Beneficial effects of dietary restriction in aging brain

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Review

Beneficial effects of dietary restriction in aging brain Ibanylla Kynjai Hynniewta Hadem, Teikur Majaw, Babiangshisha Kharbuli, Ramesh Sharma

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Department of Biochemistry, North-Eastern Hill University, Shillong 793022, Meghalaya, India

A R T I C L E I N F O

A B S T R A C T

Keywords: Aging Dietary restriction Cognition Neurodegeneration Neuroinflammation Insulin/IGF-1 mTOR AMPK Sirtuins

Aging is a multifactorial complex process that leads to the deterioration of biological functions wherein its underlying mechanism is not fully elucidated. It affects the organism at the molecular and cellular level that contributes to the deterioration of structural integrity of the organs. The central nervous system is the most vulnerable organ affected by aging and its effect is highly heterogeneous. Aging causes alteration in the structure, metabolism and physiology of the brain leading to impaired cognitive and motor-neural functions. Dietary restriction (DR), a robust mechanism that extends lifespan in various organisms, ameliorates brain aging by reducing oxidative stress, improving mitochondrial function, activating anti-inflammatory responses, promoting neurogenesis and increasing synaptic plasticity. It also protects and prevents age-related structural changes. DR alleviates many age-associated diseases including neurodegeneration and improves cognitive functions. DR inhibits/activates nutrient signaling cascades such as insulin/IGF-1, mTOR, AMPK and sirtuins. Because of its sensitivity to energy status and hormones, AMPK is considered as the global nutrient sensor. This review will present an elucidative potential role of dietary restriction in the prevention of phenotypic features during aging in brain and its diverse mechanisms.

1. Introduction Aging, a naturally occurring process, is an inevitable time-dependent decline in systemic functions. It is characterized by random changes in the structure and functions at various molecular and cellular levels that increase the vulnerability to diseases and probability of death. Natural phenomenon such as greying of hair, wrinkling of skin, dementia, reduction in muscle tone and motor coordination are some of the observable features of aging. The cause of aging is multifactorial and its underlying mechanism is not well elucidated. Unraveling how these factors interplay in governing lifespan can help us to better decode the mechanism of aging. Cumulative evidence has suggested that these varied factors act in synergy to direct the aging process of an organism, mostly controlled in combination by genetic and epigenetic factors. (Sharma and Dkhar, 2014). Understanding the aging process will pave the way to novel approaches to a healthier life, even in old age. Thus, over the years researchers have proposed a number of theories of aging (Jin, 2010). The various theories have been proposed in an attempt to explain the mechanism of aging, but till date none of them appears to stand alone. Some of them such as the classical theory of programmed death by Weismann in 1891, which stated that aging evolved as an advantage for the species has become obsolete (McDonald, 2014). Later on, Weismann postulated that aging resulted as organisms allocated more energy for reproduction rather than

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maintaining the soma, which was then modified by Kirkwood (1977) to the disposable soma hypothesis, in which it was hypothesised that a balance must be maintained between maintenance of the soma and reproduction. We can see that the antagonistic pleiotropy theory (a factor that is important early in life may be detrimental later in life) of aging by Williams (1957) derived its basis from the mutation accumulation theory of aging by Medawar in 1952. Hence, the theories put forward by Weissman, Kirkwood, Medawar and Williams are considered to be the classical evolutionary theories of how aging evolved. It can also be pointed out that the codon restriction theory (Strehler et al., 1971), error catastrophe theory (Medvediev, 1962; Orgel, 1963), the oxidative stress or free radical theory by Harman (1956) and the mitochondrial theory of aging (Miquel et al., 1980) revolve around the notion that is implied as in the mutation accumulation theory of aging (Medawar, 1952). These theories presume that aging occurs as a result of time-dependent accumulation of damaged biomolecules in the body. The cross-linking theory (Bjorksten, 1968; Bjorksten and Tenhu, 1990) also suggests that aging occurs due to the accumulation of cross-linked proteins with molecules like glucose (glycation) leading to the formation of aberrant non- functional proteins. Lately, the free radical theory of aging is facing some debate (Gladyshev, 2014), and the hyperfunction theory of aging (Blagosklonny, 2008) totally contempt it. Yet again, the neuroendrocrine theory (Dilman and Dean, 1992), the cellular senescence theory of

Corresponding author. E-mail address: [email protected] (R. Sharma).

http://dx.doi.org/10.1016/j.jchemneu.2017.10.001 Received 19 May 2017; Received in revised form 14 September 2017; Accepted 10 October 2017 0891-0618/ © 2017 Elsevier B.V. All rights reserved.

Please cite this article as: Hadem, I.K.H., Journal of Chemical Neuroanatomy (2017), http://dx.doi.org/10.1016/j.jchemneu.2017.10.001

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grey matter is due to neuronal cell death. However, the reduction in synaptic spines and the declined synapse transmission most likely are responsible for the reduction in grey matter (Fjell and Walhovd, 2010). The alterations of dendritic spine density, arbour and synapse are the physical changes associated with aging (Peinado et al., 1997). These dendritic spines play a role in the formation and retention of memory. They are important for specific neural connections and their turnover are crucial for synaptic plasticity (Yuste, 2010, Frankfurt and Luine, 2015). The basis for memory and learning results from the physiological plasticity that includes long-term potentiation (LTP) and longterm depression (LTD) (Frankfurt and Luine, 2015). In hippocampus, it has been shown that the increase in dendritic spine density is associated with increased LTP and its decrease is related to LTD (Matsuzaki et al., 2004; Bosch and Hayashi, 2012). In rat dentate gyrus, increased LTP causes the formation of new dendritic spines (Yuste, 2010). Studies have suggested that memory may induce both LTP and dendritic spines. Hence, the role of LTP, dendritic spines and memory may have a strong interaction in the hippocampus (Frankfurt and Luine, 2015). As spines are important in learning and memory, their loss play key roles in impaired brain plasticity (Dicksteina et al., 2013). The plasticity of the neural system is believed to have an impact on cognitive functions. As observed from Alzheimer’s disease (AD) animal model and post-mortem brain, impaired synaptic plasticity plays a part in memory loss associated with AD. In the hippocampus, evidence suggests a link between impaired synaptic plasticity and the interference of amyloid plaques in neurotransmission, but the loss of dendritic spines in both the hippocampus and the cortex region is associated with the diminished cognitive function in AD (Koleske, 2013; Lazcano et al., 2014). Both the structural and functional variation of the aged brain is responsible for many age-associated neurological disorders. The changes in vasculature result in an increase of blood pressure and can cause ischemia and stroke (Peters, 2006). The aging brain is associated with the decline in learning ability and loss of memory. The cause of these declined cognitive functions is attributed to the alteration in the anatomical and functional properties of the brain during aging. The medial temporal lobe and prefrontal lobe, which are regions in the brain responsible for tasks such as learning, memory and executive function, particularly, showed an age-dependent decline (Burke and Barnes, 2006). There are different aspects in the regulation of brain aging; these can be at the genetic level, synaptic transmission and behavioural interactions (Peters, 2006; Gkikas et al., 2014). Cognition is affected by changes in various biochemical conditions of the brain. These changes include alteration in the level of hormones and neurotransmitters and their interactions with cognate receptors. Neurotransmitters such as dopamine and serotonin have been shown to decline with age. The level of dopamine reduces by 10% from the onset of adulthood and it has been linked to the decline in both motor and cognitive functions (Mukherjee et al., 2002; Nyberg and Bäckman, 2004). Besides the decline in the level of dopamine, the effect of dopamine on brain function may be due to impaired dopaminergic pathway, from the frontal cortex to the striatum, with increasing age, reduced receptors and/or low binding efficiency to the receptors (Nyberg and Bäckman, 2004). Serotonin level reduces with advancing age and it is implicated to play a role in many physiological processes such as circadian rhythm, sleeping, eating and cognition. The dysregulation of this neurotransmitter has also been associated with AD (Mattson et al., 2004). One of the neurotransmitters closely associated with the etiology of AD is acetylcholine. The loss of cholinergic neurons or the reduced level of acetylcholine has been correlated with the cognitive decline in dementia. Hence, this decline in cognition can be ameliorated by supplementing acetylcholine agonist or modulating the enzymatic action of acetylcholine esterase, an enzyme that breaks down acetylcholine (Drachman, 2006; Suchiang and Sharma, 2011). Memory and its decline with age have also been shown to be affected by hormonal imbalance. Hormones implicated in impaired brain functions are

aging (Hayflick and Moorhead, 1961) and the immunological theory consider aging to be a pre-programmed process. Modern theories like the theory of inflammaging (Franceschi et al., 2000) or chronic lowgrade inflammation in aging is subtly linked to the immunological theory (Walford, 1964), the oxidative stress theory and the epigenetic theory of aging. Moreover, some older theories like the dysdifferentiation theory (Cutler, 1991) have been modified to the epigenetic theory, a modern theory that is gaining much attention. This theory is supported by a study which compares monozygotic twins of old (50 years) and young (3 years) ages. The findings of the study showed that the patterns of DNA methylation and histone acetylation in the circulating lymphocytes between the older pairs as compared to the younger pairs varies (Fraga et al., 2005). These findings draw the idea that an identical genome went through different epigenetic modifications throughout life, possibly resulting in differences in the rate of aging and/or in their susceptibility to illnesses. The basic concept behind these theories is that there would be a gradual deterioration of the biological systems over time ultimately draining the overall health of an organism causing death finally. 2. The aging brain One of the harmful effects of aging is the deterioration in brain function. The greatest risk for the decline in cognitive functions and enhanced neurodegeneration is age of an organism. As the organism ages, several changes develop in the brain such as alteration in morphology, anatomy, vasculature and cognition (Peters, 2006). The changes in the aging brain are highly heterogeneous (Trollor and Valenzuela, 2001). Although Peters (2006) reviewed that the greater changes are observed in the prefrontal cortex, followed by the striatum, other studies suggest that aging affects the hippocampus the most (Anderton, 2002; Barnes, 2003). The other regions altered with age are the temporal cortex, thalamus, accumbens, and putamen. The least affected region is the occipital cortex (Raz, 2004; Fjell and Walhovd, 2010). A five-year longitudinal study by Raz et al. (2005) showed that there is differential shrinkage in various regions of the brain with the caudate, hippocampus, cerebellum and the cortices showing considerable shrinkage. After the age of 40, there is a 5% decline per decade in the brain volume, which increases further after the age of 70 years (Svennerholm et al., 1997; Scahill et al., 2003). However, findings by Elobeid et al. (2016) indicated that the brain of nonagenarians and above weighs 11% less than those from people in their fifties. White matter lesions are structural changes that affect the brain function. White matter region consists of myelinated axons that are important for neural connections between different areas of the brain. Therefore, its integrity is important in proper cognitive functions (Charlton et al., 2006). Even though previous studies reported that white matter volume does not alter with age, evidence indicated that white matter volume decreases with age. This change was detectable after 70 years of age. (Courchesne et al., 2000). Furthermore, even though the onset of white matter decrease is later in life, its loss is more rapid than grey matter. The prefrontal white matter is most vulnerable to age-related changes. (Bahcelioglu et al., 2001; Jernigan and Gamst, 2005; Fjell and Walhovd, 2010). While it may be noted that the agerelated white matter deterioration occurs roughly in an anterior to posterior gradient (Head et al., 2004; Pfefferbaum et al., 2005), with the cingulum showing the earliest degeneration (Yoon et al., 2008). On the contrary, myelination maturation of the fetal brain begins from the posterior end i.e., the cortico-spinal tracts, followed by the optic radiations and the corpus callosum (Zanin et al., 2011). The changes in the white matter with age may play a part in the decline of episodic memory, executive function and the speed of processing information. There is a widespread reduction in grey matter volume with age, which starts at an early age (Courchesne et al., 2000; Terribilli et al., 2011) and it has been suggested that the reason for the shrinkage of the brain 2

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feeding. This type of DR has been shown to gradually decrease the food intake by 20–30% in mice (Qiu et al., 2010). Another form of DR is the restriction of diet either at a defined percentage of the overall diet received by ad libitum fed animals or a restriction in a particular macro/ micro nutrient. However, it should be noted that DR above 60% may be detrimental to the both the lifespan and overall health of the organism (Speakman and Mitchell, 2011). Predominantly, DR extends the lifespan of many organisms such as worms, flies, rodents and non-human primates but certain studies reported that this is not universal. It has been suggested that the effect of DR is more pronounced in rats than in mice and in particular mouse strains, DR has a negative impact on lifespan (Wahl et al., 2016). A recent study in rhesus monkey by Mattison et al. (2012) at NIA indicates that DR has no effect on lifespan extension but the animals exhibit a more healthy life. On the contrary, another study by Colman et al. (2009) indicates an increase in both healthspan and lifespan of the primate when dietary restricted. These differences may be attributed to the difference in diet composition and DR protocols. However, the major observable beneficial effect of DR in these models is its ability to extend the healthspan of the organism. Lately, the data from these two parallel studies concluded that DR not only imparts health benefits but the survivability of the experimental animals increases with DR (Mattison et al., 2017). DR has also been shown to improve the healthspan of model organisms by ameliorating many age-associated diseases (Fusco and Pani, 2013). Since DR modulates the healthspan of the organism, it has been proposed to be involved in regulating brain health. Indeed, studies demonstrated that DR could also modulate and improve brain functions (Fig. 1).

reduced levels of estrogen, progesterone, thyroxine and melatonin and increased levels of stress hormones such as cortisol and cortisone (Veiga et al., 2004; Lupien et al., 2009). Growth factors were also shown to affect cognition. One such factor is the insulin-like growth factor-1 (IGF-1) which plays important roles in brain development and normal cognition. IGF-1 controls development by promoting neuronal survival (Suh et al., 2013). Further studies indicate that the reduction in IGF-1 and its signaling pathway promotes lifespan extension (Wrigley et al., 2017). Overexpression or underexpression studies of IGF-1 in various model organisms suggest that the expression of this hormone is necessary for the proper development of the brain. Knockout transgenic studies indicate that the development of the brain is compromised when its level is reduced. The high level in the developing brain is responsible for neuronal maturation, survival, adult neurogenesis and is neuroprotective. Hence, diminishing levels of IGF-1 would contribute to brain aging (Wrigley et al., 2017). However, other reports suggest that reduced IGF-1 signaling increases the lifespan of the organism and modulate the effects of aging in the brain. An AD mouse model with reduced IGF-1 signaling showed decreased neuronal loss and better behavioural state, which may be attributed to tighter Aβ plaque aggregation resulting in lowered proteotoxicity as compared to models with normal IGF-1 signaling (Cohen et al., 2009). Extensive studies have demonstrated the role of gender differences and cognition. Men are better in spatial and motor tasks while women perform better in memory and verbal skills (Gur and Gur, 2002). Sex hormones are known to play an important role in CNS development and function, as well as regulating the differential susceptibility of the gender difference towards aging of the brain. For instance, women are more protected from age-related decline in cognition when compared to men and data from young adults displayed that men are more susceptible to decline in neurocognitive domains (Meinz and Salthouse, 1998; Gur and Gur, 2002). While in men, aging mainly affects the temporal and frontal lobes; in women, hippocampus and the parietal lobe are the region that gets affected (Murphy et al., 1996; Compton et al., 2001). In women, menopause (reduction in the circulating level of estrogens with age) is well associated with dementia and reduced brain function and has been linked with increased incidence of AD (Tan and Pu, 2001; Bates et al., 2005). As in female, a condition called andropause is observed in male wherein the level of androgen declines with age. In elderly men, the level of serum testosterone was found to be linked with cognitive performance, as men with higher level of testosterone are likely to perform better on cognitive test in contrast to those with low level of testosterone (Yaffe et al., 2002). Andropause is linked with loss of muscle and bone mass, lethargy, sexual dysfunction and cognitive impairment (Tan and Pu, 2001). Aging of the brain is also associated with physiological changes, which include disruption of Ca2+ homeostasis and elevated reactive oxygen species (ROS) levels. The disturbance in Ca2+ homeostasis in aged neurons leads to aberrant polarization potential that can cause cognitive deficits. Evidence indicates that ROS levels increases with age and is one of the markers of neurodegeneration (Anderton, 2002; Chakrabarti et al., 2007; Dkhar and Sharma, 2014).

3.1. Cognitive functions It is observed that certain individuals experience successful cognitive function with the advancement of age; that is, there is less development of cognitive impairment. While others show a deteriorating decline in these parameters with age. Cognition includes memory, attention, language, reasoning, processing speed and problem-solving. Generally, the most affected cognition during aging is memory (Deary et al., 2009). There are four parts of memory; episodic memory, semantic memory, procedural memory and working memory (Parkin, 1997). All these memory types decline as a function of age (Glisky, 2007). The steps in memory formation include acquisition- the stage where the information is obtained, consolidation- the stage where the acquired information is stored and retrieval- where the stored memory

3. Dietary restriction in ameliorating brain functions decline One of the factors that contributes to brain aging is the dysregulation of metabolism. In healthy non-diabetic old individuals, high blood glucose has been associated with lower cognitive function and alteration of the microstructure of hippocampus, signifying that excess of nutrients may be responsible for the decline in brain function (Kerti et al., 2013). Dietary restriction (DR) is a well-known reliable mechanism shown to slow down the onset of age-associated pathologies and increase the lifespan of many organisms (Speakman and Mitchell, 2011). DR may be defined as the reduction in food intake without causing any malnutrition. There are different forms of DR protocol, which include intermittent fasting that is, alternate day fasting and re-

Fig. 1. Effect of dietary restriction (DR) on brain function by modulating various cellular and molecular phenotypes. DR enhances cognitive function, modulates nutrient sensing pathways, alter redox status, decreases neuroinflammation and prevents neurodegeneration.

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resulted in the preservation of the grey matter volume in both the hippocampus and the subcortical regions in rhesus macaques (Colman et al., 2009; Willette et al., 2013). Late onset DR in rats also protects the age-related changes in the dendritic spines density. The spine densities of the dietary restricted rats (24–30-month-old) were comparable to those of 6-month-old animals indicating that DR has a protective effect on age-related loss of dendritic spines (Moroi-Fetters et al., 1989). DR of 40% in aging mice preserves white matter integrity, energy production and long-term memory (Guo et al., 2015). It also attenuates age-related synaptic changes studied in skeletal neuromuscular junction of aged (24-month-old) mice (Valdez et al., 2010). Additionally, DR in mice has a protective effect on cerebral blood flow and blood-brain barrier, which enhances neurovascular function and cognition (Parikh et al., 2016) and also contributes against neurodegenerative diseases like AD (Schafer et al., 2015a). Dietary restriction influences the memory and learning ability in human beings as well. In older humans, DR has been shown to control dementia (Wahl et al., 2016). There are reports that DR improves memory in healthy (normal to overweight) elderly (average 60.5 years) humans that were subjected to a decrease in 30% calorie intake (Witte et al., 2009). A study performed in healthy subjects demonstrated that a 20–30% dietary restriction for 6 months has positive effect on physical activities and improvement of mood disorders such as depression. Nonetheless, the effect on cognitive performance is still unclear which may be caused by the variations in dietary protocols, the constitution of experimental groups and the assessment of cognitive performance (Redman and Ravussin, 2011). Although the exact mechanism of DR is not fully elucidated, evidence suggests that DR ameliorates brain aging by reducing oxidative stress, improving mitochondrial function, activating anti-inflammatory response, promoting neurogenesis and synaptic plasticity (FontánLozano et al., 2008; Gillette-Guyonnet and Vellas, 2008; Fusco and Pani, 2013; Lin et al., 2014). Diet can influence the microbiome of an organism and alteration of the gut microbiome can in turn control the health of an organism. The changes in the microbiota can affect central nervous system (CNS) and brain function. This is because there is a bidirectional communication between the gut and the brain, which is regulated by the gut microbiota thus creating a “microbiota-gut-brain axis” (Rhee et al., 2009; Leung and Thuret, 2015). Although the gutbrain axis is suggested to be responsible for the alteration in the brain plasticity and cognitive aging, the exact mechanism on how the microbiome changes the brain function is unknown. Evidence indicates that certain metabolites produced by the gut microbes, such as propionate and butyrate, can cross the blood brain barrier and regulate cellular processes like cell signaling and neurotransmitter synthesis and release, which in turn affect the function of CNS (Borgo et al., 2017). However, it has been suggested that the gut microbiome may regulate cognitive function through immune, neuroendocrine and metabolic pathways (Mayer et al., 2014). Recent studies show that the gut microbiome can also influence different food choices of the animal. The initial study in Drosophila showed that the different types of bacteria, like Acetobacter pomorum and Lactobacilli, present in the gut might be able to induce some metabolic activities that can directly act on the brain and alter the appetite preference of the fly for different food content. Flies fed with a diet lacking essential amino acids tend to choose foods that are rich in protein whereas flies with a normal diet explore the different food choices available (Corrales-Carvajal et al., 2016; Leitão-Gonçalves et al., 2017). In addition, a study by PintoSanchez et al. (2017) reported that patients with irritable bowel syndrome and mild anxiety/depression, when given a probiotic containing Bifidobacterium longum showed a reduction in depression but not anxiety scores with increased quality of life than the patients given the placebo. It may be suggested from these studies that the alteration in the gut microbiota plays a role on altering brain activity. Various types of dietary restriction regimens such as restriction of calorie intake, protein restriction and intermittent fasting have been shown to affect the plasticity and function of the brain (Witte et al., 2009; Singh et al.,

that are encoded into the brain can be recollected (Abel and Lattal, 2001). Memory deficits accompanied during aging is usually due to the aberration in consolidation and retrieval process. This type of age-related memory loss may be attributed to the alteration in multiple factors such as neurotransmitters, hormones, neurotrophic factors, mitochondrial dysfunction, ROS generation, and accumulation of macromolecular damages (Yankner et al., 2008). Decreased cognitive and motor performances are also associated with alterations of the volumetric and microstructural brain integrity. DR in aged rhesus macaques exhibits an improvement in the executive function and motor task, which are correlated with the changes of the brain structure. The brain-behaviour correlation indicates a potential protective effect of DR on these animals (Sridharan et al., 2012). As discussed earlier, the structural, biochemical and physiological changes observed during aging can contribute to cognitive decline. These changes may be attributed to the various lifestyle choices such as eating habits and exercise, which affect genes regulating brain plasticity. While overeating or excess of nutrient intake can adversely affect the cognitive function of the organism, long-term reduction in food intake can improve cognition, prevents senescence and neurodegeneration in rodents (Fontán-Lozano et al., 2007; Adams et al., 2008; Fusco and Pani, 2013). High-fat diet or “fast food diet” has been shown to adversely affect the learning and memory in middle-age rodents. The analyses of the brain exhibit the increase in markers of oxidative stress and inflammation caused by the high caloric diet (Granholm et al., 2008). Martin et al. (2006) indicated that the neurons in the rodent brain are more resistant to various types of stress when the animal is subjected to either alternate day fasting (intermittent fasting, IF) or continuous restriction in dietary energy intake. Moreover, Johnson et al. (2007) reported that alternate day fasting in overweight adults with moderate asthma results in the reduction of oxidative stress and pro-inflammatory markers. Hence, it may be suggested that the underlying mechanism for these impairments may be the increased oxidative stress and inflammation. DR also reduces the markers of inflammation in young to middle age mice as compared to ad libitum controls (Arumugam et al., 2010). High-fat diet can impair cognition by regulating neurogenesis and synaptic plasticity. This may be due to the dysregulation of neurotrophic factors (Lipsky and Marini, 2007). Neurogenesis is the process of generating new cells from neural precursor cells (NPC), which are considered to be significant for learning, memory consolidation and tissue repair after injury (Snyder et al., 2001; Dash et al., 2001). Brainderived neurotrophic factor (BDNF), one of the neurotrophic factors, is crucial for neurogenesis and synaptic plasticity and it is regulated by dietary restriction. In rats, the level of BDNF decreases with age and is associated with cognitive deficits (Navarro-Martinez et al., 2015). Additionally, BDNF and its high-affinity receptor, tropomyosin-related kinase B (trkB) are decreased in frontal cortex and hippocampus of AD patients (Ferrer et al., 1999). BDNF in the hippocampus is necessary for proper cognitive function. It activates a signaling pathway that leads to an induction of the expression of genes that enhance synaptic plasticity and cell survival (Bramham and Messaoudi, 2005). Low calorie diet (as low as 15%) initiated at adolescence in female rats is beneficial for adult cognition by increasing neurogenesis as well as BDNF level in the hippocampus and pre-frontal cortex region (Zaptan et al., 2015). Depletion of neurotrophic factors contributes to the increased cognitive impairment observed during physiological and pathological aging process (Balietti et al., 2012). BDNF is also responsible for regulating NPCs levels and animals on DR showed higher expression of BDNF which might contribute to increased neurogenesis and attenuation of age-related reduction in NPCs (Maswood et al., 2004; Vasconcelos et al., 2014). DR protects the age-related structural changes as well. The hippocampus and prefrontal cortex are important regions for memory and the deterioration in these two regions with age contributes to cognitive deficits (West, 1996). A 30% reduction in calories initiated at adulthood 4

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influences feeding behaviour and formation of memory in the hippocampus (Garelick and Kennedy, 2011). Besides, mTOR regulates autophagy, an important clearance system of aggregate-prone proteins in an organism. Defects in autophagy have been linked to accumulation of these proteins and are the cause of many neurodegenerative disorders. In mice hippocampus, the decreased autophagy leads to neuronal loss and exacerbates age-related cognitive impairment. However, the inhibition of mTOR, a negative regulator of autophagy, by dietary restriction activates autophagy, which in turn protects the hippocampal neurons from damage and thereby ameliorating the age-associated cognitive decline (Yang et al., 2014; Dong et al., 2016). Another nutrient sensor that plays a role in brain function is sirtuin, NAD+ dependent deacetylase. Sirt1, the closest homolog of the yeast Sir2 has been shown to be involved in many physiological processes in response to metabolism and is one of the mediators that underlie the beneficial effect of dietary restriction (Fusco et al., 2012; Duan, 2013). The overall upregulated expression of Sirt1 in the organism does not necessarily increase lifespan but it has beneficial effect on the healthspan of the organism (Herranz et al., 2010). In the brain, Sirt1 is expressed in varied regions such as the hippocampus, cortex, hypothalamus and cerebellum. It is primarily expressed in the neurons (Ramadori et al., 2008). Recent studies have indicated that Sirt1 is extensively expressed in the hypothalamus of mice under varied dietary restriction regimen, and influences food intake, physical activities and body temperature (Satoh et al., 2010). Besides the behavioural regulation, Sirt1 is also involved in neuroprotection. Sirt1 may enhance health benefits by either slowing down cell death or by promoting cell repair (Wang et al., 2010). Apart from histones, Sirt1 has many other substrates. DR upregulates Sirt1, which in turn activates PGC1α (peroxisome proliferator-activated receptor gamma coactivator 1α) and enhance mitochondrial biogenesis (Nemoto et al., 2005; Rasouri et al., 2007). Sirt1 can interact with NF-κB by deacetylating p65 and retards its transactivation potential (Salminen et al., 2008). It is a potent regulator of autophagy by deacetylating many autophagy-related protein (Atg). Sirt1 can interact with AMPK to regulate metabolic energy homeostasis. AMPK activates Sirt1 by increasing the level of NAD+ while Sirt1 can regulate AMPK via its upstream regulator liver kinase B (LKB1) (Lan et al., 2008; Canto and Auwerx, 2009). IGF-1, a growth factor, is an important nutrient sensor that is responsible for many cellular processes. As discussed earlier, IGF-1 plays an important role during early brain development, neurogenesis and successful cognitive performance. We have recently reported that dietary restriction in old age reduces the signaling pathway of IGF-1 in hippocampus and we suggest that this reduction may lead to enhanced expression of FoxO3 transcription factors, which contribute to oxidative stress resistance and hence protects from neurodegenerative diseases (Hadem and Sharma, 2017). Coherent with our study, Qin et al. (2008) demonstrated that the suppression of amyloid pathology in AD is mediated through FoxO3. In addition, the reduction in insulin signaling, through dietary restriction, in NPCs leads to FoxO3 activation, which in turn help in preservation of the number and functional capacity of neural stem cells and hence delay brain aging (Rafalski and Brunet, 2011). Although, reduced insulin/IGF-1 signaling is associated with delayed brain aging, interestingly; insulin resistance, a condition characterized by reduced tissue responsiveness to insulin action, is associated with higher risks of AD. Insulin resistance is associated with an increase in brain amyloid deposition in middle-aged adults (Willette et al., 2015). This could be due to the defects in insulin/IGF-1 pathways that lead to the increased expression of amyloid β precursor protein, which in turn cause an accumulation of amyloid β (de la Monte, 2012). Recent studies in mice demonstrated that the reduction of insulin signaling by the action of dietary restriction shifts the energy metabolism in the brain from glucose to ketone bodies metabolism. It additionally alleviates insulin resistance and through the inhibition of mTOR pathway, it enhances the clearance of mis-folded protein including beta amyloid (Aβ) (Guo et al., 2015). Hence, dietary restriction retards the

2012). Zhang et al. (2013) observed that there is a structural modulation in the gut microbiota of mice subjected to both high-fat or low-fat dietary restriction. They reported that long-term dietary restriction alters the composition of gut microbiota, as observed by the enrichment of phylotypes that positively regulate lifespan, such as Lactobacillus, and the reduction of phylotypes that have a negative impact on lifespan. Based on the role that dietary restriction can alter the gut microbiota and the role of microbiome on brain function, it is plausible that dietary restriction may influence cognition by affecting the microbiome of the gut. 3.1.1. Nutrient sensing A theory was proposed on how DR increases brain health. Accordingly, during nutrient limitation, an organism is challenged to use its intelligence in search of food. This induces mild stress on the neurons leading to activation of signaling cascades that subsequently improve brain functions (Mattson, 2015). The molecular network underlying the positive response of brain function to dietary restriction is through the cascade of nutrient-sensing molecules and pathways. The major nutrient-sensing pathways are mTOR, AMPK, sirtuins and insulin/IGF-1, which sense the availability of macronutrients (glucose, amino acids and lipids) or the energy status of the cell (AMP/ATP or NAD+/NADH ratio). These pathways regulate several cellular processes such as autophagy, metabolism, oxidative stress and gene expression (Koubova and Guarente, 2003). During DR, these different nutrient sensors detect the changes in the level of nutrients and the metabolic status of the cells eventually regulating various cellular processes that result in improved neuronal plasticity and better cognition (Fusco and Pani, 2013). The brain is also sensitive to the changes in the nutrient level, which in turn regulate feeding and neuroendocrine response. Specialized neurons are present in the brain, particularly the arcuate nucleus in the hypothalamus that detects changes in the levels of glucose and lipids (Banks, 2006). The changes in the glucose level can alter electrical potential of the hypothalamic neurons leading to the activation/inhibition of these neurons resulting in the conversion of electrical signals to chemical signals that consequently regulate feeding activities (Burdakov et al., 2005). The neurons in the arcuate nucleus are divided into two types: one type expresses the peptide Agouti/neuropeptide Y (AgRP/NPY), which are activated by low glucose levels and have orexigenic action. The other type of neurons expresses proopiomelanocortin (POMC), which is stimulated by high glucose concentrations and is anorexigenic (Fan et al., 1997; Gropp et al., 2005; Lee et al., 2006). Hormones (for example leptin) also regulate the AgRP/NPY and POMC neurons in response to nutrients (Minokoshi et al., 2004; Belgardt et al., 2009). The changes in the level of glucose and lipids, sensed by hypothalamic neurons, are integrated into the central nervous system as evident by the increase in the intracellular level of malonyl-CoA, an inhibitor of beta fatty acid oxidation, during hyperglycemia. When the level of blood glucose is low, such as during DR, synthesis of malonyl-CoA is inhibited (Wolfgang et al., 2007). This is mediated by the action of AMP-activated protein kinase (AMPK), an evolutionarily conserved serine/threonine kinase, whereby its activation by high AMP/ATP status leads to the inhibition of Acetyl-CoA carboxylase, an enzyme involved in the biosynthesis of malonyl-CoA (Xue and Kahn, 2006). Additionally, AMPK is a mediator of the hormonal action of leptin (Minokoshi et al., 2004). Because of the sensitivity of AMPK to energy status and hormonal action, this protein is considered as a global nutrient sensor and main regulator of feeding behaviour (Fusco and Pani, 2013). AMPK is also linked to another nutrient sensor mTOR where it negatively regulates its action. The restriction of food intake inhibits mTOR (mammalian target of rapamycin) signaling in the brain, and is beneficial for the improvement of cognition. When the level of nutrient is limited, AMPK is activated which in turn inhibits mTOR. Studies indicate that mTOR also 5

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and inflammation (Patel et al., 2005). In one study of the neurodegenerative disease, Machado-Joseph disease (MJD), evidence strongly suggests that DR not only mitigates the associated neuropathology, but also improves motor functions in two mouse models afflicted with MJDTg and lentiviral MJD models (Cunha-Santos et al., 2016). MJD is also called spinocerebellar ataxia Type 3 (SCA3), and is a rare autosomal dominantly inherited form of ataxia. This disease is caused by a genetic mutation that results in an abnormal expansion of “CAG” trinucleotide repeats in the ATXN3 gene, translating into a polyglutamine (polyQ) tract resulting in an abnormal form of the protein ataxin thus causing degeneration of cells in the cerebellum. The mechanism by which DR alleviates this disorder is mediated by the upregulation of SIRT1 expression, subsequently resulting in inhibition of neuroinflammation and autophagy activation (Cunha-Santos et al., 2016). DR even seems to be prophylactic and advantageous by supressing microglial cells activation, and downstream inflammatory mediators protecting neurons from secondary injury (Loncarevic-Vasiljkovic et al., 2012).

progression of AD and is beneficial for healthy brain aging. 3.1.2. Inflammation Inflammation is the body’s defense system against harmful stimuli however; with old age, chronic inflammation can be deleterious. With the advancement of age, the immune system undergoes senescence and becomes dysregulated (Deleidi et al., 2015). This result in the generation of low-grade chronic inflammatory responses called inflammaging, which is a significant risk factor for many age-associated disorders (Franceschi et al., 2007). Inflammaging is characterized by the generation of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), intelukin-6 (IL-6) and reactive oxygen species (ROS). The dysregulation between innate and adaptive immunity, as well as cellular senescence contributes to inflammaging (Franceschi et al., 2000, 2007). Senescent cells secrete proinflammatory agents like cytokines, chemokines, growth factors and proteases, which are collectively called as senescent-associated secretory phenotype (SASP) (Chinta et al., 2014). SASP induces chronic inflammatory environment, the primary source for the progression of age-associated diseases (Ovadya and Krizhanovsky, 2014). In the central nervous system, microglia constitutes the innate immune system, which also undergoes senescence and may contribute to neurological disorders associated with aging (Wong, 2013). In aged brain of human, senescent microglial cells have been reported (Streit et al., 2004). Microglial cells have important roles in brain development and support neural connections. When immunologically challenged, they release various aforementioned molecules that have beneficial functions in removal of pathogens and cellular debris. However, in aging brain, these characteristics play a role in the dysfunction and death of neurons (Flanary et al., 2007; Kettenmann et al., 2011; Hefendehl et al., 2014). Among various inflammatory molecules, NF-κB plays a major role in brain aging. Its expression is increased in many regions of the aging brain particularly in the hypothalamus and it has been implicated in regulation of various gene expressions during aging including secretion of pro-inflammatory cytokines (Gabuzda and Yankner, 2013). NF-κB is found abundantly in neurons and glial cells (Bakalkin et al., 1993; Kaltschmidt et al., 2005) where it regulates neuron survival, CNS development, learning and memory, and neuronal plasticity (Bakalkin et al., 1993; Kaltschmidt et al., 1999, 2005; Koulich et al., 2001; Bhakar et al., 2002). Persistent activation of microglia has been associated with neuroinflammation and brain aging (Yin et al., 2016). The neuroprotective effects of DR are linked with production of neurotrophic factors and cytoprotective protein chaperones in neurons. Schafer et al. (2015b) stated that DR is powerful in suppressing agedependent transcriptional changes by upregulating gene expression of neuroprotective factors. They demonstrated within the hippocampal CA1 region, long-term DR can achieve a global attenuation in brain aging. From their studies, it has been shown that long-term DR feeding suppresses age-dependent signatures of 882 genes functionally associated with synaptic transmission-related pathways, such as calcium signaling, long-term potentiation (LTP), and CREB signaling in wildtype mice. They also identified conserved upregulation of proteome quality control and calcium buffering genes, like heat shock 70 kDa protein 1b and 5 (Hspa1b and Hspa5). DR also increases expression levels of neuroprotective factors like klotho (Kl) and transthyretin (Ttr) in adulthood. Furthermore, DR mitigates the age-related activation of astrocytes and microglia, which are responsible for neuroinflammation, thereby decreasing the odds of neurodegeneration and cognition impairments (Morgan et al., 2007). Findings by Patel et al. (2005) showed that in two transgenic mouse models of AD that displayed an early onset of Aβ-plaques, short-term DR in early adulthood attenuated these depositions. DR was also found to selectively modify activation of glial cells. Glial fibrillary acidic protein or GFAP, a well-known activation marker of astrocytes was attenuated by DR around the plaque too, which otherwise remains elevated during chronic neurodegeneration

3.1.3. Neurodegeneration Aging of the brain is characterized by neuronal- loss and −death, a condition usually called neurodegeneration. The brain is exposed to various insults during aging that leads to molecular, cellular and structural changes. These changes may succumb the brain to many neurodegenerative cascades resulting in many neurological disorders. Although, the brain employs mechanisms to repair injury and maintain the integrity of neural circuit, however, these are challenged by aging process that is further superimposed upon by environmental factors and genetic make-up. In Alzheimer’s disease (AD), amyloid β-peptide (Aβ) deposition is associated with various biochemical changes in neurons including increased cellular oxidative stress, impaired energy metabolism (Butterfield and Stadtman, 1997; Mattson et al., 1999), mitochondrial dysfunction (Gibson et al., 1998) and perturbed calcium homeostasis (Grynspan et al., 1997). The increasing neuronal loss in AD patients may be well correlated with increased memory loss. As to AD, Parkinson’s disease (PD) is another neurological disorder associated with loss of dopaminergic neurons and accumulation of modified αsynuclein in neurons in the substantia nigra (De Lau and Breteler, 2006; Wang et al., 2015). Dietary restriction can reduce the risk of pathology of AD and PD. The potential mechanisms by which DR is beneficial to ameliorate neurodegenerative diseases include stimulation of neuroprotective factors and stress proteins expression. These induced factors protect neurons from oxidative damage, inhibiting apoptosis, and enhance autophagy (Mattson et al., 2001; Mizushima et al., 2004; Alirezaei et al., 2010). Nevertheless, it is quite interesting that DR for 3 months in adult brain of rodents increases a number of newly generated neural cells suggesting that this may enhance brain plasticity and self-repair (Mattson et al., 2001). Brain from rats and mice maintained on a DR regimen shows increased level of stress proteins such as HSP70 and GPR78 (Duan and Mattson, 1999; Lee et al., 1999; Yu and Mattson, 1999). Prominent characteristic of AD, PD, amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) is the intracellular accumulation of altered macromolecules (protein aggregates), cellular organelles and decrease cellular turnover. DR ameliorates these age-dependent changes via induction of autophagy (Alirezaei et al., 2010; Liu et al., 2017). Autophagy helps in clearance of damaged biomolecules and it is induced under condition such as DR (Cuervo et al., 2005). Being a rejuvenating process, activation of autophagy may be another mechanism by which DR acts as a neuroprotective intervention owing to the activation of ATG genes. In response to ATG genes activation, formation of autophagosomes follows, which direct the degradation of its cellular contents in lysosomes. In the process, the breakdown products are subsequently recycled into cytoplasm (Levine and Klionsky, 2004). In this way, autophagy rejuvenates the intracellular milieu clearing away any macromolecular aggregates or non-functional organelles. DR in 6

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young mice inhibits mTOR thereby synergistically activating autophagy (Fok et al., 2013). Interestingly, the findings by Bayliss et al. (2016) in mouse model of PD, have indicated that another mechanism by which DR exhibits its neuroprotective effect is through triggering the gut hormone, ghrelin. Mouse model of PD subjected to DR shows that loss of substantia nigra (SN) dopaminergic neurons was attenuated but was not observed in ghrelin-KO mice, demonstrating that ghrelin mediates DR’s neuroprotective effect and maintain neuronal survival. These findings implicate that DR exhibits neuroprotective effect through a diverse mechanisms, which, nevertheless, is essential for safeguarding the insults particularly induced by aging process. 3.1.4. Redox status Aging is associated with increased production of reactive oxygen and nitrogen species. ROS are the by-products of various metabolic activities and mitochondrial dysfunction is the main source of ROS (Balaban et al., 2005). The increase toxic level of the ROS is due to the imbalance between their production and removal. Among all tissues, brain is most vulnerable to oxidative damage brought about by these ROS. Because the brain requires high oxygen demand (due to its high level of metabolic activities as it forms the central organ that orchestrates many systemic and physiological functions), it has high amount of oxidizable polyunsaturated fatty acids (PUFA) and low level of antioxidants activities (Sohal and Weindruch, 1996), it appears that neurodegeneration is well connected to ROS-mediated damage. The brain has various defense mechanisms to protect against the toxic effect of ROS such as protein refolding or degradation, lipid turnover and DNA base excision and repair. However, when such mechanisms fail, oxidative stress ensues (Wang and Michaelis, 2010). It is particularly interesting to note that not all regions of the brain are equally vulnerable to oxidative damage by ROS. The age-associated neuron loss and death only occur in selected group of neurons such as cholinergic neurons of the forebrain and of the sympathetic neurons (Baquet et al., 2004; Wang and Michaelis, 2010). Similarly, neurons of hippocampus CA1 region, frontal cortex and amygdala are more sensitive to oxidative stress as compared to the neurons of hippocampal CA3 regions (Schmidt-Kastner and Freund, 1991; Wang et al., 2005). Further, neurons in the cerebellar granule are prone to oxidative stress-induced death rather than those neurons of the cerebral cortex (Satoh et al., 1998; Wang et al., 2009). While the mechanism is not fully elucidated, it is likely that the difference in genetic profile among neurons in the brain provide each specific neuron with unique morphological, biochemical characteristics and chemical composition that pre-determine some to be vulnerable to such oxidative-induced damage (Wang and Michaelis, 2010). Therefore, it is plausible that such neurons may be the first to exhibit functional decline and cell death during aging and in age-associated diseases. Studies from our lab have indicated that redox processes may significantly contribute to neuronal dysfunction as indicated by the increased content of protein carbonyl species in the brain of aging mice as compared to the younger ones (Dkhar and Sharma, 2010). Several studies including ours, indicate that natural intervention including dietary restriction, as well as various nutraceuticals (curcumin and ascorbic acid) can posit to be neuroprotective by ameliorating the production of various reactive oxygen species (Redman and Ravussin, 2009; Dkhar and Sharma, 2010, 2011, 2014). The anti-oxidative properties of DR also prevent many other phenotypes of aging brain from loss of myenteric neurons and other degenerative conditions (Thrasivoulou et al., 2006). Although the mechanism by which DR exhibits its anti-oxidative role is complex but it is regulated by many factors such as sex, species, and the time of DR and type of ROS measured. The anti-oxidative property of DR is mediated by three mechanisms: reduction of reactive oxygen species, increased antioxidant enzyme activities and increase turnover of oxidized molecules (Walsh et al., 2014). DR is shown to increase mitochondrial functions by efficiently reducing membrane potential and balanced bioenergetics with remarkable maintenance of ATP production that effectively reduces

Fig. 2. Schematic diagram representing the changes in the brain during aging that occur at the structural, biochemical and physiological level. These changes critically impinge on the overall cognitive functions through regulation of synaptic plasticity and various neurological changes. Dietary restriction counteracts the effects of aging, cumulatively resulting in the augmentation of cognitive functions by improving synaptic plasticity, increasing neurogenesis, enhancing neuroprotection and promoting neural survivability.

generation of reactive oxygen species. One of the significant mechanisms by which DR enhances efficient mitochondrial function and biogenesis is brought about by the upregulation of neuronal transcription factor PGC-1, a master regulator of cellular respiration (López-Lluch et al., 2006). Glutathione is critical to maintain the redox balance in the brain and disruption of the same has been associated with brain aging (Przedborski et al., 1996). An enhanced glutathione redox system during DR serves as a critical mechanism by which DR ameliorates brain aging (Walsh et al., 2014).

4. Conclusion Evidently, brain aging is an intricate process, which is regulated by a cascade of physiological, morphological and biochemical changes (Fig. 2). These changes are the downstream effects of alteration at the molecular and cellular levels including changes in various important regulatory factors such as growth factors. Due to the complicated nature of the brain structure and functions, much is still left in unraveling a single factor that regulates aging process of the brain. Although promising demonstrations indicate that nutrient sensing factors such as IGF-1, mTOR, sirtuin and AMPK form the central platform at the molecular level. DR seems to have neuroprotective property through various mechanisms elucidating that its effect is diverse in nature that efficiently enhances brain plasticity, and more interestingly, it acts to revitalize brain with mechanistic strategies for self-repairing. Dietary restriction is pleiotropic in action that far exceeds simple body weight reduction and studies in various organisms suggest that DR maintains neuronal health, survival and delays brain aging but more work need to be done to evaluate similar approach in human (Table 1). Although, adherence to long-term DR in human is particularly difficult, but a better insight into molecular and cellular mechanisms underlying the diverse effect of DR will impact on novel approach that help guide towards development of clinically significant nutraceutical agents that mimic and achieve similar results as that of DR in future.

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Table 1 Summary of the beneficial effects of DR on brain aging. Organisms

Age of DR onset

Type of DR/Duration

CNS regions

Morphology/Anatomy /Physiology function

References

Mice

16 weeks

Long-term (20- months) 40% DR

Skeletal neuromuscular junction

↑Neurovascular, cognition

Valdez et al. (2010)

14–15 weeks

Long-term (18–20months) 40% DR Long-term (12.5 months) 30% DR

Varied regions (Hippocampus, Frontal Cortex) Hippocampus CA 1 neurons

↓Axonal atrophy ↑Neurovascular function, Preserves white matter integrity and cognition

Guo et al. (2015) and Parikh et al. (2016)

↓Aβ burden

Schafer et al. (2015a,b)

2.5 months

6 weeks

8 weeks

16–18 months

Long-term (10-months) Low-calorie diet Long-term (6–8 months) Intermittent feeding, IF 3-months Intermittent feeding, IF

↑Hspa1b and Hspa5 ↑Klotho and transthyretin Activate autophagy. Preserves learning and memory

Hippocampus

Dong et al. (2016)

Hippocampus

↑Synaptic plasticity, learning

Fontán-Lozano et al. (2007)

Cerebrum, cerebellum, Cortex, Hippocampus, striatum

Protects neurons against acute tissue injury,

Arumugam et al. (2010), Dkhar and Sharma (2010), Suchiang and Sharma (2011) and Hadem and Sharma (2017)

↓Protein carbonyl species ↓ IGF-1 signaling ↓Acetylcholinesterase ↓mTOR ↑Autophagy ↓Amyloidβ plaques

12 weeks old

30 days DR

hippocampus

14–15 weeks

Short −term (2 weeks) 40% DR 9 weeks 30% DR

Cortex and hippocampus

6–7 weeks old

24/48 h DR

Cortical neurons

↑SIRT1 ↑Autophagy ↓Neuroinflammation ↑Neuronal autophagy

8–10 weeks old

30% DR

Substantia Nigra

↑Dopaminergic neurons

14 weeks

Long-term (24- months) 40% DR

Lin et al. (2014)

14 weeks

Hippocampus CA 3

Adolescent

Long-term (29–32 months) 60% DR 15% DR

Improves mitochondrial function, preserves metabolic function and neuronal activity Prevents learning and memory decline

↑BDNF, improves cognition

Zaptan et al. (2015)

Adult onset

Intermittent Feeding IF

Hippocampus and Prefrontal cortex Substantia nigra

Duan and Mattson (1999)

12 weeks

30 days

Hippocampus

19 and 25 months

5 months Intermittent feeding, IF

Neocortex

↑Hsp-70 ↑Glc regulated protein-78 Preserves cognitive function in bacterial infection model Protects age-related decline in spine density

Adult-onset 14 years 19–31 years

Long-term (20-years) 30% DR 30% DR

Grey matter (GM) volume

↓Brain atrophy, preserves GM volume

Colman et al. (2009)

↓IL-8, 〈IL-10, 〈 white matter volume

Willette et al. (2013)

Adult (9–17 years)

6-months 30% DR PD model

Hippocampus and prefrontal cortex Striatal region

↑BDNF, ameliorates PD

Maswood et al. (2004)

Elderly (60.5 years)

3 months 30% DR

↑Cognition (memory performance)

Witte et al. (2009)

6 weeks

MJD/Cerebeller cortex

Liu et al. (2017) Patel et al. (2005) Cunha-Santos et al. (2016)

Mizushima et al. (2004) and Alirezaei et al. (2010) Bayliss et al. (2016)

↑pAMPK Rats

Rhesus macaque

Humans

Adams et al. (2008)

Vasconcelos et al. (2014) Moroi-Fetters et al. (1989)

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