Abstract The therapeutic potential of calorie restriction and the ketogenic diet have been repeatedly demonstrated in clinical settings and in various animal models of neurological disease. The underlying mechanisms involve an improvement in mitochondrial function, a decrease in the expression of apoptotic factors and an increase in the activity of neurotrophic factors. Clinical applications of ketogenic diets have been significantly hampered however by poor tolerability and potentially serious side-effects. Recent research aimed at identifying a mediator that can reproduce the neuroprotective effects of calorie restriction with less demanding changes to dietary intake suggests that ketone bodies might represent an appropriate candidate. Ketone bodies protect neurons against multiple types of neuronal injury and the underlying mechanisms are similar to those of calorie restriction and of the ketogenic diet. The present review describes the neuroprotective effects of calorie restriction, the ketogenic diet and ketone bodies and compare the molecular mechanisms of action of these interventions. Keywords: calorie restriction, neuroprotection, ketone bodies, ketogenic diet, oxidative stress, mitochondria, brain

1. 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 effects of fasting, has been difficult to use in clinical settings despite proven efficacy. As a consequence, considerable effort has been invested to understand the mechanisms underlying the neuroprotective effects of calorie restriction (and potentially of the ketogenic diet) with the hope of developing alternative therapeutic options. The present article reviews findings supporting the neuroprotective effects of calorie restriction, summarizes the mechanisms activated by calorie restriction and describes a mediator that could possibly replicate the neuroprotective effects of calorie restriction. Specifically, we propose that ketone bodies mediate, at least in part, the neuroprotective effects of calorie restriction by showing that ketone bodies are equally neuroprotective and that calorie restriction and ketone bodies act on neural cells by similar mechanisms.

6. Conclusion Calorie restriction and the ketogenic diet share two characteristics: reduced carbohydrate intake and a compensatory rise in ketone bodies. The neuroprotective effects of reduced carbohydrate per se are being investigated by several research groups (Mattson et al. 2003; Ingram et al. 2006). We have evaluated the possibility that ketone bodies might mediate the neuroprotective effects of calorie restriction and of the ketogenic diet. An expanding body of evidence indicates that ketone bodies are indeed neuroprotective and that the underlying mechanisms are similar to those associated with calorie restriction - specifically at the mitochondrial level. However, several important questions remain unanswered. The effects of ketone bodies on gene expression have not been investigated, although inhibition of glycolysis with 2-deoxyglucose (which blocks phosphofructose isomerase) has been reported to inhibit BDNF expression and kindling progression in rats (Garriga-Canut et al, 2006). Moreover, the neuroprotective of ketone bodies in vivo have not been thoroughly examined. For instance, it is imperative to demonstrate that the neuroprotective effects of ketone bodies are associated with a preservation of clinically relevant functions such as cognition. Finally, it is crucial to determine if the anti-apoptotic properties of ketone bodies might potentially increase the risk of carcinogenesis. Intriguingly, both the calorie restriction and the ketogenic diet have been associated with anti-neoplastic properties and similarly, preliminary data suggest that the ketone bodies β-hydroxybutyrate and acetoacetate have anti-neoplastic effects on human glioblastoma cell lines (Patel et al. 2004; Jolly 2006 Zhou et al. 2007). Further research will hopefully further clarify the mechanisms underlying the neuroprotective properties of calorie restriction and ketone bodies and explain the counter-intuitive effects on carcinogenesis.