Abstract
The ketone body beta-hydroxybutyrate (βHB) 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 βHB supplementation on the lifespan ofC. elegans nematodes. βHB supplementation extended mean lifespan by approximately 20%. RNAi knockdown of HDACs hda-2 or hda-3 also increased lifespan and further prevented βHB-mediated lifespan extension. βHB-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. βHB did not extend lifespan in a genetic model of dietary restriction indicating that βHB is likely functioning through a similar mechanism. βHB addition also upregulated ΒHB 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 βHB dehydrogenase activity induced by βHB addition, suggesting that F55E10.6 functions as an inducible βHB dehydrogenase. Furthermore, βHB 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-βHB extends lifespan through inhibiting HDACs and through the activation of conserved stress response pathways.
Highlights
Aging leads to a progressive decline of cell and tissue function and is the primary risk factor for many ailments, including the prevalent neurodegenerative disorders Alzheimer’s disease (AD) and Parkinson’s disease (PD)
Addition of 2, 10, or 20 mM DL-beta-hydroxybutyrate to the culture medium of C. elegans feeding on heat-killed E. coli increased lifespan with 20 mM having the greatest effect, increasing mean lifespan by 26%, from 17.2 to 21.7 days (Figure 1A). 50 mM and 100 mM concentrations decreased lifespan (Supplementary Table 1)
And as previously found by others [33], sodium butyrate extended lifespan, but strikingly the combination of sodium butyrate and βHB led to a slightly decreased lifespan. This data is consistent with the possibility that βHB is functioning as an histone deacetylase (HDAC) inhibitor as HDAC inhibitors such as valproic acid are known to cause decreased lifespan at higher concentrations in C. elegans ([32] and Supplementary Table 1)
Summary
Aging leads to a progressive decline of cell and tissue function and is the primary risk factor for many ailments, including the prevalent neurodegenerative disorders Alzheimer’s disease (AD) and Parkinson’s disease (PD). Slight inhibition of mitochondrial respiration can lead to small increases in reactive oxygen species (ROS) production and extend the lifespan of yeast, C. elegans, Drosophila, and mice [36]. The ketone body beta-hydroxybutyrate (βHB) has been described as a DR mimetic compound [13], in part because it increases in the plasma during DR and when administered exogenously leads to decreased levels of oxidative stress [14]. ΒHB is produced in the liver, primarily from the catabolic breakdown of fatty acids, and is used as an alternative energy source when blood glucose is low. This is especially important in the brain where only a very limited amount of fatty acid beta-oxidation takes place www.impactaging.com
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