Elsevier

Brain Research Reviews

Volume 59, Issue 2, March 2009, Pages 293-315
Brain Research Reviews

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

https://doi.org/10.1016/j.brainresrev.2008.09.002Get rights and content

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.

Introduction

The anticonvulsant properties of fasting have been recognized since antiquity, strongly suggesting that fasting, and more generally, calorie restriction probably represents the first effective treatment for epileptic seizures in medical history. In addition, more recent evidence suggests that the benefits of calorie restriction, elicited either by daily reduction of energy intake or by intermittent fasting, are not limited to epilepsy, and might in fact include a generalized neuroprotective effect applicable to many acute and chronic neurological diseases. In view of the present obesity epidemic, however, the scientific and medical communities have realized that calorie restriction is often not a practical treatment option. Similarly, the ketogenic diet, a high-fat, low-carbohydrate diet designed to reproduce the biochemical effects of fasting, has been challenging to use in clinical settings despite proven efficacy. Consequently, there is now considerable effort expended to understand the mechanisms underlying the neuroprotective effects of calorie restriction and of the ketogenic diet with the hope of developing alternative therapeutic options. The present article reviews findings supporting the neuroprotective effects of calorie restriction and of the ketogenic diet, summarizes the mechanisms activated by these diets and proposes that ketone bodies could possibly replicate some of their neuroprotective properties by activating common mechanisms at the mitochondrial level.

Section snippets

Human studies of calorie restriction

Obesity is associated with an increased risk of dementia (Kivipelto et al., 2005). On imaging studies, decreased hippocampal volume and increased white matter hyperintensities – two radiological hallmarks of pathological brain aging – are more common in obese patients (Jagust et al., 2005). In contrast, apart from the well-known effects of fasting on seizure frequency, low dietary energy intake is associated with enhanced longevity (Redman et al., 2008) and decreased incidence of Alzheimer's

The ketogenic diet

Calorie restriction in animals is achieved by either daily reduction of food intake or by intermittent fasting. Both protocols induce similar physiological and metabolic changes except for one important difference: intermittent fasting leads to a much larger increase in blood levels of the ketone body β-hydroxybutyrate (Mattson et al., 2003, Mattson, 2005). Interestingly, this rise in β-hydroxybutyrate concentration is associated with a more significant reduction in the vulnerability of

Ketone bodies

Despite mounting evidence supporting the anticonvulsant and neuroprotective effects of ketogenic diets, the difficulty of adhering to a restrictive diet and the risk of systemic complications such as growth retardation, nephrolithiasis and hyperlipidemia preclude more widespread implementation (Kwiterovich et al., 2003, Kang et al., 2004, Hartman and Vining, 2007). Therefore, investigators have sought a safer, yet efficacious alternative. Within this context, ketone bodies have become the

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

Our review of the cellular and molecular mechanisms associated with calorie restriction, the ketogenic diet ketone bodies has identified several similarities between these neuroprotective interventions, most importantly the prevention of disease related-mitochondrial dysfunction. Another similarity is the inhibition of apoptosis, although the specific mechanisms underlying the anti-apoptotic effects of each intervention might differ amongst the interventions discussed. Interestingly, recent

Concluding remarks

Calorie restriction and the ketogenic diet share two metabolic characteristics: reduced carbohydrate intake and a compensatory rise in ketone bodies. The neuroprotective effects of reduced carbohydrates per se are being investigated by several research groups (Mattson et al., 2003, Ingram et al., 2006). In this review, we have examined the possibility that ketone bodies might replicate some of the neuroprotective properties of calorie restriction and of the ketogenic diet. In support of this

Acknowledgments

This work was supported in part by NIH grant NS 044846 (JMR), the Barrow Neurological Foundation (JMR) and the Intramural Research Program of the National Institute on Aging (MPM).

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