Ketone Bodies and Aging
We are broadly interested in how signals from the environment, such as what and how we eat, are transmitted into cells throughout the body to affect aging and disease. Some of these signals may offer windows into fundamental mechanisms of aging. Research targeting the process of aging holds out the hope of delaying or improving multiple chronic diseases simultaneously (such as diabetes, heart disease, and Alzheimer’s disease) while also having similar benefits on multifactorial geriatric syndromes like frailty or delirium. Interventions targeting the process of aging might therefore help older adults remain healthier and independent longer.
Model organism studies have identified a number of genes and interventions that simultaneously affect various aspects of aging and induce resistance to multiple stressors. The best-characterized longevity intervention to date is dietary restriction (DR), which in many species can prolong lifespan and delay a variety of age-related diseases. Many of the benefits of DR are due to specific nutrient-responsive pathways that can be manipulated independently of diet, such as insulin/insulin-like growth factor (IGF) pathways, target of rapamycin (mTOR) pathways, and the sirtuin NAD+-dependent deacetylases. For example, rapamycin and metformin extend lifespan when fed to normal mice, and SIRT3 mediates DR’s prevention of age-related hearing loss in mice.
A common feature of varied DR regimens is the production of ketone bodies, small lipid-derived molecules that serve as a source of energy in times of fasting. Our group recently found that the major ketone body in humans, b-hydroxybutyrate (BHB), inhibits histone deacetylases (HDACs) at concentrations reached during CR or fasting. Alterations in protein acetylation control many aspects of cellular function through epigenetic regulation of gene expression, as well as via post-translational protein modification. Inhibition of HDACs by BHB is one of several ways in which BHB is not just a simple carrier of energy, but acts as a signal as well (Figure 1).
We found that BHB inhibits class I deacetylases in vitro and causes histone hyperacetylation in vivo. Dietary states that elevate BHB, including CR and fasting, also cause histone hyperacetylation (Figure 2). BHB specifically causes histone hyperacetylation at the promoters of FOXO3 (a transcription factor implicated in longevity) and MT2 (an antioxidant protein). This results in up-regulation of FOXO3 and MT2 expression, and increases resistance to oxidative stress in the mouse kidney.
Interestingly, a link between modulation of HDAC function and aging is well-established in model organisms. A modest reduction in the activity of class I HDACs via genetic manipulation or drug treatment prolongs lifespan in yeast and flies, and reduces age-related cognitive decline in mice. HDACs control many cellular pathways relevant to aging. b-hydroxybutyrate is the only endogenous, small-molecule inhibitor of deacetylases so far identified in mammals. We hypothesize that ketone bodies, as endogenous HDAC inhibitors, may therefore be an epigenetic mediator of some of the benefits of DR by reprogramming gene expression and causing up-regulation of genes involved in pathways that promote healthspan and longevity (Figure 3).
1. Shimazu T, MD Hirschey, J Newman, W He, K Shirakawa, N Le Moan, CA Grueter, H Lim, LR Saunders, RD Stevens, CB Newgard, RV Farese, R de Cabo, S Ulrich, K Akassoglou, and E Verdin. Suppression of oxidative stress by b-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science. 339(6116):211-4 (2013) PMID: 23223453.
2. Newman JC and E Verdin. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 25(1):42-52 (2014). PMID: 24140022. (review)
3. Newman JC and E Verdin. b-hydroxybutyrate: Much more than a metabolite. Diabetes Res Clin Pract. 106(2):173-81 (2014). PMID: 25193333. (review)