Diet and Autophagy in the Brain

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

food intake. Proceedings of the National

Vanden Berghe P. Effects of high-fructose diets on central appetite signaling and cognitive function. Frontiers in Nutrition. 2015;**2**:5. DOI: 10.3389/fnut.2015.00005

[46] Wu HW, Ren LF, Zhou X, Han DW.

[47] Harrell CS, Burgado J, Kelly SD, Johnson ZP, Neigh GN. Highfructose diet during periadolescent development increases depressivelike behavior and remodels the hypothalamic transcriptome in male rats. Psychoneuroendocrinology. 2015;**62**:252-264. DOI: 10.1016/j.

[48] Hsu TM, Konanur VR, Taing L, Usui R, Kayser BD, Goran MI, et al. Effects of sucrose and high fructose corn syrup consumption on spatial memory function and hippocampal neuroinflammation in adolescent rats. Hippocampus. 2015;**25**:227-239. DOI:

[49] Reddy BR, Maitra S, Jhelum P, Kumar KP, Bagul PK, Kaur G, et al. Sirtuin 1 and 7 mediate resveratrolinduced recovery from hyper-anxiety in high-fructose-fed prediabetic rats. Journal of Biosciences. 2016;**41**:407-417

[50] Zemdegs J, Quesseveur G,

Jarriault D, Penicaud L, Fioramonti X, Guiard BP. High-fat diet-induced metabolic disorders impairs 5-HT function and anxiety-like behavior in mice. British Journal of Pharmacology. 2016;**173**:2095-2110. DOI: 10.1111/

psyneuen.2015.08.025

10.1002/hipo.22368

Academy of Sciences. 2008;**105**: 16871-16875. DOI: 10.1073/

[45] Lowette K, Roosen L, Tack J,

A high-fructose diet induces hippocampal insulin resistance and exacerbates memory deficits in male Sprague-Dawley rats. Nutritional Neuroscience. 2015;**18**:323-328. DOI: 10.1179/1476830514Y.0000000133

pnas.0809255105

**52**

bph.13343

**55**

**Chapter 4**

Health

**Abstract**

Dietary Impact on Neuronal

*Claudia Ntsapi, Andre du Toit and Ben Loos*

neuronal autophagy, in the context of preserving brain health.

**2. The role of protein aggregation in Alzheimer's disease**

neurodegeneration, autophagosome, lysosome

**1. Introduction**

**Keywords:** autophagic flux, caloric restriction, proteotoxicity, Alzheimer's disease,

At the beginning of the twentieth century, life expectancy at birth was about 45 years. Today, this figure has markedly increased to nearly 77 years [1]. Recent estimates [1] predict that in the next four decades, the world's proportion of people aged 65 years and older will account for nearly 22% of the total population—from the present 800 million to 2 billion people. Although this increase in life expectancy is reflective of the healthcare achievements [2], the socioeconomic costs associated with a higher chronic disease burden have necessitated the development of robust prevention and management strategies that are both safe and immediately executable.

Alzheimer's disease (AD) is a debilitating neurodegenerative disease, affecting 40 million people worldwide [3]. The prevalence of AD is strongly correlated with age,

Autophagy Control and Brain

Autophagy is the major intracellular system which is critical for the removal of harmful protein aggregates and malfunctioning organelles. Dysfunctional autophagy is associated with a multitude of human diseases, such as protein aggregation in Alzheimer's disease and non-successful aging. Major interest exists in the dietary manipulation of the autophagy pathway activity, so as to tune the cell's protein degradation capabilities and to prevent cell death onset. It has recently become clear that the machinery required to degrade protein cargo has a distinct activity level which can be altered through specific dietary modulation. Moreover, this activity may differ from that of the proteinaceous cargo. Overall, brain health and successful aging are characterized by limited protein aggregation, with a distinct molecular signature of maintained autophagy function. However, it is largely unclear how to control autophagy through dietary interventions with a precision that would allow to maintain minimal levels of toxic proteins, preserving neuronal cell viability and proteostasis. In this chapter, we carefully dissect the relationship between autophagy-modulating drugs, including caloric restriction mimetics and their impact on

## **Chapter 4**

## Dietary Impact on Neuronal Autophagy Control and Brain Health

*Claudia Ntsapi, Andre du Toit and Ben Loos*

## **Abstract**

Autophagy is the major intracellular system which is critical for the removal of harmful protein aggregates and malfunctioning organelles. Dysfunctional autophagy is associated with a multitude of human diseases, such as protein aggregation in Alzheimer's disease and non-successful aging. Major interest exists in the dietary manipulation of the autophagy pathway activity, so as to tune the cell's protein degradation capabilities and to prevent cell death onset. It has recently become clear that the machinery required to degrade protein cargo has a distinct activity level which can be altered through specific dietary modulation. Moreover, this activity may differ from that of the proteinaceous cargo. Overall, brain health and successful aging are characterized by limited protein aggregation, with a distinct molecular signature of maintained autophagy function. However, it is largely unclear how to control autophagy through dietary interventions with a precision that would allow to maintain minimal levels of toxic proteins, preserving neuronal cell viability and proteostasis. In this chapter, we carefully dissect the relationship between autophagy-modulating drugs, including caloric restriction mimetics and their impact on neuronal autophagy, in the context of preserving brain health.

**Keywords:** autophagic flux, caloric restriction, proteotoxicity, Alzheimer's disease, neurodegeneration, autophagosome, lysosome

## **1. Introduction**

At the beginning of the twentieth century, life expectancy at birth was about 45 years. Today, this figure has markedly increased to nearly 77 years [1]. Recent estimates [1] predict that in the next four decades, the world's proportion of people aged 65 years and older will account for nearly 22% of the total population—from the present 800 million to 2 billion people. Although this increase in life expectancy is reflective of the healthcare achievements [2], the socioeconomic costs associated with a higher chronic disease burden have necessitated the development of robust prevention and management strategies that are both safe and immediately executable.

### **2. The role of protein aggregation in Alzheimer's disease**

Alzheimer's disease (AD) is a debilitating neurodegenerative disease, affecting 40 million people worldwide [3]. The prevalence of AD is strongly correlated with age,

imposing a greater socioeconomic burden as life expectancy continues to increase. Clinically, AD is associated with the progressive loss of essential cognitive functions and progressive hippocampal and cortical brain atrophy [4]. Current AD treatment Food and Drug Administration (FDA)-approved drugs include N-methyl-D-aspartic acid (NMDA) receptor antagonist memantine and cholinesterase inhibitors donepezil, galantamine, and rivastigmine [5]. These drugs augment cholinergic neurotransmission or attenuate excitotoxic neuronal injury. However, they only provide palliative benefits at best, with limited impact on the underlying disease mechanisms. Therefore, there is an urgent need for interventions that not only impact the aging process in favor of sustained brain health but also promote successful brain aging in the context of neurodegenerative diseases. AD is pathologically defined by the widespread brain distribution of amyloid-beta peptide (Aβ) plaques, neurofibrillary tangle (NFT) formation, as well as synaptic and neuronal loss [6]. Despite growing understanding of the disease, it remains unclear how these pathological features relate to the specific disease processes. The amyloid cascade hypothesis continues to serve as the predominant model of AD pathology. This hypothesis suggests the overproduction of Aβ, particularly an increase in Aβ [42] relative to Aβ [40], as the causal trigger in the disease process [7]. Aβ is derived from the amyloidogenic cleavage of the amyloid precursor protein (APP), protein cleaved by two endoproteases: the betasite APP-cleaving enzyme 1 (BACE1/β-secretase) and γ-secretase enzyme. Briefly, APP is cleaved by BACE1, releasing sAPPβ and leaving the membrane-bound C99 carboxy-terminal fragment that is subsequently processed by γ-secretase to generate Aβ, a nontoxic P3 peptide, and the APP intracellular domain (AICD) [7]. γ-Secretase cleavage results in a C-terminal heterogeneity of the resulting Aβ peptide population. Hence, Aβ peptides of different lengths exist, with Aβ40 being the most abundant (~80–90%), followed by the more hydrophobic and fibrillogenic Aβ42 (~5–10%) form which is the principal peptide aggregated in the AD brain [8].

Similar to AD, protein aggregation is also a hallmark of neuronal cell death onset in Parkinson's disease (PD). PD is pathologically defined by the formation of intraneuronal inclusions consisting of aggregated α-synuclein (α-syn) and the presence of Lewy neurites and Lewy bodies (LBs) [9]. This neuropathology is associated with impaired functioning of intracellular protein degradation mechanisms [10]. Thus, strategies to either degrade or prevent the initial accumulation of Aβ oligomers and α-syn may be promising in the treatment or prevention of AD and PD, respectively.

### **3. Protein quality surveillance machinery**

The postmitotic nature of neuronal cells makes them highly susceptible to the accumulation of protein aggregates. Hence, the maintenance of protein homeostasis is critical to maintain neuronal function, particularly with age. Although the etiology and molecular mechanisms underlying the pathological changes in AD are not fully understood, studies suggest that localized deficits in the autophagy pathway are likely to precede the formation of Aβ plaques or NFTs [11]. Autophagy is a highly conserved catabolic process that is critical for the systemic removal of long-lived proteins, protein aggregates, and dysfunctional organelles and serves as a major regulator of longevity in various species [12]. This process is triggered by various stressors, e.g., low nutrient levels, and proteotoxicity [13]. Proteotoxicity is by the of functional conformation as mature proteins misfold due to normal aging, posttranslational modifications, or inherent mutations [14]. In the absence of intracellular corrective mechanisms, this proteotoxicity can lead to uncontrolled protein aggregation, impair the cells' ability to maintain protein homeostasis, and promote cell death onset [14]. Depending on the cargo sequestered, and the mechanism

**57**

*Dietary Impact on Neuronal Autophagy Control and Brain Health*

through which cargo is delivered to the lysosome, autophagy encompasses at least three subtypes: microautophagy, chaperone-mediated autophagy (CMA), and

be exploited to promote brain health and successful brain aging.

*Schematic model of the three main types of autophagy described in mammalian cells.*

Autophagy serves as the cell's principal quality control system which mediates the degradation of entire cytoplasmic materials through a series of stages characterized by the *de novo* formation of double-membraned vesicles, termed autophagosomes, which sequester cytoplasmic cargo and fuse with lysosomes to form autolysosomes. This process culminates in cargo degradation and subsequent recycling of the resulting macromolecules. To date, more than 30 highly conserved

**4. The tight orchestration of autophagy**

In microautophagy, lysosomal membrane invaginations mediate the internalization of cytosolic cargo into small vesicles that detach into the lumen for degradation [15]. CMA refers to a selective form of autophagy, whereby cytosolic proteins containing a CMA targeting motif—an amino-acid sequence biochemically similar to KFERQ—are bound by heat shock-cognate chaperone of 70 kDa (HSC70). HSC70 targets these proteins to the lysosomal membrane, where after binding to the cytosolic tail of lysosome-associated membrane protein type-2A (LAMP2A), proteins are unfolded and translocated across the lysosomal membrane aided by the lysosome-resident form of HSC70 (lys-hsc70) for degradation by the luminal proteases [16]. Of the three pathways, macroautophagy (hereafter referred to as autophagy) is the most extensively characterized and most relevant to AD. Therefore, this review will focus on the role of macroautophagy as the key mechanism which may

*DOI: http://dx.doi.org/10.5772/intechopen.85228*

macroautophagy (**Figure 1**).

**Figure 1.**

*Dietary Impact on Neuronal Autophagy Control and Brain Health DOI: http://dx.doi.org/10.5772/intechopen.85228*

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

form which is the principal peptide aggregated in the AD brain [8].

**3. Protein quality surveillance machinery**

Similar to AD, protein aggregation is also a hallmark of neuronal cell death onset in Parkinson's disease (PD). PD is pathologically defined by the formation of intraneuronal inclusions consisting of aggregated α-synuclein (α-syn) and the presence of Lewy neurites and Lewy bodies (LBs) [9]. This neuropathology is associated with impaired functioning of intracellular protein degradation mechanisms [10]. Thus, strategies to either degrade or prevent the initial accumulation of Aβ oligomers and α-syn may be promising in the treatment or prevention of AD and PD, respectively.

The postmitotic nature of neuronal cells makes them highly susceptible to the accumulation of protein aggregates. Hence, the maintenance of protein homeostasis is critical to maintain neuronal function, particularly with age. Although the etiology and molecular mechanisms underlying the pathological changes in AD are not fully understood, studies suggest that localized deficits in the autophagy pathway are likely to precede the formation of Aβ plaques or NFTs [11]. Autophagy is a highly conserved catabolic process that is critical for the systemic removal of long-lived proteins, protein aggregates, and dysfunctional organelles and serves as a major regulator of longevity in various species [12]. This process is triggered by various stressors, e.g., low nutrient levels, and proteotoxicity [13]. Proteotoxicity is by the of functional conformation as mature proteins misfold due to normal aging, posttranslational modifications, or inherent mutations [14]. In the absence of intracellular corrective mechanisms, this proteotoxicity can lead to uncontrolled protein aggregation, impair the cells' ability to maintain protein homeostasis, and promote cell death onset [14]. Depending on the cargo sequestered, and the mechanism

imposing a greater socioeconomic burden as life expectancy continues to increase. Clinically, AD is associated with the progressive loss of essential cognitive functions and progressive hippocampal and cortical brain atrophy [4]. Current AD treatment Food and Drug Administration (FDA)-approved drugs include N-methyl-D-aspartic acid (NMDA) receptor antagonist memantine and cholinesterase inhibitors donepezil, galantamine, and rivastigmine [5]. These drugs augment cholinergic neurotransmission or attenuate excitotoxic neuronal injury. However, they only provide palliative benefits at best, with limited impact on the underlying disease mechanisms. Therefore, there is an urgent need for interventions that not only impact the aging process in favor of sustained brain health but also promote successful brain aging in the context of neurodegenerative diseases. AD is pathologically defined by the widespread brain distribution of amyloid-beta peptide (Aβ) plaques, neurofibrillary tangle (NFT) formation, as well as synaptic and neuronal loss [6]. Despite growing understanding of the disease, it remains unclear how these pathological features relate to the specific disease processes. The amyloid cascade hypothesis continues to serve as the predominant model of AD pathology. This hypothesis suggests the overproduction of Aβ, particularly an increase in Aβ [42] relative to Aβ [40], as the causal trigger in the disease process [7]. Aβ is derived from the amyloidogenic cleavage of the amyloid precursor protein (APP), protein cleaved by two endoproteases: the betasite APP-cleaving enzyme 1 (BACE1/β-secretase) and γ-secretase enzyme. Briefly, APP is cleaved by BACE1, releasing sAPPβ and leaving the membrane-bound C99 carboxy-terminal fragment that is subsequently processed by γ-secretase to generate Aβ, a nontoxic P3 peptide, and the APP intracellular domain (AICD) [7]. γ-Secretase cleavage results in a C-terminal heterogeneity of the resulting Aβ peptide population. Hence, Aβ peptides of different lengths exist, with Aβ40 being the most abundant (~80–90%), followed by the more hydrophobic and fibrillogenic Aβ42 (~5–10%)

**56**

**Figure 1.** *Schematic model of the three main types of autophagy described in mammalian cells.*

through which cargo is delivered to the lysosome, autophagy encompasses at least three subtypes: microautophagy, chaperone-mediated autophagy (CMA), and macroautophagy (**Figure 1**).

In microautophagy, lysosomal membrane invaginations mediate the internalization of cytosolic cargo into small vesicles that detach into the lumen for degradation [15]. CMA refers to a selective form of autophagy, whereby cytosolic proteins containing a CMA targeting motif—an amino-acid sequence biochemically similar to KFERQ—are bound by heat shock-cognate chaperone of 70 kDa (HSC70). HSC70 targets these proteins to the lysosomal membrane, where after binding to the cytosolic tail of lysosome-associated membrane protein type-2A (LAMP2A), proteins are unfolded and translocated across the lysosomal membrane aided by the lysosome-resident form of HSC70 (lys-hsc70) for degradation by the luminal proteases [16]. Of the three pathways, macroautophagy (hereafter referred to as autophagy) is the most extensively characterized and most relevant to AD. Therefore, this review will focus on the role of macroautophagy as the key mechanism which may be exploited to promote brain health and successful brain aging.

## **4. The tight orchestration of autophagy**

Autophagy serves as the cell's principal quality control system which mediates the degradation of entire cytoplasmic materials through a series of stages characterized by the *de novo* formation of double-membraned vesicles, termed autophagosomes, which sequester cytoplasmic cargo and fuse with lysosomes to form autolysosomes. This process culminates in cargo degradation and subsequent recycling of the resulting macromolecules. To date, more than 30 highly conserved autophagy-related (ATG) genes have been implicated in the core autophagy machinery [17]. The autophagic process is tightly regulated, with distinct sets of Atg proteins forming diverse complexes which control different stages of this pathway under basal and stressful conditions.

The induction of autophagy is primarily mediated by two complexes. Firstly, the initiation complex, which triggers the formation of a phagophore structure (or isolation membrane), comprises the Unc-51-like kinase-1 (ULK1), Atg13, Atg101 and the focal adhesion kinase family-interacting protein of 200 kDa (FIP200) [17]. Secondly, the nucleation complex drives the phosphorylation of phosphatidylinositol (PI) to produce phosphatidylinositol 3-phosphate (PI3P), a membrane-bound lipid which requires the class III phosphatidylinositol 3-kinase (C3PI3K) vacuolar protein sorting 34 (Vps34) to recruit Beclin1, Vps15, Atg14L, or Ambra1 in the region of phagophore formation, termed the omegasome [17]. Autophagosome formation is mediated by two ubiquitin-like conjugation reactions. The first reaction results in the formation of the Atg12-Atg5-Atg16L1 conjugation complex which facilitates the expansion of the phagophore membrane. In the second reaction, Atg12-Atg5 associates with Atg16L1 and localizes to the outer membrane of the pre-autophagosomal structures, in turn catalyzing the recruitment and conjugation of microtubule-associated protein 1 light chain 3 (MAP1LC3/Atg8/LC3) with a membrane phospholipid, phosphatidylethanolamine (PE), through the action of Atg4, Atg7, and Atg3 [18]. Atg4 catalyzes the conversion of the cytosolic form of LC3 (LC3-I) to the autophagosome membrane-associated form (LC3-II), which serves as an indicator of autophagosome pool size at a given time [18]. Mature autophagosomes ultimately fuse with lysosomes to form autolysosomes, in which sequestered cargo is degraded and released back into the cytosol for reuse [18]. Autophagic flux, the rate of protein degradation through the autophagy pathway [19, 20], provides an accurate measure of this dynamic process.

### **5. Key signaling pathways in the regulation of autophagy during nutrient stress**

The mammalian target of rapamycin complex 1 (mTORC1) is a component of mTOR, the master regulator of cellular metabolism in response to environmental cues. mTORC1 integrates various signaling networks to promote protein synthesis by suppressing catabolic processes under nutrient-rich conditions [21]. In addition to the class I phosphatidylinositol-3-kinase (PI3K) and the Akt signaling pathway, the tuberous sclerosis (TSC) tumor suppressor complex (TSC1/TSC2) is an important upstream regulator of mTORC1, with loss-of-function mutations in either complex leading to the constitutive activation of mTORC1 [22]. Under conditions of nutrient excess, growth factors such as insulin-like growth factor 1 (insulin/ IGF1) activate their cognate receptors, subsequently activating the PI3K/Akt pathway [23]. Activated Akt inhibits TSC1/TSC2, resulting in the activation of mTORC1 [23]. Subsequently, mTORC1 suppresses autophagy activity by phosphorylating (i) components of the ULK1 complex; (ii) Atg14L or Beclin1 regulator (Ambra1); (iii) the Beclin1-binding protein, UV radiation resistance-associated gene (UVRAG); or (iv) the transcription factor EB (TFEB), a key regulator of lysosomal and autophagy gene expression [24]. Therefore, mTORC1 can inhibit autophagy by targeting different components of the core autophagy machinery (**Figure 2**).

Under conditions of nutrient stress, mTORC1 activity is suppressed, resulting in the activation of the ULK1 complex [24]. Cellular energetic sensor, AMPactivated protein kinase (AMPK), positively regulates autophagy to maintain energy

**59**

perturbations.

**Figure 2.**

**6. Decreased autophagy with age**

*Regulation of autophagy by cellular nutrient status.*

*Dietary Impact on Neuronal Autophagy Control and Brain Health*

homeostasis under energy depleted conditions. Briefly, AMPK phosphorylates TSC2- and mTORC1-binding partner regulatory-associated protein (Raptor) [25], thereby suppressing mTORC1 activity. Additionally, AMPK can bind and phosphorylate ULK1, freeing this complex to initiate autophagy under both nutrient and ATP deplete conditions [26]. Thus, initiation of autophagy can be jointly regulated by mTORC1 and AMPK, to increase the cell's capacity to adapt to metabolic

Consistent with the transcriptional downregulation of autophagy during healthy

aging in the human brain [27], the impairment of autophagy has been found to decrease life span in various model systems [28]. Screening for chronological aging factors, Matecic et al. [29] published one of the earliest findings implicating impaired autophagy activity in the shortened life span of *S. cerevisiae* mutants. Most compelling findings came from Atg5 [30] or Atg7 [31] knockout mice which revealed that impaired autophagic function led to early postnatal death, the accumulation of intracellular inclusion bodies, and neurodegeneration. Since insufficient/impaired autophagy contributes to aging, it is conceivable that increasing the activity of this process could influence aging, in favor of life span extension. Indeed, it is becoming increasingly clear that modulation strategies that enhance autophagy activity attenuate proteotoxicity, while defects in this pathway have been implicated in increased

*DOI: http://dx.doi.org/10.5772/intechopen.85228*

*Dietary Impact on Neuronal Autophagy Control and Brain Health DOI: http://dx.doi.org/10.5772/intechopen.85228*

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

pathway under basal and stressful conditions.

measure of this dynamic process.

**nutrient stress**

autophagy-related (ATG) genes have been implicated in the core autophagy machinery [17]. The autophagic process is tightly regulated, with distinct sets of Atg proteins forming diverse complexes which control different stages of this

**5. Key signaling pathways in the regulation of autophagy during** 

different components of the core autophagy machinery (**Figure 2**).

Under conditions of nutrient stress, mTORC1 activity is suppressed, resulting in the activation of the ULK1 complex [24]. Cellular energetic sensor, AMPactivated protein kinase (AMPK), positively regulates autophagy to maintain energy

The mammalian target of rapamycin complex 1 (mTORC1) is a component of mTOR, the master regulator of cellular metabolism in response to environmental cues. mTORC1 integrates various signaling networks to promote protein synthesis by suppressing catabolic processes under nutrient-rich conditions [21]. In addition to the class I phosphatidylinositol-3-kinase (PI3K) and the Akt signaling pathway, the tuberous sclerosis (TSC) tumor suppressor complex (TSC1/TSC2) is an important upstream regulator of mTORC1, with loss-of-function mutations in either complex leading to the constitutive activation of mTORC1 [22]. Under conditions of nutrient excess, growth factors such as insulin-like growth factor 1 (insulin/ IGF1) activate their cognate receptors, subsequently activating the PI3K/Akt pathway [23]. Activated Akt inhibits TSC1/TSC2, resulting in the activation of mTORC1 [23]. Subsequently, mTORC1 suppresses autophagy activity by phosphorylating (i) components of the ULK1 complex; (ii) Atg14L or Beclin1 regulator (Ambra1); (iii) the Beclin1-binding protein, UV radiation resistance-associated gene (UVRAG); or (iv) the transcription factor EB (TFEB), a key regulator of lysosomal and autophagy gene expression [24]. Therefore, mTORC1 can inhibit autophagy by targeting

The induction of autophagy is primarily mediated by two complexes. Firstly, the initiation complex, which triggers the formation of a phagophore structure (or isolation membrane), comprises the Unc-51-like kinase-1 (ULK1), Atg13, Atg101 and the focal adhesion kinase family-interacting protein of 200 kDa (FIP200) [17]. Secondly, the nucleation complex drives the phosphorylation of phosphatidylinositol (PI) to produce phosphatidylinositol 3-phosphate (PI3P), a membrane-bound lipid which requires the class III phosphatidylinositol 3-kinase (C3PI3K) vacuolar protein sorting 34 (Vps34) to recruit Beclin1, Vps15, Atg14L, or Ambra1 in the region of phagophore formation, termed the omegasome [17]. Autophagosome formation is mediated by two ubiquitin-like conjugation reactions. The first reaction results in the formation of the Atg12-Atg5-Atg16L1 conjugation complex which facilitates the expansion of the phagophore membrane. In the second reaction, Atg12-Atg5 associates with Atg16L1 and localizes to the outer membrane of the pre-autophagosomal structures, in turn catalyzing the recruitment and conjugation of microtubule-associated protein 1 light chain 3 (MAP1LC3/Atg8/LC3) with a membrane phospholipid, phosphatidylethanolamine (PE), through the action of Atg4, Atg7, and Atg3 [18]. Atg4 catalyzes the conversion of the cytosolic form of LC3 (LC3-I) to the autophagosome membrane-associated form (LC3-II), which serves as an indicator of autophagosome pool size at a given time [18]. Mature autophagosomes ultimately fuse with lysosomes to form autolysosomes, in which sequestered cargo is degraded and released back into the cytosol for reuse [18]. Autophagic flux, the rate of protein degradation through the autophagy pathway [19, 20], provides an accurate

**58**

**Figure 2.** *Regulation of autophagy by cellular nutrient status.*

homeostasis under energy depleted conditions. Briefly, AMPK phosphorylates TSC2- and mTORC1-binding partner regulatory-associated protein (Raptor) [25], thereby suppressing mTORC1 activity. Additionally, AMPK can bind and phosphorylate ULK1, freeing this complex to initiate autophagy under both nutrient and ATP deplete conditions [26]. Thus, initiation of autophagy can be jointly regulated by mTORC1 and AMPK, to increase the cell's capacity to adapt to metabolic perturbations.

## **6. Decreased autophagy with age**

Consistent with the transcriptional downregulation of autophagy during healthy aging in the human brain [27], the impairment of autophagy has been found to decrease life span in various model systems [28]. Screening for chronological aging factors, Matecic et al. [29] published one of the earliest findings implicating impaired autophagy activity in the shortened life span of *S. cerevisiae* mutants. Most compelling findings came from Atg5 [30] or Atg7 [31] knockout mice which revealed that impaired autophagic function led to early postnatal death, the accumulation of intracellular inclusion bodies, and neurodegeneration. Since insufficient/impaired autophagy contributes to aging, it is conceivable that increasing the activity of this process could influence aging, in favor of life span extension. Indeed, it is becoming increasingly clear that modulation strategies that enhance autophagy activity attenuate proteotoxicity, while defects in this pathway have been implicated in increased

risk for cell death onset with age [28]. Autophagy dysfunction has been extensively documented in AD progression, where the accumulation of incompletely degraded cytoplasmic within autophagic vacuoles (AVs) has been shown to be a pathological hallmark of insufficient autophagic induction in AD [32]. This process is further exacerbated by the presence of APP and its processing enzymes within the AVs [33], indicating that autophagy may regulate both Aβ generation and clearance. Indeed, insufficient expression of autophagy core protein Beclin1 has been shown to increase the expression levels of APP, Aβ, and the C-terminal fragment (CTF) in cultured neurons, in early AD patients, and mouse models of AD, while Beclin1 overexpression had the opposite effect [34]. Therefore, the modulation of autophagy may ameliorate the loss of proteostasis in AD. Indeed, rapamycin, an mTORC1 inhibitor, has been shown to reduce Aβ load and tau pathology and improve cognitive function [35], with this reduction being most pronounced when rapamycin was administered prior to the widespread deposition of Aβ [36]. Therefore, the identification of novel treatment strategies, or repurposing of readily available autophagy-inducing drugs to promote successful brain aging, has attracted considerable attention. Additionally, drugs/strategies with dual-functional capabilities in both the inhibition of Aβ production and upregulation of its clearance may prove especially beneficial in the attenuation of Aβ pathology. To this end, the use of calorie restriction (CR) dietary interventions and CR mimetics (CRMs) may offer a relatively simple, safe, and inexpensive avenue to induce autophagy and offset the decline of autophagy activity associated with age. CR, here defined as a reduction in caloric/energetic intake without causing malnutrition, remains not only the most robust and reproducible dietary intervention known to increase life span and delay aging but is also a most potent physiological inducer of autophagy [37]. In fact, short-term fasting in mice has been shown to markedly induce neuronal autophagy, translating in neuroprotection [38].

## **7. CR effects on aging and neurodegeneration**

#### **7.1 CR regimes**

Intermittent fasting (IF) is the most studied CR regime in humans. IF involves alternating between periods of *ad libitum* (AL) caloric intake and partial or complete CR in which food intake is restricted for prolonged time periods [39]. The majority of IF animal studies have involved either alternating IF (AIF) or time-restricted intermittent fasting (TRIF), with both resulting in neuroprotection, as evidenced by the enhancement of neuronal plasticity, increased levels of brain-derived neurotrophic factor (BDNF), and increased resistance to metabolic stress [40]. Goodrick and colleagues revealed that rats maintained on a lifelong AIF regime lived nearly twice as long as rats fed AL [41]. More recently, CR regimes have also been shown to attenuate Aβ neuropathology in the brains of AD mouse models [42]. In agreement, AD mice maintained for 1 year on either AIF or a 40% CR diet beginning from 5 months of age were not found to exhibit the cognitive impairments observed in AL fed AD mice [43]. However, the beneficial effects of CR on aging and maximal life span in humans remain unclear given the ethical controversies associated with long-term survival studies in normal-weight humans, the lack of validated biomarkers of aging, and the limited compliance to prolonged CR regimes [44]. Notably, gender-based differences have been reported in response to CR regimes [45]. For example, work by Martin et al. [46] revealed that while male and female rats maintained on a CR regime for 6 months had similar levels of circulating triglycerides and energy-regulating hormones (insulin, leptin, adiponectin, and ghrelin), the changes were quantitatively greater in males.

**61**

**7.3 SIRT1**

**7.4 AMPK**

SIRT1 is a nicotine amide NAD+

*Dietary Impact on Neuronal Autophagy Control and Brain Health*

The most compelling support for the beneficial effects of CR on longevity stems from epidemiological studies of the older Okinawan population, which is the longest lived population to date [47]. The longevity and apparent rarity of progressive neurodegenerative diseases amongst? this population are associated with strict adherence to their traditional Okinawan diet, consisting of soybean-based foods, unrefined carbohydrates, and moderate protein intake with emphasis on root vegetables (sweet potatoes), fish, and lean meats [48]. However, given the paucity of long-term CR studies in humans, there is insufficient data to determine the optimal

CR regimen and the degree of CR needed to achieve sustained brain health.

During the aging process, neuronal cells are exposed to increased oxidative and metabolic stress associated with numerous cellular modifications [49]. These modifications are aggravated in neurodegenerative diseases, where neuronal injury is most pronounced in the hippocampus and cortex region. Strong evidence from animal studies suggests that CR promotes enhanced synaptic plasticity, resulting in increased brain resistance to metabolic stressors, and delays brain aging [50]. Studies suggest that long-term CR, from 3 to 11 months of age, had a survival-promoting effect on newly formed glial cells in the hippocampus region of 2-, 18-, and 24-month-old mice [51]. In AD mouse models maintained on a 6–14 week CR regime, a significant reduction in Aβ and astrocytic activation was observed [52]. Hence, exploitation of the mechanisms through which CR augments brain health may aid in the development of lifestylebased therapeutics in the treatment of AD and other neurodegenerative diseases. Although the exact mechanisms through which CR promotes health and life span are not fully understood, nutrient signaling pathways have been implicated (**Figure 3**). Of considerable importance to the CR-induced effects on brain aging is the induction of autophagy following the activation of metabolic energy sensors AMPK and sirtuin-1 (SIRT1) or the inhibition of the insulin/IGF1 pathway and mTORC1 signaling [53].

its increased expression following CR in many tissues, including the brain [54]. Importantly, SIRT1 overexpression has also been shown to promote autophagy by activating essential Atg proteins [55]. SIRT1 can further stimulate autophagy by deacetylating and activating the Forkhead box (FOXO) family of transcription factors which act as key regulators of longevity under CR conditions [56]. SIRT1 may further promote longevity through FOXO-dependent induction of stress response genes [56].

AMPK is activated in response to low energy levels, e.g., under CR conditions [57], suggesting that AMPK may play a role in CR-induced longevity. Indeed, increased AMPK activity has been found to extend life span in *C. elegans* and *Drosophila* model systems, while its inhibition shortened life span [58]. The mechanism underlying AMPK-induced life span extension under CR is thought to involve the direct phosphorylation of peroxisome proliferator-activated receptor G coactivator-1α (PGC-1α), a key regulator of mitochondrial metabolism and biogenesis, and FOXO transcription factors, thereby targeting these components for SIRT1-mediated activation [59]. Importantly, AMPK stimulates autophagy through the direct phosphorylation of ULK1, or the activation of TSC1/TSC2, which in turn

inhibits mTORC1 [25], thereby allowing autophagy induction.


*DOI: http://dx.doi.org/10.5772/intechopen.85228*

**7.2 CR and brain health**

*Dietary Impact on Neuronal Autophagy Control and Brain Health DOI: http://dx.doi.org/10.5772/intechopen.85228*

The most compelling support for the beneficial effects of CR on longevity stems from epidemiological studies of the older Okinawan population, which is the longest lived population to date [47]. The longevity and apparent rarity of progressive neurodegenerative diseases amongst? this population are associated with strict adherence to their traditional Okinawan diet, consisting of soybean-based foods, unrefined carbohydrates, and moderate protein intake with emphasis on root vegetables (sweet potatoes), fish, and lean meats [48]. However, given the paucity of long-term CR studies in humans, there is insufficient data to determine the optimal CR regimen and the degree of CR needed to achieve sustained brain health.

#### **7.2 CR and brain health**

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

risk for cell death onset with age [28]. Autophagy dysfunction has been extensively documented in AD progression, where the accumulation of incompletely degraded cytoplasmic within autophagic vacuoles (AVs) has been shown to be a pathological hallmark of insufficient autophagic induction in AD [32]. This process is further exacerbated by the presence of APP and its processing enzymes within the AVs [33], indicating that autophagy may regulate both Aβ generation and clearance. Indeed, insufficient expression of autophagy core protein Beclin1 has been shown to increase the expression levels of APP, Aβ, and the C-terminal fragment (CTF) in cultured neurons, in early AD patients, and mouse models of AD, while Beclin1 overexpression had the opposite effect [34]. Therefore, the modulation of autophagy may ameliorate the loss of proteostasis in AD. Indeed, rapamycin, an mTORC1 inhibitor, has been shown to reduce Aβ load and tau pathology and improve cognitive function [35], with this reduction being most pronounced when rapamycin was administered prior to the widespread deposition of Aβ [36]. Therefore, the identification of novel treatment strategies, or repurposing of readily available autophagy-inducing drugs to promote successful brain aging, has attracted considerable attention. Additionally,

drugs/strategies with dual-functional capabilities in both the inhibition of Aβ production and upregulation of its clearance may prove especially beneficial in the attenuation of Aβ pathology. To this end, the use of calorie restriction (CR) dietary interventions and CR mimetics (CRMs) may offer a relatively simple, safe, and inexpensive avenue to induce autophagy and offset the decline of autophagy activity associated with age. CR, here defined as a reduction in caloric/energetic intake without causing malnutrition, remains not only the most robust and reproducible dietary intervention known to increase life span and delay aging but is also a most potent physiological inducer of autophagy [37]. In fact, short-term fasting in mice has been shown to markedly induce neuronal autophagy, translating in neuroprotection [38].

Intermittent fasting (IF) is the most studied CR regime in humans. IF involves

alternating between periods of *ad libitum* (AL) caloric intake and partial or complete CR in which food intake is restricted for prolonged time periods [39]. The majority of IF animal studies have involved either alternating IF (AIF) or time-restricted intermittent fasting (TRIF), with both resulting in neuroprotection, as evidenced by the enhancement of neuronal plasticity, increased levels of brain-derived neurotrophic factor (BDNF), and increased resistance to metabolic stress [40]. Goodrick and colleagues revealed that rats maintained on a lifelong AIF regime lived nearly twice as long as rats fed AL [41]. More recently, CR regimes have also been shown to attenuate Aβ neuropathology in the brains of AD mouse models [42]. In agreement, AD mice maintained for 1 year on either AIF or a 40% CR diet beginning from 5 months of age were not found to exhibit the cognitive impairments observed in AL fed AD mice [43]. However, the beneficial effects of CR on aging and maximal life span in humans remain unclear given the ethical controversies associated with long-term survival studies in normal-weight humans, the lack of validated biomarkers of aging, and the limited compliance to prolonged CR regimes [44]. Notably, gender-based differences have been reported in response to CR regimes [45]. For example, work by Martin et al. [46] revealed that while male and female rats maintained on a CR regime for 6 months had similar levels of circulating triglycerides and energy-regulating hormones (insulin, leptin, adiponectin, and ghrelin), the changes were quantitatively greater in males.

**7. CR effects on aging and neurodegeneration**

**7.1 CR regimes**

**60**

During the aging process, neuronal cells are exposed to increased oxidative and metabolic stress associated with numerous cellular modifications [49]. These modifications are aggravated in neurodegenerative diseases, where neuronal injury is most pronounced in the hippocampus and cortex region. Strong evidence from animal studies suggests that CR promotes enhanced synaptic plasticity, resulting in increased brain resistance to metabolic stressors, and delays brain aging [50]. Studies suggest that long-term CR, from 3 to 11 months of age, had a survival-promoting effect on newly formed glial cells in the hippocampus region of 2-, 18-, and 24-month-old mice [51]. In AD mouse models maintained on a 6–14 week CR regime, a significant reduction in Aβ and astrocytic activation was observed [52]. Hence, exploitation of the mechanisms through which CR augments brain health may aid in the development of lifestylebased therapeutics in the treatment of AD and other neurodegenerative diseases. Although the exact mechanisms through which CR promotes health and life span are not fully understood, nutrient signaling pathways have been implicated (**Figure 3**). Of considerable importance to the CR-induced effects on brain aging is the induction of autophagy following the activation of metabolic energy sensors AMPK and sirtuin-1 (SIRT1) or the inhibition of the insulin/IGF1 pathway and mTORC1 signaling [53].

#### **7.3 SIRT1**

SIRT1 is a nicotine amide NAD+ -dependent histone deacetylase, which exhibits increased expression following CR in many tissues, including the brain [54]. Importantly, SIRT1 overexpression has also been shown to promote autophagy by activating essential Atg proteins [55]. SIRT1 can further stimulate autophagy by deacetylating and activating the Forkhead box (FOXO) family of transcription factors which act as key regulators of longevity under CR conditions [56]. SIRT1 may further promote longevity through FOXO-dependent induction of stress response genes [56].

#### **7.4 AMPK**

AMPK is activated in response to low energy levels, e.g., under CR conditions [57], suggesting that AMPK may play a role in CR-induced longevity. Indeed, increased AMPK activity has been found to extend life span in *C. elegans* and *Drosophila* model systems, while its inhibition shortened life span [58]. The mechanism underlying AMPK-induced life span extension under CR is thought to involve the direct phosphorylation of peroxisome proliferator-activated receptor G coactivator-1α (PGC-1α), a key regulator of mitochondrial metabolism and biogenesis, and FOXO transcription factors, thereby targeting these components for SIRT1-mediated activation [59]. Importantly, AMPK stimulates autophagy through the direct phosphorylation of ULK1, or the activation of TSC1/TSC2, which in turn inhibits mTORC1 [25], thereby allowing autophagy induction.

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

#### **Figure 3.**

*The targeting of nutrient-triggered pathways by selective calorie restriction mimetics in longevity and the promotion of brain health. CR, calorie restriction; CRM, caloric restriction mimetic; IF, intermittent fasting; SIRT1, sirtuin-1; mTORC1, mammalian target of rapamycin complex 1; AMPK, AMP-dependent protein kinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-α; insulin/IGF-1, insulin/ insulin-like growth factor-1; PI3K, phosphoinositide 3-kinase; FOXO, Forkhead box O; EP300, E1A-binding protein p300.*

#### **7.5 Insulin/IGF1 signaling**

Inhibition of insulin/IGF1 signaling following CR or growth factor removal has been reported to increase life span, delay the onset of age-related diseases, and increase oxidative stress resistance in various species, including humans [60]. CR-induced downregulation of the insulin/IGF1 pathway in turn induces the activation of SIRT1, resulting in the activation of FOXO transcription factors [61].

#### **7.6 mTORC1 signaling**

mTORC1 is activated by growth factors, amino acids, or increased glucose levels, and is thought to control life span through various mechanisms, including the regulation of autophagy [62]. Indeed, autophagy has been shown to be essential for life span expansion in mTOR knockout yeast [63] and *C. elegans* model systems in which impaired autophagic function has been shown to abolish the life span extension induced by mTOR inhibition under CR conditions [28]. The convergence of CR-induced signaling pathways on autophagy supports the assertion that this process is intricately involved in aging. Therefore, the precision control of brain autophagy activity could mediate sustained brain health with age.

**63**

treatment of AD.

*Dietary Impact on Neuronal Autophagy Control and Brain Health*

Given the challenge to adhere to prolonged CR regimes, as well as selective side effects, such as decreased body temperature [64] and slowed wound healing [65], compounds that elicit similar beneficial effects on aging, health, and life span as CR could be a more practical alternative. This area of research has sparked considerable interest in the use CRM drugs, or CRM supplements as adjuvant therapy to delay the aging process, particularly during mid- to late life. Currently, the most widely studied CRM candidates are resveratrol, rapamycin, 2-deoxy-D-glucose (2DG),

Resveratrol is a polyphenol compound isolated from the skins of red grapes, with red wine (5 mg/L on average) being the principal source of this compound [66]. Daily consumption of grape and blueberry polyphenols has also gained interest as CRMs for the prevention and treatment of neurodegenerative diseases. For example, studies indicate that the combined dietary supplementation of grape and blueberry polyphenols may have beneficial effects on age-related cognitive decline, improving episodic memory impairment in elderly subjects [67] and preventing the onset of learning and cognitive deficits in aged mice [68]. However, resveratrol has been found to be the most potent polyphenol compound and is to date the most thoroughly studied CRM, first identified and implicated in life span extension in a yeast model system [69]. Work by Baur et al. [70] revealed that resveratrol significantly increased survival in middle-aged mice on a high-calorie diet compared to that of mice on a standard diet by nearly 31%. In addition, resveratrol increased insulin sensitivity, reduced IGF1 levels, activated AMPK/PGC-1α signaling, and improved motor function [70]. Similar benefits have been reported in response to resveratrol supplementation in nonhuman primate models fed a high-fat diet [71, 72]. In the latter study, resveratrol improved adipose insulin levels and reduced the inflammatory response caused by the high-fat diet [72], while the former study revealed that resveratrol prevented diet-induced arterial

Naturally sourced resveratrol is poorly absorbed in humans [73]. Hence, high-purity resveratrol-mimetic drugs, such as ResVida™, have been developed to ensure its sustained release [74]. In a recent study, 30-day resveratrol supplementation (150 mg/day ResVida™) in humans led to a decrease in circulating glucose levels, inflammatory markers, triglycerides, and systolic blood pressure [74]. In contrast, others have reported no significant changes in the above parameters in obese men following resveratrol supplementation [75]. Longevinex® is another commercially available resveratrol supplement shown to induce SIRT1 and PGC-1α and increase mitochondrial biogenesis in the brain [76]. Prolonged Longevinex® supplementation has been shown to result in increased levels of LC3-II, Beclin1, and FOXO transcription factors. Therefore, it appears conceivable that prolonged Longevinex® may influence brain health, in part, by inducing neuronal autophagy. Work by Vingtdeux et al. [77] has also revealed that resveratrol can decrease extracellular Aβ accumulation by inducing autophagy through the activation of AMPK. Long-term resveratrol treatment is well tolerated in humans [78], with significantly reduced Aβ levels and improved memory retention observed in AD mouse models [79], making this compound a promising CRM candidate for the

**8. Antiaging pharmacological CR mimetics**

*DOI: http://dx.doi.org/10.5772/intechopen.85228*

metformin, and spermidine (**Figure 3**).

**8.1 Resveratrol**

wall inflammation [71].

## **8. Antiaging pharmacological CR mimetics**

Given the challenge to adhere to prolonged CR regimes, as well as selective side effects, such as decreased body temperature [64] and slowed wound healing [65], compounds that elicit similar beneficial effects on aging, health, and life span as CR could be a more practical alternative. This area of research has sparked considerable interest in the use CRM drugs, or CRM supplements as adjuvant therapy to delay the aging process, particularly during mid- to late life. Currently, the most widely studied CRM candidates are resveratrol, rapamycin, 2-deoxy-D-glucose (2DG), metformin, and spermidine (**Figure 3**).

## **8.1 Resveratrol**

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

Inhibition of insulin/IGF1 signaling following CR or growth factor removal has been reported to increase life span, delay the onset of age-related diseases, and increase oxidative stress resistance in various species, including humans [60]. CR-induced downregulation of the insulin/IGF1 pathway in turn induces the activation of SIRT1, resulting in the activation of FOXO transcription factors [61].

*The targeting of nutrient-triggered pathways by selective calorie restriction mimetics in longevity and the promotion of brain health. CR, calorie restriction; CRM, caloric restriction mimetic; IF, intermittent fasting; SIRT1, sirtuin-1; mTORC1, mammalian target of rapamycin complex 1; AMPK, AMP-dependent protein kinase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-α; insulin/IGF-1, insulin/ insulin-like growth factor-1; PI3K, phosphoinositide 3-kinase; FOXO, Forkhead box O; EP300, E1A-binding* 

mTORC1 is activated by growth factors, amino acids, or increased glucose levels, and is thought to control life span through various mechanisms, including the regulation of autophagy [62]. Indeed, autophagy has been shown to be essential for life span expansion in mTOR knockout yeast [63] and *C. elegans* model systems in which impaired autophagic function has been shown to abolish the life span extension induced by mTOR inhibition under CR conditions [28]. The convergence of CR-induced signaling pathways on autophagy supports the assertion that this process is intricately involved in aging. Therefore, the precision control of brain autophagy activity could mediate sustained brain health with age.

**62**

**7.5 Insulin/IGF1 signaling**

**Figure 3.**

*protein p300.*

**7.6 mTORC1 signaling**

Resveratrol is a polyphenol compound isolated from the skins of red grapes, with red wine (5 mg/L on average) being the principal source of this compound [66]. Daily consumption of grape and blueberry polyphenols has also gained interest as CRMs for the prevention and treatment of neurodegenerative diseases. For example, studies indicate that the combined dietary supplementation of grape and blueberry polyphenols may have beneficial effects on age-related cognitive decline, improving episodic memory impairment in elderly subjects [67] and preventing the onset of learning and cognitive deficits in aged mice [68]. However, resveratrol has been found to be the most potent polyphenol compound and is to date the most thoroughly studied CRM, first identified and implicated in life span extension in a yeast model system [69]. Work by Baur et al. [70] revealed that resveratrol significantly increased survival in middle-aged mice on a high-calorie diet compared to that of mice on a standard diet by nearly 31%. In addition, resveratrol increased insulin sensitivity, reduced IGF1 levels, activated AMPK/PGC-1α signaling, and improved motor function [70]. Similar benefits have been reported in response to resveratrol supplementation in nonhuman primate models fed a high-fat diet [71, 72]. In the latter study, resveratrol improved adipose insulin levels and reduced the inflammatory response caused by the high-fat diet [72], while the former study revealed that resveratrol prevented diet-induced arterial wall inflammation [71].

Naturally sourced resveratrol is poorly absorbed in humans [73]. Hence, high-purity resveratrol-mimetic drugs, such as ResVida™, have been developed to ensure its sustained release [74]. In a recent study, 30-day resveratrol supplementation (150 mg/day ResVida™) in humans led to a decrease in circulating glucose levels, inflammatory markers, triglycerides, and systolic blood pressure [74]. In contrast, others have reported no significant changes in the above parameters in obese men following resveratrol supplementation [75]. Longevinex® is another commercially available resveratrol supplement shown to induce SIRT1 and PGC-1α and increase mitochondrial biogenesis in the brain [76]. Prolonged Longevinex® supplementation has been shown to result in increased levels of LC3-II, Beclin1, and FOXO transcription factors. Therefore, it appears conceivable that prolonged Longevinex® may influence brain health, in part, by inducing neuronal autophagy. Work by Vingtdeux et al. [77] has also revealed that resveratrol can decrease extracellular Aβ accumulation by inducing autophagy through the activation of AMPK. Long-term resveratrol treatment is well tolerated in humans [78], with significantly reduced Aβ levels and improved memory retention observed in AD mouse models [79], making this compound a promising CRM candidate for the treatment of AD.

#### **8.2 Rapamycin**

The suppression of mTORC1 activity is associated with a significant improvement in both health and life span in various organisms, while increased activity is associated with old age in humans [80]. Hence, the use of mTORC1 inhibitor rapamycin may have potential applications as a CRM. Currently, rapamycin is clinically used as an immunosuppressant to prevent the rejection of kidney transplants in patients [66]. In AD mouse models, rapamycin treatment has been shown to improve cognitive ability and reduce Aβ and tau pathology, with these observations being linked to increased autophagic induction [81]. However, it has been reported that prolonged rapamycin treatment in rodents leads to the development of hyperlipidemia, glucose intolerance, and high levels of free fatty acids in skeletal muscle [82]. In contrast, lifelong intermittent administration of rapamycin for 2 weeks/month was found to extend life span in mice [81], suggesting that intermittent rapamycin administration may be more beneficial. In a separate study, adult mice maintained on lifelong rapamycin treatment, starting at 2 months of age, performed significantly better on a task measuring spatial learning and memory compared to age-matched mice on the control diet [83]. However, rapamycin did not improve cognition in adult mice with pre-existing agedependent cognitive deficits [83], suggesting that rapamycin may have better cognitive outcomes prior to the onset of cognitive deficits.

Rapamycin is unstable in water; thus, different oral preparations such as nanoparticles [84] have been formulated to increase its bioavailability. Rapatar, a rapamycin formulation based on Pluronic block copolymers as nanocarriers, has been shown to have significantly higher bioavailability after oral administration [85]. Rapatar has been shown to increase life span and delay carcinogenesis during lifelong treatment administered at intermittently low doses (0.5 mg/kg) in tumorprone mice [86]. The advantage of rapamycin is its FDA-approved status for various clinical applications in humans; however, the relevance for longevity in humans has yet to be established given its immunosuppressive effects.

#### **8.3 Metformin**

Metformin is a first-line drug approved for the treatment of diabetes [87], which also targets the insulin/IGF1 pathway, mTORC1, AMPK, and SIRT1 [88]. Metformin is rapidly distributed to many tissues following partial absorption, whereas the luminal concentration in the gastrointestinal tract remains high after a single oral dose [89]. Patients with type 2 diabetes have an increased risk of developing AD [90], as insulin has been shown to prevent Aβ oligomer formation in a dose-dependent matter [90]. A 12-year cohort study revealed that metformin supplementation reduced the AD risk in type 2 diabetes patients, with the risk being further reduced when metformin was combined with an antihyperglycemic agent, sulfonylurea [91]. In contrast, a case-control study revealed that long-term metformin-treated type 2 diabetes patients had a slightly higher risk of developing AD [92]. Despite these contradictory findings, metformin remains a promising CRM, but further research is required to unravel its effects on brain health.

#### **8.4 2DG**

2DG is a well-established glycolysis inhibitor first identified by Lane et al. [93] as a potential CRM drug. In this study, rats fed with a 2DG supplemented diet at varying weight-dependent doses revealed that 2DG was toxic at a high dosage, while at the lower dosage, 2DG supplementation had beneficial effects, including reduced blood insulin levels [93]. Rodents maintained on a 2DG-supplemented

**65**

*Dietary Impact on Neuronal Autophagy Control and Brain Health*

diet for 2 weeks increased neuronal resistance in AD [94] and PD [95] models. While 7 weeks of 2DG supplementation at a dosage of 0.04% has been shown to attenuate amyloid pathology and increase the levels of BDNF in an AD mouse model [96], toxicity studies revealed that 2DG supplementation at a dosage of 0.2–0.4% may induce cardiotoxicity [97]. 2DG has been linked to the upregulation of CR-related signaling pathways, specifically increased activation of AMPK and SIRT1 [93]. Hence, 2DG remains a viable CRM candidate provided the dose-

Given the cell's declining capacity to sustain efficient autophagic degradation with age, it is not surprising that autophagy dysfunction plays a key role in pathological processes common to aging and neurodegeneration in the elderly [98]. The modulation of autophagic activity may thus be a promising strategy to offset the progression of neurodegenerative processes with age [99]. In addition to adhering to low CR regimes, and the use of CRM drugs, autophagy-induced life extension may also be mediated using the histone acetylase inhibitor, spermidine. Unlike other autophagy-inducing drugs, spermidine has shown no adverse effects during lifelong administration in mice [100], with clinical data indicating good safety and tolerability in elderly subjects during long-term dietary supplementation [101].

Spermidine is a naturally occurring polyamine that has been shown to decline throughout the aging process in humans [102]. Accordingly, spermidine dietary supplementation in mice (26 weeks) and humans (2 months) has been shown to increase blood polyamine concentrations [103, 104]. Studies reveal that spermidine influences life span, partly, by inducing autophagy through the suppression of E1Abinding protein p300 (EP300), an acetyltransferase that transfers acetyl groups from acetyl coenzyme A to core Atg proteins, thereby inhibiting this pathway [105]. Indeed, He et al. [99] revealed that spermidine's life-extending effects were abolished when autophagy activity was suppressed through *Atg7* or *Beclin1* knockdown *in vivo*, consistent with a causal connection between autophagy induction, neuro-

Spermidine's autophagy-inducing potency has been quantified to be equivalent to that of rapamycin [106]. Although dietary supplementation with spermidine has emerged as a promising prevention strategy in aging individuals with an elevated risk of developing AD, the spermidine concentration required for optimal autophagy activity with healthy aging in humans remains unknown. A recent study revealed that spermidine supplementation had no toxic effects even at high concentrations in mice and in older adults at risk for AD [101]. Improved memory performance was reported in the aged subjects after 3 months of spermidine intake compared to the placebo group [107], suggesting that nutritional spermidine may

Considerable efforts have been made to identify autophagy-inducing drugs which may attenuate the risk for age-associated diseases. Recently, Kaizuka et al. [108] developed an autophagic flux probe which was used to rank

*DOI: http://dx.doi.org/10.5772/intechopen.85228*

dependent toxicity can be fully established.

**9. Autophagy-inducing agents**

**9.1 Spermidine**

protection, and longevity.

potentially delay memory loss with age.

**10. Screening for autophagy-inducing CRMs**

*Dietary Impact on Neuronal Autophagy Control and Brain Health DOI: http://dx.doi.org/10.5772/intechopen.85228*

diet for 2 weeks increased neuronal resistance in AD [94] and PD [95] models. While 7 weeks of 2DG supplementation at a dosage of 0.04% has been shown to attenuate amyloid pathology and increase the levels of BDNF in an AD mouse model [96], toxicity studies revealed that 2DG supplementation at a dosage of 0.2–0.4% may induce cardiotoxicity [97]. 2DG has been linked to the upregulation of CR-related signaling pathways, specifically increased activation of AMPK and SIRT1 [93]. Hence, 2DG remains a viable CRM candidate provided the dosedependent toxicity can be fully established.

### **9. Autophagy-inducing agents**

Given the cell's declining capacity to sustain efficient autophagic degradation with age, it is not surprising that autophagy dysfunction plays a key role in pathological processes common to aging and neurodegeneration in the elderly [98]. The modulation of autophagic activity may thus be a promising strategy to offset the progression of neurodegenerative processes with age [99]. In addition to adhering to low CR regimes, and the use of CRM drugs, autophagy-induced life extension may also be mediated using the histone acetylase inhibitor, spermidine. Unlike other autophagy-inducing drugs, spermidine has shown no adverse effects during lifelong administration in mice [100], with clinical data indicating good safety and tolerability in elderly subjects during long-term dietary supplementation [101].

#### **9.1 Spermidine**

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

outcomes prior to the onset of cognitive deficits.

yet to be established given its immunosuppressive effects.

The suppression of mTORC1 activity is associated with a significant improvement in both health and life span in various organisms, while increased activity is associated with old age in humans [80]. Hence, the use of mTORC1 inhibitor rapamycin may have potential applications as a CRM. Currently, rapamycin is clinically used as an immunosuppressant to prevent the rejection of kidney transplants in patients [66]. In AD mouse models, rapamycin treatment has been shown to improve cognitive ability and reduce Aβ and tau pathology, with these observations being linked to increased autophagic induction [81]. However, it has been reported that prolonged rapamycin treatment in rodents leads to the development of hyperlipidemia, glucose intolerance, and high levels of free fatty acids in skeletal muscle [82]. In contrast, lifelong intermittent administration of rapamycin for 2 weeks/month was found to extend life span in mice [81], suggesting that intermittent rapamycin administration may be more beneficial. In a separate study, adult mice maintained on lifelong rapamycin treatment, starting at 2 months of age, performed significantly better on a task measuring spatial learning and memory compared to age-matched mice on the control diet [83]. However, rapamycin did not improve cognition in adult mice with pre-existing agedependent cognitive deficits [83], suggesting that rapamycin may have better cognitive

Rapamycin is unstable in water; thus, different oral preparations such as nanoparticles [84] have been formulated to increase its bioavailability. Rapatar, a rapamycin formulation based on Pluronic block copolymers as nanocarriers, has been shown to have significantly higher bioavailability after oral administration [85]. Rapatar has been shown to increase life span and delay carcinogenesis during lifelong treatment administered at intermittently low doses (0.5 mg/kg) in tumorprone mice [86]. The advantage of rapamycin is its FDA-approved status for various clinical applications in humans; however, the relevance for longevity in humans has

Metformin is a first-line drug approved for the treatment of diabetes [87], which also targets the insulin/IGF1 pathway, mTORC1, AMPK, and SIRT1 [88]. Metformin is rapidly distributed to many tissues following partial absorption, whereas the luminal concentration in the gastrointestinal tract remains high after a single oral dose [89]. Patients with type 2 diabetes have an increased risk of developing AD [90], as insulin has been shown to prevent Aβ oligomer formation in a dose-dependent matter [90]. A 12-year cohort study revealed that metformin supplementation reduced the AD risk in type 2 diabetes patients, with the risk being further reduced when metformin was combined with an antihyperglycemic agent, sulfonylurea [91]. In contrast, a case-control study revealed that long-term metformin-treated type 2 diabetes patients had a slightly higher risk of developing AD [92]. Despite these contradictory findings, metformin remains a promising CRM, but further research is required to unravel its effects on brain health.

2DG is a well-established glycolysis inhibitor first identified by Lane et al. [93] as a potential CRM drug. In this study, rats fed with a 2DG supplemented diet at varying weight-dependent doses revealed that 2DG was toxic at a high dosage, while at the lower dosage, 2DG supplementation had beneficial effects, including reduced blood insulin levels [93]. Rodents maintained on a 2DG-supplemented

**8.2 Rapamycin**

**8.3 Metformin**

**64**

**8.4 2DG**

Spermidine is a naturally occurring polyamine that has been shown to decline throughout the aging process in humans [102]. Accordingly, spermidine dietary supplementation in mice (26 weeks) and humans (2 months) has been shown to increase blood polyamine concentrations [103, 104]. Studies reveal that spermidine influences life span, partly, by inducing autophagy through the suppression of E1Abinding protein p300 (EP300), an acetyltransferase that transfers acetyl groups from acetyl coenzyme A to core Atg proteins, thereby inhibiting this pathway [105]. Indeed, He et al. [99] revealed that spermidine's life-extending effects were abolished when autophagy activity was suppressed through *Atg7* or *Beclin1* knockdown *in vivo*, consistent with a causal connection between autophagy induction, neuroprotection, and longevity.

Spermidine's autophagy-inducing potency has been quantified to be equivalent to that of rapamycin [106]. Although dietary supplementation with spermidine has emerged as a promising prevention strategy in aging individuals with an elevated risk of developing AD, the spermidine concentration required for optimal autophagy activity with healthy aging in humans remains unknown. A recent study revealed that spermidine supplementation had no toxic effects even at high concentrations in mice and in older adults at risk for AD [101]. Improved memory performance was reported in the aged subjects after 3 months of spermidine intake compared to the placebo group [107], suggesting that nutritional spermidine may potentially delay memory loss with age.

### **10. Screening for autophagy-inducing CRMs**

Considerable efforts have been made to identify autophagy-inducing drugs which may attenuate the risk for age-associated diseases. Recently, Kaizuka et al. [108] developed an autophagic flux probe which was used to rank


#### **Table 1.**

*Autophagy inducers identified using a sensitive autophagic flux probe.*

**Figure 4.**

*Matching autophagy induction with autophagic flux decline and dysfunction in brain health and pathology associated with cognitive impairment.*

**67**

neuronal proteotoxicity.

aging [48].

*Dietary Impact on Neuronal Autophagy Control and Brain Health*

autophagy-inducing drugs according to their level of potency by screening an approved drug library. The autophagic flux probe, i.e., GFP-LC3-RFP-LC3∆G, is a fusion protein consisting of GFP-LC3 and RFP-LC3, with the C-terminal glycine of RFP-LC3 being deleted. An equal amount of GFP-LC3 and RFP-LC3∆G is generated in the cytosol, and upon autophagy induction, GFP-LC3 is degraded within autolysosomes, while RFP-LC3∆G remains in the cytosol and serves as an internal control. GFP-LC3-RFP-LC3∆G-expressing cells were treated with candidate drugs at varying concentrations for 24 hrs under both nutrient-rich and starvation conditions. The resulting GFP/RFP signal ratio was measured using a microplate reader, with a low GFP/RFP ratio indicating a robust autophagy inducer (**Table 1**). Caution is recommended during cell transfection, as homologous recombination can occur between the two LC3 proteins of the probe. Thus, the isolation of properly expressing GFP-LC3-RFP is recommended. Expression levels of the probe may also vary among different cells/tissues; thus, cells/tissues with similar RFP expression levels should be compared. Lastly, the probe has a relatively low time resolution, making it more ideal for the detection of basal

Of the 47 autophagy inducers identified, 3 were of relevance to neuroprotection. Importantly, these data indicate firstly, that autophagy activity can be measured accurately and hence standardized and, secondly, that neuronal autophagy decline in aging or neurodegeneration may be matched with an autophagy inducer that is suitable to offset autophagy dysfunction at the respective levels of autophagy activity (**Figure 4**). Further studies using these drugs in the context of healthy brain

Other antiaging nutrients identified to date, including antioxidants (vitamins A, C, D, and E; quercetin; and coenzyme Q10), and phytochemicals, such as curcumin and epigallocatechin-3-gallate, have been shown to enhance autophagy activity [114]. However, there is a paucity of studies on their overall health benefits in humans.

Research on the "nutrition transition" reveal that urban areas of developing north and sub-Saharan African countries, Asia, Latin America, and the Middle East share similar dietary pattern shifts [115]. One commonality of this shift is the increased consumption of fat and sugar-laden foods associated with increased risk for age-associated and lifestyle-based diseases. The consumption of nutritionally dense CRM foods, such as marine-based carotenoid-rich food, sweet potatoes, legumes, low-GI grains, fruits, and various flavonoids used in the Okinawan diet, is thought to be the most beneficial food choices for successful

Should we restrict our calories/frequently consume CRMs in order to preserve brain health and maintain a sufficiently high neuronal autophagic flux with age? Cumulative evidence from over 70 years of CR research provides compelling support for the role of CR-induced autophagic activity in brain health and longevity [116]. Therefore, a CR regime, alone or in combination with the dietary supplementation of a potent autophagy-inducing CRM, could contribute substantially to successful brain aging, delaying the onset of detrimental effects associated with

*DOI: http://dx.doi.org/10.5772/intechopen.85228*

aging as well as AD pathology are required.

**11. Healthier dietary patterns for successful aging?**

**12. Future considerations for successful brain aging**

autophagy [108].

#### *Dietary Impact on Neuronal Autophagy Control and Brain Health DOI: http://dx.doi.org/10.5772/intechopen.85228*

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

47 Azacitidine 70.0 Hematopoiesis

*Autophagy inducers identified using a sensitive autophagic flux probe.*

29 Loperamide

*Modified from Kaizuka et al. [108].*

**Table 1.**

hydrochloride

**Rank Drug GFP/RFP (%) Pathology Reference** Ciclopirox olamine 17.3 Cancer Zhou et al. [109] Cladribine (2-CDA) 51.1 AD model Hayes et al. [110] Sertraline hydrochloride 58.8 Depression Rainey et al. [111]

61.7 Huntington's

disease model

disorders

Williams et al. [112]

Abdulhaq and Rossetti [113]

*Matching autophagy induction with autophagic flux decline and dysfunction in brain health and pathology associated* 

**66**

**Figure 4.**

*with cognitive impairment.*

autophagy-inducing drugs according to their level of potency by screening an approved drug library. The autophagic flux probe, i.e., GFP-LC3-RFP-LC3∆G, is a fusion protein consisting of GFP-LC3 and RFP-LC3, with the C-terminal glycine of RFP-LC3 being deleted. An equal amount of GFP-LC3 and RFP-LC3∆G is generated in the cytosol, and upon autophagy induction, GFP-LC3 is degraded within autolysosomes, while RFP-LC3∆G remains in the cytosol and serves as an internal control. GFP-LC3-RFP-LC3∆G-expressing cells were treated with candidate drugs at varying concentrations for 24 hrs under both nutrient-rich and starvation conditions. The resulting GFP/RFP signal ratio was measured using a microplate reader, with a low GFP/RFP ratio indicating a robust autophagy inducer (**Table 1**). Caution is recommended during cell transfection, as homologous recombination can occur between the two LC3 proteins of the probe. Thus, the isolation of properly expressing GFP-LC3-RFP is recommended. Expression levels of the probe may also vary among different cells/tissues; thus, cells/tissues with similar RFP expression levels should be compared. Lastly, the probe has a relatively low time resolution, making it more ideal for the detection of basal autophagy [108].

Of the 47 autophagy inducers identified, 3 were of relevance to neuroprotection. Importantly, these data indicate firstly, that autophagy activity can be measured accurately and hence standardized and, secondly, that neuronal autophagy decline in aging or neurodegeneration may be matched with an autophagy inducer that is suitable to offset autophagy dysfunction at the respective levels of autophagy activity (**Figure 4**). Further studies using these drugs in the context of healthy brain aging as well as AD pathology are required.

Other antiaging nutrients identified to date, including antioxidants (vitamins A, C, D, and E; quercetin; and coenzyme Q10), and phytochemicals, such as curcumin and epigallocatechin-3-gallate, have been shown to enhance autophagy activity [114]. However, there is a paucity of studies on their overall health benefits in humans.

## **11. Healthier dietary patterns for successful aging?**

Research on the "nutrition transition" reveal that urban areas of developing north and sub-Saharan African countries, Asia, Latin America, and the Middle East share similar dietary pattern shifts [115]. One commonality of this shift is the increased consumption of fat and sugar-laden foods associated with increased risk for age-associated and lifestyle-based diseases. The consumption of nutritionally dense CRM foods, such as marine-based carotenoid-rich food, sweet potatoes, legumes, low-GI grains, fruits, and various flavonoids used in the Okinawan diet, is thought to be the most beneficial food choices for successful aging [48].

## **12. Future considerations for successful brain aging**

Should we restrict our calories/frequently consume CRMs in order to preserve brain health and maintain a sufficiently high neuronal autophagic flux with age? Cumulative evidence from over 70 years of CR research provides compelling support for the role of CR-induced autophagic activity in brain health and longevity [116]. Therefore, a CR regime, alone or in combination with the dietary supplementation of a potent autophagy-inducing CRM, could contribute substantially to successful brain aging, delaying the onset of detrimental effects associated with neuronal proteotoxicity.

## **Acknowledgements**

The authors acknowledge financial support from the South African National Research Foundation (NRF), the South African Medical Research Council (SAMRC), and the Cancer Association of South Africa (CANSA).

## **Author details**

Claudia Ntsapi, Andre du Toit and Ben Loos\* Department of Physiological Sciences, Faculty of Natural Sciences, University of Stellenbosch, Stellenbosch, South Africa

\*Address all correspondence to: bloos@sun.ac.za

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**69**

*Dietary Impact on Neuronal Autophagy Control and Brain Health*

the National Academy of Sciences of the United States of America.

[10] Xilouri M, Brekk OR, et al. Alpha-Synuclein and protein degradation systems: A reciprocal relationship. Molecular Neurobiology.

[11] Correia SC, Resende R, et al. Alzheimer's disease-related misfolded proteins and dysfunctional organelles on autophagy menu. DNA and Cell

[12] Vellai T, Takács-Vellai K, et al. The regulation of aging: Does autophagy underlie longevity? Trends in Cell Biology. 2009;**19**(10):487-494

[13] Kroemer G, Mariño G, et al. Autophagy and the integrated stress response. Molecular Cell.

[14] Scrivo A, Bourdenx M, et al. Selective autophagy as a potential therapeutic target for neurodegenerative

[15] Li W, Li J, Bao J. Microautophagy: Lesser-known self-eating. Cellular and Molecular Life Sciences. 2012;**69**(7):1125-1136

[16] Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy. Nature Reviews. Molecular Cell Biology. 2018;**19**(6):365-381

[17] Mizushima N, Yoshimori T, et al. The role of Atg proteins in autophagosome formation. Annual Review of Cell and Developmental

[18] Ravikumar B, Moreau K, et al. Plasma membrane contributes to the formation of pre-autophagosomal

Biology. 2011;**27**:107-132

disorders. Lancet Neurology.

2010;**40**(2):280-293

2018;**17**(9):802-815

Biology. 2015;**34**(4):261-273

1998;**95**(11):6469-6473

2013;**47**(2):537-551

*DOI: http://dx.doi.org/10.5772/intechopen.85228*

[1] Bloom DE, Chatterji S, et al. Macroeconomic implications of population ageing and selected policy responses. The Lancet. 2015;**385**(9968):649-657

[2] Lopreite M, Mauro M. The effects of population ageing on health care expenditure: A Bayesian VAR analysis using data from Italy. Health Policy (Amsterdam, Netherlands).

[3] Hebert LE, Weuve J, et al. Alzheimer disease in the United States (2010- 2050) estimated using the 2010 census. Neurology. 2013;**80**(19):1778-1783

[4] Sabuncu MR, Desikan RS, et al. The dynamics of cortical and hippocampal atrophy in Alzheimer disease. Archives of Neurology. 2011;**68**(8):1040-1048

[5] Behrens S, Rattinger GB, et al. Use of FDA approved medications for Alzheimer's disease in mild dementia is associated with reduced informal costs of care. International Psychogeriatrics.

2018;**30**(10):1499-1507

[6] Blennow K, Hampel H, et al. Cerebrospinal fluid and plasma

[7] Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science. 2002;**297**(5580):353-356

[8] Saito T, Suemoto T, et al. Potent amyloidogenicity and pathogenicity of Aβ43. Nature Neuroscience.

[9] Spillantini MG, Crowther RA, et al. Alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proceedings of

2011;**14**(8):1023-1032

biomarkers in Alzheimer disease. Nature Reviews. Neurology. 2010;**6**(3):131-144

2017;**121**(6):663-674

**References**

*Dietary Impact on Neuronal Autophagy Control and Brain Health DOI: http://dx.doi.org/10.5772/intechopen.85228*

## **References**

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

(SAMRC), and the Cancer Association of South Africa (CANSA).

The authors acknowledge financial support from the South African National

Research Foundation (NRF), the South African Medical Research Council

**Acknowledgements**

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Physiological Sciences, Faculty of Natural Sciences, University of

**68**

**Author details**

provided the original work is properly cited.

Claudia Ntsapi, Andre du Toit and Ben Loos\*

\*Address all correspondence to: bloos@sun.ac.za

Stellenbosch, Stellenbosch, South Africa

[1] Bloom DE, Chatterji S, et al. Macroeconomic implications of population ageing and selected policy responses. The Lancet. 2015;**385**(9968):649-657

[2] Lopreite M, Mauro M. The effects of population ageing on health care expenditure: A Bayesian VAR analysis using data from Italy. Health Policy (Amsterdam, Netherlands). 2017;**121**(6):663-674

[3] Hebert LE, Weuve J, et al. Alzheimer disease in the United States (2010- 2050) estimated using the 2010 census. Neurology. 2013;**80**(19):1778-1783

[4] Sabuncu MR, Desikan RS, et al. The dynamics of cortical and hippocampal atrophy in Alzheimer disease. Archives of Neurology. 2011;**68**(8):1040-1048

[5] Behrens S, Rattinger GB, et al. Use of FDA approved medications for Alzheimer's disease in mild dementia is associated with reduced informal costs of care. International Psychogeriatrics. 2018;**30**(10):1499-1507

[6] Blennow K, Hampel H, et al. Cerebrospinal fluid and plasma biomarkers in Alzheimer disease. Nature Reviews. Neurology. 2010;**6**(3):131-144

[7] Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer's disease: Progress and problems on the road to therapeutics. Science. 2002;**297**(5580):353-356

[8] Saito T, Suemoto T, et al. Potent amyloidogenicity and pathogenicity of Aβ43. Nature Neuroscience. 2011;**14**(8):1023-1032

[9] Spillantini MG, Crowther RA, et al. Alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson's disease and dementia with lewy bodies. Proceedings of

the National Academy of Sciences of the United States of America. 1998;**95**(11):6469-6473

[10] Xilouri M, Brekk OR, et al. Alpha-Synuclein and protein degradation systems: A reciprocal relationship. Molecular Neurobiology. 2013;**47**(2):537-551

[11] Correia SC, Resende R, et al. Alzheimer's disease-related misfolded proteins and dysfunctional organelles on autophagy menu. DNA and Cell Biology. 2015;**34**(4):261-273

[12] Vellai T, Takács-Vellai K, et al. The regulation of aging: Does autophagy underlie longevity? Trends in Cell Biology. 2009;**19**(10):487-494

[13] Kroemer G, Mariño G, et al. Autophagy and the integrated stress response. Molecular Cell. 2010;**40**(2):280-293

[14] Scrivo A, Bourdenx M, et al. Selective autophagy as a potential therapeutic target for neurodegenerative disorders. Lancet Neurology. 2018;**17**(9):802-815

[15] Li W, Li J, Bao J. Microautophagy: Lesser-known self-eating. Cellular and Molecular Life Sciences. 2012;**69**(7):1125-1136

[16] Kaushik S, Cuervo AM. The coming of age of chaperone-mediated autophagy. Nature Reviews. Molecular Cell Biology. 2018;**19**(6):365-381

[17] Mizushima N, Yoshimori T, et al. The role of Atg proteins in autophagosome formation. Annual Review of Cell and Developmental Biology. 2011;**27**:107-132

[18] Ravikumar B, Moreau K, et al. Plasma membrane contributes to the formation of pre-autophagosomal

structures. Nature Cell Biology. 2010;**12**(8):747-757

[19] Klionsky DJ, Abdelmohsen K, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;**12**(1):1-222

[20] Loos B, du Toit A, J-HS H. Defining and measuring autophagosome flux—Concept and reality. Autophagy. 2014;**10**(11):2087-2096

[21] Jhanwar-Uniyal M, Amin AG, et al. Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects. Advances in Biological Regulation. 2017;**64**:39-48

[22] Inoki K, Li Y, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biology. 2002;**4**(9):648-657

[23] Ikenoue T, Inoki K, et al. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. The EMBO Journal. 2008;**27**(14):1919-1931

[24] Medina DL, Settembre C, et al. Methods to monitor and manipulate TFEB activity during autophagy. Methods in Enzymology. 2017;**588**:61-78

[25] Inoki K, Zhu T, et al. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;**115**(5):577-590

[26] Laker R, Drake J, et al. Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nature Communications. 2017;**8**(1):548

[27] Lipinski M, Zheng B, et al. Genomewide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proceedings of the National Academy

of Sciences of the United States of America. 2010;**107**(32):14164-14169

[28] Tóth M, Sigmond T, et al. Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy. 2008;**4**(3):330-338

[29] Matecic M, Smith D, et al. A microarray-based genetic screen for yeast chronological aging factors. PLoS Genetics. 2010;**6**(4):e1000921

[30] Hara T, Nakamura K, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;**441**(7095):885-889

[31] Komatsu M, Waguri S, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;**441**(7095):880-884

[32] Cataldo A, Hamilton D, et al. Properties of the endosomal-lysosomal system in the human central nervous system: Disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease. Journal of Neuroscience: The Official Journal of the Society for Neuroscience. 1996;**16**(1):186-199

[33] Yu WH, Cuervo AM, et al. Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. The Journal of Cell Biology. 2005;**171**(1):87-98

[34] Pickford F, Masliah E, et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. The Journal of Clinical Investigation. 2008;**118**(6):2190-2199

[35] Spilman P, Podlutskaya N, et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS One. 2010;**5**(4):e9979

**71**

*Dietary Impact on Neuronal Autophagy Control and Brain Health*

and metabolism. Metabolism. 2015;**64**(11):1395-1407

Cell Cycle (Georgetown, Tex.).

[46] Martin B, Pearson M, et al. Sex-dependent metabolic, neuroendocrine, and cognitive responses to dietary energy

2007;**148**(9):4318-4333

2007;**1114**:434-455

2006;**82**(964):84-88

One. 2011;**6**(1):e16581

2004;**25**(3):333-340

2005;**26**(7):995-1000

restriction and excess. Endocrinology.

[47] Rosenbaum MW, Willcox BJ, et al. Okinawa: A Naturally Calorie Restricted Population. Aging and Longevity. Netherlands: Springer; 2010. pp. 43-53

[48] Willcox BJ, Willcox DC, et al. Caloric restriction, the traditional Okinawan diet, and healthy aging: The diet of the world's longest-lived people and its potential impact on morbidity and life span. Annals of the New York Academy of Sciences.

[49] Peters R. Ageing and the brain. Postgraduate Medical Journal.

selectively enhanced during chronic caloric restriction or resveratrol supplementation in a primate. PLoS

[51] Bondolfi L, Ermini F, et al. Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice. Neurobiology of Aging.

[52] Patel NV, Gordon MN, et al. Caloric restriction attenuates Abetadeposition in Alzheimer transgenic models. Neurobiology of Aging.

[50] Dal-Pan A, Pifferi F, et al. Cognitive performances are

2015;**14**(1):46-55

[45] Anisimov VN, Popovich IG, et al. Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin.

*DOI: http://dx.doi.org/10.5772/intechopen.85228*

[36] Majumder S, Richardson A, et al. Inducing autophagy by Rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS One.

[37] Madeo F, Zimmermann A, et al. Essential role for autophagy in life span extension. The Journal of Clinical Investigation. 2015;**125**(1):85-93

[38] Alirezaei M, Kemball C, et al. Short-term fasting induces profound neuronal autophagy. Autophagy.

[39] Patterson RE, Laughlin GA, et al. Intermittent fasting and human metabolic health. Journal of the Academy of Nutrition and Dietetics.

[40] Mattson MP. Lifelong brain health is a lifelong challenge: From evolutionary principles to empirical evidence. Ageing Research Reviews.

[41] Goodrick CL, Ingram DK, et al. Effects of intermittent feeding upon growth, activity, and life span in rats allowed voluntary exercise. Experimental Aging Research.

[42] Schafer MJ, Alldred MJ, et al. Reduction of β-amyloid and γ-secretase

[43] Halagappa VKM, Guo Z, et al. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-

[44] Anastasiou CA, Karfopoulou E, et al. Weight regaining: From statistics and behaviors to physiology

transgenic mouse model of Alzheimer's disease. Neurobiology of Disease.

by calorie restriction in female Tg2576 mice. Neurobiology of Aging.

2011;**6**(9):e25416

2010;**6**(6):702-710

2015;**115**(8):1203-1212

2015;**20**:37-45

1983;**9**(3):203-209

2015;**36**(3):1293-1302

2007;**26**(1):212-220

*Dietary Impact on Neuronal Autophagy Control and Brain Health DOI: http://dx.doi.org/10.5772/intechopen.85228*

[36] Majumder S, Richardson A, et al. Inducing autophagy by Rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS One. 2011;**6**(9):e25416

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

of Sciences of the United States of America. 2010;**107**(32):14164-14169

[29] Matecic M, Smith D, et al. A microarray-based genetic screen for yeast chronological aging factors. PLoS

Genetics. 2010;**6**(4):e1000921

[30] Hara T, Nakamura K, et al. Suppression of basal autophagy in neural cells causes neurodegenerative

[31] Komatsu M, Waguri S, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006;**441**(7095):880-884

[32] Cataldo A, Hamilton D, et al. Properties of the endosomal-lysosomal system in the human central nervous system: Disturbances mark most neurons in populations at risk to degenerate in Alzheimer's disease. Journal of Neuroscience: The Official Journal of the Society for Neuroscience.

disease in mice. Nature. 2006;**441**(7095):885-889

1996;**16**(1):186-199

[33] Yu WH, Cuervo AM, et al.

Biology. 2005;**171**(1):87-98

2008;**118**(6):2190-2199

2010;**5**(4):e9979

Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. The Journal of Cell

[34] Pickford F, Masliah E, et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice. The Journal of Clinical Investigation.

[35] Spilman P, Podlutskaya N, et al. Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS One.

[28] Tóth M, Sigmond T, et al. Longevity pathways converge on autophagy genes to regulate life span in Caenorhabditis elegans. Autophagy. 2008;**4**(3):330-338

structures. Nature Cell Biology.

[19] Klionsky DJ, Abdelmohsen K, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;**12**(1):1-222

[20] Loos B, du Toit A, J-HS H. Defining

and measuring autophagosome flux—Concept and reality. Autophagy.

[21] Jhanwar-Uniyal M, Amin AG, et al. Discrete signaling mechanisms of mTORC1 and mTORC2: Connected yet apart in cellular and molecular aspects. Advances in Biological Regulation.

[22] Inoki K, Li Y, et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biology. 2002;**4**(9):648-657

2008;**27**(14):1919-1931

2017;**588**:61-78

2003;**115**(5):577-590

[24] Medina DL, Settembre C, et al. Methods to monitor and manipulate TFEB activity during autophagy. Methods in Enzymology.

[25] Inoki K, Zhu T, et al. TSC2 mediates cellular energy response to control cell growth and survival. Cell.

[26] Laker R, Drake J, et al. Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy. Nature Communications. 2017;**8**(1):548

[27] Lipinski M, Zheng B, et al. Genomewide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer's disease. Proceedings of the National Academy

[23] Ikenoue T, Inoki K, et al. Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling. The EMBO Journal.

2014;**10**(11):2087-2096

2017;**64**:39-48

2010;**12**(8):747-757

**70**

[37] Madeo F, Zimmermann A, et al. Essential role for autophagy in life span extension. The Journal of Clinical Investigation. 2015;**125**(1):85-93

[38] Alirezaei M, Kemball C, et al. Short-term fasting induces profound neuronal autophagy. Autophagy. 2010;**6**(6):702-710

[39] Patterson RE, Laughlin GA, et al. Intermittent fasting and human metabolic health. Journal of the Academy of Nutrition and Dietetics. 2015;**115**(8):1203-1212

[40] Mattson MP. Lifelong brain health is a lifelong challenge: From evolutionary principles to empirical evidence. Ageing Research Reviews. 2015;**20**:37-45

[41] Goodrick CL, Ingram DK, et al. Effects of intermittent feeding upon growth, activity, and life span in rats allowed voluntary exercise. Experimental Aging Research. 1983;**9**(3):203-209

[42] Schafer MJ, Alldred MJ, et al. Reduction of β-amyloid and γ-secretase by calorie restriction in female Tg2576 mice. Neurobiology of Aging. 2015;**36**(3):1293-1302

[43] Halagappa VKM, Guo Z, et al. Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the tripletransgenic mouse model of Alzheimer's disease. Neurobiology of Disease. 2007;**26**(1):212-220

[44] Anastasiou CA, Karfopoulou E, et al. Weight regaining: From statistics and behaviors to physiology and metabolism. Metabolism. 2015;**64**(11):1395-1407

[45] Anisimov VN, Popovich IG, et al. Sex differences in aging, life span and spontaneous tumorigenesis in 129/Sv mice neonatally exposed to metformin. Cell Cycle (Georgetown, Tex.). 2015;**14**(1):46-55

[46] Martin B, Pearson M, et al. Sex-dependent metabolic, neuroendocrine, and cognitive responses to dietary energy restriction and excess. Endocrinology. 2007;**148**(9):4318-4333

[47] Rosenbaum MW, Willcox BJ, et al. Okinawa: A Naturally Calorie Restricted Population. Aging and Longevity. Netherlands: Springer; 2010. pp. 43-53

[48] Willcox BJ, Willcox DC, et al. Caloric restriction, the traditional Okinawan diet, and healthy aging: The diet of the world's longest-lived people and its potential impact on morbidity and life span. Annals of the New York Academy of Sciences. 2007;**1114**:434-455

[49] Peters R. Ageing and the brain. Postgraduate Medical Journal. 2006;**82**(964):84-88

[50] Dal-Pan A, Pifferi F, et al. Cognitive performances are selectively enhanced during chronic caloric restriction or resveratrol supplementation in a primate. PLoS One. 2011;**6**(1):e16581

[51] Bondolfi L, Ermini F, et al. Impact of age and caloric restriction on neurogenesis in the dentate gyrus of C57BL/6 mice. Neurobiology of Aging. 2004;**25**(3):333-340

[52] Patel NV, Gordon MN, et al. Caloric restriction attenuates Abetadeposition in Alzheimer transgenic models. Neurobiology of Aging. 2005;**26**(7):995-1000

[53] Pani G. Neuroprotective effects of dietary restriction: Evidence and mechanisms. Seminars in Cell & Developmental Biology. 2015;**40**:106-114

[54] Nisoli E, Tonello C, et al. Calorie restriction promotes mitochondrial biogenesis by inducing the expression of eNOS. Science. 2005;**310**(5746):314-317

[55] Lee IH, Cao L, et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proceedings of the National Academy of Sciences of the United States of America. 2008;**105**(9):3374-3379

[56] Martins R, Lithgow GJ, Link W. Long live FOXO: Unraveling the role of FOXO proteins in aging and longevity. Aging Cell. 2016;**15**(2):196-207

[57] Hardie DG, Ashford MLJ. AMPK: Regulating energy balance at the cellular and whole body levels. Physiology. 2014;**29**(2):99-107

[58] Apfeld J, O'Connor G, et al. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to life span in C. Elegans. Genes & Development. 2004;**18**(24):3004-3009

[59] Cantó C, Jiang L, et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metabolism. 2010;**11**(3, 3):213-219

[60] Kenyon CJ. The genetics of ageing. Nature. 2010;**464**(7288):504-512

[61] Hulbert AJ, Pamplona R, et al. Life and death: Metabolic rate, membrane composition, and life span of animals. Physiological Reviews. 2007;**87**(4):1175-1213

[62] Alers S, Löffler A, et al. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: Cross talk, shortcuts, and feedbacks. Molecular and Cellular Biology. 2012;**32**(1, 1):2-11

[63] Kamada Y, Sekito T, et al. Autophagy in yeast: A TOR-mediated response to nutrient starvation. Current Topics in Microbiology and Immunology. 2004;**279**:73-84

[64] Soare A, Cangemi R, et al. Long-term calorie restriction, but not endurance exercise, lowers core body temperature in humans. Aging. 2011;**3**(4):374-379

[65] Hunt N, Li G, et al. Effect of calorie restriction and refeeding on skin wound healing in the rat. Age (Dordrecht, Netherlands). 2012;**34**(6):1453-1458

[66] Nikolai S, Pallauf K, et al. Energy restriction and potential energy restriction mimetics. Nutrition Research Reviews. 2015;**28**(2):100-120

[67] Bensalem J, Dudonné S, et al. Polyphenols from grape and blueberry improve episodic memory in healthy elderly with lower level of memory performance: A bicentric double-blind, randomized, placebo-controlled clinical study. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences. 2018

[68] Bensalem J, Dudonné S, et al. Polyphenol-rich extract from grape and blueberry attenuates cognitive decline and improves neuronal function in aged mice. Journal of Nutritional Science. 2018;**7**:e19

[69] Howitz K, Bitterman K, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae life span. Nature. 2003;**425**(6954):191-196

[70] Baur J, Pearson K, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;**444**(7117):337-342

**73**

*Dietary Impact on Neuronal Autophagy Control and Brain Health*

Alzheimer disease. Neurology.

[79] Porquet D, Griñán-Ferré C, et al. Neuroprotective role of transresveratrol in a murine model of familial Alzheimer's disease. The Journal of Alzheimer's Disease.

[80] Passtoors W, Beekman M, et al. Gene expression analysis of mTOR pathway: Association with human longevity. Aging Cell. 2013;**12**(1):24-31

[81] Anisimov V, Zabezhinski M, et al. Rapamycin increases life span and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle (Georgetown, Tex.).

[82] Cunningham J, Rodgers J, et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature.

[83] Majumder S, Caccamo A, et al. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1β and

enhancing NMDA signaling. Aging Cell.

International Journal of Nanomedicine.

nanoformulated micelles of rapamycin,

[85] Samidurai A, Salloum F, et al. Chronic treatment with novel

Rapatar, protects diabetic heart against ischaemia/reperfusion injury. British Journal of Pharmacology.

[86] Comas M, Toshkov I, et al. New nanoformulation of rapamycin Rapatar extends life span in homozygous

2017;**174**(24):4771-4784

2015;**85**(16):1383-1391

2014;**42**(4):1209-1220

2011;**10**(24):4230-4236

2007;**450**(7170):736-740

2012;**11**(2):326-335

2012;**7**:2197-2208

[84] Woo H, Chung H, et al. Preclinical evaluation of injectable sirolimus formulated with polymeric nanoparticle for cancer therapy.

*DOI: http://dx.doi.org/10.5772/intechopen.85228*

[72] Jimenez-Gomez Y, Mattison J, et al. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metabolism. 2013;**18**(4):533-545

[74] Timmers S, Konings E, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metabolism.

[75] Poulsen M, Vestergaard P, et al. High-dose resveratrol supplementation in obese men: An investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes. 2013;**62**(4):1186-1195

[76] Mukherjee S, Ray D, et al. Effects of Longevinex on cardioprotection and its mechanisms of action. Canadian Journal of Physiology and Pharmacology.

[77] Vingtdeux V, Giliberto L, et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism. The Journal of Biological Chemistry.

[78] Turner RS, Thomas R, et al. A randomized, double-blind, placebocontrolled trial of resveratrol for

[71] Mattison J, Wang M, et al. Resveratrol prevents high fat/ sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metabolism.

[73] Gambini J, Inglés M, et al. Properties of resveratrol: In vitro and In vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxidative Medicine and Cellular Longevity.

2015;**2015**:837042

2011;**14**(5):612-622

2010;**88**(11):1017-1025

2010;**285**(12):9100-9113

2014;**20**(1, 1):183-190

*Dietary Impact on Neuronal Autophagy Control and Brain Health DOI: http://dx.doi.org/10.5772/intechopen.85228*

[71] Mattison J, Wang M, et al. Resveratrol prevents high fat/ sucrose diet-induced central arterial wall inflammation and stiffening in nonhuman primates. Cell Metabolism. 2014;**20**(1, 1):183-190

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

of autophagy: Cross talk, shortcuts, and feedbacks. Molecular and Cellular

Autophagy in yeast: A TOR-mediated response to nutrient starvation. Current Topics in Microbiology and Immunology. 2004;**279**:73-84

Biology. 2012;**32**(1, 1):2-11

[63] Kamada Y, Sekito T, et al.

[64] Soare A, Cangemi R, et al. Long-term calorie restriction, but not endurance exercise, lowers core body temperature in humans. Aging.

[65] Hunt N, Li G, et al. Effect of calorie restriction and refeeding on skin wound healing in the rat. Age (Dordrecht, Netherlands).

[66] Nikolai S, Pallauf K, et al. Energy restriction and potential energy

Reviews. 2015;**28**(2):100-120

Medical Sciences. 2018

2018;**7**:e19

[67] Bensalem J, Dudonné S, et al. Polyphenols from grape and blueberry improve episodic memory in healthy elderly with lower level of memory performance: A bicentric double-blind, randomized, placebo-controlled clinical study. The Journals of Gerontology. Series A, Biological Sciences and

[68] Bensalem J, Dudonné S, et al. Polyphenol-rich extract from grape and blueberry attenuates cognitive decline and improves neuronal function in aged mice. Journal of Nutritional Science.

[69] Howitz K, Bitterman K, et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae life span. Nature. 2003;**425**(6954):191-196

[70] Baur J, Pearson K, et al. Resveratrol

improves health and survival of mice on a high-calorie diet. Nature.

2006;**444**(7117):337-342

restriction mimetics. Nutrition Research

2011;**3**(4):374-379

2012;**34**(6):1453-1458

[53] Pani G. Neuroprotective effects of dietary restriction: Evidence and mechanisms. Seminars in Cell & Developmental Biology.

[54] Nisoli E, Tonello C, et al. Calorie restriction promotes

2005;**310**(5746):314-317

2008;**105**(9):3374-3379

2014;**29**(2):99-107

mitochondrial biogenesis by inducing the expression of eNOS. Science.

[55] Lee IH, Cao L, et al. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy. Proceedings of the National Academy of Sciences of the United States of America.

[56] Martins R, Lithgow GJ, Link W. Long live FOXO: Unraveling the role of FOXO proteins in aging and longevity.

[57] Hardie DG, Ashford MLJ. AMPK: Regulating energy balance at the cellular and whole body levels. Physiology.

Aging Cell. 2016;**15**(2):196-207

[58] Apfeld J, O'Connor G, et al. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to life span in C. Elegans. Genes & Development.

2004;**18**(24):3004-3009

[59] Cantó C, Jiang L, et al.

Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metabolism. 2010;**11**(3, 3):213-219

[60] Kenyon CJ. The genetics of ageing. Nature. 2010;**464**(7288):504-512

[61] Hulbert AJ, Pamplona R, et al. Life and death: Metabolic rate, membrane composition, and life span of animals. Physiological Reviews.

[62] Alers S, Löffler A, et al. Role of AMPK-mTOR-Ulk1/2 in the regulation

2007;**87**(4):1175-1213

2015;**40**:106-114

**72**

[72] Jimenez-Gomez Y, Mattison J, et al. Resveratrol improves adipose insulin signaling and reduces the inflammatory response in adipose tissue of rhesus monkeys on high-fat, high-sugar diet. Cell Metabolism. 2013;**18**(4):533-545

[73] Gambini J, Inglés M, et al. Properties of resveratrol: In vitro and In vivo studies about metabolism, bioavailability, and biological effects in animal models and humans. Oxidative Medicine and Cellular Longevity. 2015;**2015**:837042

[74] Timmers S, Konings E, et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metabolism. 2011;**14**(5):612-622

[75] Poulsen M, Vestergaard P, et al. High-dose resveratrol supplementation in obese men: An investigator-initiated, randomized, placebo-controlled clinical trial of substrate metabolism, insulin sensitivity, and body composition. Diabetes. 2013;**62**(4):1186-1195

[76] Mukherjee S, Ray D, et al. Effects of Longevinex on cardioprotection and its mechanisms of action. Canadian Journal of Physiology and Pharmacology. 2010;**88**(11):1017-1025

[77] Vingtdeux V, Giliberto L, et al. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism. The Journal of Biological Chemistry. 2010;**285**(12):9100-9113

[78] Turner RS, Thomas R, et al. A randomized, double-blind, placebocontrolled trial of resveratrol for

Alzheimer disease. Neurology. 2015;**85**(16):1383-1391

[79] Porquet D, Griñán-Ferré C, et al. Neuroprotective role of transresveratrol in a murine model of familial Alzheimer's disease. The Journal of Alzheimer's Disease. 2014;**42**(4):1209-1220

[80] Passtoors W, Beekman M, et al. Gene expression analysis of mTOR pathway: Association with human longevity. Aging Cell. 2013;**12**(1):24-31

[81] Anisimov V, Zabezhinski M, et al. Rapamycin increases life span and inhibits spontaneous tumorigenesis in inbred female mice. Cell Cycle (Georgetown, Tex.). 2011;**10**(24):4230-4236

[82] Cunningham J, Rodgers J, et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007;**450**(7170):736-740

[83] Majumder S, Caccamo A, et al. Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1β and enhancing NMDA signaling. Aging Cell. 2012;**11**(2):326-335

[84] Woo H, Chung H, et al. Preclinical evaluation of injectable sirolimus formulated with polymeric nanoparticle for cancer therapy. International Journal of Nanomedicine. 2012;**7**:2197-2208

[85] Samidurai A, Salloum F, et al. Chronic treatment with novel nanoformulated micelles of rapamycin, Rapatar, protects diabetic heart against ischaemia/reperfusion injury. British Journal of Pharmacology. 2017;**174**(24):4771-4784

[86] Comas M, Toshkov I, et al. New nanoformulation of rapamycin Rapatar extends life span in homozygous

p53−/− mice by delaying carcinogenesis. Aging. 2012;**4**(10):715-722

[87] Viollet B, Guigas B, et al. Cellular and molecular mechanisms of metformin: An overview. Clinical Science (London, England: 1979). 2012;**122**(6):253-270

[88] Nelson L, Valentine R, et al. A novel inverse relationship between metformin-triggered AMPK-SIRT1 signaling and p53 protein abundance in high glucose-exposed HepG2 cells. American Journal of Physiology. Cell Physiology. 2012;**303**(1, 1):C4-C13

[89] Foretz M, Guigas B, et al. Metformin: From mechanisms of action to therapies. Cell Metabolism. 2014;**20**(6):953-966

[90] Sridhar G, Lakshmi G, et al. Emerging links between type 2 diabetes and Alzheimer's disease. World Journal of Diabetes. 2015;**6**(5):744-751

[91] Hsu C-C, Wahlqvist M, et al. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. The Journal of Alzheimer's Disease. 2011;**24**(3):485-493

[92] Imfeld P, Bodmer M, et al. Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: A population-based case-control study. Journal of the American Geriatrics Society. 2012;**60**(5):916-921

[93] Lane M, Ingram D, Roth GS. 2-Deoxy-D-glucose feeding in rats mimics physiologic effects of calorie restriction. Journal of Anti-Aging Medicine. 1998;**1**(4):327-337

[94] Lee J, Bruce-Keller A, et al. 2-Deoxy-D-glucose protects hippocampal neurons against excitotoxic and oxidative injury: Evidence for the involvement of stress proteins. Journal of Neuroscience Research. 1999;**57**(1, 1):48-61

[95] Duan W, Mattson M. Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease. Journal of Neuroscience Research. 1999;**57**(2):195-206

[96] Yao J, Chen S, et al. 2-Deoxy-Dglucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer's disease. PLoS One. 2011;**6**(7):e21788

[97] Minor R, Smith D, et al. Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats. Toxicology and Applied Pharmacology. 2010;**243**(3):332-339

[98] Martinez-Lopez N, Athonvarangkul D, et al. Autophagy and aging. Advances in Experimental Medicine and Biology. 2015;**847**:73-87

[99] He L, Lu J, Yue Z. Autophagy in ageing and ageing-associated diseases. Acta Pharmacologica Sinica. 2013;**34**(5):605-611

[100] Eisenberg T, Abdellatif M, et al. Cardioprotection and life span extension by the natural polyamine spermidine. Nature Medicine. 2016;**22**(12):1428-1438

[101] Schwarz C, Stekovic S, et al. Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline. Aging. 2018;**10**(1):19-33

[102] Eisenberg T, Knauer H, et al. Induction of autophagy by spermidine promotes longevity. Nature Cell Biology. 2009;**11**(11):1305-1314

[103] Soda K, Dobashi Y, et al. Polyamine-rich food decreases ageassociated pathology and mortality in

**75**

*Dietary Impact on Neuronal Autophagy Control and Brain Health*

pathway. Nature Chemical Biology.

[113] Abdulhaq H, Rossetti J. The role of azacitidine in the treatment of myelodysplastic syndromes. Expert Opinion on Investigational Drugs.

[114] Cătană C-S, Atanasov A, et al. Natural products with anti-aging potential: Affected targets and

molecular mechanisms. Biotechnology Advances. 2018;**36**(6):1649-1656

[115] Popkin B, Adair LS, et al. Global nutrition transition and the pandemic of obesity in developing countries. Nutrition Reviews. 2012;**70**(1):3-21

[116] Mattison J, Vaughan K. An overview of nonhuman primates in aging research. Experimental Gerontology. 2017;**94**:41-45

2008;**4**(5):295-305

2007;**16**(12):1967-1975

*DOI: http://dx.doi.org/10.5772/intechopen.85228*

aged mice. Experimental Gerontology.

[104] Soda K, Kano Y, et al. Increased polyamine intake inhibits age-associated alteration in global DNA methylation

and 1,2-dimethylhydrazineinduced tumorigenesis. PLoS One.

[105] Eisenberg T, Schroeder S, et al. A histone point mutation that switches on autophagy. Autophagy.

[106] du Toit A, Hofmeyr J-HS, Gniadek TJ, Loos B. Measuring autophagosome flux. Autophagy.

[107] Wirth M, Benson G, et al. The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial. Cortex: A Journal Devoted to the Study of the Nervous System and

[108] Kaizuka T, Morishita H, et al. An Autophagic flux probe that releases an internal control. Molecular Cell.

[109] Zhou H, Shang C, et al. Ciclopirox Olamine inhibits mTORC1 signaling by activation of AMPK. Biochemical Pharmacology. 2016;**116**:39-50

[110] Hayes C, Dey D, et al. Chronic Cladribine administration increases amyloid Beta peptide generation and plaque burden in mice. PLoS One.

[111] Rainey M, Korostyshevsky D, et al. The antidepressant sertraline targets intracellular Vesiculogenic membranes in yeast. Genetics.

[112] Williams A, Sarkar S, et al. Novel targets for Huntington's disease in an mTOR-independent autophagy

2010;**185**(4):1221-1233

2009;**44**(11):727-732

2013;**8**(5):e64357

2014;**10**(6):1143-1145

2018;**14**(6):1060-1071

Behavior. 2018;**109**:181-188

2016;**64**(4):835-849

2012;**7**(10)

*Dietary Impact on Neuronal Autophagy Control and Brain Health DOI: http://dx.doi.org/10.5772/intechopen.85228*

aged mice. Experimental Gerontology. 2009;**44**(11):727-732

*Feed Your Mind - How Does Nutrition Modulate Brain Function throughout Life?*

[95] Duan W, Mattson M. Dietary restriction and 2-deoxyglucose administration improve behavioral outcome and reduce degeneration of dopaminergic neurons in models of Parkinson's disease. Journal of Neuroscience Research.

[96] Yao J, Chen S, et al. 2-Deoxy-Dglucose treatment induces ketogenesis, sustains mitochondrial function, and reduces pathology in female mouse model of Alzheimer's disease. PLoS

[97] Minor R, Smith D, et al. Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats. Toxicology

[98] Martinez-Lopez N, Athonvarangkul D, et al. Autophagy and aging. Advances in Experimental Medicine and Biology.

[99] He L, Lu J, Yue Z. Autophagy in ageing and ageing-associated diseases. Acta Pharmacologica Sinica.

[100] Eisenberg T, Abdellatif M, et al. Cardioprotection and life span extension by the natural polyamine spermidine. Nature Medicine.

[101] Schwarz C, Stekovic S, et al. Safety and tolerability of spermidine supplementation in mice and older adults with subjective cognitive decline.

[102] Eisenberg T, Knauer H, et al. Induction of autophagy by spermidine promotes longevity. Nature Cell Biology.

1999;**57**(2):195-206

One. 2011;**6**(7):e21788

and Applied Pharmacology.

2010;**243**(3):332-339

2015;**847**:73-87

2013;**34**(5):605-611

2016;**22**(12):1428-1438

Aging. 2018;**10**(1):19-33

2009;**11**(11):1305-1314

[103] Soda K, Dobashi Y, et al. Polyamine-rich food decreases ageassociated pathology and mortality in

p53−/− mice by delaying carcinogenesis.

[87] Viollet B, Guigas B, et al. Cellular and molecular mechanisms of metformin: An overview. Clinical Science (London, England: 1979).

[88] Nelson L, Valentine R, et al. A novel inverse relationship between metformin-triggered AMPK-SIRT1 signaling and p53 protein abundance in high glucose-exposed HepG2 cells. American Journal of Physiology. Cell Physiology. 2012;**303**(1, 1):C4-C13

[89] Foretz M, Guigas B, et al. Metformin: From mechanisms of action to therapies. Cell Metabolism.

[90] Sridhar G, Lakshmi G, et al. Emerging links between type 2 diabetes and Alzheimer's disease. World Journal

of Diabetes. 2015;**6**(5):744-751

[92] Imfeld P, Bodmer M, et al. Metformin, other antidiabetic drugs, and risk of Alzheimer's disease: A population-based case-control study. Journal of the American Geriatrics Society. 2012;**60**(5):916-921

[93] Lane M, Ingram D, Roth GS. 2-Deoxy-D-glucose feeding in rats mimics physiologic effects of calorie restriction. Journal of Anti-Aging Medicine. 1998;**1**(4):327-337

[94] Lee J, Bruce-Keller A, et al. 2-Deoxy-D-glucose protects hippocampal neurons against excitotoxic and oxidative injury: Evidence for the involvement of stress proteins. Journal of Neuroscience Research. 1999;**57**(1, 1):48-61

[91] Hsu C-C, Wahlqvist M, et al. Incidence of dementia is increased in type 2 diabetes and reduced by the use of sulfonylureas and metformin. The Journal of Alzheimer's Disease.

2014;**20**(6):953-966

2011;**24**(3):485-493

Aging. 2012;**4**(10):715-722

2012;**122**(6):253-270

**74**

[104] Soda K, Kano Y, et al. Increased polyamine intake inhibits age-associated alteration in global DNA methylation and 1,2-dimethylhydrazineinduced tumorigenesis. PLoS One. 2013;**8**(5):e64357

[105] Eisenberg T, Schroeder S, et al. A histone point mutation that switches on autophagy. Autophagy. 2014;**10**(6):1143-1145

[106] du Toit A, Hofmeyr J-HS, Gniadek TJ, Loos B. Measuring autophagosome flux. Autophagy. 2018;**14**(6):1060-1071

[107] Wirth M, Benson G, et al. The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial. Cortex: A Journal Devoted to the Study of the Nervous System and Behavior. 2018;**109**:181-188

[108] Kaizuka T, Morishita H, et al. An Autophagic flux probe that releases an internal control. Molecular Cell. 2016;**64**(4):835-849

[109] Zhou H, Shang C, et al. Ciclopirox Olamine inhibits mTORC1 signaling by activation of AMPK. Biochemical Pharmacology. 2016;**116**:39-50

[110] Hayes C, Dey D, et al. Chronic Cladribine administration increases amyloid Beta peptide generation and plaque burden in mice. PLoS One. 2012;**7**(10)

[111] Rainey M, Korostyshevsky D, et al. The antidepressant sertraline targets intracellular Vesiculogenic membranes in yeast. Genetics. 2010;**185**(4):1221-1233

[112] Williams A, Sarkar S, et al. Novel targets for Huntington's disease in an mTOR-independent autophagy

pathway. Nature Chemical Biology. 2008;**4**(5):295-305

[113] Abdulhaq H, Rossetti J. The role of azacitidine in the treatment of myelodysplastic syndromes. Expert Opinion on Investigational Drugs. 2007;**16**(12):1967-1975

[114] Cătană C-S, Atanasov A, et al. Natural products with anti-aging potential: Affected targets and molecular mechanisms. Biotechnology Advances. 2018;**36**(6):1649-1656

[115] Popkin B, Adair LS, et al. Global nutrition transition and the pandemic of obesity in developing countries. Nutrition Reviews. 2012;**70**(1):3-21

[116] Mattison J, Vaughan K. An overview of nonhuman primates in aging research. Experimental Gerontology. 2017;**94**:41-45

**77**

Section 5

Brain-Visceral Interactions

in Enteral Feeding

Section 5
