Fasting's potential in fighting cognitive decline needs more human trials

By Hugo Francisco de SouzaApr 2 2024Reviewed by Susha Cheriyedath, M.Sc.

In a recent perspective review published in the journal Advances in Nutrition, researchers reviewed 14 relevant publications on human neurodegenerative disease (ND) research to unravel clinical protocols wherein fasting and caloric reductions (CRs) are used as anti-ND interventions. Unfortunately, despite preliminary results in murine models suggesting positive therapeutic promise for the field, human clinical trials were found to be exceedingly rare. This study highlights the need for additional human clinical trials before CR protocols are optimized to the point of presenting an effective weapon in clinicians’ arsenal in the fight against age-associated cognitive decline.

Perspective: The Impact of Fasting and Caloric Restriction on Neurodegenerative Diseases in Humans. Image Credit: Marcin Malicki / Shutterstock

The link between diet and cognition and the potential for fasting as a therapeutic intervention

Neurodegenerative diseases (NDs) are the colloquial umbrella term for a spectrum of complex chronic neurological conditions characterized by a progressive decline in cognitive function, eventually resulting in the patient’s inability to perform even routine daily tasks. The condition is known to result from the age-associated denaturation of neurons comprising the brain and the central and peripheral nervous systems. Alarmingly, despite substantial advancements in clinical interventions against the condition, recent reports suggest that the global incidence of these diseases is on the rise, with more cases of multiple sclerosis (MS), Alzheimer’s disease (AD), and Parkinson’s disease (PD) recorded than ever before.

Decades of research suggest that NDs arise from a combination of genetic and environmental factors, with patients’ age presenting the strongest predictor of ND risk. Recently, studies have explored the potential of lifestyle interventions, particularly dietary modifications, in preventing or treating NDs, most of which remain without a cure. ‘Healthy diets’ which prioritize the consumption of fresh, unprocessed, predominantly plant-based foods, are increasingly being evaluated for their anti-cognitive-decline potential, with the Mediterranean diets (MDs) and ketogenic diets (KDs) consisting the most popular examples of these dietary patterns.

“Fasting (i.e., caloric restriction [CR] in various forms) has been used as an intervention to promote health since the beginning of civilization and has spread independently among different regions, cultures, and religions worldwide. It is believed to have already been established as a treatment method by Hippocrates in the 5th century BCE and has been used ever since by numerous medical schools to treat acute and chronic diseases.”

Unfortunately, while the positive impacts of fasting and CRs have been extensively proven and established in other chronic human diseases, including rheumatoid arthritis and some cancers, studies exploring the associations between these dietary practices and NDs remain rare, with a bulk of the literature highlighting the benefits of CRs in animal models, but limited human evidence remaining confounding.

About the study

In the present review, researchers aim to present a comprehensive, comparative ‘perspective’ on the associations between fasting or CRs and ND outcomes in humans while further attempting to elucidate the mechanisms by which the dietary practices may improve physical (and, by extension, cognitive) health. The review includes ND outcomes in individuals with and without clinically confirmed mild cognitive impairment (MCI). More than 70 papers were evaluated for study inclusion. However, only 14 met the review criteria (human clinical trials and primary intervention studies) and were included in the perspective’s synthesis.

Based on the outcomes reported by these 14 publications, the present review begins by defining fasting and calorific restrictions, presenting examples of beneficial dietary interventions, and highlighting the differences between the methodologies and applications of various fasting techniques, including intermitted fasting (IF), prolonged fasting (PF), and time-restricted eating (TRE). The research then explores and discusses evidence of CRs’ therapeutic potential in AD, PD, MS, and general MCI.

Finally, they discuss the potential mechanisms (e.g., gut microbiota perturbations) that may explain beneficial fasting-associated ND outcomes and compare and contrast fasting and ketogenic diets to help clinicians and the health-conscious make informed decisions about optimal health behavioral choices in this regard.

Study findings and conclusions

Of the 14 publications included in this review, four were conducted on patients with MS, only one on patients with AD, and alarmingly, none for PD patients (with the notable exception of the ongoing ExpoBiome study). The remaining studies, comprising the majority of human NR literature, explore the associations between fasting, CR, and MCI but are restricted to patients who are elderly, overweight, or obese.

While observed ND and MCI outcomes were found to be generally positive (beneficial to human health), results from fasting and CR studies investigating cognitive declines in aging adults (the most common MCI risk factor) produce heterogeneous and confounding results. This can be attributed to a common limitation of most ND human clinical trials – low sample size and suboptimal methodology.

Mechanistic investigations revealed that a majority of fasting and CR benefits may be attributed to gut microbial population modulations. As is the case with most non-ND chronic non-communicable diseases, gut microbial dysregulations were associated with hastened cognitive decline in patients with mild MCI. However, encouragingly, gut microbial eubiotics were found to slow or even reverse mild MCI symptoms, highlighting this field’s potential in future interventions against these debilitating conditions.

“Dietary recommendations for ND and the imminent application of the latter as a standard therapeutic intervention in daily clinical practice are of critical importance. Ongoing clinical trials, such as the ExpoBiome study, will provide insight into the mechanisms of fasting and the microbiota–gut–brain axis in relation to ND. Overall, this perspective emphasizes the need for additional clinical trials studying various fasting protocols, as this might potentially constitute a powerful new tool for preventing and treating ND.”