The mTOR and insulin receptor pathways are critical for sensing cellular energy metabolism and coordinate anabolism, which leads to the potentiation of protein or lipid synthesis, ribosome neogenesis, mitochondrial metabolism, cell growth, and mitosis (Ben-Sahra and Manning, 2017). Under excess nutritional status, tissue mTOR is hyperactivated, which results in a change in protein catabolism and an elevated production of mitochondrial ROS; simultaneously, autophagy is inhibited, which results in an inflammatory response (Kapahi et al., 2010). Therefore, a persistently activated mTOR pathway accelerates the aging process, and the inhibition of mTOR signaling mimics the effect of CR in potentiating the immune response and extends the lifespan (Harrison et al., 2009; Selman et al., 2009). Adenosine monophosphate-activated protein kinase (AMPK) is a signaling protein for sensing low-energy status, and it can inhibit the mTOR cascade reaction by phosphorylating the tuberous sclerosis complex 2 (TSC2) complex (Inoki et al., 2003). As the “hungry sensor” of cells, the AMPK pathway responds to low-energy levels to antagonize the aging process (Mair et al., 2011; Martin-Montalvo et al., 2013; Hardie, 2015) and is related to CR-induced neuroprotective effects (Ma et al., 2018). Thus, the AMPK and mTOR pathways antagonize each other to maintain the metabolic homeostasis of tissues.

Both mTOR and AMPK pathways play important roles in the pathogenesis of aging-related neurodegenerative diseases and are responsive to CR. For example, the deposition of Aβ proteins has been shown to activate neuronal mTOR, which facilitates de novo protein synthesis and inhibits autophagy, accelerating the aggregation of Aβ and Tau proteins. Therefore, as a specific mTOR inhibitor, rapamycin can improve cognitive functions, as demonstrated in AD animal models (Caccamo et al., 2010). Similarly, the inhibition of mTOR can induce cell autophagy to relieve disease symptoms (Ravikumar et al., 2004), and food restriction and exercise training have been shown to improve syndromes (Mattson, 2012). A further mechanistic link was provided by the induction of neuronal AMPK phosphorylation by CR via the upregulation of fibroblast growth factor 21 to suppress mTOR activity and relieve the hyperphosphorylation of tau proteins (Rühlmann et al., 2016). In examinations of Aβ, although no study has directly investigated the relationship between CR and Aβ deposition, the known effect of AMPK activation in relieving Aβ aggregates (Chen et al., 2021) and its potentiation under CR (Cantó and Auwerx, 2011) indicates that Aβ pathology may be relieved by reducing calorie intake. Thus, the regulation of cellular homeostasis by mTOR and AMPK prevents the body from metabolic imbalance (González et al., 2020). Moreover, both AMPK and mTOR play important roles in the hypothalamic regulation of body metabolism (Martínez de Morentin et al., 2014). However, further studies are needed to understand how the coordination between these two molecular pathways influences energy metabolism and the brain aging process.

Sirtuin is an evolutionally conserved family of deacetylase that plays specific roles in extending the lifespan (Bishop and Guarente, 2007). Allosteric regulation of nicotinamide adenine dinucleotide (NAD) activates Sirtuin, which further affects histones and transcription factors to regulate gene expression, and CR can also activate this deacetylase to relieve oxidative stress (Qiu X. et al., 2010). Moreover, Sirtuin works synergistically with other nutrition-sensitive proteins that are activated by CR, such as AMPK (Cantó et al., 2009; Price et al., 2012) and peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α; Cantó and Auwerx, 2009), to exert neuroprotective effects. Moreover, CR has been reported to relieve post-surgical memory deficits in aging mice by activating deacetylase to relieve endoplasmic reticulum stress in the hippocampus (Yao et al., 2019). Furthermore, the effect of Sirtuin on the cellular microenvironment has been demonstrated by previous studies that showed that the activation of cellular autophagy (Lee et al., 2008) and the inhibition of neuroinflammation dependent on NF-κB (Yeung et al., 2004) relieves neurogenerative diseases.

Different environmental and internal stimuli, such as nutrition, hormones, and growth factors, can activate the cAMP-responsive element-binding (CREB) protein family, which profoundly affects the expression of brain-derived neurotrophic factor (BDNF) to mediate the survival, growth, differentiation, and plasticity of neurons (Lonze and Ginty, 2002). CREB also modulates the transcriptional activation of tyrosine receptor kinase B, which is the major receptor for BDNF (Tabuchi et al., 2002). CR potentiates CREB expression and activation via the AMPK cascade pathways; thus, CREB is a hub for nutritional sensors and neuronal growth. It has been found that a deficiency in the CREB pathway in mature neurons reduces the response of mice toward 30% CR, which is in stark contrast to wild-type mice, in which cognitive functions and electrophysiological parameters were enhanced after CR. However, CREB can directly activate Sirtuin1 in the mouse hippocampus (Fusco et al., 2012). In neurodegenerative diseases, Sirtuin1 can potentiate CREB-target of rapamycin complex 1 transcriptional activity to improve disease symptoms (Jeong et al., 2011). Therefore, the CREB–Sirtuin1 axis is critical for multi-layered brain responses under CR; however, upstream hormonal factors that induce the CREB cascade require further investigation.

Neurotrophic factors (NTFs) are a group of naturally occurring proteins that regulate the development, maturation, and functional integration of the nervous system. During CR, the expression level of NTFs, such as BDNF, neurotrophic factor 3 (NT3), glial cell line-derived neurotrophic factor (GDNF), and fibroblast growth factor 2 (FGF2), are increased in the brain, which is likely a compensatory mechanism against physiological stress (Qiu G. et al., 2010).

Numerous studies have shown that BDNF plays a critical role in mediating synaptic plasticity, neurogenesis, and neuronal stress resistance, especially during learning and memory. For example, the hippocampal BDNF level was positively correlated with the performance of a spatial learning task (Hall et al., 2000), whereas BDNF knockout mice showed impaired memory formation (Mizuno et al., 2000). In previous experiments, CR/intermittent fasting (IF) increased BDNF expression across different brain regions in rodents, including the hippocampus and cortex (Duan et al., 2001). In addition, Type 2 diabetes mellitus (T2DM) is known to be associated with an increased risk of dementia, and 12-week fasting in T2DM rats improves behavior and brain function by increasing the levels of NT3 and BDNF. NT3 is involved in the synaptic release of numerous neurotransmitters in both peripheral and central nervous systems and affects tissue development (Tyler et al., 2002). Similar to BDNF, GDNF has been shown to exert neuroprotective effects in primate PD models and is currently being used in clinical trials in PD patients (Gill et al., 2003). CR significantly increases the concentration of GDNF by almost three times that in the control group and leads to activated neuroprotective signaling pathways of DA neurons (Maswood et al., 2004). Both in vivo and in vitro studies have shown that GDNF and BDNF protect neurons from excitatory toxicity and metabolic and oxidative damage (Maswood et al., 2004). Moreover, other NTFs are likely related to brain aging, such as FGF2, which has been suggested to be involved in modulating synaptic plasticity during food deprivation, although its specific mechanisms remain unclear (Graham and Richardson, 2011; Mattson et al., 2018). Insulin-like growth factor 1 (IGF-1) is a phylogenetically ancient neurotrophic hormone that plays a crucial role in central nervous system development and maturation. Fasting mimicking diet (FMD) increases the expression of IGF-1 and its receptor in the dentate gyrus (DG) of the hippocampus and subsequently potentiates adult neurogenesis (Brandhorst et al., 2015). Taken together, the elevated NTFs induced by CR are essential for the effects of CR on brain aging and nerve regeneration.

Recent epigenetics research has revealed that CR affects the progression of aging and related diseases by regulating gene expression through epigenetic modifications (Molina-Serrano and Kirmizis, 2017). As an environmental stimulus, CR affects DNA methylation levels to alter chromosome structure, which modulates the expression of genes related to aging and neurodegenerative diseases (Hahn et al., 2017). With CR in aging mice, DNA methyltransferases (DNMT) 1 activity increases to relieve the hypomethylation of senescent DNA, whereas the DNMT3a expression level in the hippocampus changes to protect brain function (Chouliaras et al., 2012). Sirtuin 1 is a member of the NAD⁺–dependent histone deacetylase family. Numerous experiments have demonstrated the role of SIRT1 in mediating the anti-aging effect of CR, such as deacetylation effect of histones at H4K16 and H3K9 sites, to maintain gene silencing for resisting environmental stress and aging (Gong et al., 2015).

In addition to gene transcripts, non-coding RNAs, such as microRNAs and lncRNAs, are critical for maintaining homeostasis of the body as well as for the development of neurodegenerative diseases. CR increases the expression of microRNA necessary for mitochondrial protein translation (Zhang et al., 2019). CR markedly increases global and mitochondrial microRNA levels; moreover, microRNA-122 has been found to specifically activate mitochondrial translation (Zhang et al., 2019). In a second study, microRNA-235 was induced by CR to mediate body longevity via the Wnt signaling pathway (Xu et al., 2019). In brain tissues of CR-treated mice, the downregulation of three microRNAs, 34a, 30e, and 181a, helped maintain neuronal survival (Khanna et al., 2011). Recent studies (Khanna et al., 2011; Wood et al., 2015; Makwana et al., 2017; Xu et al., 2019; Zhang et al., 2019; Shastri et al., 2020; Yamada et al., 2020) have demonstrated that CR/dietary restriction (DR) regulates the expression of aging-related microRNA, as shown in Table 1. In examinations of lncRNA, CR helped protect cardiomyocytes by mediating lncRNA metastasis associate lung adenocarcinoma transcript 1 (MALAT1) and GAS5 (Rajagopalan et al., 2020). In addition, in a Drosophila model, lncRNAs mediated the aging pathway during CR treatment (Yang et al., 2016). In sum, non-coding RNAs participate in the process of cell growth, development, and aging primarily by affecting the p53 and P16 signaling pathways.

When the body faces increased demands of oxidation or damaged mitochondria, mitochondrial biogenesis (MB) is induced via the PGC-1α pathway (López-Lluch et al., 2008). Two CR-related cellular metabolic sensors are AMPK and Sirtuin1, which modulate PGC-1α activity by phosphorylation and deacetylation, respectively. Mouse models have shown that PGC-1α inhibition relieves brain oxidative injury and neurodegeneration (St-Pierre et al., 2006). For example, the mutant huntingtin protein inhibits the transcription of PGC-1α to induce mitochondrial damage, which leads to oxidative stress and metabolic failure, whereas overexpression of PGC-1α prevents such cellular damage (Cui et al., 2006). CR can potentiate MB via the upregulation of nitric oxide synthase (NOS) to enhance cellular respiration to improving neuronal survival during brain aging (Nisoli et al., 2005). Moreover, MB participates in hippocampal synaptogenesis and plasticity (Wrann et al., 2013) and thus, exerts neuroprotective effects at the tissue level.

Autophagy is a widely studied catabolic process in which damaged organelles or large biomolecules are encapsulated by autophagosomes, which are subsequently fused with lysosomes to digest cell debris (Mizushima and Komatsu, 2011). The dual roles of autophagy of cellular debris degradation and byproduct recycling provide substrates for the biosynthesis of large molecules as well as energy resources under conditions of nutritional deficiency (Mizushima and Komatsu, 2011). As a mechanism that counteracts energy insufficiency, autophagy restores cellular activity by clearing damaged mitochondria, abnormally folded proteins, and deposited lipids (Tschopp, 2011). For example, in an AD model, CR facilitated autophagy and activated glial cells to reduce neuronal Aβ loads (Gregosa et al., 2019). Moreover, recent studies have revealed that CR activates cellular autophagy in hepatocytes, adipocytes, skeletal muscle, and hypothalamic tissues, which indicates a close relationship between autophagy and CR (Martinez-Lopez et al., 2017). One study also showed that short-term fasting leads to a dramatic upregulation in neuronal autophagy (Alirezaei et al., 2010). A summary of the major molecular pathways of CR is provided in Figure 2.

The brain–gut axis is a complex bidirectional communication system that includes neuroimmune, neuroendocrine, and neural pathways (Osadchiy et al., 2019). The communication between gut microbes and the central nervous system affects mood, behavior, and cognitive functions as well as the processes of aging and neurodegenerative diseases (Zarrinpar et al., 2014). Dietary factors, such as food types and dietary patterns, not only directly affect the central nervous system by influencing nerve cell membranes, neurotransmitters, and cerebrovascular functions but also interact with the central nervous system through the intestinal microbiome. Therefore, interventions of dietary style can significantly alter the composition and function of gut microbes (Attaye et al., 2020).

Caloric restriction can alleviate neuroinflammation and neurodegeneration through intestinal flora and its metabolites, which then relieve the symptoms of aging and neurodegenerative diseases. On one hand, dietary patterns may alter the composition and metabolites of the gut microbiome, some of which activate immune cells and microglia in the brain to affect neuroinflammation (Zhang et al., 2020). Furthermore, CR can decrease the biosynthesis of lipid A, a critical component of lipopolysaccharides, and its downregulation further facilitates the infiltration of eosinophils that originate from adipose tissues and the polarization of anti-inflammatory macrophages (Fabbiano et al., 2018). In PD mice, FMD was shown to lower the number of glial cells to reduce the release of TNF-α and IL-1β by altering the intestinal flora and its metabolites (Zhou et al., 2019). On the other hand, CR can affect the metabolism of intestinal microorganisms, which alters the generation of neurotransmitters, neurotransmitter precursors, and other metabolites, such as serotonin, tryptophan, and short-chain fatty acids (SCFAs). Intestinal microbial metabolites have been widely recognized to affect emotional behavior, neurogenesis, and the integrity of the BBB (Luczynski et al., 2016). For example, SCFAs produced by the intestinal microbiota can cross the BBB, and butyrate has been found to exert neuroprotective effects by relieving neuroinflammation and increasing BDNF (Zhou et al., 2019). In addition, the intestinal and vagus nerves are important signal communication pathways in the gut–brain axis and warrant further study; the effect of CR remains unexplored. The possible mechanism of CR in alleviating aging and neurodegenerative diseases through the gut–brain axis is summarized in Figure 3.

Chronic inflammation is the common pathological feature of various metabolic disorders (Hotamisligil and Erbay, 2008). During the aging process, persistent systemic inflammation aggravates tissue degeneration (Franceschi and Campisi, 2014). Moreover, chronic inflammation induces metabolic disorders, such as insulin resistance, which leads to the disruption of neuronal functions and the acceleration of neurodegeneration (Heneka et al., 2013). In addition, neuroinflammation damages hypothalamic nuclei, which are the centers responsible for the homeostasis of energy and blood glucose; thus, causing obesity and diabetes (Jordan et al., 2010). The anti-inflammatory effects of CR have been demonstrated in both animal models and human patients (Mercken et al., 2013; Park et al., 2019). For example, CR and intermittent feeding relieve neuroinflammation in the rodent hypothalamus and hippocampus (Radler et al., 2014; Vasconcelos et al., 2014). CR also decreases serum and brain concentrations of proinflammatory cytokines via the suppression of NF-kB activity and elevates BDNF expression (Vasconcelos et al., 2014), which offers protective effects during acute brain damage (Manzanero et al., 2011) and brain aging.

In addition to the suppression of neuroinflammation discussed above, CR also helps to maintain normal BBB permeability and function primarily by improving cerebral vascular homeostasis and the gut–brain axis. Recent studies have revealed a beneficial effect of CR on brain vascular health. Low caloric diets help to maintain blood vessel homeostasis, which includes the reduction of oxidative stress, enhancement of nitric oxide bioactivity, and the suppression of vascular inflammation. Studies on the molecular mechanisms showed that critical cytokines and pathways, such as AMPK, mTOR, and endothelial nitric oxide synthase (eNOS) pathways, all participated in the maintenance of vascular homeostasis (Liu et al., 2014). CR attenuates neuronal loss, induction of heme oxygenase-1, and BBB breakdown induced by impaired oxidative metabolism (Calingasan and Gibson, 2000). Furthermore, moderate CR has neuroprotective effects: it reduces p53-mediated neurovascular damage and microglia activation after hypoxic ischemia to maintain normal permeability of the BBB (Tu et al., 2012). However, the protein and ion channels mediated by CR responsible for the protection of BBB permeability require further study.

Both long- and short-term CR potentiates eNOS expression in endothelial vascular cells (Minamiyama et al., 2007). Such information from peripheral vessels indicates the beneficial effects of CR on cerebral vessels. In a high-fat diet mouse model, CR treatment significantly relieved BBB leakage (Kim et al., 2016). Another aging mouse model showed that CR significantly preserved cerebral blood flow at 20 months of age when cerebrovascular function should be compromised under normal feeding conditions (Parikh et al., 2016). In addition, intestinal flora promotes the integrity and functional stability of the BBB, and CR has been shown to have positive effects on intestinal flora. Specifically, CR promotes the expression of tight junction proteins in brain endothelial cells by changing SCFA production in the intestinal flora and thus maintaining the integrity of the BBB (Logsdon et al., 2018). These data illustrate the potentially important role of CR in maintaining the integrity of the BBB and cerebrovascular functions. Overall, the integrity and normal function of the BBB increase the stability of the brain microenvironment, which alleviates the symptoms of aging and neurodegenerative diseases.

Synaptic plasticity is critical for learning and memory functions (Mattson, 2012), which are dependent on synaptic density, morphology, and function. In rodents, brain aging is accompanied by weakened synaptic plasticity, as reflected by impaired long-term potentiation in the hippocampus, down-expression of synaptic proteins, and impaired BDNF expression or receptors. CR can prevent these aging-related adverse effects and improve cognitive deficits (Fontán-Lozano et al., 2008). Specifically, in mice, CR enhances cognitive functions by increasing the spine density of the hippocampal DG region (Wahl et al., 2018). Because synaptic plasticity is highly dependent on the mitochondrial activity at axonal terminals (Levy et al., 2003), CR can potentiate synaptic plasticity by enhancing NOS-dependent MB (Nisoli et al., 2005). Moreover, CR can also benefit synaptic plasticity by activating anti-inflammatory pathways under brain aging or acute cerebral injury conditions (Pani, 2015).

In addition to the enhancement of synaptic plasticity, CR may also facilitate adult neurogenesis, which occurs in specific brain regions including the subventricular zone (SVZ) and hippocampal DG nuclei. The constitutive proliferation and differentiation of neural progenitor cells generate both neurons and glial cells, which actively replace damaged cells and participate in the homeostatic regulation of the brain microenvironment and thus, play specific roles in learning and motor regulation (Zhang et al., 2008). It has also been shown that CR increases the expression of BDNF in the hippocampus (Kaptan et al., 2015), which elevates the number of proliferating neural progenitor cells and facilitates their differentiation toward mature neurons and glial cells (Park and Lee, 2011).

Neural autoimmunity refers to the autoimmune response that specifically targets the nervous system, leading to neurodegenerative diseases, such as MS and AD (Singh, 1997). During these responses, cellular immunity plays a key role in the development of autoimmunity and inflammation. For example, MS is characterized by T cell-mediated demyelination and neurodegeneration in the central nervous system (Friese and Fugger, 2005; Sospedra and Martin, 2005). In experimental autoimmune encephalomyelitis (EAE) animal models, activated myelin-specific TH1 and TH17 cells were shown to cross the BBB and migrate to the central nervous system, where they were subsequently activated by local antigen-presenting cells to promote inflammation (Dhib-Jalbut, 2007; Goverman, 2009). Recent studies have found that CR can reverse immunosuppression or immune aging associated with chemotherapy or hematopoietic stem cell-based regeneration (Cheng et al., 2014; Brandhorst et al., 2015). Similarly, animal experiments have indicated that FMD reduces the number of dendritic cells and increases the relative number of naive T cells, which reduces the infiltration of immune cells into the spinal cord (Choi et al., 2016). Moreover, FMD reduces the clinical severity of EAE in mice, and these improvements were associated with an increase in the number of regulatory T cells and decreases in the levels of proinflammatory cytokines, TH1 and TH 17 cells, and antigen-presenting cells (Choi et al., 2016). In addition, FMD promotes oligodendrocyte progenitor cell regeneration and myelin regeneration in both MS and EAE models, which supports its inhibitory effect on autoimmunity and myelin regeneration (Choi et al., 2016). Numerous studies have confirmed the effects of CR on systemic immunity and chronic inflammation, although further evidence is needed to validate the effect of CR on neural autoimmunity.