worm thermotolerance and partially prevented glucose toxicity. It also delayed Alzheimer's amyloid-beta toxicity and decreased Parkinson's alpha-synuclein aggregation. The results indicate that D-beta HB extends lifespan through inhibiting HDACs and through the activation of conserved stress response pathways.