Fasting Triggers Neuroprotective Changes That May Slow the Progression of Dementia

A new review reveals how time-restricted eating patterns trigger a chain of events in the gut and brain that may help prevent Alzheimer's, Parkinson's and other neurodegenerative diseases.

Intermittent Fasting and the Gut-Brain Axis

A review published in the journal Nutrients examined existing preclinical and limited clinical data showing that intermittent fasting (IF) can help reduce protein toxic load, maintain synaptic function, and restore glial and immune homeostasis in multiple models of different neurodegenerative disorders.

Studies have linked IG to increased levels of bacteria known to produce beneficial metabolites and regulate immune responses. Of these metabolites, short-chain fatty acids (SCFAs), important signaling molecules in the gut-brain axis (GBA), play a special role. Evidence suggests a role for IG in increasing the number of SCFA-producing bacteria such as Eubacterium rectale, Roseburia spp., and Anaerostipes spp. Preclinical studies have linked this to increased synapse density in the hippocampus and decreased tau phosphorylation in animal models of Alzheimer’s disease.

IG activates microbial gene expression, particularly promoting the growth of butyrate-producing taxa. It also modifies bile acid metabolism and regulates tryptophan pathways, improving the production of neuromodulatory metabolites such as serotonin and kynurenine. IG is associated with a decrease in the number of circulating monocytes, which play a critical role in the body's inflammatory response.

Chronic low-grade inflammation and inflammatory aging of the gut are increasingly recognized as key drivers of neurodegeneration. Increased intestinal permeability (so-called “leaky gut”) allows microbial endotoxins to enter the systemic circulation, triggering immune responses and proinflammatory cytokine production. IH can increase the number of SCFA-producing microbes, which improves epithelial integrity and reduces endotoxin exposure.

Recent evidence suggests that IG affects gut-derived neurotransmitter pathways, particularly those involved in tryptophan and serotonin metabolism. Under IG conditions, microbial conversion of tryptophan to indole derivatives is increased, which may mediate neuroprotective effects via aryl hydrocarbon receptor (AhR) signaling. This also promotes a balance between gut and immune function.

Neuroinflammation is sensitive to circadian rhythms: hypothalamic inflammation may be enhanced by disrupted dietary patterns. IG reduces hypothalamic lipocalin-2 expression, restores hypothalamic homeostasis, and enhances astrocytic clearance pathways. IG effects on circadian rhythms may also affect brain redox homeostasis and alter mitochondrial dynamics.

Metabolic Reprogramming, Neuroprotection and Intermittent Fasting

IG can enhance mitochondrial efficiency and antioxidant capacity by shifting metabolic activity from glucose to lipid and ketone substrates such as β-hydroxybutyrate (BHB). BHB exerts neuroprotective effects through its antioxidant properties, modulation of mitochondrial function, and the gut-brain axis. BHB preserves mitochondrial membrane potential in preclinical models and improves cognitive function in Alzheimer's disease and epilepsy. It also promotes gut health by strengthening the integrity of the intestinal barrier. Combining BHB with GBA and IG provides a robust framework for reducing oxidative stress and enhancing mitochondrial bioenergetics.

IG activates autophagy by stimulating SIRT1 and suppressing mTOR. SCFAs also affect the epigenetic regulation of autophagy genes. Increased expression of brain-derived neurotrophic factor (BDNF), decreased amyloid plaques and tau hyperphosphorylation in Alzheimer's disease models, as well as similar effects in Parkinson's disease models, support the potential of IG.

Existing studies of neuroimmune interactions have shown that IG modulates glial-neuronal cell interactions and maintains blood-brain barrier integrity. IG influences neuroimmune homeostasis through integrated gut-brain axis signals that regulate glial activity, cytokine networks, and immune-metabolic resilience. These adaptations are key for long-term cognitive function and neuroprotection.

Application in clinical practice and prospects

The use of IG in clinical practice requires careful assessment of mechanisms of action, safety, personalization, and ethical considerations. This can be challenging in vulnerable groups such as the elderly due to risks of hypoglycemia, dehydration, and micronutrient deficiencies. Adherence can also be challenging, especially when cognitive decline interferes with routine maintenance, making self-administration of IG potentially dangerous. Caregiver-monitoring platforms, in-app timers, and other digital solutions can help overcome these challenges.

There is a shift towards precision (personalized) fasting based on growing evidence that genetic, epigenetic, metabolomic, and microbiome factors shape individual responses to fasting. The inclusion of circadian biomarkers such as melatonin rhythm, sleep phase, and cortisol amplitude opens a promising avenue for a personalized chrono-nutrition approach. This may be particularly useful for people with neurodegenerative disorders, who often have disrupted circadian rhythms.

The pleiotropic effects of IG make it an ideal basis for multimodal therapeutic strategies. This is particularly important in neurodegeneration, where monotherapeutic approaches rarely yield long-term clinical benefits. Combining aerobic or resistance training with IG has yielded additional neurocognitive benefits in some preclinical and pilot clinical studies.

IH is emerging as a potentially scalable neurotherapeutic strategy. As clinical applications advance, it will be important to integrate IH into a comprehensive personalized medicine framework using digital health technologies, multi-omics biomarkers, and complementary therapies. However, it should be noted that most supporting data currently come from preclinical animal studies, and large-scale human studies are still limited.

Future studies should include randomized controlled trials using stratified designs, integrating longitudinal biomarkers, and taking into account real-world adherence.