Neurotrophic effects of intermittent fasting, calorie restriction and exercise: a review and annotated bibliography

In the last decades, important progress has been achieved in the understanding of the neurotrophic effects of intermittent fasting (IF), calorie restriction (CR) and exercise. Improved neuroprotection, synaptic plasticity and adult neurogenesis (NSPAN) are essential examples of these neurotrophic effects. The importance in this respect of the metabolic switch from glucose to ketone bodies as cellular fuel has been highlighted. More recently, calorie restriction mimetics (CRMs; resveratrol and other polyphenols in particular) have been investigated thoroughly in relation to NSPAN. In the narrative review sections of this manuscript, recent findings on these essential functions are synthesized and the most important molecules involved are presented. The most researched signaling pathways (PI3K, Akt, mTOR, AMPK, GSK3β, ULK, MAPK, PGC-1α, NF-κB, sirtuins, Notch, Sonic hedgehog and Wnt) and processes (e.g., anti-inflammation, autophagy, apoptosis) that support or thwart neuroprotection, synaptic plasticity and neurogenesis are then briefly presented. This provides an accessible entry point to the literature. In the annotated bibliography section of this contribution, brief summaries are provided of about 30 literature reviews relating to the neurotrophic effects of interest in relation to IF, CR, CRMs and exercise. Most of the selected reviews address these essential functions from the perspective of healthier aging (sometimes discussing epigenetic factors) and the reduction of the risk for neurodegenerative diseases (Alzheimer’s disease, Huntington’s disease, Parkinson’s disease) and depression or the improvement of cognitive function.


Introduction
Exercise, intermittent fasting and calorie restriction (EIC) have common beneficial effects on energy metabolism and signaling pathways: All three can induce metabolic switching from glucose to ketone bodies (g-to-k) as cellular fuel source when glucose is scarce . By lowering of available cellular energy and through the cellular sensing of limited availability of nutrients 1 which ensues, they can induce the activation or inhibition of several signaling pathways relevant for neuroprotection, synaptic plasticity and neurogenesis (NSPAN) (e.g., Van Praag et al., 2014;Mattson, 2019;García-Rodríguez & Giménez-Cassina, 2021). This can have short-term implications for cognitive performance (e.g., Diano et al., 2006). The benefits of EIC are achieved in part through the influence of hunger hormone ghrelin on glucose homeostasis and the activity of the insulin receptor (Chabot et al., 2014;Bayliss et al., 2016) which is an upstream effector of signaling pathways relevant for NSPAN (Sadria & Layton, 2021). The hormone ghrelin also plays a role in other signaling pathways regulating NSPAN (Diano et al., 2006;Gahette et al., 2011;Bayliss et al., 2016;Buntwal et al., 2019;Davies, 2022). Exerkines can also regulate the activity of these pathways among others (e.g., Chow et al., 2022;Vints et al., 2022;Reddy et al., 2023). Calorie restriction mimetics (CRMs; polyphenols and other sirtuin activators as well as precursors of nicotinamide adenine dinucleotide, in particular) do not rely upon glucose depletion, but they can produce similar effects, including enhanced energy metabolism, decreased oxidative stress and inflammation and enhanced NSPAN and cognition (Testa et al., 2014). The efficacy of CRMs with regards to overall physiological parameters has been questioned by Handschin (2016), but general consensus in the literature points out to the potential of CRMs in the prevention and treatment of neurodegenerative disorders (e.g., Bonkowski & Sinclair, 2016). CRMs are considered promising in this area (e.g., Bonkowski & Sinclair, 2016;Heberden, 2016;Carosi & Sargeant, 2019;Sharman et al., 2019;Almendariz-Palacios et al., 2020;Hofer et al., 2021;Martel et al., 2021;Xue et al., 2021), but the state of current knowledge is insufficient to recommend CRMs for the treatment of individuals presenting with neurodegenerative disorders. For instance, Heger (2017) mentions that only 17 of 45 trials, at that time, show an efficacy of curcumin (in relation to diverse clinical targets). Hofer et al. (2021) provide a summary of human clinical trials interested in various CRMs relating to a diversity of outcomes; Martel et al. (2021) focus on human clinical trials interested in CRMs and the extension of human healthy lifespan, including neuroprotection and neurogenesis, discussing advantages and disadvantages. Treatment should always be provided after sufficient clinical trials have been conducted, but early in the progression of the disease (e.g., ;Carosi & Sargeant, 2019;Sharman et al., 2019).
EIC and CRMs are beneficial in the attenuation of epigenetic changes induced by aging, which are important contributors to neurodegeneration among other risks Madeo et al., 2019;Almendariz-Palacios et al., 2020;Maharajan et al., 2020;Xue et al., 2021). The aims of this article are threefold: A) to discuss the relevance of EIC and CRMs to NSPAN relying upon recent publications, B) to briefly present some of the biochemical processes involved in metabolism, oxidative stress and NSPAN and C) to present a selective annotated bibliography of existing literature reviews (summaries in Appendix) that focus on the ways in which EIC and CRMs can improve NSPAN, cognitive function, and brain resilience (e.g., van Praag et al., 2014).
2 The relevance of exercise, calorie restriction (CR) and intermittent fasting (IF) and CRMs in neurogenesis and neuroprotection and other neurotrophic effects The body can transition from using glucose for energy to using ketone bodies (García-Rodríguez & Giménez-Cassina, 2021; for more details, see section B below): The liver glycogen store can contain up to the equivalent of about 700 calories. It is depleted when energy intake does not occur for a period of 10-12 h at least, or during periods of high energy expenditure (e.g., running for 1 hour following a 4 hours period after the last meal)  as glycogen is also stored in the skeletal muscles (Richter & Hargreaves, 2013). EIC can result in the depletion of the glycogen store and thus can activate the g-to-k metabolic switch. The k-to-g metabolic switch occurs when the glycogen store is repleted, after energy intake. The repeated switching between glucose and ketone bodies as main sources of cellular fuel has advantages at the organism level in terms of cellular regeneration and protection, including in the brain in terms of neurogenesis and neuroprotection (Matteson et al., 2018). CRMs such as resveratrol and rapamycin have potential in the prevention and treatment of neurodegenerative diseases (Albani et al., 2010;Baur & Sinclair, 2006;dos Santos et al., 2022;Rege et al., 2014). " [B]oth compounds also show impressive effects in rodent models of age-associated diseases." (Kaeberlin, 2010, p. 96). This could be because they can modulate cell signaling close to a fasting state (e.g., resveratrol: Chatam et al., 2022;rapamycin;Blagosklonny, 2019). A sustainable alternation of exercise, IF or CR and the use of CRMs might lead to benefits similar to those of the continued reliance upon a single modality of NSPAN intervention. In this contribution, the potential benefits of EIC and CRMs will be dwelved upon, including the metabolic and signaling processes trough which these advantages are achieved.

Neurodegenerative diseases and depression
The large majority of the papers mentioned in this review mention the devastating consequences of aging as one of the motors of research in the neurotrophic effects of EIC and CRMs, including NSPAN. A variety of essential restorative functions are decreased with age, which leads to brain aging (e.g., Zia et al., 2021). In addition, aging increases damage to DNA and tissues, including in neurons, stem cells and their niches, (Maharajan et al., 2020;Brunet et al., 2022). A bibliometric analysis of the literature on cognitive aging is provided by Othman et al. (2022). Some of the consequences of aging are due to epigenic changes in signaling pathways (e.g., Iside et al., 2020;Wang K. et al., 2022). For instance, aging-related impaired AMPK signaling (see below) is related to atherosclerosis and cardiovascular diseases, increased risks of insulin resistance and diabetes, obesity, chronic inflammation, nonalcoholic fatty liver diseases and polycystic ovary syndrome, cancer and neurodegenerative diseases (Yadav et al., 2017). Neurodegenerative diseases share some ethiological processes, such as oxidative stress, post-translational modifications, metabolic changes, cell death mechanisms, disturbed immune response (Fan et al., 2017;Balusu et al., 2023). These factors have (epi)genetic causes and environmental and behavioral causes (Fan et al., 2017).
The most frequent neurodegenerative diseases are Alzheimer's disease and Parkinson's disease (McGregor & Nelson, 2019). Alzheimer's disease is characterized by an aggregation of amyloid beta peptide and accumulation of misfolded tau proteins, which can result from epigenetic dysregulations of cell signaling, including mitochondrial and metabolic disfunctions (Bloom, 2014;Aman et al., 2021;Amorim et al., 2022;Guo et al., 2022;Balusu et al., 2023). Examples of dysregulated processes linked to neurodegenerative impairments in Alzheimer's disease are endocytosis, proteastasis and phagocytosis in microglia, inflammation and metal ion homeostasis in astrocytes, as well as myelin loss and lipid deposits in oligodendrocytes (Balusu et al., 2023). Parkinsons' disease is characterized by the presence of Lewy bodies in different areas of the brain and neurodegenerative cell loss, dopaminergic neurons in particular (McGregor & Nelson, 2019;Balusu et al., 2023). Examples of dysregulated processes associated with neurodegeneration in Parkinsons' disease are: proteostasis, potassium ion transport and phagocytosis in the microglia, heatshock response and metal ion homeostasis in astrocytes, as well as proteostasis and zinc homeostasis in oligodendrocytes (Balusu et al., 2023).
Major depression is the most important factor associated with disability among all causes (Craske et al., 2017). The search for biomarkers of major depression is challenging due to the heterogeneity of the description of the disorder (e.g., increased appetite/sleep, decreased appetite/sleep; decreased emotionality, increased nervousness; feeling slow, feeling restless); dysregulated cell signaling protein pathways in relation to inflammation and metabolism are candidate biomarkers for major depression (van Haeringen et al., 2022).

Exercise
The American College of Sports Medicine (ACSM, 2013) defines physical exercise as planned voluntary physical activity performed with the aim of maintaining or improving the fitness of the body. There are several types of exercise. Distinctions include: aerobic vs. anaerobic exercise and strength vs. endurance training (ACSM, 2013). In aerobic exercise, the body relies on aerobic metabolism (oxygen provided by pulmonary respiration) to generate the adenosine triphosphate (ATP) necessary for the activity, whereas in anaerobic exercise anaerobic glycolysis is relied upon for ATP production. Strength training aims to increase the force of the muscle. Endurance training aims to increase the potential duration of exertion (ACSM, 2013). While exercise can reduce oxidative stress and chronic inflammation (e.g., Gomez-Cabrera et al., 2008;Beavers et al., 2010), exercise is also a source of reactive oxygen species (ROS) and thereby can increase oxidative stress (Bloomer et al., 2005; and the antioxidative benefits of exercise therefore depend upon its duration, type and intensity (Gomez-Cabrera et al., 2008;Fisher-Wellman & Bloomer, 2009). The importance of the redox balance is relation to exercise is discussed in Sutkowy et al. (2021).
Exercise can still provide benefits even when it is oxidative. These benefits include the activation of 5' adenosine monophosphate-activated protein kinase (AMPK, see below) (Richter & Ruderman, 2009;Richter & Hargreaves, 2013) and of sirtuins (SIRTs) (Radak et al., 2020). In addition to these, the indirect increase in the concentration of brain-derived neurotrophic factor (BDNF) is also a potential consequence of exercise (Leckie et al., 2014). "BDNF mediates beneficial effects of energetic challenges such as vigorous exercise and fasting on cognition, mood, cardiovascular function and peripheral metabolism." (Marosi & Mattson, 2014, p.89). But these benefits can be balanced by the inflammation stemming from oxidative stress. In the recent years, the important role of exerkines-defined as "any humoral factors secreted into circulation by tissues in response to exercise" (Magliulo et al., 2022, p. 105)-has been highlighted in the explanation of the benefic effects of exercise (e.g., Chow et al., 2022;Magliulo et al., 2022;Vints et al., 2022;Reddy et al., 2023). Vints et al. (2022) discuss the implications of exercises (and exerkines) with regards to synaptic plasticity. A recent meta-analysis (Pillon et al., 2020) has focused on studies relying upon transcriptomic profiling to identify genes of which the expression is modified by exercise in the skeletal muscles. The mechanisms at play in exercise-induced tissue regeneration including in the central nervous system (neurogenesis as well as neuron myelin and axon regeneration for instance) are described by Chen J. et al. (2022). Cortes and De Miguel (2022) highlight the sex differences in CNS responses to exercise.

Intermittent fasting
The overconsumption of food is an issue in modern societies because of its constant availability. Discussing the detrimental effects of overconsumption for cognitive functioning and the damaging implications regarding neurodegenerative diseases, Mattson (2019) specifies that "[t]he underlying molecular mechanisms involve epigenetic modifications (. . .), that alter the expression of genes involved in neuroplasticity" (p. 204) and lead to "synaptic dysfunction, impaired neurogenesis [and] neuronal degeneration" (p. 205). Nutritional practices that re-establish "adaptive cellular signalling," such as IF and CR, can mitigate the negative effects of food overconsumption on cognition by enhancing NSPAN (Mattson, 2019).
"Intermittent fasting (IF) is a regimen in which there are repeating cycles of ad libitum eating and fasting" (Erbaba et al., 2021, p. 2). Four main forms of IF are frequently studied (in addition to religious forms of fasting): alternate day fasting (important lowering of energy intake every 2 days), whole day fasting (one or 2 days of food abstinence a week) and time restricted feeding (energy intake limited to a time window of 8-12 h, generally) and periodic fasting (were 5 days of ad libitum diet are followed by 2 days of fasting) (e.g., Tinsley & La Bounty, 2015;Seidler & Barrow, 2022;Bhoumik et al., 2023;Li et al., 2023). Similar benefits as those of CR (e.g., improved neurogenesis, Baik et al., 2020), which are discussed next, are observed for IF and fasting mimicking diets (Baik et al., 2020;Seidler & Barrow, 2022;Zhao et al., 2022), which consist of limiting the intake of calories and proteins for cycles of a few days to a week (see Seidler & Barrow, 2022). Chen J. et al. (2022) provide a bibliometric analysis on intermittent fasting. Li et al. (2023) provide a balanced view of intermittent fasting (including potential disadvantages) and summaries of processes relating IF to circadian rhythms.

Calorie restriction
CR entails the limitation of energy intake from food-"A rough guideline would be 1,800-2,200 kcal/day for men and 1,600-2,000 calories for women" (Mattson, 2019, p. 8)-for a prolonged period of time (Mattson, 2019). The availability of nutrients (such as the ratio of adenosine monophosphate over ATP; Yadav et al., 2017) regulates several signaling pathways of relevance for NSPAN. Through various mechanisms, CR can delay the cognitive effects of aging (Gillespie et al., 2016). For instance, CR leads to the reduction of oxidative stress (Almendariz-Palacios et al., 2020;Yu Q. et al., 2020), to the proliferation of new neurons (Mattson & Arumugam, 2018;Maharajan et al., 2020), and to a better regulation of autophagy of neurons, i.e., the recycling of the material of deficient or damaged cells which is increased when energy is scarce (in the Appendix, see the summary of Ntsapi & Loos, 2016). Other examples include: the increase of antiinflammatory hormones, the decrease of chronic inflammation, and the modulation of cell survival (e.g., through apoptosis) (Testa et al., 2014). Some of the signaling pathways involved in these processes and others are described in the next section.

Calorie restriction mimetics
CRMs share some of the benefits of EIC (Testa et al., 2014;Xue et al., 2021). For instance, Bonkowski & Sinclair (2016; see Appendix) discuss the increasing use of nicotinamide adenine dinucleotide precursors and activators of SIRTs in clinical trials in the context of (neurodegenerative) disease prevention and treatment and the promotion of longevity. Several reviews summarized in the Appendix discuss the role of polyphenols in the modulation of synaptic plasticity, increased neuronal proliferation, and the reduction of oxidative stress and of neurotoxicity in particular (e.g., Rendeiro et al., 2015;Moosavi et al., 2016;. It should be noted that Miller et al. (2011) found that resveratrol and simvastatin did not provide longevity benefits in rodents, whereas rapamycin did. These three CRMs thus impacted longevity differently in Miller et al. (2011) (but see Madeo et al., 2019). Sharman et al. (2019) note a low success rate of phytocomponents (among which nicotinamide adenine dinucleide boosters and sirtuins upstream effectors) in terms of symptom reduction in human trials of Alzheimer's patients. Importantly, the safety of nicotinamide mononucleotide, a nicontinamide adenine dinucleotide precursor, needs to be further investigated (Nadeeshani et al., 2022).

Neurogenesis
Adult neurogenesis refers to the formation of new neurons in the adult central nervous system (Overall et al., 2016). A description of the different stages of neurogenesis, starting with the stem cell and leading to the mature neuron, is provided by Overall et al. (2016). New neurons are hyperexcitable and less receptive to inhibitory neurotransmitters (e.g., gamma-Aminobutyric acid-GABA), which confers on them more influence than older neurons in a neural circuit (Fares et al., 2019). Adult neurogenesis has been documented in different mammals (Lucassen et al., 2020). Studies on the matter overwhelmingly conclude that neurogenesis occurs in the adult human hippocampus (see Kempermann et al., 2018;Lucassen et al., 2020). The hippocampus fulfills important functions with respect to spatial and episodic memory and is involved in emotional processes (Anacker & Hen, 2017). Neurogenesis in this region-accounting to 700 new neurons every day (2% of the total; Spalding et al., 2013)-might be required for flexible representations and behavior, i.e., in dealing with new situations adaptively (Tuncdemir et al., 2019). Reduced hippocampal neurogenesis is associated with diminished ability to form new memories and the forgetting of old memories (Frankland et al., 2013), whereas increasing hippocampal neurogenesis allows for more flexibility in strategy choice, and can compensate preceding deficiencies in the aging brain (Bergugo-Vega et al., 2020).
Adult neurogenesis can be induced or enhanced through EIC and CRMs, which slows down cognitive decline and can also enhance cognition (e.g., Mattson & Arumugam, 2018;Chow et al., 2022). Overall et al. (2016) describe the different mechanisms through which neurogenesis is promoted by physical activity. Maharajan et al. (2020) and Negredo et al. (2020) discuss the potential of CR in maintaining the health of stem cells and stem cell niche regeneration. Fares et al. (2019) provide a historical perspective on the study of neurogenesis.

Neuroprotection
EIC and CRMs can promote neuroprotection and thereby delay cognitive aging (e.g., Mattson & Arumugam, 2018;Burtcsher et al., 2022;Reddy et al., 2023). This is achieved through several mechanisms. Two are addressed in this paragraph, while others are briefly mentioned in the pages that follow. The first of these mechanisms is the protection of the neuron and of the microenvironment of neurons from oxidative stress (e.g., protection of membrane and DNA integrity; Li et al., 2022;Lüscher et al., 2022). The second related mechanism is the regulation of cell survival (e.g., Ying et al., 2020): In ideal conditions, the survival of healthy cells is promoted, while the survival of senescent and otherwise deficient cells can be impeded through different mechanisms (e.g., autophagy and apoptosis) (e.g., Laberge et al., 2013;Bortner & Cidlowsky, 2020), with neuroprotective effects thereby achieved in the brain (Bhaduri et al., 2023). At the cellular level, different molecules and signaling pathways play a role in determining the fate of the cells, including neurons (e.g., Krieglstein et al., 2002;Fayad et al., 2005;Yamamoto et al., 2007;Huang et al., 2008;Bathina & Das, 2015;Jaworski et al., 2019;Rai et al., 2019;Zhao et al., 2019;Ying et al., 2020;Li et al., 2022;Lüscher et al., 2022;Nordvall et al., 2022). EIC and CRMs can regulate such processes (e.g., Mattson & Arumugam, 2018).

Synaptic plasticity
Synaptic plasticity is also an important neurotrophic effect of EIC and CRMs (e.g., Rendeiro et al., 2015;Seidler & Barrow, 2022;Reddy et al., 2023). The ability of the brain to reorganize following internal and external events is key to learning and adaptive conduct; one such mechanism is synaptic plasticity (McAllister et al., 1999;Bliss et al., 2018;Magee & Grienberger, 2020). Neurotrophins (in particular BDNF, see below in the current section) play an important role in synaptic plasticity as well as synaptic transmission (McAllister et al., 1999;Gómez-Palacio-Schjetnan & Escobar, 2013). Magee and Grienberger (2020) discuss several forms of synaptic plasticity, including the form most commonly studied: Hebbian plasticity (the strength of the synapse depends on how often the presynaptic neuron fires toward the postsynaptic neuron). Abraham (2008) discusses meta-plasticity, which they refer to as the tuning of synapses and neuron networks for plasticity. "Metaplasticity entails a change in the physiological or biochemical state of neurons or synapses that alters their ability to generate synaptic plasticity" (Abraham, 2008, p. 387): Alternations between phases of high stimulation and phases of low stimulation are paradigmatic of the promotion of meta-plasticity, and physical exercise can induce high stimulation.
3 Energy metabolism, oxidative stress, neuroprotection, synaptic plasticity andadult neurogenesis: biochemical processes In this section, several of the processes that are responsible for the effects of EIC and CRMs on NSPAN are discussed. Further, other neurotrophic and protective effects of signaling pathways that are elicited by EIC and CRMs are presented for comprehensiveness.

Energy metabolism
Liver glycogen storage provides the body with continued access to 'fuel' as long as the supply lasts through the release of glucose to the bloodstream (Hardie, 2018). Glucose transporters are proteins that mediate the entry of glucose across cell membranes and the blood brain barrier (BBB) (e.g., Simpson et al., 1999;Thorens & Mueckler, 2010). Cellular respiration results in the production of ATP in cell mitochondria (Korla & Mitra, 2014). This process also releases H2O and CO2. Cellular respiration starts with glycolysis (the transformation of glucose to pyruvate, then to acetyl-coenzyme-A; Acetyl-CoA), of which the availability of nicotinamide adenine dinucleotide is an important requirement. It continues with the Krebs cycle, and ends with oxidative phosphorylation-itself involving the electron transport chain (ETC) and chemiosmosis (Zhao et al., 2019).
When energy is necessary in the cell, notably through hydrolysis (the binding of H2O with ATP), ATP is converted to: adenosine diphosphate (ADP) + one phosphate that can be consumed as energy (Yadav et al., 2017). The same can occur for ADP, leading to adenosine monophosphate (AMP) + one phosphate. The ratios ADP:ATP and AMP:ATP are thus indicators of the energy requirements in the cell (Yadav et al., 2017).
Hydrolysis of triglycerides occurs when ADP:ATP or AMP:ATP ratios are high and results in the synthesis of fatty acids, which are then converted to ketone bodies through oxidation to fuel the cells (g-to-k metabolic switching; Newman and Verdin, 2017;Martínez-Reyes and Chandel, 2020. Energy expenditure (e.g., exercise), increases ROS in the organism . A major contributor of ROS is the slippage of electrons through the, ETC, in the mitochondria (Zhao et al., 2019;Mazat et al., 2020;Shofield & Schafer, 2021). Proton slippage is partially downregulated by uncoupling proteins (UCPs; Demine and Arnould, 2019;Haas & Barnstable, 2021). Holmström & Finkel (2014) discuss other sources of ROS. The processes of ROS generation and the role of antioxidants and ROS inhibitors are reviewed by Brieger et al. (2012).
Oxidative stress ensues from an elevated production of ROS coupled with insufficient availability of antioxidants (ROS imbalance) (Aon et al., 2010;Shofield & Schafer, 2021). "As signaling molecules, ROS play an important role in cell proliferation, hypoxia adaptation and cell fate determination, but excessive ROS can cause irreversible cell damage and even cell death" (Zhao et al., 2019, p. 3). Oxidative stress more generally can also lead to such negative consequences (Murphy, 2009;Di Meo et al., 2016;Shofield & Schafer, 2021). Zeliger (2013) discusses diseases linked with oxidative stress, their comorbidity and prevention, as well as the Oxidative Stress Index questionnaire, which permits to assess the potential future onset of noncommunitive chronic diseases and a list of environmental sources of ROS.
A moderate ROS is ideal for the endocrine, immune and cognitive functions (Brieger et al., 2012) and thus both low and high ROS are related to metabolic disfunctions and diseases (Brieger et al., 2012). Importantly, an elevated ROS is associated with a range of neurodegenerative diseases . Dunn et al. (2015) present the anti-microbial function of ROS. Holmström & Finkel (2014) discuss redox signaling. Chun et al. (2010) discuss the antioxidant intake of Americans from several sources.

Nucleotides, metabolites and neurotrophic factors
3.2.1 Nicotinamide adenine dinucleotide NAD+ is involved in DNA repair and mitophagy (the process of recycling of non-essential or damaged mitochondria; Schofield & Schafer, 2021) as it is required for SIRT1 activation (Fang & Bohr, 2017;Chen et al., 2020). NAD+ participates in glycolysis and is reduced to NADH in the process (Ying et al., 2020;Navas & Carnero, 2021). As mentioned above, a high level of ROS is an important threat to mitochondrial and cellular integrity. Increased NAD+ can upregulate immunity, inflammation and DNA repair through the activation of NAD+ dependent enzymes such as SIRTs and poly(ADP-ribose) polymerases (PARPs) (Xie et al., 2020;Yang et al., 2020;Navas & Carnero, 2021). Although it has been reported that NAD+ acts as a proinflammatory cytokine (e.g., Xie et al., 2020;Navas & Carnero, 2021), it has also been shown that NAD+ and its precursors can regulate chronic inflammation and reduce ROS, and, thereby, inflammation (Covarrubias et al., 2021;Xie et al., 2020). NAD+ also modulates the effect of different enzymes, facilitates energy metabolism and helps in the synchronization of the circadian clock (Xie et al., 2020). NAD+ and NADH also play important roles in cell survival and death , including through their role in ADP-ribosylation Lüscher et al., 2022). Aging is related to NAD+ deficiency and such deficiency is related to accelerated aging (e.g., increased mitochondrial disfunctions; Xie et al., 2020). This constitutes a vicious circle-which can be thwarted for instance by supplementation of NAD+ precursors (Bonkowski & Sinclair, 2016) and the upregulation of AMPK signaling through exercise (Richter & Hargreaves, 2013) and calorie restriction (Mattson & Arumugam, 2018). Consequences include disturbed circadian rhythms, increased inflammation, poor immunity, hampered DNA repair, and increased risk of cancer, which is aggravated by high levels of ROS (Xie et al., 2020;Navas & Carnero, 2021).
Three pathways are at play in the synthesis of NAD+: the de novo, Preiss-Handler and Salvage pathways (Lautrup et al., 2019;Xie et al., 2020;Ying et al., 2020). Synthesis of NAD+ through the de novo pathway has neuroprotective and neurotoxic effects (Lautrup et al., 2019). It "starts with the catabolism of the amino acid tryptophan that is converted via two steps to the intermediate kynurenine, which can generate NAD+, kynurenic acid, or xanthurenic acid." (Lautrup et al., 2019, p. 630). NAD+ is synthesized from nicotinic acid (NA) through the Preiss-Handler pathway and from nicotinamide riboside (NR) and the reuse of nicotinamide (NAM) through the Salvage pathway (Lautrup et al., 2019;Xie et al., 2020;Ying et al., 2020). Both the Preiss-Handler and Salvage pathways rely upon the intermediary synthesis of nicotinic acid mononucleotide (NAMN, Lautrup et al., 2019;Xie et al., 2020;Ying et al., 2020). It is worth noting that "ATP may be consumed to replete NAD+ when NAD+ is selectively depleted by enzymes such as PARP-1; vice versa, NAD+ may also be consumed to regenerate ATP under the pathological conditions when ATP is selectively depleted." (Ying et al., 2020). The therapeutic potential of nicotinamide riboside supplementation is examined by Mehmel et al. (2020).

Ketone bodies
Fatty acids are synthesized (through hydrolysis of triglycerides) when glucose is lacking, for instance following EIC, and then converted into the three ketone bodies: βhydroxy-butyrate (BHB), acetone (Ace) and acetoacetic acid (also referred to as acetoacetate, AcAc) (Newman & Verdin, 2017). Ketone bodies are then distributed to the cells of the organs, including the brain, through their release in blood circulation. Ketone bodies can be used as alternate fuel sources to glucose: In the cell, they are catabolized into Acetyl-CoA (Newman & Verdin, 2017). Acetyl-CoA is then converted to ATP as a result of the Krebs cycle (for details, see Martínez-Reyes & Chandel, 2020). Ketone bodies also have regulatory roles, such as the response to oxidative stress, cell excitability, the regulation of protein expression, and signaling more generally in and out of the brain (see Koppel & Swerdlow, 2018;García-Rodríguez & Giménez-Cassina, 2021). There is evidence that increases in ketone bodies, BHB in particular, result in neuroprotection (e.g., Kolb et al., 2021). BHB can be transported across the BBB by monocarboxylic acid transporters (MCT). The amount of MCT regulates BHB in the brain, where it is responsible for a variety of actions (Newman & Verdin, 2017). Some of these are briefly mentioned: An important role of BHB is the upregulation, through activation of NF-κB, of the hippocampal expression of BDNF in case of either scarce or sufficient glucose supply (Hu et al., 2018;Mattson & Arumugam, 2018). In other words, BHB increases BDNF even in the absence of g-to-k metabolic switching. BHB affects sympathetic tone through inhibition of the free fatty acid receptor 3 (Newman & Verdin, 2017). It upregulates gene expression and suppresses oxidative stress by inhibiting class I histone deacetylases (HDAC; Newman & Verdin, 2017;Shimazu et al., 2013). It appears BHB is capable of stimulating PGC-1α (mitochondrial biogenesis and mitophagy) and FOXO1 (metabolic regulation, reduced sympathetic tone, apoptosis; Santo & Paik, 2018) without AMPK modulation through the Phosphoinositide 3kinase-Protein kinase B (PI3K/Akt) pathway (Kim et al., 2019). Through the activation of macrophages, BHB and nicotinic acid (NA), activate the hydroxy-carboxylic acid receptor 2 (HCAR2) which induce neuroprotection through the reduction of neuroinflammation and also regulates lipid metabolism (Rahman et al., 2014;Newman & Verdin, 2017). BHB is also involved in synaptic plasticity (Mattson & Arumugam, 2018) and GABAergic regulation (Newman & Verdin, 2017) and plays a major role in cognition and health in general (Cavaleri & Bashar, 2018).

Brain-derived neurotrophic factor (BDNF)
BDNF, a member of the neurotrophins family, is a main protagonist in NSPAN that can be increased through exercise (Zhao et al., 2008;Bathina & Das, 2015;Kallies et al., 2019). Neurotrophins are a family of proteins that regulate neural function, growth and survival, and neuroplasticity through various signaling pathways (Huang et al., 2008;Bathina & Das, 2015). There are four neurotrophins: nerve growth factor (NGF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4) and BDNF. The role played by BDNF in regulating neurophysiological processes, modulating synaptic interactions, neuroplasticity and neuroprotection has been extensively studied (Kowiański et al., 2018). Such functions are mediated by several downstream effectors, including the Trk family of tyrosine kinase family of receptors (Foltran & Diaz, 2016). Activation of the tyrosine receptor kinase B (TrkB) kinase promotes signaling along two pathways: PI3K/Akt and Raf/MEK/ERK (Foltran & Diaz, 2016). A few examples of the more specific roles of BDNF are now provided. Research has found that BDNF increases axonal arborization through tyrosine receptor kinase B (TrkB) signaling, a process which is regulated by the phosphitylation of the mitogen-activated protein kinases (MAPK; Cheng et al., 2011;Jeanneteau et al., 2010). TrkB is further involved in neural plasticity (Johnstone & Mobley, 2020). BDNF also increases the activation of neuronal stathmins (Cardinaux et al., 1997). Stathmins induce plasticity, the generation of new neurons and their development (Chauvin & Sobel, 2015). It is notable that BDNF also upregulates mTORC1, which can be detrimental; but this action is inhibited by AMPK and its effect on SIRT signaling through the upregulation of NAD+ metabolism (Ishizuka et al., 2013;Sadria & Layton, 2021). Reduced levels of BDNF are associated with neurodegenerative diseases (for reviews, see: Bathina & Das, 2015;Autry & Monteggia, 2012-who mention its relation with neurotransmitter serotonin). In the body and in the brain, BDNF is also involved in energy homeostasis and regulation of the parasympathetic tone (Marosi & Mattson, 2014).

Protein and lipid kinases involved in NSPAN
Kinases are enzymes which add a phosphor group to their target when activated (phosphorylation, Taylor & Kornev, 2011). In this sub-section, several protein and lipid kinases involved in NSPAN are briefly presented. The main actions of these effectors are summarized in Table 1.

Phosphoinositide 3 (PI3K)
IF and CR are involved in the improvement of mitochondrial function through the regulation of PI3K and its effectors (Lu et al., 2019;Zhao et al., 2022). PI3K dysregulation is implicated in neurodegenerative diseases such as AD (Kumar & Bansal, 2022), which has been associated with increased chronic microglia activation following such dysregulation (Chu et al., 2021): "considerable evidence suggests that chronically activated microglia continually secrete neurotoxic molecules to sustain neuroinflammation" (p. 3). Further, PI3K is involved in the regulation of autophagy, cellular growth and survival and synaptogenesis, notably through its direct or indirect influence on Note. This table has been created with the help of GPT-3.5 and its content thoroughly verified.

Protein kinase B (Akt)
Akt dysregulation is implicated in neurodegenerative diseases such as AD (Kumar & Bansal, 2022). Akt is involved in neuroprotection in several ways as: up or downregulation of the functions of other proteins responsible for apoptosis (programmed death of deficient cells), and survival and proliferation of cells-including autophagy, notably neurons and the regulation of neuronal toxicity (Fayad et al., 2005;Chen et al., 2013;Rai et al., 2019). Examples include the downregulation of AMPK-through a decrease in the AMP: ATP ratio and the upregulation of mTOR (Hahn-Windgassen et al., 2005). Fayad et al. (2005) mention that other pathways may also regulate pathways modulated by Akt. Akt also phosphorylates FOXO and the tuberous sclerosis complex (TSC1 and TSC2, important regulators of mTOR; Huang et al., 2008;Sadria & Layton, 2021) and regulates the antiapoptotic and pro-survival extracellular signal-regulated kinases (ERK) (Rai et al., 2019). Vadlakonda et al. (2013) discuss the interplay ('interactions and feedback loops') between Akt and mTOR and the mediating role of AMPK and FOXO in particular.

Unc-51 like autophagy activating kinase (ULK)
The ULK complex is composed of ULK1 and ULK2. ULK1 is involved in autophagy (recycling of cell materials) in conditions of cellular stress, which can affect the functioning of the cells and their survival or death (Nie et al., 2016). The ULK complex is also involved in mitophagy, which is the quality control process of the mitochondria with functions such as the "degradation of damaged and superfluous mitochondria, prevent[ion of] detrimental effects [of ROS and mitochondrial disfunction] and reinstat [ion of] cellular homeostasis in response to stress" (Chen et al., 2020, p. 1). Disfunctions in autophagy and mitophagy are importantly linked to neurodegenerative disorders (e.g., Chen et al., 2020). ULK is upregulated by AMPK and inhibited by mTOR (Sadria & Layton, 2021;Yu et al., 2021).
However, "MAPKs are implicated in the pathogenesis of many conditions" (Wancket et al., 2012, p. 244). MAPK phosphatases (MKPs) downregulate MAPKs and MAPKs increase the activity of MKPs (Wancket et al., 2012) this feedback loop allows for the beneficial functions of MAPKs to be achieved, while keeping their activity under control. Ras, and Raf indirectly, are upregulated by PI3K leading to the activation of some MAPKs (e.g., ERK; Peyssonnaux & Eychène, 2001). "On the one hand, hypoglycemia [e.g., which can be achieved through EIC] decreases anabolic hormones (e.g., insulin, GH, and IGF1), as well as sex and thyroid hormones, increases the expression of the catabolic cortisol, and subsequently inhibits the MAPK pathway (i.e., RAS/ RAF/MEK/ERK) and the PI3K/Akt/mTOR pathway. On the other hand, the inhibition of ERK avoids mTOR activation and subsequently induces autophagy activity, which contributes to the suppression of inflammation by downregulation of both IFN [i.e., interferons] and proinflammatory cytokine responses." (Kökten et al., 2021(Kökten et al., , p. 1561).

Other signaling proteins involved in NSPAN
Other signaling proteins which play an important role in NSPAN are presented here. Their main actions are summarized in Table 1.

Sirtuins (SIRT)
SIRTs are a class of histone deacetylases (Carafa et al., 2016). "The seven members of this family of enzymes are considered potential targets for the treatment of human pathologies including neurodegenerative diseases, cardiovascular diseases, and cancer." Carafa et al., 2016, p. 1). The availability of NAD+ is required for the activation of all 7 SIRTs (Cantó et al., 2009;Tang, 2016;Elkhwanky & Hakkola, 2018;Fagerli et al., 2022). Such requirement fulfills energy sensing functions: Thereby, SIRTs can optimally respond to cellular energy requirements (Elkhwanky & Hakkola, 2018). SIRT1, SIRT6 and SIRT7 are present in the cell nucleus, whereas SIRT2 is present in cytosol and SIRT3, SIRT4, and SIRT5 are present in the mitochondria (Elkhwanky & Hakkola, 2018;Fargeli et al., 2022). Morris (2013; focus on aging) and Yamamoto et al. (2007) addresses in detail the functions of SIRTs, notably: gluconeogenesis, lipid metabolism, mitochondrial respiration, cellular proliferation and differentiation, cell cycle control, gene expression, apoptosis, inflammation, insulin secretion, neuroprotection and axonal protection, DNA repair. Elkhwanky & Hakkola (2018) discuss the important role of extranuclear SIRTs. SIRT1, of which the activity has been in particular associated with increased longevity (for details, see Tang, 2016) has been the focus of most research on SIRTs. In what follows, the activity of SIRTs is discussed in very general terms, as the signaling of SIRTs is especially complex and would require much space (but see Cantó et al., 2009;Tang, 2016;Elkhwanky & Hakkola, 2018;Fagerli et al., 2022). Specific mentions of SIRT signaling are found in the other sections.
Increased activity of SIRTs (e.g., by AMPK, or indirectly by exercise, CR or CRMs; e.g., Chen J. et al., 2022) is related to energy homeostasis (e.g., regulation of the Krebs cycle and oxidative phosphorylation, triggering of glucose uptake, fatty acid oxidation and ketogenesis), mitochondrial homeostasis and integrity (notably: reduction of ROS and DNA repair through activation of PARPs, see below), and NSPAN (regulation of synaptic plasticity; mitochondrial biogenesis in neurons importantly; reduction of ROS) (Elkhwanky & Hakkola, 2018;Fagerli et al., 2022). Some of the functions in which SIRTs are indirectly involved in rely upon ADP-ribosylation signaling (see below) in which PARPs play a major role (Hottiger, 2015). A higher risk of neurodegenerative diseases ensues the decreased activity of SIRTs, such as mitochondrial and cardio-vascular diseases, and neurodegenerative diseases (Elkhwanky & Hakkola, 2018;Jiao & Gong, 2020;He et al., 2022). Importantly, SIRTs can activate LKB1, which in turn can activate AMPK and downregulate mTOR (Woods et al., 2003;Shaw, 2009;Sadria & Layton, 2021) and regulate PGC-1α (Cantó et al., 2013). The modulation of SIRTs, for instance using resveratrol among other SIRT activators, is a promising prevention and treatment target for neurodegenerative disorders and cancer (Carafa et al., 2016;Cao et al., 2018). Leite et al. (2022) discuss the relevance of targeting SIRTs pharmacologically for the prevention and treatment of neurodegenerative disorders in particular. Fang et al. (2019) discuss the role of SIRTs in the regulation of stem cells.

Sonic hedgehog (Shh)
A recurrent finding has been that signaling pathways essential to the brain development are also active in neurogenesis and synaptic plasticity (Yao et al., 2016). This is demonstrably the case of hedgehog dependent pathways, in particular those dependent upon Shh (Yao et al., 2016). In particular, Shh is active in brain development and also in the maintenance and proliferation of neural stem cells in the adult brain (Carballo et al., 2018;Schwarz el al., 2012). The action of Shh on neurogenesis appears to be regulated by the primary cilia of hippocampal neurons (Breunig et al., 2008). Shh also participates in axon regeneration (see the bibliometric analysis by Chou et al., 2022). The interplay of the Notch and Shh pathways, where Notch signalling potentiates the cell proliferative effect of Shh has been a recurrent finding in the recent years (Yao et al., 2016). Crosstalk between Shh and Wnt has also been documented (Carballo et al., 2018). Dysfunctions in Shh signalling is present in neurodegenerative diseases, metabolic disorders and depression (Yao et al., 2016;Tayyab et al., 2018;Garg et al., 2022).

Notch
Increased Notch signalling has been observed following intermittent fasting and exercise (Brandt et al., 2010;Baik et al., 2020). During development, Notch-dependant pathways ensure neural stem cells maintenance in the developing brain (Ehm et al., 2010). The Notch signaling pathway also plays an important role in the regulation and plasticity of neural stem cells and neural progenitor cells in several niches of the adult brain (Brandt et al., 2010;Ehm et al., 2010;Bagheri-Mohammni, 2022). Disfunctions of Notch signaling are present in AD and other neurodegenerative diseases (Ables et al., 2011). Notch is a master regulator of neuronal life cycle and synaptic plasticity (Ables et al., 2011). "Notch signaling deeply participates in the development and homeostasis of multiple tissues and organs" (Zhou et al., 2022, p. 1). Transcriptional activation is the most known way Notch activity is enhanced, but protein activation is also possible ('non-canonical' signalling). (Ables et al., 2011). Precursors of Notch receptors are generated by transcription and translation in the endoplasmic reticulum, after which they undergo maturation in the Golgi apparatus (Zhou et al., 2022). Inhibition of GSK-3 by PI3K-Akt increases the activity of Notch. Notch signalling can enhance the activity of the Hedgehog pathway, including its Ssh ligand (Jacobs & Huang, Frontiers in Aging frontiersin.org 2021). The hedgehog pathway also regulates Notch signaling (Jacobs & Huang, 2021). Notch activity can be both carcinogenic and anticarinogenic (Zhou et al., 2022).

Wnt
The Wnt pathways is also important in its neurotrophic activity, including in adult neurogenesis (Arredondo et al., 2020;Alkailani et al., 2022): "[T]he Wnt signaling pathway plays multiple roles in adult hippocampal neurogenesis, including regulation of proliferation, fate-commitment, and maturation of adult-born neurons." (Arredondo et al., 2022, p. 636). The Wnt/b-catenin pathway is potentiated by AMPK and GSK3β which phosphorylate β-catenin (Zhao et al., 2010;Hermida et al., 2017). Wnt also plays a major role in the differentiation of neuronal precursor cells (Arredondo et al., 2020). General blockade of Wnt almost completely impedes neurogenesis (Arredondo et al., 2020). (Neural) cell proliferation and differentiation which results from autophagy, which is regulated by Wnt (Lorzadeh et al., 2021). Wnt also participates in presynaptic differentiation (e.g., remodeling of the axon and synapse button), presynaptic and post synaptic assembly in the CNS, particularly in the hippocampus, as well as the regulation of the distribution of synapses (Salinas, 2013). Wnt also participates in axon regeneration (Chou et al., 2022). While some have mentioned that deficient Wnt signaling is linked with brain tumor genesis (Alkailani et al., 2022), others have found that increased Wnt signaling due to high glucose might be responsible for the link between diabetes and cancer (García-Giménez et al., 2014). Wnt has been reported to activate mTOR through GSK-3 inhibition, which promotes cell growth (Inoki et al., 2006). The association between Wnt signaling and carcinogenesis thus remains to be clarified. Wnt activity is inhibited by Notch and mTOR (Zeng et al., 2018;Acar et al., 2021). A bibliometric analysis of Wnt is provided by Xu et al. (2021).

Poly(ADP-ribose) polymerases (PARPs)
PARPs participate in anti-aging functions such as the promotion of chromosome integrity, metabolic and cell cycle regulation, inflammation, and protein expression and RNA transcription and processing) (Cantó et al., 2013;Bai, 2015). Epigenetic alterations in PARP activities are linked to neurodegenerative diseases and other aging-related diseases due to genomic instability (Amorim et al., 2022;Mao & Zhang, 2022). EIC are modulator of the activity of PARPs (D'Souza et al., 2017;Hofer et al., 2022). Through ADPribosylation (the reversible post-translational modification of proteins), the function of the substrate is altered Lüscher et al., 2022). ADP-ribosylation plays an important role in neurodevelopment, signal transduction, the maintenance of DNA integrity, RNA expression, as well as (neuron) cell fate under conditions of cellular stress Lüscher et al., 2022). Li et al. (2022) detail the process of ADP-ribosylation and its functioning in regulating physiological and pathological processes, including the roles of different molecules as writers (e.g., NAD+, PARPs), readers (e.g., PARPs, histones) and erasers (e.g., macrodomain-containing proteins) of ADPribosylation.
PARPs play a major role in ADP-ribosylation (Cantó et al., 2013;Lüscher et al., 2022). There are 17 PARPs, which are not detailed here (see Bai, 2015), except for the mention that ADP-ribosylation signaling is mainly regulated by PARP1 and to a lesser extent by other PARPs (Cantó et al., 2013;Lüscher et al., 2022). PARPs are activated following DNA damage (Xie et al., 2020). Indeed, the most important function of PARPs is DNA repair, particularly under cellular stress (Cantó et al., 2013).
They are also involved in the regulation of gene expression, immune cell maturation and influence energy metabolism and response to inflammation (Cantó et al., 2013;Bai, 2015). The chronic activity of PARPs can induce NAD+ depletion, which can result in the shutdown of mitochondrial function and glycolytic slowdown through the reduction of NAD+ availability for other processes such as the activation of SIRTs and elevated PARP activation through ROS increase can lead to several diseases affecting major organs (Cantó et al., 2013;Bai, 2015), including increased tumor growth; therefore PARP inhibitors are actively researched .

Presentation of the annotated bibliography
In the sub-section focusing on exercise, the following literature reviews are summarized: Radak et al. (2007) focused on the role of exercise in regulating ROS in the brain and discussed the implications with regards to neuroprotection; Powers et al. (2020) described exercise as a producer of ROS and a cause for oxidative stress-mentioning the hormesis hypothesis (the experience of mild stress prepares neurons and tissues to more important stressors); Walsh et al. (2020) which focused on the link between exercise, BDNF, as well as cognition; Reddy et al. (2023) which discussed the cellular processes involved in exercise-induced neuroregulation; Chow et al. (2022) focused exerkines' health implications, including cognitive decline; Mattson & Arumugam (2018) discussed epigenetic changes leading to mitochondrial disfunctions (e.g., decreased NAD+:NADH ratio, leading to decreased SIRT signaling) and the alleviating role of exercise and IF; Lucassen et al. (2010) focused on the neuroprotective role of exercise and sleep, as well as the deteriorating effects of stress and inflammation.
In the section on IF, the following literature reviews are summarized. : focused on the importance of intermittent metabolic switching (involved in both IF and CR) in NSPAN and the neurodegenerative danger of lifestyles without opportunities for intermittent metabolic switching; Seidler & Barrow (2022) examined the role of BDNF in the relation of IF with cognitive function; Cherif et al. (2016) examined IF, CR and Ramadan fasting in relation to cognitive function-mentioning the upregulation by IF; Wang et al. (2020) focused on the influence of IF on inflammatory markers-which are related to NSPAN.
In the section on CR, the literature reviews that follow are summarized: Almendariz-Palacios et al. (2020-updated review): focused on the signaling pathways involved in reduced cellular aging stemming from CR (relevant aspects summarized under this subsection) and CRMs (relevant aspects summarized in the next sub-section); Ntsapi & Loos (2016): focused on the regulation of autophagy by means of different cycle durations of CR, distinguishing between macroautophagy (starting from 30 min of glucose depletion), microautophagy, and CMA (starting from 10 h of glucose depletion)-CMA as being more targeted than the other forms of autophagy; de Mello et al. (2019); focused on the triumvirate insulin, autophagy, and neurodegeneration-examining the signaling pathways involved; Maharajan et al. (2020): discusses the regulation of stem cells aging and stem cell niches by means of CR-with a focus on signaling pathways; : focused on the optimization of brain extracellular microenvironment through CR and its role towards neuroprotection; Yu H. et al. (2020): examined the restauration and maintenance of cognitive function through CR.
In the section on CRMs, the literature reviews that follow are summarized: Almendariz-Palacios et al. (2020-summary continues); Bonkowski & Sinclair (2016): explained the use of NAD+ precursors and other SIRTs activators in relation with disease prevention-including neurodegeneration and longevity, with a focus on signaling pathways; Isde et al. (2020): focused on the activation of SIRT1 in particular through phytochemicals, CRMs included; Hofer et al. (2021): examined clinical trials focusing on CRMs and discusses a list of CRMs available through nutrition; Moosavi et al. (2016): focused on the neurotrophic actions of polyphenols, discussing NSPAN; Oluwole et al. (2022) detailed the role of different polyphenol (sub)classes: tannins, phenolic acid, lignans, flavonoids and stilbenes in health including the main outcomes of interest; Rendeiro et al. (2015): examined the effect (direct and indirect) of flavonoids in alleviating neurodegeneration in particular; : focused on the (pre)-clinical uses of resveratrol, addressing neuroprotection through its anti-inflammatory effect; Moradi et al. (2022): focused on the mechanisms of neuronal regeneration following polyphenol intake, addressing ROS scavenging, reduced beta-amyloid accumulation, regulation of apoptosis and gene expression; Grewal et al. (2021): detailed the mechanisms of neuroprotection afforded by quercetin and implications regarding neurodegenerative diseases; Ravula et al. (2021): provided an updated literature review on the prospects for treatment of neurodegenerative disorders offered by fisetin.
In the sub-section on other nutrients inducing neurotrophic effects, summaries of the following reviews are provided. Hebergen (2016): examined the role of n-3 polyunsaturated fatty acids and polyphenols in the promotion of adult neurogenesis; Carneiro et al. (2021): provided an updated systematic literature review on the neuroprotective effects of coffee, focusing on several of its compounds; Chen et al. (2010): addressed the protective role of caffeine on the BBB specifically; Cui et al. (2017): focused on the role of vitamin D in brain development, neuroprotection and immunity, distinguishing between genomic and non-genomic actions.

Discussion
In the first pages of this contribution (Section A), firstly, the literature on the promotion of NSPAN through EIC and CRMs has been briefly presented. The question of the g-to-k metabolic switch has been addressed and the k-to-g metabolic switching has been mentioned. It was made clear that it is the repetition of these cycles that affords the most health benefits, as "repeating cycles of a metabolic challenge that induces ketosis (fasting and/or exercise) followed by a recovery period (eating, resting and sleeping), may optimize brain function and resilience throughout the lifespan" (Mattson et al. (2018, p. 81). Thus, in section B, glucose metabolism and expenditure as well as oxidative stress have been discussed, the latter being the result of cellular respiration (electron slippage through the, ETC, leading increase in ROS). The introduction continued with the review of the main nucleotides (ATP, ADP, AMP), metabolites (NAD+, NADH, BHB), and neurotrophic factors (primarily BDNF), as well as protein kinases, and signaling proteins involved, such as PI3K, Akt, mTOR, AMPK, GSK3β, ULK, MAPK, PGC-1α, NF-κB, and sirtuins as well as Notch, Shh and Wnt; and selected signaling pathways. While the focus here has been on neurogenesis and neuroprotection, other important functions involved have been discussed (e.g., the regulation of energy metabolism, oxidative stress and inflammation, immune function, apoptosis, autophagy, gene expression and protein synthesis as well as tumor suppression), since beyond their primary role, these functions support the main outcomes of interest. Beckervordersandforth (2017) discuss the role of mitochondrial metabolism in adult neurogenesis. Guo et al. (2022) review the literature on aging in more general terms, related diseases and interventions. Carrasco et al. (2022) and Mittelbrunn & Kroemer (2021) examine the role of T cells in neurodegenerative diseases among others health consequences related to inflammaging.
In Section C, a selective list of reviews of interest has been included and a summary of each is provided in the Appendix. The selection of reviews was organized in five sub-sections covering, in relation to neuroprotection and/or neurogenesis: exercise, IF, CR, CRMs as well as other nutrients inducing neurotrophic effects. The aim here was that each sub-section provided overall a general overview of the benefits of its topic (e.g., CR) in relation to neuroprotection and neurogenesis, with each summarized literature review adding specific aspects to this goal.

Other implications for healthy individuals and policy
Pharmacological cognitive enhancement (PCE) has not yet been mentioned per se in this contribution. While improving or maintaining NSPAN requires months if not years, PCE usually focuses on the hope of rapid gains and is particularly relied upon by students and pressured professionals (Franke & Lieb, 2013;Mayor et al., 2020). Users of PCE rely upon pharmacological solutions (e.g., methylphenidate, Adderall, or modafinil), generally deviating from the inteded use of these medications, or rely upon illicit drugs. The attitude of the public towards PCE is generally rather negative (Mayor et al., 2019), due to the conception of PCE as focusing on short term performance at school or on the workplace that is considered artificial and therefore unfair and undeserved (Faber et al., 2016). The adoption of NSPAN, with a focus on individual health and collective welfare rather than on achievement might be more acceptable to the public: O'Connor and Joffe (2015) have for instance indicated that individuals are more tolerant of CE when its aim is to compensate for a cognitive deficiency or the maintenance of healthy brain function. This might be even more true in periods of collective challenges, such as the COVID-19 pandemic (Mayor et al., 2022a;Mayor et al., 2022b;Massell et al., 2022), as the importance of the greater good might be paramount.
The regulation of PCE is an important consideration for government policy, which aims to tackle the task of balancing benefits and risks, that are not negligible in the case of PCE as usually conceived; i.e., with a focus on neurotransmitters and the short term functioning of brain regions (Outram & Racine, 2011). Advocating in favor of NSPAN through EIC and CRMs might be a good strategy, as the benefits (e.g., reduced health burden for the individual and the collectivity) far surpass those of PCE-while allowing for maintained or improved cognitive functioning in the long run; and their risks are inappreciable when performed within reason: for instance, exercise is a source of ROS (Bloomer et al., 2005) and should therefore not be performed in excess. Calorie restriction should not lead to malnutrition.

Further studies
The literature presented in the main text, and the reviews summarized in the annotated bibliography have exhibited the implications of EIC and the potential of CRMs towards the enhancement of NSPAN, including in the context of neurodegenerative diseases. Notwithstanding the focus of basic research on rodents, it is believed that the discovered mechanisms are present in humans as well as they relate to the functioning of the eukaryotic cell, which has largely been conserved in mammals . But whether or not adult neurogenesis exists in human remains to be definitely established (Denoth-Lippuner & Jessberger, 2021).
In the majority of cases, studies do not compare the effect of the regulation of different signaling pathways on NSPAN, and more often than not, the effect of exercise, calorie restriction, intermittent fasting, and calorie restriction mimetics are not compared either. It thus remains unclear which intervention is more appropriate to achieve improved NSPAN, or in the best case this is a matter of the judgement of the researcher. Further, the same signaling pathway might operate in opposite directions in relation to NSPAN. For instance, the activation of NF-κB has been linked to neuroprotective and neurodegenerative actions (Mincheva-Tasheva et al., 2013;Capece et al., 2022) and it might be related to the decreased risk of depression through the upregulation of BDNF, but NF-κB is also related to increased neuroinflammation, a risk factor for depression (Roy et al., 2023). It is also unclear whether the heightened activation of Wnt is beneficial or not overall, as it is involved in both carcinogenesis and carcinoprevention (Inoki et al., 2006;García-Giménez et al., 2014). Another such example is SIRT6, which is elevated in chronically exercised individuals and performs both protective and pejorative actions in relation to cancer Song et al., 2022); recommendations with regards to NSPAN should consider which effect is more important (protective/pejorative) with regards to the different pathways regulated by EIC and CRM in establishing minimal and optimal thresholds across modalities.
Studies should investigate dose-response and robust effect sizes in all these areas and compare them across modalities of EIC/CRM and signaling pathways as a prerequisite to the setting of thresholds for recommendations with regards to EIC and CRM. Such elements are very infrequently reported in literature reviews (but see Lucassen et al., 2010) and are absent from the large majority of studies in the field. Examples of exceptions are Walsch et al. (2020), which mention that 30 min of exercise are necessary for significant changes in BDNF to occur, whereas, in a study in a related field, Moore et al. (2020) note that blood glucose is affected by single short bouts of exercise in a dose-response manner, with benefits starting after only 1 minute. It follows the target duration of exercise or IF depends on the parameter one wishes to increase, but the information on such aspects and the reliability of these estimates are frequently lacking in the literature . Further research could also compare, in relation to dose-response and effect sizes, studies focusing on EIC and CRMs to those on ketogenic diets which show promise in the prevention of AD (e.g., Neth et al., 2020).
The comparison of the effect of EIC and CRMs on different signaling pathways and modalities of EIC/CRM should ideally be performed within the same study as to minimize the risk of differences in effects being due to methodological differences between studies. In a review (Sharman et al., 2019) only few human trials focusing on phytocomponents in the treatment of Alzheimer's patients were successful. It should also be noted that the sample size should be sufficient to detect small or moderate improvement with adequate power, for instance a sample size of 128 at least for a two-tailed test of the difference in symptoms between two balanced independent groups with a Cohen D of 0.5 (medium effect size) and a statistical power of 0.8 (calculated with G*Power 3) at a p-value of 0.05. Below the minimal required sample size to achieve a relevant power, most studies will fail to detect the desired effect size. Further, the use of meta-analyses is not well implanted in the field; the examples of Pillon et al., Wang et al., 2020 were mentioned above. An increased reliance upon meta-analyses could provide precious information on these aspects, should their use not be precluded by the heterogeneity in existing studies or the lack of reporting of effect sizes (Melsen et al., 2014).
An important element should be the determination of minimum and optimal thresholds for the adoption of EIC and CRM modalities in humans (e.g., Rendeiro et al., 2015;Yu Q. et al., 2020;Kelly et al., 2020), if this is possible, or to find reliable and reproducible means for targeting the ideal quantities to individual needs, which is a hallmark of precision medicine (Wang et al., 2023). Importantly, the needs of members of specific groups should be considered.
In the future, research should clarify whether EIC and CRM can play an important role in targeted metabolic reprogramming, which is already successfully used in the treatment of cancer, and might be beneficial with regards to NSPAN (El-Sahli & Wang, 2020;Mela et al., 2020;Wang Q. et al., 2022;Pateras et al., 2023). This also entails, ideally, setting objectives in realistic expected improvements prior to running such research programs.
Studies relying upon mass-spectrometry and nuclear magnetic resonance have the potential to further highlight the value of EIC and CRMs in terms of NSPAN and might help in identifying additional signaling metabolites and other effectors affected by EIC and CRMs which could be investigated in further detail in a second step, but massspectrometry and nuclear magnetic resonance are uncommonly used for related research questions (Kristal et al., 2007;Luan et al., 2019;Kelly et al., 2020;Baker & Rutter, 2023).
Timing is important in signal transduction, as also within the cell processes unfold through time, with uninterrupted successions of events (Koseska & Bastiaens, 2017). An overwhelming majority of studies examine the effect of EIC and CRMs at a single timepoint, blurring the complexity of the orchestration of events. Live cell imaging has potential in further determining distinctions in signaling dynamics in the cross-talk between different pathways (Valls & Esposito, 2022) in starved cells and those with high availability of nutrients.

Conclusion
This review and annotated bibliography has synthesized recent efforts at understanding the mechanisms of through which EIC and CRMs afford enhanced NSPAN. The mentioned benefits of the different approaches in terms of the enhancement of NSPAN, as well as explanations of the pathways and mechanisms through which this goal can be achieved, have highlighted the potential of EIC and CRMs for a healthier aging.

Author contributions
EM is the sole contributor to all the aspects involved in this work. Table 1 was prepared with the help of GPT-3.5 and thoroughly checked. In addition, GPT-3.5 and GPT-4 have been used to support ideation in the revised version of the manuscript (discussion). Except for some elements of Table 1, no content written by generative pretrained transformers was included in this article.

Conflict of interest
The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note
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SUPPLEMENTARY TABLE S1
The annotated bibliography is presented in the document ' Table 1.docx'.