Caloric restriction and intermittent fasting: two potential diets for successful brain aging

Abstract

The vulnerability of the nervous system to advancing age is all too often manifest in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. In this review article we describe evidence suggesting that two dietary interventions, caloric restriction (CR) and intermittent fasting (IF), can prolong the health-span of the nervous system by impinging upon fundamental metabolic and cellular signaling pathways that regulate life-span. CR and IF affect energy and oxygen radical metabolism, and cellular stress response systems, in ways that protect neurons against genetic and environmental factors to which they would otherwise succumb during aging. There are multiple interactive pathways and molecular mechanisms by which CR and IF benefit neurons including those involving insulin-like signaling, FoxO transcription factors, sirtuins and peroxisome proliferator-activated receptors. These pathways stimulate the production of protein chaperones, neurotrophic factors and antioxidant enzymes, all of which help cells cope with stress and resist disease. A better understanding of the impact of CR and IF on the aging nervous system will likely lead to novel approaches for preventing and treating neurodegenerative disorders.

Fig. 1

Dietary restriction and the healthy aging of man. Taking Da Vinci's Man as a paragon of humanity we have described how he may live beyond the years normally ascribed to renaissance homo sapiens through alterations in caloric intake. Both gross and cellular physiology is profoundly affected by caloric restriction (CR) or intermittent fasting (IF) regimes. With respect to gross physiology there is of course a significant reduction of body fat and mass, which supports a healthy cardiovascular system and reduces incidents of myocardial infarction. In addition to cardioprotection a greater tolerance to stress is induced in the liver, the nutrient core of homo sapiens. The presence of alternative energy stores such as ketone bodies (e.g. β-hydroxybutyrate) enable homo sapiens to survive additional stresses of life. Excessive and deleterious blood glucose is curtailed by an enhanced sensitivity to insulin (Ins) and glucose and its utilization as an energy source. The elevation of neurotrophic factors also supports the maintenance of complex neuronal circuits required for memory retention and cognition. At the molecular level many of the beneficial effects of CR/IF are recapitulated. Proteins and nucleic acids are protected from damaging post-transaltional modifications via upregulations of sirtuin histone deacetylases and heat shock proteins (Hsp). To maintain Man during the beneficial periods of fasting, peroxisome proliferator-activated receptors (PPAR) are activated to mobilize fat stores for energy usage. During these times of energy deficit, cell survival is supported by the activation of forkhead box-other (FoxO) transcription factors and through the generation of neurotrophic agents such as brain-derived neurotrophic factor (BDNF). Inflammatory cytokines, upregulated by CR/IF can even serve to allow enhanced synaptic strength during the times of energy deficit.