D-beta-hydroxybutyrate extends lifespan in C. elegans.

ABSTRACT: The ketone body beta-hydroxybutyrate (?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 ?HB supplementation on the lifespan ofC. elegans nematodes. ?HB supplementation extended mean lifespan by approximately 20%. RNAi knockdown of HDACs hda-2 or hda-3 also increased lifespan and further prevented ?HB-mediated lifespan extension. ?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. ?HB did not extend lifespan in a genetic model of dietary restriction indicating that ?HB is likely functioning through a similar mechanism. ?HB addition also upregulated ?HB 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 ?HB dehydrogenase activity induced by ?HB addition, suggesting that F55E10.6 functions as an inducible ?HB dehydrogenase. Furthermore, ?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-?HB extends lifespan through inhibiting HDACs and through the activation of conserved stress response pathways.

SUBMITTER: Edwards C 

PROVIDER: S-EPMC4169858 | biostudies-other | 2014 Aug

REPOSITORIES: biostudies-other