Review
Feature Review
Ketone bodies as signaling metabolites

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Highlights

Traditionally, the ketone body β-hydroxybutyrate (βOHB) has been looked upon as a carrier of energy from liver to peripheral tissues during fasting or exercise. However, βOHB also signals via extracellular receptors and acts as an endogenous inhibitor of histone deacetylases (HDACs). These recent findings support a model in which βOHB functions to link the environment, in this case the diet, and gene expression via chromatin modifications. We review the regulation and functions of ketone bodies, the relationship between ketone bodies and calorie restriction, and the implications of HDAC inhibition by the ketone body βOHB in the modulation of metabolism and in diseases of aging.

Section snippets

Metabolites in aging pathways

The past two decades have witnessed an explosion of knowledge of the genetic and metabolic factors that affect aging and lifespan. Calorie restriction (CR; see Glossary) remains the surest path to increased longevity and resilience to diseases of aging across many organisms, from yeast to monkeys and perhaps humans [1]. Many of the beneficial effects of CR appear to be due to modification of specific nutrient-responsive pathways such as the insulin/insulin-like growth factor (IGF-1) pathway,

Metabolism, regulation, and function of ketone bodies

Ketone bodies are small lipid-derived molecules that serve as a circulating energy source for tissues in times of fasting or prolonged exercise. Fatty acids in adipose tissue contain over 80% of the stored energy of the human body [9]. During fasting, muscle and liver stores of glycogen are depleted first. Then, fatty acids are mobilized from adipocytes and transported to the liver for conversion to ketone bodies. Ketone bodies are then distributed via the circulation to metabolically active

Signaling functions of βOHB

Although βOHB has long been known to be a circulating source of energy in the fasting state, its signaling functions were only recognized much more recently. In addition to its predictable effects on cellular energy balance and metabolites, βOHB acts through at least two cell surface receptors and as an endogenous inhibitor of HDACs.

Ketone bodies, fasting metabolism, and the ketogenic diet

Energy-restricted metabolic states, such as CR or intermittent fasting (every other day), extend lifespan in animals [1]. All such states in vertebrates are necessarily associated with elevations in ketone bodies, whether consistent and modest as in CR or periodic and substantial as in intermittent fasting (see above). Surprisingly, the health benefits of intermittent fasting do not require overall reduced caloric intake. Mice fed every other day have increased longevity [62], and mice fed only

Ketone bodies are neuroprotective and cytoprotective

Fasting has been used as an anticonvulsive therapy since ancient times, and the ketogenic diet has been in clinical use for over a century. It continues to be an effective therapy, particularly for some childhood epilepsies that are resistant to anticonvulsant medications [88]. Ketogenic diets are clinically beneficial in mouse models of several common human neurodegenerative diseases, with promising early data from limited human clinical trials. In the triple-transgenic (3 × TgAD) mouse model of

HDACs in longevity and diseases of aging

As discussed above, inhibition of HDACs by βOHB indicates that βOHB has specific regulatory effects in addition to its metabolic effects, particularly on HDACs and histone acetylation. Interestingly, reduced HDAC activity, either by genetic or pharmacologic means, also has beneficial metabolic and cytoprotective effects similar to those of βOHB. Moreover, HDACs regulate a variety of pathways implicated in longevity, including autophagy and IGF signaling (Figure 4), and modulation of HDAC

Concluding remarks and future perspectives

Ketone bodies are emerging as crucial regulators of metabolic health and longevity via their ability to regulate HDAC activity and thereby epigenetic gene regulation. Ketogenic diets provide a partial phenocopy of CR through their effects on insulin, IGF, FOXO3, fatty acid metabolism, AMPK, and mTOR. The finding that βOHB is an inhibitor of HDACs, together with the coincidence of biological effects of ketone bodies and HDAC inhibition, suggests the fascinating possibility that βOHB could be an

Acknowledgments

We thank John Carroll for artistic assistance. E.V. is supported by funds from the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the Gladstone Institutes. J.C.N. is supported by funds from the Larry L. Hillblom Foundation, the John A. Hartford Foundation, the Glenn Foundation for Medical Research, and an NIH/National Institute on Aging (NIA) T32 training grant.

Glossary

β-Hydroxybutyrate (βOHB)
a molecule that can be used as an energy source by the brain when blood glucose is low. It is one of three metabolically related molecules known collectively as ketone bodies but is itself technically a carboxylic acid. It can also be used for the synthesis of biodegradable plastics, such as poly(3-hydroxybutyrate).
Calorie restriction (CR)
is defined as reduced calorie intake. CR without malnutrition slows the aging process, resulting in increased lifespan in a variety of

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