The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies

Abstract

Both calorie restriction and the ketogenic diet possess broad therapeutic potential in various clinical settings and in various animal models of neurological disease. Following calorie restriction or consumption of a ketogenic diet, there is notable improvement in mitochondrial function, a decrease in the expression of apoptotic and inflammatory mediators and an increase in the activity of neurotrophic factors. However, despite these intriguing observations, it is not yet clear which of these mechanisms account for the observed neuroprotective effects. Furthermore, limited compliance and concern for adverse effects hamper efforts at broader clinical application. Recent research aimed at identifying compounds that can reproduce, at least partially, the neuroprotective effects of the diets with less demanding changes to food intake suggests that ketone bodies might represent an appropriate candidate. Ketone bodies protect neurons against multiple types of neuronal injury and are associated with mitochondrial effects similar to those described during calorie restriction or ketogenic diet treatment. The present review summarizes the neuroprotective effects of calorie restriction, of the ketogenic diet and of ketone bodies, and compares their putative mechanisms of action.

Figure 1

Mechanisms underlying the neuroprotective effects of calorie restriction. Neuronal injury, either acute (for example following ischemia) or chronic (such as amyloid toxicity) impairs mitochondrial function, resulting in increased formation of reactive oxygen species (ROS) and decreased ATP synthesis, and activates apoptotic pathways. Calorie restriction abrogates mitochondrial impairment, inhibits apoptotic pathway (mainly by activating Sirt1) and increases neurotrophic activity, thereby increasing neuronal resistance to injury.

Figure 2

Mechanisms underlying the neuroprotective effects of ketone bodies. Ketone bodies improve mitochondrial respiration and, as a result, increase NAD levels relative to NADH, decrease reactive oxygen species (ROS) formation and enhance ATP production. Ketone bodies also decrease the activity of the apoptotic enzyme protein phosphatase 2A (PP2A), possibly by inhibiting the ROS-dependent formation of ceramide, a PP2A activator. Sirt1 involvement is possible given the increased NAD to NADH ratio, but this has yet to be demonstrated.