Brain response to calorie restriction

Abstract

Calorie restriction extends longevity and delays ageing in model organisms and mammals, opposing the onset and progression of an array of age-related diseases. These beneficial effects also extend to the maintenance of brain cognitive functions at later age and to the prevention, at least in rodents, of brain senescence and associated neurodegenerative disorders. In recent years, the molecular mechanisms underlying brain response to calorie restriction have begun to be elucidated, revealing the unanticipated role of a number of key nutrient sensors and nutrient-triggered signaling cascades in the translation of metabolic cues into cellular and molecular events that ultimately lead to increased cell resistance to stress, enhanced synaptic plasticity, and improved cognitive performance. Of note, the brain's role in CR also includes the activation of nutrient-sensitive hypothalamic circuitries and the implementation of neuroendocrine responses that impact the entire organism. The present review addresses emerging molecular themes in brain response to dietary restriction, and the implications of this knowledge for the understanding and the prevention of brain disorders associated with ageing and metabolic disease.

Fig. 1

How calorie restriction prevents brain ageing. Improved neurogenesis, increased synaptic plasticity, and neuroprotection are the basis for the enhancement of brain health by a calorie-restricted diet. A nutrient-restricted regimen induces a mild stress able to modulate the expression of key molecules for both neuron activity as well as for the resistance to stronger stress that can induce nervous system damage. Moreover, dietary restriction preserves the neural stem cells pool, that contributes to formation of new neural circuits during memory consolidation, and attenuates age-dependent functional decline and neurodegeneration. Calorie restriction, through these cellular mechanisms, extends mindspan and prevents neurodegenerative diseases

Fig. 2

Metabolic regulation of stem cell fate by nutrients and insulin. Restricted nutrient availability, as under calorie restriction, reduces insulin and mTOR signaling and promotes “fasting-mode” responses by activating FoxO (by nuclear translocation) Sirt1 (by increasing the NAD+/NADH ratio) and CREB (by promoting its phosphorylation and association with Sirt1); this results in stem cell quiescence state with low oxidative burden and extended self-renewal. Conversely, chronic activation of the “feeding response” as in obesity and diabetes (high insulin and mTOR signaling, inhibition of FoxO, inactivation of Sirt1 and CREB) drives stem cells from quiescence to cycling, increases oxidative burden, and promotes stem cell proliferation and maturation at the expense of self-renewal, leading to premature exhaustion and tissue ageing. The scheme refers to a general stem cell model that also applies to neural stem cells. The possible involvement of CREB and Sirt1 in NSC self-renewal is still to be fully validated and is presented here as largely hypothetical

Fig. 3

Brain-centered control of organismal metabolism. Calorie restriction regulates nutrient-sensitive molecules including CREB, Sirt1, AMPK and mTOR in several tissues including brain (cell autonomous mechanism), thus promoting central behavioral adaptations (food seeking, appetite, alertness) and peripheral metabolic modifications (gluconeogenesis, lipolysis). In parallel, brain integrates nutrient-related cues and coordinates, through neuroendocrine and autonomic signals, organismal response to fasting (non cell-autonomous mechanism)