Neuroprotective Effects of Intermittent Fasting in the Aging Brain

Degenerative brain diseases that affect cognition, such as various types of dementia, are largely driven by aging [1]. Nutritional interventions that slow aging, particularly calorie restriction (CR) and intermittent fasting (IF), are currently receiving much attention. Earlier research focused on adjusting dietary macronutrient ratios and evaluating the impacts of this approach on longevity and lifespan [2]. Research on CR and IF in animals has shown that reduced food intake significantly increases lifespan. Thus, it is now possible to determine whether nutritional interventions that slow aging, particularly those that have a general impact on brain aging and cognition, represent novel means for preventing age-related neurodegenerative diseases such as dementia.

Here, we review studies in animals and humans that have shown how IF affects dementia and slows or reverses aging-related dementia and suggest future directions in this research field. In addition, this review discusses the underlying neuroprotective mechanisms by which IF alleviates aging-related dementia, providing a basis for the use of IF to treat cognitive impairment in elderly individuals.

IF and CR are two different methods of food restriction linked to improvements in numerous metabolic factors, including body weight management [3]. CR is a commonly used food restriction strategy in which daily energy intake is restricted without incurring malnutrition. IF refers to cycles of fasting and intermittent feeding windows over a given time schedule [4]. Many of the health advantages of IF have been demonstrated to go beyond weight loss and decreased free radical production in both humans and animals [5, 6]. IF can induce adaptable, evolutionarily conserved cellular responses that link organs and improve glucose management, increase stress tolerance, and reduce inflammation. For example, innate cellular defenses against oxidative and metabolic stress as well as the ability of cells to remove or fix damaged components are increased during fasting [6]. In addition, cells take part in tissue-specific growth and plasticity-related activities during the feeding phase [7].

Triglycerides are converted into fatty acids and glycerol, which are used as fuel during fasting [8]. During fasting, the liver transforms fatty acids into ketone bodies, which are a primary source of energy for many tissues, particularly the brain. In humans, blood ketone levels are low in the fed state and increase within 8–12 h of fasting, reaching levels as high as 2–5 mm by 24 h [9]. Within 4–8 h of the start of fasting, rodent plasma ketone levels increase and reach 1 mm within 24 h [10]. The timing of this response provides some insight into the proper fasting windows for IF regimens [11]. Currently, alternate-day fasting, 5:2 IF (fasting 2 days per week), and daily time-restricted meals are the three IF regimens that have been the subject of most research in humans [12] (Table 1). During fasting, ketone body levels are greater when caloric intake is drastically reduced on at least one weekday [13]. A lower respiratory exchange ratio (the ratio of carbon dioxide produced to oxygen consumed) results from the metabolic switch from the use of glucose as a fuel source to the use of fatty acids and ketone bodies, which indicates greater metabolic flexibility and efficient energy production from fatty acids and ketone bodies. Therefore, nutritional habits cannot simply be reduced to the quantity and macromolecular quality of food eaten; instead, the frequency and timing of meals and the duration of fasting are also important. IF is a dietary pattern in which eating time, not the amount or composition of food consumed, is limited.

In the hippocampus, neuron-to-neuron transmission decreases with age, which may be caused by dysregulation of genes involved in the production of synaptic proteins [14]. Age-related cognitive impairment may be partially due to this change. Gradual loss of synapses has been observed in some areas of the human brain starting around the age of twenty [15]. In recent years, this change has been linked to an increase in inflammation and oxidative stress [16]. Additionally, behavioral and cognitive changes that have been observed in humans, primates, and rodents are correlated with age-related molecular and cellular alterations in the brain. The involvement of the prefrontal cortex and the hippocampus in spatial memory is significant [17]; therefore, it is not surprising that aging is accompanied by a decline in spatial and associative memory [18]. The prefrontal cortex, in addition to the hippocampus, is essential for high-level cognitive and executive function as well as for working memory [19]. It has been proposed that the reduction in cognitive performance associated with aging is largely caused by the degeneration of these two brain regions (the prefrontal cortex and hippocampus).

The finding that nutritional and pharmacological measures that slow aging and also slow brain aging and dementia indicates that dementia is a natural aspect of aging. Currently, only 0.1% of people younger than 65 have dementia, while 300 times more people older than 85 years and the majority of people older than 90 years experience dementia [20]. Moreover, individuals aged 85 years or older carry an Alzheimer’s disease (AD) risk equivalent to that of an individual with all other known genetic and environmental risk factors [21]. Notably, the role of aging in the pathogenesis of dementia and the idea that the aging process can be modified, however, have received less attention in dementia research than the role of hereditary and modifiable risk factors in dementia.

Clinically, AD histopathology is characterized by beta-amyloid plaques, Tau and phosphorylated Tau-containing neurofibrillary tangles, and dystrophic neuritic plaques [22]. Frontotemporal dementia is a heterogeneous group of proteinopathies characterized by progressive degeneration of the frontal and/or temporal lobes. Clinically, this disease is characterized by progressive deterioration in behavior, speech production, or language, with relative sparing of memory and visuospatial function [23]. In addition, dementia with Lewy bodies (DLB) is one of the three disorders classified under the term “Lewy body diseases,” describing neurodegenerative disorders characterized by abnormal intracellular deposition of α-synuclein in Lewy bodies in the brain. The two other Lewy body diseases are Parkinson’s disease (PD) and Parkinson’s disease with dementia (PDD) [24]. The distinction between DLB and PDD is primarily temporal: if dementia is a presenting feature or develops within a year of motor symptom onset, it is classified as DLB, whereas PDD is diagnosed if dementia develops over a year after the onset of parkinsonism [25].

Currently, it is believed that the effects of aging on mortality and AD risk are comparable; starting at age 30 years, mortality doubles every 7.5 years, whereas the risk of dementia doubles every 5 years [26]. Additionally, dementia is intimately linked to frailty and multimorbidity, two important clinical signs of aging [27]. Biologically, many of the significant cellular and molecular changes associated with aging, such as those that affect DNA damage, oxidative stress, mitochondrial function, telomere length, advanced glycation end products, and autophagy, as well as significant systemic changes, including microvascular disease and inflammation, have been linked to AD and dementia in general [28]. Dementia has been connected to each of these processes, and these processes are thought to contribute to the development of disease [29]. Currently, it is believed that dietary interventions are most effective at delaying aging, and researchers have studied how nutrition affects aging, health, and lifespan [30]. For instance, aging is a key risk factor for both PD and AD, with symptoms often appearing in adults older than 70 years. Because medical advancements have allowed people who would otherwise die from cardiovascular disease, cancer, or diabetes at an earlier age to live beyond the age of 70 years, the number of older people with AD or PD is increasing quickly [31]. Since there are no medications that can stop the progression of AD or PD in patients, lifelong dietary and lifestyle changes that slow the aging process and lower disease risk may be extremely beneficial. In animal experiments, IF may increase longevity and protect against major chronic illnesses such as cancer, diabetes, and kidney disease [5]. However, the scientific data linking IF with neuroprotection in the aging brain have not been thoroughly examined. Thus, we describe various mechanisms underlying the neuroprotective effect of IF in the aging brain, reviewed recent studies on IF in the context of memory and cognitive performance, and offer our thoughts on potential future directions for this area of research (Fig. 1).

The effect of IF on cognitive function, including its effect in modulating BDNF and synaptic plasticity, remains an understudied area in human research. However, emerging evidence supports the potential benefits of fasting interventions on brain health. For example, previous studies showed that compared with CR, IF (time-restricted feeding) significantly improves cognitive performance in overweight women in addition to increasing weight loss without impacting eating behavior, mood, sleep quality, or quality of life [32]. In addition, in a high-quality 3-year prospective cohort study of 99 older Malaysian adults with mild cognitive impairment who practiced regular IF, irregular IF, or no fasting [33], regular IF (long-term fasting) was associated with significantly improved cognitive performance in all behavioral tests compared to the control [33]. A similar exploratory investigation specifically on adult hippocampal neurogenesis, which is related to cognition, in healthy men and women with central obesity showed significantly improved cognitive performance and pattern separation memory in those who participated in isocaloric IF (5:2) diets or CR (25%) [34].

According to previous studies, IF may improve synaptic plasticity by increasing the levels of brain-derived neurotrophic factor (BDNF), which subsequently impacts bioenergetics and protein synthesis in neurons [35]. Although basic fibroblast growth factor is expressed in blood vessels and is responsible for promoting the formation of new blood vessels (angiogenesis), BDNF is widely expressed in the brain and is responsible for numerous physiological functions in the brain by promoting the survival of existing neurons, the growth and development of dendrites and synapses (synaptic plasticity), and the differentiation of new neurons from neural stem cells (neurogenesis) [36‒38]. Both BDNF and basic fibroblast growth factor mediate their neuroprotective effects by binding to membrane-bound tyrosine kinase receptor B (TrkB) and fibroblast growth factor receptor 1 (FGFR1), respectively, which activates the PI3-kinase (PI3K)/Akt (protein kinase B) and extracellular signal-regulated kinase (ERK) signaling pathways [5, 39, 40]. Additionally, research on the rat dentate gyrus has demonstrated that IF increases the survival of newly formed neurons [41]. In the dentate gyrus of the hippocampus, a major area associated with learning and memory, neural precursor cells are necessary for the development of new neurons that integrate into the hippocampal circuitry and play roles in spatial pattern separation. BDNF also plays a critical role in this process [42].

BDNF also plays an important role in synaptic plasticity and synaptic transmission [43]. The sustained signal needed for neuroplasticity and LTP is realized by self-amplification of BDNF via cAMP-response element binding, followed by upregulation of postsynaptic proteins. This feedback cycle is important for maintaining adequate signal strength for synaptic maturation and function [44]. For example, the effect of IF a well as neurogenesis and synaptic plasticity was demonstrated to involve BDNF/TrkB signaling [35]. Previous studies have described IF as a metaplastic priming signal extending the duration of tags and thus the time window between activations [45].

Increased mitochondrial respiration is another mechanism by which IF exerts neuroprotective effects [46]. According to numerous indications, IF may increase neuronal survival under oxidative stress via a variety of possible mechanisms, including reducing mitochondrial production and the release of reactive oxygen species (ROS) and boosting antioxidant defenses in the brain [47, 48]. Recent experimental studies have suggested that IF may reduce the production and release of ROS in mitochondria [49]. Upregulation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a master regulator of mitochondrial respiration and contributor to mitochondrial biogenesis and detoxification, is partially responsible for this effect of IF [50]. Additionally, nitric oxide, which has antioxidant and protective effects on the endothelium and may help to preserve the brain microvasculature, is differentially expressed when PGC-1α is upregulated [51]. PGC-1α also plays a crucial role in maintaining dendritic spines in the hippocampus’s dentate gyrus, underscoring its significance for memory processes [52]. Therefore, IF may cause moderate chronic uncoupling in mitochondria to reduce the amount of ROS produced by mitochondria in the rodent brain through a variety of mechanisms [53]. Generally, the aforementioned modifications may ultimately increase the metabolic respiratory activity of neuronal mitochondria, which boosts their oxidative buffering capacity and adaptive cellular stress resistance through mechanisms that are still being fully elucidated. However, these studies demonstrate the potential intrinsic neuroprotective effects of IF against oxidative stress through increased mitochondrial activity and neuronal adaptability to bioenergetic challenges in the aging brain.

In response to fasting, autophagy, an essential cellular process [54], is increased in cerebral cortical and cerebellar neurons [55]. Fasting may cause the breakdown of cellular components to maintain cellular energy levels and thus promote cell survival during dietary restriction and alter the activity of mammalian target of rapamycin (mTOR) to mediate increased autophagic flux. Long-term changes in synaptic strength are thought to be essential for learning and memory, and mTOR regulates the local production of proteins in dendrites [56] and is also involved in some forms of synaptic plasticity [57]. If exercise and synaptic plasticity improve cognition, it will be crucial to identify the precise roles that mTOR and autophagy control play in the structural and functional changes that occur in neural networks [58] (Fig. 2).

mTOR is an endogenous protein kinase that is triggered by oxidative stress via the PI3K/Akt pathway. It is thought to be responsible for boosting cell growth and proliferation as well as for the generation of proinflammatory cytokines to trigger an immunological response [59]. Thus, by boosting autophagy via a decrease in mTOR activity, IF can facilitate the elimination of inflammatory stimuli such as toxins, cellular components, and dysfunctional/damaged organelles [60], as allowing it to exert a neuroprotective effect. In response to fasting and intense exercise, the cellular energy status-responsive enzyme adenosine 5′-monophosphate-activated protein kinase (AMPK) regulates the activation of autophagy and the downregulation of mTOR in muscle cells [61]. Recent research has suggested that AMPK also mediates neural adaptive responses. Hippocampal AMPK is activated in rats that exercise on a treadmill daily [62], and alterations in AMPK activity improve contextual fear memory in mice [63]. Fasting causes an increase in AMPK activity and is necessary for the development of dendritic spines and synaptic functional plasticity in hypothalamic arcuate nucleus neurons [64]. Increases in cognitive and motor performance are observed in mice treated with an AMPK agonist, which is consistent with the role of AMPK in promoting neuroplasticity [65]. Importantly, while brief AMPK activation caused by physiological bioenergetic challenges (a reduction in bioenergetic production) can promote neuroplasticity, prolonged AMPK activation can reduce axonal and dendritic plasticity [66], consistent with the importance of recovery from fasting for optimal neuroplasticity.

In response to IF, several neuroactive signaling molecules are released into the blood from peripheral organs. Because of its effects on the hypothalamic regulation of food intake, ghrelin is one of the signals that has been the subject of the most extensive research. Food consumption prevents the release of ghrelin, which is produced in a subpopulation of cells in the gut and released into the blood in response to fasting. The plasticity and resilience of neuronal circuits throughout the brain, including those related to motivation and cognition, are also impacted by ghrelin and the additional peripheral signals produced when the metabolic switch is flipped [67]. Ghrelin, for instance, improves hippocampus-dependent learning and memory by stimulating serotonergic neurons in the brainstem raphe nucleus, which innervates the hippocampus, and by acting directly on hippocampal cells [68]. Ghrelin can also help mice feel less anxious [69]. It is unknown, however, whether ghrelin mediates the beneficial effects of IF on behavior and neuroplasticity.

Although interleukin 6 (IL-6) is well recognized for mediating immune cell responses to pathogens and tissue injury, it is also produced in and released from muscle cells in response to strenuous exercise and fasting, increasing muscle cell sensitivity to insulin [70]. The important roles of IL-6 in CNS neuroplasticity, including the control of hippocampus-dependent learning and memory, have been identified by studies using IL-6-knockout animals [71]. Additionally, astrocytes and neurons both synthesize the myokines insulin-like growth factor I (IGF1) and fibroblast growth factor 2 (FGF2) in response to fasting and exercise [72]. IGF1 and FGF2, two neurotrophic hormones, can improve neuroplasticity and shield neurons from oxidative and metabolic stress [73]. Because fasting lowers circulating IGF1 levels by reducing IGF1 production in the liver and exercise increases circulating IGF1 levels, peripheral organ-derived IGF1 is involved in the positive effects of metabolic switching on the brain.

Currently, evidence suggests that IF may protect neurons and promote neuronal survival in the presence of inflammation in a variety of ways, including by either reducing the expression of proinflammatory genes or removing inflammatory stimuli from the brain [74]. Nuclear factor kappa-B (NF-κB) has been linked to increased expression of proinflammatory genes, including cytokines (TNF-α, IL-1, and IL-6), chemokines (CCL2/MCP-1 and CXCL2/MIP2), and endothelial cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1), in the rodent brain. Experimental studies have suggested that IF (time-restricted feeding) may reduce the activity of the NF-κB signaling pathway [74, 75]. An increase in the activity of SIRT1 [76], which deacetylates the p65 subunit of NF-κB and inhibits its transactivation potential [77], may be one of the mechanisms by which IF reduces the activity of the NF-κB signaling pathway. In addition, alternate-day fasting exerts neuroprotective effects against age-induced inflammation by inhibiting NF-κB and mitogen-activated protein kinase (MAPK) activation and oxidative damage [78]. In addition, NF-κB is relevant to neurodegeneration [79]. In particular, chronic NF-κB activation has been implicated in the progression of PD symptoms [80]. Currently, there is evidence supporting a dual role for NF-κB in the central nervous system in neurodegenerative diseases; the activation of NF-κB in neurons promotes their survival, whereas its activation in glial and immune cells mediates pathological inflammatory processes [81].

Recent research has shown that IF (time-restricted feeding) can reduce the expression and activation of NLRP inflammasome components, as well as associated proinflammatory cytokines, including IL-1 and IL-18 [82]. As previously noted, proinflammatory and proapoptotic proteins may be expressed in mouse neurons and glial cells as a result of the activation of the NF-κB and MAPK signaling pathways [83]. Therefore, it appears that the neuroprotective properties of IF are likewise linked to a marked decrease in IL-1 and IL-18 production and activation in the brain [82]. Additionally, IF dramatically inhibits the maturation of both of these proinflammatory cytokines as well as the generation of cleaved caspase-1 and caspase-11, which are hallmarks of apoptosis, and the activation of caspase-3, another marker of apoptosis. A growing body of research also suggests that cleaved caspase-1 can trigger both intrinsic and extrinsic apoptotic cell death by directly activating caspase-3, caspase-7, and BH3-interacting death domain agonist (Bid) [84, 85]. Furthermore, there is evidence that in mouse neurons and glial cells, cleaved caspase-11 can activate caspase-3 and cause apoptotic cell death [86]. It has also been proposed that the ability of caspase-1 to promote the maturation of both IL-1 and IL-18 precursors in murine peripheral immune cells may be dependent on its interaction with caspase-11 [87].

Inflammasome assembly may be decreased by IF, which could be an additional mechanism by which IF (time-restricted feeding) reduces inflammasome signaling in the brain. This may be accomplished by IF-induced increases in the expression and activity of SIRT1/2 or SIRT1/2 activators, which continuously deacetylate microtubules [88]. This in turn may prevent the buildup of acetylated α-tubulin in the cytosol during times of cellular stress. This process has been demonstrated to be necessary for mediating inflammasome assembly by facilitating the ability of the NLRP3 receptor on the endoplasmic reticulum to form the NLRP3 inflammasome [89, 90]. The question of whether IF also reduces NLRP1 inflammasome assembly mediated by SIRT1/2 remains unanswered.

It has been hypothesized in numerous studies that dietary restriction may increase the production of ketone bodies, particularly β-hydroxybutyrate. This ketone body was recently shown to inhibit the formation of the NLRP3 inflammasome by preventing potassium (K⁺) efflux in murine macrophages, which is needed for NLRP3 receptor activation and inflammasome formation [91, 92]. However, whether IF also reduces NLRP1 inflammasome assembly caused by β-hydroxybutyrate has yet to be determined. Therefore, it is expected that through these neuroprotective mechanisms, IF lessens inflammasome activation by inhibiting the synthesis of cleaved caspase-1 and caspase-11, as well as the development of both IL-1 and IL-18 precursors in the brain.

Finally, given that exercise reduces histone deacetylation in the hippocampus, while fasting increases histone acetylation in peripheral mouse tissue, it is likely that the inhibitory effects of ketones on HDACs are amplified during fasted exercise [93]. Additionally, β-hydroxybutyrate activates the cytoplasmic transcription factor NF-κB in neurons through mitochondrial activity, which causes NF-κB to translocate to the nucleus and increase BDNF expression [94]. These findings imply that β-hydroxybutyrate is not only an indicator of metabolic switching and a source of energy for neurons but also an activator of neural signaling pathways that improve cognition, synaptic plasticity, and stress tolerance in neurons [95]. In fact, it has been shown that giving rats oral β-hydroxybutyrate ester for 5 days improves their spatial learning and memory as well as their endurance on a treadmill [96]. In addition to its role as an energy substrate and signaling molecule, β-hydroxybutyrate is also a precursor to membrane lipids in brain cells, including neurons and oligodendrocytes [97], suggesting that IF promotes axonal myelination.

Dietary factors, such as caloric consumption and macronutrient composition, affect how the brain functions, particularly during aging. Nutritional therapies that slow aging and numerous age-related illnesses have been discovered through research on the biology of aging. Therefore, it is conceivable that therapeutic approaches that slow aging might be applied for the treatment and prevention of dementia and brain aging. In recent years, the fasting-mimicking diet (FMD) has gained attention and is considered to have significant potential among various dietary restriction regimens [98]. The FMD is a plant-based diet, low in protein and sugar but relatively high in fat, which aims to mimic the effects of fasting while still allowing some food intake [99]. The FMD has been associated with various health benefits, such as improved metabolic markers, reduced inflammation, and potential longevity benefits. While such a diet offers numerous potential health advantages, we should note its associated side effects, including dizziness, headache, fatigue, and general weakness. Thus, further monitoring and appropriate recruitment of subjects are necessary to confirm the safety and efficacy of the FMD, especially in elderly individuals. Importantly, it can be practically difficult to implement this diet in individuals with dementia, especially those with behavioral impairments [99].

As discussed in this review, preclinical research and clinical trials have demonstrated that IF is beneficial for treating a wide range of medical problems, including neurological disorders. Clinical studies have generally focused on relatively short-term interventions over a period of months, but it has been demonstrated in animal models that IF improves health over the course of life. It has yet to be shown whether humans can sustain IF for a period of years and possibly gain the advantages seen in animal models. In addition, there are still several issues regarding the difference between preclinical and clinical data to be addressed. For example, female animal models are usually not used in preclinical studies due to the cyclical changes in sex hormone levels due to the menstrual cycle. In clinical studies, we should assess whether IF has an effect on older females. The levels of circulating metabolites, such as blood glucose, β-hydroxybutyric acid, and insulin, greatly change after IF. Some of them might mediate the neuroprotective of IF. Since the levels of these metabolites can easily be altered through clinical interventions, we suggest further investigations of the role of these metabolites in the effect of IF in future clinical studies. Metabolic switching and cellular stress resistance are two positive impacts of IF, although the precise mechanisms underlying these effects are still poorly understood. In addition, the functions of specific nutrients in the brain have been studied, but it is unclear how their functions are related to how the brain ages. Nutrition is complex, and this complexity can be elucidated utilizing cutting-edge methods such as IF to guide future studies and dietary recommendations for the prevention of dementia and brain aging. The risks and advantages of IF must be discussed with patients during clinical treatment, as with any other therapeutic option. Because the advantages of utilizing IF to prevent AD and dementia in elderly individuals are not clear, the risks must also be determined.

The authors acknowledge the Department of Pharmacy, West China Hospital of Sichuan University and the Department of Pharmacy, Xindu District People’s Hospital of Chengdu, for supporting this work.

The authors declare that there are no conflicts of interest.

This research was supported by National Key Clinical Specialities Construction Program.

H.D. prepared and wrote the first draft of the manuscript. S.W., C.H., M.W., and T.Z. collected academic papers and provided critical advice on the manuscript. The study was conceptualized by Y.Z., who also supervised the work and reviewed the entire manuscript.