Sirtuin Biology in Cancer and Metabolic Disease: Cellular Pathways for Clinical Discovery

By Kenneth Maiese

Sirtuin Biology in Cancer and Metabolic Disease: Cellular Pathways for Clinical Discovery offers a compelling and thought-provoking perspective for the examination of the intriguing biology of sirtuins that ties cancer and metabolic disease together and provides a critical platform for the development of sirtuin-based novel therapeutic strategies to effectively treat cancer and metabolic disorders with precision in order to minimize any potentially detrimental clinical outcomes. An exciting prospect for the development of innovative therapeutics for cancer and metabolic disorders involves sirtuins. Sirtuins are histone deacetylases that have an intricate role in the onset and development of cancer and metabolic disease. Implementing a translational medicine format, this innovative reference highlights the ability of sirtuins to oversee critical pathways that involve stem cell maintenance, cellular proliferation, metabolic homeostasis, apoptosis, and autophagy that can impact cellular dysfunction and unchecked cellular growth that can occur during cancer and metabolic disease. Each chapter offers an intuitive perspective of advances on the application of sirtuin pathways for cancer and metabolic disease that will be become a "go-to" resource for a broad audience of scientists, physicians, pharmaceutical industry experts, nutritionists, and students.

• Chapters are authored by internationally recognized experts who elucidate the intimate relationship between cancer and metabolic disease that intersects with sirtuin pathways
• Presents the basic and clinical role of sirtuins in regard to cancer and metabolic disease
• Summarizes the multidiscipline views and publications for this exciting field of sirtuins for the development of new clinical treatments for cancer and metabolic disease
• Provides a vital foundation for a broad audience of healthcare providers, scientists, drug developers, and students in both clinical and research settings

• Language: English
• Publisher: Academic Press
• Release date: Feb 20, 2021
• ISBN: 9780128224847

Book preview

reality.

Section I

Sirtuins and metabolic disease

Outline

Chapter 1 Sirtuins in metabolic disease: innovative therapeutic strategies with SIRT1, AMPK, mTOR, and nicotinamide

Chapter 2 Sirtuins in metabolic and epigenetic regulation of stem cells

Chapter 3 Sirtuins and metabolic regulation: food and supplementation

Chapter 4 Sirtuins in diabetes mellitus and diabetic kidney disease

Chapter 5 Sirtuins and mitochondrial dysfunction

Chapter 6 Sirtuins in immunometabolism

Chapter 7 Mitochondrial sirtuins at the crossroads of energy metabolism and oncogenic transformation

Chapter 1

Sirtuins in metabolic disease: innovative therapeutic strategies with SIRT1, AMPK, mTOR, and nicotinamide

Kenneth Maiese¹, ²,    ¹Biotechnology and Venture Capital Development, Office of Translational Alliances and Coordination, National Heart, Lung, and Blood Institute,    ²Cellular and Molecular Signaling, New York, NY, United States

Abstract

Metabolic disorders including diabetes mellitus (DM) are considered a significant component of the increasing prevalence of noncommunicable diseases (NCDs) occurring throughout the world. It is predicted that the number of individuals with DM is expected to rise to 700 million individuals by the year 2045. Furthermore, the care for disorders such as DM can consume more than 17% of the Gross Domestic Product in nations such as the United States. Given that present therapies for metabolic disorders may offer some clinical benefit and gradually slow disease progression, metabolic diseases can affect multiple organs of the body and ultimately lead to disability and death. Given these challenges, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and its associated pathways with AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), and the vitamin nicotinamide offer exciting prospects for the development of innovative therapeutic strategies that are highly warranted. SIRT1 is intimately tied to AMPK, mTOR, and nicotinamide during metabolic disease to limit oxidative stress, increase life span, improve insulin sensitivity, maintain mitochondrial function, oversee nutritional intake, regulate β-cell function, and limit the development of obesity. Yet these pathways hold a complex relationship that also involves the regulation of autophagy, apoptosis, and growth factors, such as erythropoietin (EPO), that requires a fine balance to maintain glucose homeostasis and limit potential cellular toxicity. Future studies for SIRT1 and its association with AMPK, mTOR, and nicotinamide are critical to gain further insight for novel treatment strategies for metabolic diseases that limit potential unwarranted clinical outcomes.

Keywords

Alzheimer’s disease; AMPK; autophagy; apoptosis; diabetes mellitus; dementia; FoxO; erythropoietin; mTOR; mTORC1; mTORC2; NAD+; nicotinamide; oxidative stress; SIRT1

Outline

Outline

Abbreviations 3

1.1 Noncommunicable diseases 4

1.2 Metabolic disorders 4

1.3 Novel therapeutic strategies with sirtuins for metabolic disease 6

1.4 Silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) 6

1.5 SIRT1, metabolic function, and obesity 7

1.6 SIRT1 and AMP-activated protein kinase 8

1.7 SIRT1, mTOR, and metabolic disease 9

1.8 SIRT1, nicotinamide, and cellular metabolism 10

1.9 Future considerations 11

Acknowledgments 13

References 13

Abbreviations

AGEs advanced glycation end products

AgRP agouti-related peptide

AD Alzheimer’s disease

AMPK AMP-activated protein kinase

Aβ β-amyloid

Bad BCL2-associated agonist of cell death

Deptor DEP domain-containing mTOR interacting protein

DNA deoxyribonucleic acid

DM diabetes mellitus

EPO erythropoietin

4EBP1 eukaryotic initiation factor 4E (eIF4E)-binding protein 1

FRAP FKBP12-rapamycin-associated protein

SGK1 glucocorticoid induced protein kinase 1

HbA1c hemoglobin A1c

IGF-1 insulin growth factor-1

IRS-1 insulin receptor substrate 1

FoxOs mammalian forkhead transcription factors

mLST8 mammalian lethal with Sec13 protein 8, termed mLST8

mSIN1 mammalian stress-activated protein kinase interacting protein

mTOR mechanistic target of rapamycin

mRNA messenger ribonucleic acid

mTORC1 mTOR Complex 1

mTORC2 mTOR Complex 2

NAD+ nicotinamide adenine dinucleotide

NADP+ nicotinamide adenine dinucleotide phosphate

NMN nicotinamide mononucleotide

NCDs noncommunicable diseases

NF-κB nuclear factor-κB

p70S6K p70 ribosomal S6 kinase

PPAR peroxisome proliferator-activated receptor

PGC peroxisome proliferator-activated receptor gamma coactivator

PS phosphatidylserine

PDK1 phosphoinositide-dependent kinase 1

PI 3-K phosphotidylinositide 3-kinase

PRAS40 proline rich Akt substrate 40 kDa

POMC proopiomelanocortin

Akt protein kinase B

AGC protein kinase A/protein kinase G/protein kinase C

PKCα protein kinase C-α

PTP protein tyrosine phosphatase

LKB1 serine-threonine liver kinase B1

SIRT1 silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae)

TNF-α tumor necrosis factor-α

UCP uncoupling protein

1.1 Noncommunicable diseases

Metabolic disorders, that include diabetes mellitus (DM), are considered to be a leading cause of death in the world as part of noncommunicable diseases (NCDs) [1–5]. NCDs are increasing in incidence throughout the world [2,6–8] and according to the World Health Organization, almost 70% of deaths that are documented each year are the result of NCDs [9,10]. Both wealthy and low-income countries are affected by NCDs. Greater than 10% of the population less than 60 years of age is affected in high-income countries [9]. NCDs affect a greater proportion of the population in low- and middle-income countries with at least one-third of the population under the age of 60 suffering from NCDs. Of the over 40 million individuals that die each year from NCDs, 15 million individuals are younger, with ages between 30 and 69 years old.

The rise in NCDs follows an observed increase in life expectancy of the world’s population [11,12]. After a recent reduction that has been reported in deaths from opioid overdoses, life expectancy is increasing again in the United States [13]. The age of the world’s population continues to increase with new estimates of life expectancy approaching 80 years of age [14]. With life expectancy marked by a 1% decrease in the age-adjusted death rate from the years 2000 through 2011 [15], the number of individuals over the age of 65 has been observed to double during the prior 50 years [16]. In consideration of less developed nations, the number of older individuals in large developing countries such as India and China also will increase from 5% to 10% over the next several decades [17,18]. Although many factors may account for the observed increased in life span for the world’s population, the 10 leading causes of death, which are cardiac disease, cancer, trauma, respiratory disease, stroke, Alzheimer’s disease (AD), DM, influenza and pneumonia, kidney disease, and suicide, have remained the same [13]. Yet improvements in preventive medical care, more focused public health guidelines and sanitation measures, and new treatments for multiple disorders that involve endocrine disease, metabolic disorders, and nutrition have assisted with improvements in life span longevity [3,19–26].

1.2 Metabolic disorders

As a significant component of NCDs, DM is a disorder that is increasingly being targeted for the development of new treatment strategies to reduce death and disability for the world’s population [27–29] (Table 1.1). Approximately 80% of adults with DM are living in low- and middle-income countries [4]. Currently, almost 500 million individuals have DM [5,17,30–32]. At least another 400 million individuals are believed to either suffer from metabolic disease or be at risk for developing DM [4,33–35]. In addition, according to the International Diabetes Federation the number of individuals with DM is expected to rise to 700 million individuals by the year 2045 [4]. In the United States, almost 35 million individuals, which represents approximately 10% of the population, are diagnosed with DM [1]. At least seven million individuals over the age of 18 remain undiagnosed with DM and in the year 2018 it was estimated that almost 35% of adults in the United States had prediabetes based on their fasting glucose and hemoglobin A1c (HbA1c) levels [36]. Prevalence of DM also has increased from 9.5% during the period of 1999–2002 to 12% during the period of 2013–16. In the adult population, it was noted that prevalence varied by indicators of socioeconomic status, such as education level. At least 13% of adults with less than a high school education had DM compared to almost 10% of individuals with a high school education and DM and 7.5% of individuals with greater than a high school education and DM. Risk factors for developing complications of DM included tobacco consumption, physical inactivity, hypertension, and elevated serum cholesterol [2].

Table 1.1

Obesity is considered to be another risk factor for the development of DM. Obesity results in impaired glucose tolerance that leads to DM progression [24,37–43]. Obesity and excess body fat can increase the risk of developing DM in young individuals [44] and can affect stem cell proliferation, aging, inflammation, oxidative stress injury, and mitochondrial function [39,45–51].

In regard to the financial considerations for DM, at least US$ 20,000 are required to care for each individual with DM per year. The care for patients with DM equals approximately US$ 760 billion [4]. This care consumes more than 17% of the Gross Domestic Product in the United States, per the Centers for Medicare and Medicaid Services (CMS) [52]. When considering the loss of function and disability that result from DM individuals, an estimated US$ 69 billion are consumed from reduced productivity linked to DM.

The toxic effects of DM do not exclude any organs of the body and can affect all cellular systems [53]. In the peripheral nervous system, at least 70% of individuals with DM can develop diabetic peripheral neuropathy. DM can result in autonomic neuropathy [54] and peripheral nerve disease [55–58]. Assessments of peripheral neuropathies can be challenging, since the disorder is chronic in nature, may be subclinical, and prior deficits may go undetected even after improved control over glucose homeostasis has been initiated. In the central nervous system, DM can cause insulin resistance and dementia in patients with AD [2,6,11,29,53,59–61]. DM can affect multiple cellular pathways that lead to the progression of cognitive loss [17,62–67]. DM also has been tied to mental illness [68,69], cerebral vascular injury [17,34,70–73], impairment of microglial activity [29,59–61], and can impact stem cell proliferation [17,41,62–66]. DM also can result in endothelial dysfunction [11,17,74–76], cardiovascular disease [35,37,75,77–83], retinal disease [84–86], and immune and infectious disorders [87–93].

1.3 Novel therapeutic strategies with sirtuins for metabolic disease

Given the growing prevalence of DM, the significant number of individuals that remain undiagnosed with DM, and the severe financial impact on global economies, new and innovative therapeutic strategies are vital to be developed for the treatment of metabolic disorders, such as DM. With conventional therapies, early diagnosis of DM and rapid treatment can offer some degree of protection and may inhibit the progression of DM [5,11,94–98]. However, even under the best of circumstances, tight serum glucose control does not blunt the complications that can arise during DM [2,99]. Careful nutritional and exercise management also is considered to be important for DM care, but in some cases these strategies may be less than beneficial dependent upon the degree of reduced oral intake and a decrease in organ mass through processes that involve autophagy [100]. DM also has additional risk factors when one considers the development of neurodegenerative disorders and cognitive loss that can be compounded by hypertension, low education in early life, and tobacco use [2,29,53,101]. For example, vascular disease as a result of DM may lead to dementia [2,6,8,11,53,102–104]. As a result, new avenues for therapeutic strategies to address metabolic disorders are urgently needed. One innovative strategy that offers exciting prospects involves the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and its associated pathways with AMP-activated protein kinase (AMPK), the mechanistic target of rapamycin (mTOR), and the vitamin nicotinamide (Table 1.1).

1.4 Silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae)

SIRT1 is a member of the sirtuin family (sirtuin 1) and a histone deacetylase [11,17,22,105–114] that can transfer acetyl groups from ε-N-acetyl lysine amino acids to the histones of deoxyribonucleic acid (DNA) to control transcription (Table 1.1). Seven mammalian homologues of Sir2 that include SIRT1 through SIRT7 have been identified. These histone deacetylases can control cellular metabolism, cell senescence, cell function, cell injury, and posttranslation modifications of proteins [2,8,115–118]. SIRT1 depends upon the substrate nicotinamide adenine dinucleotide (NAD+) [90,109,119–121]. Histone deacetylases are enzymes that transfer acetyl groups from ε-N-acetyl lysine amino acids that exist on the histones of DNA to regulate transcription. Although histone deacetylases primarily oversee DNA transcription, they may be involved with posttranslational changes of proteins as well such as the ability of SIRT1 to control the posttranslational phosphorylation of mammalian forkhead transcription factors [122,123]. During deacetylase reactions, sirtuins, that include SIRT1, transfer the acetyl residue from the acetyllysine residue of histones to the ADP-ribose moiety of NAD+, resulting in the production of nicotinamide, 2′-O-acetyl ADP ribose, and deacetylated proteins. SIRT1 expression is present in the brain, heart, liver, pancreas, skeletal muscle, spleen, and adipose tissues. In the cell, SIRT1 is present in the nucleus and cytoplasm with dominant expression in the nucleus [11,85,90,106,112,118,124–126].

In disorders that can lead to oxidative stress, such as DM [5,11,44,94,98,127,128], SIRT1 activation can decrease oxidative stress, prevent diabetic retinal injury, and block cell injury that would lead to memory loss [2,85,112,129–135]. Activation of SIRT1 has been associated with reduction in oxidative stress and the protection of cognition [136,137]. Oxidative stress may lead to aberrant cell cycle reentry that can lead to neuronal death during AD [138,139]. Limiting the generation of reactive oxygen species in models of AD has led to reduced toxicity of Aβ, suggesting that oxidative stress is a critical component in the pathology of AD [126]. SIRT1 may directly block Aβ and tau toxicity and preserve mitochondrial function. SIRT1 may limit the toxicity of Aβ [140–143]. SIRT1 also can oversee neurovascular protection in the brain that would be relevant for ischemic-mediated dementia that can occur during DM [17,89,90,105,112,119,120,130,144–147]. SIRT1 can increase life span in higher organisms and protect against oxidative stress in neuronal cells [129]. Pancreatic SIRT1 activation through exercise also has been shown to potentially reduce oxidative stress complications during diabetes [148].

SIRT1 can control pathways of apoptosis and autophagy [113,114] (Table 1.1). In regard to autophagy, activation of autophagy in human lung cancer cells leads to increased cell survival. SIRT1 inhibition leads to prosurvival autophagy activity and inhibition of apoptosis in these cells [149]. SIRT1 also can upregulate autophagy and mitochondria function in embryonic stem cells during periods of oxidative stress [150]. Through SIRT1 activity and autophagic flux, senescence is inhibited in vascular endothelial cells [151].

SIRT1 is also tied to apoptosis. SIRT1 activation blocks external membrane phosphatidylserine (PS) exposure during the early phases of apoptosis in mature cells [123,152–154]. SIRT1 can limit apoptosis initiated by tumor necrosis factor-α (TNF-α) in endothelial progenitor cells [155]. Loss of SIRT1 expression in endothelial progenitor cells leads to apoptotic cell death that can occur in smokers and chronic obstructive disease patients [156]. Apoptotic cell death during oxidative stress in cardiac cells is minimized through the activation of SIRT1 [157].

1.5 SIRT1, metabolic function, and obesity

SIRT1 plays a critical role in cellular metabolism [28,43,106,119,158,159] (Table 1.1). For example, SIRT1 can oversee the development of fat progression and obesity. SIRT1 in association with peroxisome proliferator-activated receptor-γ (PPAR-γ) can control adipogenesis. SIRT1 protein can repress PPAR-γ to result in the mobilization of fatty acids from white adipocytes upon fasting and lead to the loss of fat through lipolysis [160]. PPAR-γ also can interact with SIRT1 and form a negative feedback to regulate SIRT1 expression and activity [161]. SIRT1 expression has been found to be depressed in adipose tissue in obese rodents. Loss of SIRT1 in white adipose cells results in the impairment of fatty acid mobilization. Treatment with resveratrol, an activator of SIRT1, can lead to calorie restriction to prevent obesity as a result of a high calorie diet in mice [162]. SIRT1 also has been shown to be expressed in anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus and regulate food intake and cellular metabolism [163]. Overexpression of SIRT1 in the hypothalamus prevents mammalian forkhead transcription factor 1 (FoxO1), a mammalian forkhead transcription family member [8,110,164], from promoting hyperphagia and weight gain [163]. Yet lack of SIRT1 in POMC neurons leads to obesity due to reduced energy expenditure [165]. Additional studies have shown that melatonin can reduce inflammation in adipocytes that can limit obesity through pathways that involve SIRT1 [48] and that decreased expression of SIRT1 during hyperglycemia and obesity can increase stroke infarct size [72].

In relation to cellular metabolic regulation, SIRT1 regulates the activity of peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) through deacetylation. PGC-1α is a member of a family of transcriptional coactivators that includes PGC-1α, PGC-1β, and PGC-1 related coactivator (PRC). PGC-1α leads to gene transcription and increases the expression of genes that regulate mitochondrial functions and fatty acid oxidation [166]. Increased PGC-1α activity can function to protect against some metabolic diseases and improve mitochondrial biogenesis. SIRT1 can oversee PGC-1α activity in the liver to lead to gluconeogenic genes and hepatic glucose output. SIRT1 can control the ability of PGC-1α to repress glycolytic genes in response to fasting and pyruvate [167]. Hepatic SIRT1 with PPAR-α, a receptor that can increase free fatty acid uptake and decrease lipolysis, activates PGC-1α to lead to lipid homeostasis. SIRT1 deletion in the liver results in the loss of PGC-1α activity and the subsequent impairment of fatty acid oxidation, leading to the develop of hepatic steatosis during high-fat diets [168].

SIRT1 has an important role in the management of insulin sensitivity. During high-fat diets, increased SIRT1 activity can regulate glucose and hepatic lipid homeostasis and protects against metabolic syndrome [169]. SIRT1 activation also limits diabetic myocardial injury by inhibiting high mobility group box 1/nuclear factor-κB (NF-κB) pathway-associated proteins [170]. During the administration of high-fat diets, SIRT1 expression is decreased in the pancreas and liver and may be associated with insulin resistance [171]. SIRT1 has been shown to be markedly decreased in insulin-resistant cells and reduction of SIRT1 levels in gastrocnemius muscle leads to insulin resistance [172]. In addition, knockdown or blockade of SIRT1 activity impairs insulin signaling by interfering with insulin-stimulated insulin receptor phosphorylation and glycogen synthase [172]. On the other hand, overexpression of SIRT1 in the liver can attenuate hepatic steatosis and lead to improved glucose homeostasis [173]. Insulin sensitivity is improved in diabetic rats during exercise training through the activation of SIRT1 [148]. The ability of SIRT1 to improve insulin sensitivity may occur through a number of mechanisms that include modulation of fat mobilization [160], control of gluconeogenesis [167], and limiting the onset of inflammation [168]. SIRT1 also serves as a positive modulator of insulin signaling in insulin-sensitive organs and activates the insulin downstream target protein kinase B (Akt) through phosphotidylinositide 3-kinase (PI 3-K) [174]. In addition, SIRT1 can stimulate glucose-dependent insulin secretion from pancreatic β cells by repressing the uncoupling protein (UCP) gene UCP2 [175]. Resveratrol, an activator of SIRT1, can promote glucose-stimulated insulin secretion in insolinoma INS-1E cells and human islets that is dependent on the activity of SIRT1 [176].

SIRT1 also oversees insulin sensitivity through protein tyrosine phosphatase (PTP). In the PTP family [177–182], PTP1B has been identified to negatively regulate insulin signal transduction by targeting the insulin receptor. PTP1B deficiency or inhibition leads to improved insulin sensitivity and glycemic control. SIRT1 overexpression or SIRT1 activation can reduce both the PTP1B messenger ribonucleic acid (mRNA) and protein levels during insulin resistance for improved glucose homeostasis. An increase in PTP1B expression prevents SIRT1-mediated glucose uptake and insulin receptor phosphorylation in response to insulin stimulation, illustrating that SIRT1 improves insulin sensitivity through the repression of PTP1B [172].

1.6 SIRT1 and AMP-activated protein kinase

SIRT1 may regulate insulin sensitivity and metabolism through the phosphorylation of AMPK and protect against metabolic syndrome [43,53,112,183,184] (Table 1.1). Activation of AMPK through phosphorylation functions to promote insulin sensitivity, fatty acid oxidation, and mitochondrial biogenesis. This leads to the generation of ATP and reduction in oxidative stress [2,12]. AMPK has been shown to limit the disability and hyperalgesia from diabetic neuropathy in animal models [57]. Diets associated with fish oil consumption can result in increased AMPK activity and block endothelial progenitor cell dysfunction and ischemic injuries [78]. AMPK can reduce insulin resistance, since the loss of AMPK results in reduced tolerance to the development of insulin resistance [185]. During periods of dietary restriction that may increase life span [129], AMPK can be one of several pathways to shift to beneficial oxidative metabolism [186]. AMPK can reduce ischemic brain damage in diabetic animal models [187], improve memory retention in models of AD and DM [188], offer elimination of ß-amyloid (Aß) in the brain [189], facilitate tau clearance [190], modulate chronic inflammation in neurodegenerative disorders [22,184,191], and prevent Aß neurotoxicity [192].

The AMPK pathway is relevant with current treatments used for DM and SIRT1. Biguanides and metformin rely upon AMPK and autophagy to restore cellular function. Metformin blocks mTOR activity, promotes autophagy, and can function at times in an AMPK-independent manner [193]. Through metformin, AMPK can become activated, leading to autophagy induction, and protecting against diabetic apoptotic cardiac cell loss [194]. Metformin also has been shown to prevent lipid peroxidation in the brain and spinal cord and to decrease caspase activity during toxic insults [195]. These observations of metformin to offer protection during DM may be associated with the ability of autophagic pathways to limit oxidative stress under some circumstances [38,196].

AMPK can oversee metabolic pathways through both apoptosis and autophagy. During metabolic disease, autophagy can remove misfolded proteins and eliminate nonfunctioning mitochondria to maintain β-cell function and prevent the onset of DM [197]. Exercise in mice has been demonstrated to promote the induction of autophagy and regulate glucose homeostasis [198]. Autophagy can improve insulin sensitivity during the administration of high-fat diets in mice [185] and may offer protection to microglia during acute glucose fluctuations [61]. During periods of hyperglycemia, AMPK increases basal autophagy activity [110,199] and maintains endothelial cell survival [76,200]. AMPK can modulate apoptosis and autophagy during coronary artery disease [201], cholesterol efflux [202], endothelial dysfunction during hyperglycemia [76], and oxidative stress [159,203]. Antisenescence activity also can be promoted by AMPK activation and the increase of autophagic flux [151].

Activation of autophagy pathways is not always beneficial and may require careful modulation during metabolic disease [42,53,59,61,89,93,204]. Increased activity of autophagy can lead to the loss of cardiac and liver tissue in diabetic rats during attempts to achieve glycemic control through diet modification [100]. During elevated glucose exposure, advanced glycation end products (AGEs), agents that can result in DM complications, have been shown to lead to autophagy activation and vascular smooth muscle proliferation that can result in atherosclerosis [205], as well as cardiomyopathy [206]. During elevated glucose exposure, autophagy can impair endothelial progenitor cells, lead to mitochondrial oxidative stress [207], and prevent angiogenesis [208]. Chronic inflammatory conditions such as lichen planus also have been tied to mTOR inhibition and autophagy activation [209].

In regard to SIRT1, SIRT1 can control AMPK through the AMPK kinase, serine-threonine liver kinase B1 (LKB1). Overexpression of SIRT1 results in the deacetylation of LKB1, leading to its translocation from the nucleus to the cytoplasm, where LKB1 activates AMPK [210]. AMPK, in turn, can the lead to the activation of SIRT1. AMPK cannot directly activate SIRT1, but may enhance SIRT1 activity. However, AMPK-mediated impairment of muscle differentiation during glucose restriction and PGC-1α-mediated gene expression is dependent upon SIRT1. AMPK activation enhances SIRT1 activity either by increasing cellular NAD+/NADH ratio, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the PGC-1α, FoxO1, and FoxO3a [211], or by upregulating nicotinamide phosphoribosyltransferase (Nampt) during glucose restriction, leading to increased NAD+ and decreased nicotinamide, an inhibitor of SIRT1 [212]. The SIRT1 activator resveratrol also has been demonstrated to increase AMPK activity through SIRT1-dependent or -independent mechanisms [211,213]. Resveratrol increases AMPK phosphorylation to protect cells against elevated glucose concentration, improve insulin sensitivity, and stimulate glucose transport. SIRT1 and AMPK can function to prevent hyperglycemic cell death in endothelial cells [76] and maintain mitochondrial homeostasis [43]. Increased AMPK activation limits myocardial infarct size in both nondiabetic and diabetic rat hearts following ischemia/reperfusion, which may be mediated through the inhibition of mitochondrial permeability transition pore opening in cardiomyocytes [214]. AMPK signaling has been shown to reverse hyperalgesia during diabetic neuropathy in animal models [57].

1.7 SIRT1, mTOR, and metabolic disease

A significant pathway for SIRT1 to impact metabolic disease and cellular survival involves mTOR [5,28,43,115,151,215–217] (Table 1.1). mTOR is a 289-kDa serine/threonine protein kinase that is encoded by the single gene FRAP1 [2,218–220]. mTOR can be referred to by other terms such as the mammalian target of rapamycin and the FK506-binding protein 12-rapamycin complex-associated protein 1 [113,221]. The target of rapamycin (TOR) was first described in Saccharomyces cerevisiae with the genes TOR1 and TOR2 [221]. Through the use of rapamycin-resistant TOR mutants, TOR1 and TOR2 were found to encode the Tor1 and Tor2 isoforms in yeast [222]. Rapamycin is a macrolide antibiotic in Streptomyces hygroscopicus that blocks TOR and mTOR activity [34].

mTOR serves as the principal component of the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) [223–225] (Table 1.1). mTORC1 is composed of Raptor, Deptor (DEP domain-containing mTOR interacting protein), the proline rich Akt substrate 40 kDa (PRAS40), and mammalian lethal with Sec13 protein 8, termed mLST8 (mLST8) [2,113]. Rapamycin inhibits the activity of mTORC1 by binding to immunophilin FK-506-binding protein 12 (FKBP12) that attaches to the FKBP12-rapamycin-binding domain (FRB) at the carboxy (C)-terminal of mTOR to interfere with the FRB domain of mTORC1 [113]. mTORC1 is more sensitive to inhibition by rapamycin than mTORC2, but chronic administration of rapamycin can inhibit mTORC2 activity as a result of the disruption of the assembly of mTORC2 [184,220].

mTORC1 binds to its constituents through the protein Ras homologue enriched in brain (Rheb) that phosphorylates the Raptor residue serine⁸⁶³ and other residues that include serine⁸⁵⁹, serine⁸⁵⁵, serine⁸⁷⁷, serine⁶⁹⁶, and threonine⁷⁰⁶ [226]. The inability to phosphorylate serine⁸⁶³ limits mTORC1 activity, as observed through the use of site-direct mutation of serine⁸⁶³ [227]. mTOR can control Raptor activity and this activity can be blocked by rapamycin [227]. Deptor, also an inhibitor of mTORC1, prevents mTORC1 activity by binding to the FAT (FKBP12-rapamycin-associated protein (FRAP), ataxia-telangiectasia (ATM), and the transactivation/transformation domain-associated protein) domain of mTOR. If the activity of Deptor is lessened, Akt, mTORC1, and mTORC2 activities are increased [228]. PRAS40 blocks mTORC1 activity by preventing the association of p70 ribosomal S6 kinase (p70S6K) and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) with Raptor [2,113,229,230]. Akt also is important in this pathway since mTORC1 activity is increased once phosphorylation of PRAS40 occurs by Akt. This releases the binding of PRAS40 and Raptor to sequester PRAS40 in the cell cytoplasm with the docking protein 14-3-3 [231–234]. In contrast to Deptor and PRAS40, mLST8 promotes the activity of mTOR. This requires the binding of p70S6K and 4EBP1 to Raptor [235]. mLST8 also has a number of other functions. It can oversee insulin signaling through the mammalian transcription factor FoxO3 [89,236], is necessary for Akt and protein kinase C-α (PKCα) phosphorylation, and is required for Rictor to associate with mTOR [236].

In contrast to mTORC1, mTORC2 is composed of Rictor, Deptor, the mammalian stress-activated protein kinase interacting protein (mSIN1), mLST8, and the protein observed with Rictor-1 (Protor-1) [2,8,113]. mTORC2 controls cytoskeleton remodeling through PKCα and cell migration through the Rac guanine nucleotide exchange factors P-Rex1 and P-Rex2 and through Rho signaling [237]. mTORC2 fosters activity of protein kinases that include glucocorticoid induced protein kinase 1 (SGK1), a member of the AGC family of protein kinases. Protor-1, a Rictor-binding subunit of mTORC2, leads to SGK1 activity [238,239]. mSin1 is vital for the assembly of mTORC2 and for mTORC2 to phosphorylate Akt [240]. Rictor and mSIN1 phosphorylate Akt at serine⁴⁷³ and promote threonine³⁰⁸ phosphorylation through phosphoinositide-dependent kinase 1 (PDK1) to be protective for cellular survival.

mTOR is intimately tied to cellular metabolic function and disease [2,34,57,241–244]. Activation of mTOR may limit cognitive loss that can be a result of DM [2,28,113,245–247]. For example, mTOR activation can prevent microglial injury during oxidative stress and limit Aß toxicity in neurons [232,246,248,249]. In addition, mTOR activation can prevent diabetic neuropathy [58] and reduce ischemic stroke injury in conjunction with circadian clock genes [2,22,250–252].

Decreased activity of mTOR has been shown to increase mortality in murine models of DM [253]. During mTOR inhibition with rapamycin, reduced β-cell function, insulin resistance, and decreased insulin secretion can promote the progression of DM [254]. Proper translocation of glucose transporters to the plasma membrane in skeletal muscle are also affected during loss of mTOR activity [255]. mTOR activation has been found to be diminished and this loss of mTOR may possibly be responsible for insulin resistance and the increased risk of vascular thrombosis in patients with metabolic syndrome [256]. Activation of mTOR pathways that involve p70S6K and 4EBP1 can improve insulin secretion in pancreatic β-cells and increase resistance to β-cell streptozotocin toxicity and obesity in mice [257]. Loss of p70S6K activity leads to hypoinsulinemia and glucose intolerance with decreased pancreatic β-cell size [258]. mTOR activity can protect pancreatic β-cells against cholesterol-induced apoptosis [259], lead to enhanced neuronal cell survival in cell models of DM [260], and prevent glucolipotoxicity [261]. mTOR activity can allow for the differentiation of adipocytes [262], prevent endothelial cell dysfunction during hyperglycemia [76], and preserve glucose homeostasis [263]. mTOR provides protection as part of the Mediterranean diet to reduce obesity in the population. The diet may reduce Aβ toxicity in astrocytes through enhanced Akt activity by consumption of polyphenol of olives and olive oil that ultimately could prevent the onset or progression of AD