Perspective: The Impact of Fasting and Caloric Restriction on Neurodegenerative Diseases in Humans

Abstract

Neurodegenerative diseases (NDs) are characterized by the progressive functional and structural denaturation of neurons in the central and peripheral nervous systems. Despite the wide range of genetic predispositions, the increased emergence of these disorders has been associated with a variety of modifiable risk factors, including lifestyle factors. Diet has been shown to influence cognitive alterations in the elderly population with age-related brain pathologies, and specific dietary interventions might, therefore, confer preservatory protection to neural structures. Although Mediterranean and ketogenic diets have been studied, no clear guidelines have been implemented for the prevention or treatment of ND in clinical practice. Murine models have shown that intermittent fasting and caloric restriction (CR) can counteract disease processes in various age-related disorders, including NDs. The objective of this perspective is to provide a comprehensive, comparative overview of the available primary intervention studies on fasting and CR in humans with ND and to elucidate possible links between the mechanisms underlying the effects of fasting, CR, and the neuropathology of ND. We also included all currently available studies in older adults (with and without mild cognitive impairment) in which the primary endpoint was cognitive function to provide further insights into the feasibility and outcomes of such interventions. Overall, we conclude that nutritional intervention trials focusing on fasting and CR in humans with ND have been neglected, and more high-quality studies, including longitudinal clinical intervention trials, are urgently needed to elucidate the underlying immune-metabolic mechanisms in diet and ND.

Keywords: Alzheimer’s disease; Parkinson’s disease; caloric restriction; elderly; fasting; human; ketogenic diet; mild cognitive impairment; multiple sclerosis; neurodegenerative disease.

FIGURE 1

Underlying mechanisms. This figure illustrates the possible underlying mechanisms of the beneficial impact of fasting and CR on ND. While a typical western diet usually leads to gut dysbiosis and an increase in inflammation, the abstinence or reduction of food can have a positive impact on cognitive function by changing the gut microbiota composition and its metabolite secretion [41,42,46]. Several additional mechanisms including DNA repair, increased autophagy, upregulated mitochondrial function, increased insulin sensitivity, increased ketone body production, and decreased overall inflammation may result in beneficial impacts on cognitive function [[73], [74], [75]]. Abbreviations: CR, calorie restriction; ND, neurodegenerative disease. This image was generated using BioRender software (www.biorender.com).