Sirtuin Biology in Medicine: Targeting New Avenues of Care in Development, Aging, and Disease

By Kenneth Maiese

Sirtuin Biology in Medicine: Targeting New Avenues of Care in Development, Aging, and Disease provides a fascinating and in-depth analysis of sirtuins in the body during normal physiology as well during disease highlighting the targeting of sirtuin-controlled pathways for the development of innovative, efficacious, and safe therapeutic strategies for multiple disorders in the body that ultimately can affect lifespan extension. Sirtuins are expressed throughout the body, have broad biological effects, and can significantly impact both cellular survival and longevity during acute and long-term illnesses. These histone deacetylases play an intricate role in the pathology, progression, and treatment of several disease entities ranging from neurodegenerative disorders, cardiovascular disease, immune system dysfunction, reproductive dysfunction, endocrine disorders, gastrointestinal disease, drug dependency, and aging-related disorders. Implementing a translational medicine format, this unique reference highlights novel signaling pathways for sirtuins that promote stem cell proliferation, enhance cellular protection, modulate pathways of apoptosis and autophagy, and extend life span. Each chapter is presented with insightful detail that will be of interest and a comprehensive resource to audiences that include scientists, physicians, pharmaceutical industry experts, nutritionists, and students.

• Chapters are authored by internationally recognized experts who discuss the broad role of sirtuins in health and disease
• Details the basic and clinical role of sirtuins for the development of new clinical treatments
• Summarizes the multidiscipline views and publications for the compelling discipline of sirtuins by covering systems throughout the body
• Serves as an important resource 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: Mar 4, 2021
• ISBN: 9780128141199

Book preview

reality.

Section I

Sirtuins, neurodegenerative disease, lifespan extension, and aging

Outline

Chapter 1 Novel treatment strategies for neurodegenerative disease with sirtuins

Chapter 2 NAD+: a crucial regulator of sirtuin activity in aging

Chapter 3 Sirtuins and life span extension

Chapter 4 Sirtuins and aging

Chapter 5 Sirtuins in the biology of aging

Chapter 6 Sirtuins as regulators and the regulated molecules of exosomes

Chapter 7 Sirtuins in aging, age-related pathologies and their association with circadian rhythm

Chapter 8 Sirtuins, mitochondria, and the melatonergic pathway in Alzheimer’s disease

Chapter 9 Sirtuins, melatonin, and the relevance of circadian oscillators

Chapter 10 Epigenetic role of sirtuins in neurodegenerative brain disorders

Chapter 11 Sirtuins and stem cell maintenance, proliferation, and differentiation

Chapter 12 Sirtuins in mechanistic target of rapamycin complex 1 signaling

Chapter 13 Free-radical redox timer, sirtuins and aging: from chemistry of free radicals to systems theory of reliability

Chapter 14 Sirtuins, mitochondria, and exercise in health and disease

Chapter 1

Novel treatment strategies for neurodegenerative disease with sirtuins

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

Life span is increasing throughout the world and is accompanied by a rise in noncommunicable diseases (NCDs) that can lead to disability and death for over 40 million individuals each year. Neurodegenerative diseases are a significant component of NCDs and by the year 2030, it is estimated that over 80 million individuals will be impacted by neurodegenerative disorders such as dementia. In the United States alone, treatment for dementia will require over US$ 2 trillion every year to finance. Given the complexity and limited ability to treat neurodegenerative disorders, the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and its integrated pathways with mammalian forkhead transcription factors (FoxOs), the mechanistic target of rapamycin (mTOR), circadian clock genes, and noncoding ribonucleic acids (RNAs) offer exciting considerations for the development of new treatment strategies for neurodegenerative disease. SIRT1 relies upon these pathways to oversee apoptosis, autophagy, and oxidative stress, as well as cell development and cell proliferation controlled by trophic factors, such as erythropoietin (EPO), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4). However, a critical balance of activity is necessary among these pathways with SIRT1 and, if absent, can lead to cellular loss or tumorigenesis. Future investigations to gain essential insight into the extensive relationships held among SIRT1, FoxOs, mTOR, circadian clock genes, and noncoding RNAs are vital for the innovative and effective translation of these pathways into efficacious treatments for neurodegenerative disease.

Keywords

Alzheimer’s disease; autophagy; apoptosis; circular RNA; clock genes; diabetes mellitus; microRNA; dementia; erythropoietin; FoxO; mTOR; oxidative stress; SIRT1; WISP1; Wnt

Outline

Outline

Abbreviations 3

1.1 Increased life expectancy and neurodegenerative disease 4

1.2 Noncommunicable diseases and neurodegenerative disease 4

1.3 Innovative avenues for the treatment of neurodegenerative disease 5

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

1.5 SIRT1 and forkhead transcription factors 7

1.6 SIRT1 and the mechanistic target of rapamycin 9

1.7 SIRT1 and the circadian clock genes 10

1.8 SIRT1 and noncoding RNAs 11

1.9 Future considerations 11

Acknowledgments 13

References 13

Abbreviations

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

6-OHDA 6-hydroxydopamine

Aβ β-amyloid

AD Alzheimer’s disease

Akt protein kinase B

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

ATM ataxia-telangiectasia

Bad BCL2 associated agonist of cell death

BMAL1 brain and Muscle ARNT-Like 1

CBP CREB-binding protein

circRNA circular ribonucleic acid

Cry1 and Cry2 cryptochrome

Deptor DEP domain-containing mTOR interacting protein

DM diabetes mellitus

DNA deoxyribonucleic acid

EPO erythropoietin

FKHD-L forkhead-like consensus-binding site

FoxOs mammalian forkhead transcription factors

FRAP FKBP12-rapamycin-associated protein

HD Huntington’s disease

HDAC2 histone deacetylase 2

miRNA microRNA

mLST8 mammalian lethal with Sec13 protein 8, termed mLST8

mSIN1 mammalian stress-activated protein kinase interacting protein

mTOR mechanistic target of rapamycin

mTORC1 mTOR Complex 1

mTORC2 mTOR Complex 2

NAD+ nicotinamide adenine dinucleotide

NCDs noncommunicable diseases

p70S6K p70 ribosomal S6 kinase

PD Parkinson’s disease

PDK1 phosphoinositide-dependent kinase 1

Per1, Per2, and Per3 period

PKCα protein kinase C-α

PPARα peroxisome proliferator-activated receptor-alpha

PS phosphatidylserine

PRAS40 proline rich Akt substrate 40 kDa

RNA ribonucleic acid

SCN suprachiasmatic nucleus

SGK1 glucocorticoid induced protein kinase 1

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

TNF-α tumor necrosis factor-α

TSC1/TSC2 hamartin (tuberous sclerosis 1)/tuberin (tuberous sclerosis 2)

WISP1/CCN4 Wnt1 inducible signaling pathway protein 1

1.1 Increased life expectancy and neurodegenerative disease

Life expectancy is increasing throughout the world. In the United States, life expectancy was decreasing over a 4-year period. However, with a recent reduction in deaths from opioid overdoses, life expectancy is increasing again in the United States [1]. At present, life expectancy has reached 80 years of age [2]. From the years 2000 through 2011, the age-adjusted death rate for life expectancy has been marked by a 1% decrease [3]. Over the prior 50 years, it is estimated that the number of people over the age of 65 has doubled [4]. It is predicted that large countries such as China and India will see an increase in the elderly population from 5%–10% over multiple decades [5,6]. Interestingly, the 10 leading causes of death—cardiac disease, cancer, trauma, respiratory disease, stroke, Alzheimer’s disease (AD), diabetes mellitus (DM), influenza and pneumonia, kidney disease, and suicide—continue to remain the same [1]. A number of reasons can account for the observed increase in life span [7]. These include enhanced access to preventive medical care, improved public health guidelines and sanitation measures, and new treatments for multiple disease entities for both mental and physical health [8–16].

1.2 Noncommunicable diseases and neurodegenerative disease

Although the global increase in life expectancy is considered beneficial, this rise in life expectancy has unfortunately corresponded to an increased prevalence of noncommunicable diseases (NCDs) [17–20]. Approximately 70% of the annual deaths that occur each year are the result of NCDs and at least 40 million people die from NCDs on an annual basis [21]. Of these 40 million individuals, at least 15 million are between the ages of 30 and 69, illustrating that all age groups can be affected by NCDs. In addition, greater than 10% of the population under 60 years of age is affected in high-income countries [22]. In low- and middle-income countries, NCDs can affect a much larger proportion of people with greater than one-third of the population impacted under 60 years of age.

Neurodegenerative diseases are a significant component of NCDs [16,18,23–25] (Table 1.1). Nervous system diseases comprise over 600 disorders that lead to death and disability [25–27]. Both acute and chronic diseases of the nervous system affect large numbers of individuals throughout the globe that can exceed more than 1 billion individuals [27–29]. This represents approximately 15% of the world’s population and at least 7 million die each year from neurodegenerative disorders [18].

Table 1.1

Neurodegenerative disorders are expected to increase in prevalence throughout the globe as a result of the progressive increase in life span. As an example of the growing prevalence of neurodegenerative disorders, the incidence of sporadic cases of AD is expected to significantly increase throughout the globe [17,18,24,27,30]. In the United States alone, over 60 million additional medical workers and behavioral health walkers will be necessary to provide unpaid care for people with AD or other dementias [21,22,31]. Sporadic cases of AD are increasing in the world with dementia now ranked as the seventh leading cause of death [27]. Dementia occurs in all countries throughout the world at a significant financial burden [21]. Greater than 5 million people suffer with cognitive disorders in the United States and most of these cases, approximately 60%, are AD [18]. Currently, 50 million people in the world, or 5% of the global population, have dementia [5,32–34]. By 2030, dementia will affect 82 million individuals, and by 2050, 152 million individuals will be impacted by dementia. These numbers are compounded by other factors. It is also believed that dementia is underdiagnosed throughout the world [18,27,35,36]. Furthermore, assuming the diagnosis is correct, dementia can be difficult to treat, especially if the disease has progressed to later stages necessitating multiple modalities of treatment for both physical health and behavioral health.

All countries suffer a significant financial burden from neurodegenerative disorders. The cost of neurodegenerative disorders exceeds US$ 800 billion dollars in the United States alone and this includes dementia, stroke, back pain, epilepsy, trauma to the nervous system, and Parkinson’s disease (PD). Treatment for dementia is considered the most significant cost factor with more than US$ 277 billion a year required for dementia care [21]. The estimated costs for dementia care for individuals approximate at 2% of the gross domestic product (GDP) in the world. By the year 2030, necessary medical and behavior care expenses in the United States are estimated to be US$ 2 trillion annually. These projections fail to include the additional expenses necessary to provide adult living care, social outreach programs, and companion care. Other challenges for the care of individuals with neurodegenerative disorders include decisions when to address and initiate the need for healthcare workers in a timely and efficient manner.

1.3 Innovative avenues for the treatment of neurodegenerative disease

A number of challenges for addressing neurodegenerative diseases exist that include reaching the proper diagnosis and treatment as well as limiting the progression of disease. In general, for neurodegenerative diseases, treatment options are limited. For example, AD is a syndrome that is not the result of a single etiology. Multiple mechanisms may result in the loss of cognition and dementia [17,18,24,35–38]. These mechanisms can include oxidative stress, metabolic dysfunction with DM, excitotoxicity, astrocytic cell injury, induction of autophagy, acetylcholine loss, β-amyloid (Aβ) and tau toxicity, ribonucleic acid (RNA) involvement, and mitochondrial damage [7,17,18,23,26,39–46]. Present treatments for AD rely upon cholinesterase inhibitors that may alleviate symptoms but not disease progression [24,47]. Other treatments for dementia can focus on vascular disease [18,48–50] and metabolic disease, such as DM, and nutritional intake [7,17,18,37,51–56]. Yet even for underlying conditions such as DM, tight serum glucose control cannot completely inhibit possible complications from DM [18,57,58]. Nutritional control of oral intake can limit hyperglycemia and hyperlipidemia [7,55,59], but diet-mediated remedies have potential risks that can lead to a reduction in organ size with the activation of autophagy [60]. Other risk factors for neurodegenerative disorders include hypertension, limited education advancement, and tobacco use [27]. As a result of the complex nature of neurodegenerative disorders, development of innovative strategies is required to address treatments suited for the nervous system. An exciting consideration for the treatment of neurodegenerative disorders is the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1) and its integrated pathways with mammalian forkhead transcription factors (FoxOs), the mechanistic target of rapamycin (mTOR), circadian clock genes, and noncoding ribonucleic acids (RNAs) (Table 1.1).

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

SIRT1, a member of the sirtuin family (sirtuin 1), is a histone deacetylase [5,11,61–71] that can transfer acetyl groups from ε-N-acetyl lysine amino acids to the histones of deoxyribonucleic acid (DNA) to control transcription. Seven identified mammalian homologues of Sir2 include SIRT1 through SIRT7. These histone deacetylases control metabolism, proliferation and survival of cells, cell senescence, cell function, and posttranslation modifications of proteins [18,20,72–75]. SIRT1 relies upon nicotinamide adenine dinucleotide (NAD+) as a substrate [65,76–79]. Histone deacetylases are enzymes that transfer acetyl groups from ε-N-acetyl lysine amino acids that exist on DNA histones to regulate transcription. Although histone deacetylases primarily oversee DNA transcription, they can promote posttranslational changes of proteins. As an example, SIRT1 can oversee the posttranslational phosphorylation of FoxOs [80,81]. During deacetylase reactions, sirtuins, such as SIRT1, transfer the acetyl residue from the acetyllysine residue of histones to the ADP-ribose moiety of NAD+, leading to the production of nicotinamide, 2′-O-acetyl ADP ribose, and deacetylated proteins. SIRT1 protein can be found in the brain, heart, liver, pancreas, skeletal muscle, spleen, and adipose tissues. SIRT1 is present in the cell nucleus and cytoplasm with dominant expression in the nucleus [33,62,68,71,75,79,82–84].

SIRT1 is an important target for disorders such as AD [18,69,71,75,85,86]. In conjunction with 17 beta-estradiol, SIRT1 can block memory impairment during oxidative stress in murine experimental models [87]. SIRT1 can inhibit neurofibrillary degeneration that occurs during dysregulation of tau exon 10 splicing [86]. SIRT1 also can maintain mitochondrial integrity in conjunction with other mechanisms in models of Huntington’s disease (HD) [88] as well as during other injury paradigms [63,64,71,74,84,89].

Other studies suggest that SIRT1 activation can decrease oxidative stress and prevent cell injury that would lead to memory loss [18,68,90–96]. Activation of SIRT1 has been associated with reduction in oxidative stress and protection of cognition [87]. Oxidative stress may lead to aberrant cell cycle reentry that can lead to neuronal death during AD [97,98]. 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 [33]. In other models of AD, agents that reduce levels of oxidative stress with reduction in Aβ expression can result in improved cognitive function [99]. SIRT1 may function to directly block Aβ and tau toxicity as well as mitochondrial dysfunction. SIRT1 may be active against Aβ to decrease the toxicity of this protein [85,100–102]. SIRT1 also can control vascular and neuronal protection in the brain that would be relevant for ischemic-mediated dementia [5,61,68,76,77,79,91,103–107]. SIRT1 can increase life span in higher organisms and protect against oxidative stress in neuronal cells [90].

SIRT1 can oversee pathways of apoptosis and autophagy [69,70]. SIRT1 activation inhibits external membrane phosphatidylserine (PS) exposure during the early phases of apoptosis in mature cells [81,108–110]. SIRT1 can block apoptosis initiated by tumor necrosis factor-α (TNF-α) in endothelial progenitor cells [111]. Loss of SIRT1 expression in endothelial progenitor cells results in apoptotic cell death that can occur in smokers and chronic obstructive disease patients [112]. Cardiac cells can be protected from apoptotic cell death during oxidative stress through SIRT1 activation [113].

Interestingly, apoptotic cell death is intimately connected to autophagy cell survival through SIRT1. For example, autophagy induction in human lung cancer cells leads to increased cell survival. SIRT1 inhibition leads to prosurvival autophagy activity and inhibition of apoptosis in these cells [114]. SIRT1 also can upregulate autophagy and mitochondria function in embryonic stem cells during oxidative stress [115]. Agents such as nicotinamide can protect hepatocytes against palmitate-induced lipotoxicity through SIRT1-dependent induction of autophagy [116]. Through SIRT1 activity and autophagic flux, senescence is blocked in vascular endothelial cells [117].

SIRT1 also functions through the activity of tropic factors, such as erythropoietin (EPO) [118], to protect cells against toxic environments [79,119–121] (Table 1.1). In adipocytes, EPO increases metabolic activity and maintains adipose energy homeostasis to protect against metabolic dysfunction through the combined activation of peroxisome proliferator-activated receptor-alpha (PPARα) and SIRT1 [122]. EPO also uses SIRT1 to modulate skeletal myogenic differentiation [123]. EPO in endothelial cells of the brain promotes the subcellular trafficking of SIRT1 to the nucleus which is necessary for EPO to lead to vascular cell protection and to prevent mitochondrial depolarization, cytochrome c release, BCL2 associated agonist of cell death (Bad) activity, and caspase activation [109]. During injury in the presence of chemotherapy agents, EPO can protect human cardiomyocytes against mitochondrial dysfunction through SIRT1 activation [63]. EPO also may prevent the loss of cells in the brain through the upregulation of SIRT1 [124].

1.5 SIRT1 and forkhead transcription factors

In the SIRT1 pathway, FoxOs are critical factors that can oversee cellular survival [20,66,125–127]. FoxOs can target neurodegenerative disorders, especially those diseases that involve dementia and the loss of cognition [66,127,128]. Since the discovery of the Drosophila melanogaster gene forkhead, over 100 forkhead genes and 19 human subgroups have been identified that range from FOXA to FOXS [129,130]. The mammalian FOXO proteins of the O class have strong relevance to neurodegenerative disorders and include the members FOXO1, FOXO3, FOXO4, and FOXO6 [127,131–133]. FoxO proteins are homologous to the transcription factor DAuer Formation-16 (DAF-16) in the worm Caenorhabditis elegans that can oversee metabolic insulin signaling and lead to life span extension [134,135]. FoxO proteins appear to have selective expression in the nervous system that may provide clues to the biology for some FoxO proteins [131,136]. FoxO6 may control memory consolidation and emotion [137] since it is present in several regions of the brain associated with memory retrieval, such as the hippocampus, the amygdala, and the nucleus accumbens [138,139]. FoxO1 may have a role related to astrocyte survival [140], modulation of embryonic endothelial stem cell survival [141], regulation of ischemic brain injury [142], vascular disease [82,143,144], and motor and memory pathways in the striatum and subregions of the hippocampus [138]. FoxO3 may have a significant role in auditory synaptic transmission [145], cerebral endothelial vascular cell survival [109,146], oxidative stress injury in mouse cerebellar granule neurons [147], neonatal hypoxic-ischemic encephalopathy [148], erythroid cell growth [149], hippocampal neuronal injury [150,151], and PD [128].

Forkhead proteins are also known as forkhead in rhabdomyosarcoma (FKHR) (FOXO1), FKHRL1 (forkhead in rhabdomyosarcoma like protein 1) (FOXO3a), the Drosophila gene forkhead (fkh), Forkhead RElated ACtivator (FREAC)-1 and -2, and the acute leukemia fusion gene located in chromosome X (AFX) (FOXO4) [66]. The forkhead box (FOX) family of genes has a conserved forkhead domain (the forkhead box) noted as a winged helix. This is due to X-ray crystallography [152] and nuclear magnetic resonance imaging [153] that is suggestive of a butterfly-like appearance for the FOX family of genes. The forkhead domain in FoxO proteins contains three α-helices, three β-sheets, and two loops that compose the wings of the domain [132]. This is specific for the forkhead proteins, since not all winged helix domains are actually Fox proteins [154]. FoxO proteins are transcription factors that bind to DNA through the FoxO-recognized element in the C-terminal basic region of the forkhead DNA binding domain [136,155]. Once forkhead binding to DNA occurs, activation or repression of target gene expression occurs through 14 protein-DNA contacts with the primary recognition site located at α-helix H3 [152]. Posttranslational changes that include FoxO protein phosphorylation or acetylation can alter the binding of the C-terminal basic region to DNA to prevent transcriptional activity and block FoxO activity [156]. Yet other factors may affect forkhead binding to DNA. These include N-terminal region of the recognition helix variations, electrostatic distribution changes, and sequestering FoxO proteins in the nucleus of cells [157–160].

Both epigenetic and posttranslation protein modifications can control FoxOs. These pathways include phosphorylation [66,125], acetylation [126,127,161], and ubiquitylation [151]. The serine-threonine kinase protein kinase B (Akt) modulates forkhead transcription factor phosphorylation [66]. Akt can phosphorylate FoxO proteins that facilitates binding to 14-3-3 proteins, blocks nuclear translocation, and prevents transcription of target genes that can lead to apoptotic cell death [66,128]. Akt also prevents caspase activity that leads to the induction of apoptosis during inhibition of FoxO activity. If FoxO proteins, such as FoxO3a, become active, cytochrome c release can occur with caspase-induced apoptotic cell death [80,162–164]. Akt also appears to have a secondary regulatory mechanism that controls FoxO proteins to prevent caspase activity. FoxO3a cleavage by caspase 3 can produce proapoptotic amino-terminal (Nt) fragments [165]. However, during blockade of caspase 3 activity by Akt activation, phosphorylated FoxO3a is not cleaved and does not result in apoptotic cell injury during oxidative stress [81,166,167].

In addition to Akt, other pathways can lead to the phosphorylation of FoxOs and inactivate these proteins. The serum- and glucocorticoid-inducible protein kinase (SGK), a member of a family of kinases termed protein kinase A/protein kinase G/protein kinase C (AGC) that includes Akt, phosphorylates FoxO3a and maintains this protein in the cytoplasm [66,168]. Other protein kinases can phosphorylate FoxOs at specific sites and lead to the activation of FoxOs. For example, mammalian sterile 20-like kinase-1 (MST1) leads to the phosphorylation of FoxO proteins at Ser²⁰⁷, inhibits FoxOs from binding to 14-3-3 proteins, fosters the nuclear translocation and transcription activity of FoxO3a, and results in the apoptotic death of neurons and astrocytes [140,158]. In regard to targeting these pathways, it is important to realize that Akt, SGK, and MST1 use different protein sites to phosphorylate FoxOs, suggesting the development of different pathways to modulate FoxO activity [66].

Pathways associated with ubiquitylation and acetylation also control posttranslational modification of FoxO proteins [169]. Akt results in the ubiquitination and degradation of FoxOs through the 26S proteasome. Acetylation of FoxO proteins represents another mechanism of oversight of these proteins [66,126]. FoxOs can be acetylated by histone acetyltransferases that include p300, the CREB-binding protein (CBP), and the CBP-associated factor. Following acetylation, nuclear translocation of FoxOs can occur but FoxO proteins are noted to have diminished activity. This loss of FoxO activity occurs as a result of the acetylation of lysine residues on FoxO proteins limiting the ability of FoxO proteins to bind to DNA [170]. Acetylation of FoxO proteins also promotes phosphorylation of FoxOs by Akt [170].

Interestingly, deacetylation of FoxOs is controlled by sirtuins and SIRT1. SIRT1 controls DNA transcription by transferring acetyl groups from ε-N-acetyl lysine amino acids to the histones of DNA. FoxO proteins are deacetylated by SIRT1 and other histone deacetylases [69,75,171–175]. In addition, histone deacetylase 2 (HDAC2) also forms a physical complex with FoxO3a. During periods of injury with oxidative stress, the interaction between HDAC2 and FoxO3a can become reduced and ultimately lead to neuronal cell death [147].

Through these pathways that involve SIRT1 and FoxO proteins, activation of SIRT1 results in enhanced cell survival through inhibition of FoxO activity [69] (Table 1.1). In addition, feedback mechanisms also exist. FoxO proteins can bind to the SIRT1 promoter region to alter forkhead transcription. This promoter region has a cluster of five putative core binding repeat motifs (IRS-1) and a forkhead-like consensus-binding site (FKHD-L). As a result, FoxOs function through potential autofeedback mechanisms to regulate SIRT1 activity (Table 1.1). With SIRT1, FoxO proteins are critical for preimplantation embryo development and control SIRT1 protein expression through autofeedback pathways [176]. FoxO proteins, such as FoxO1, also have been shown to modulate SIRT1 transcription and increase SIRT1 expression [177]. FoxOs and SIRT1 can function synergistically to increase the survival of cells [5]. In studies examining the protective effects of hydrogen-rich water to prevent Aβ toxicity in the brain, SIRT1 and FoxO3a were demonstrated to block Aβ injury that affected mitochondria and limit the toxicity of oxidative stress [178]. In additional studies, increased FoxO3a and SIRT1 activity during reduced autophagy activity limits oxidative stress in human bronchial epithelial cells exposed to cigarette smoke condensates [179]. Loss of the forkhead transcription factors FoxO1 and FoxO3 in combination with decreased SIRT1 activity during oxidative stress results in a reduction of autophagy activity and subsequent chondrocyte cell death, suggesting that SIRT1 with FoxOs may be required for cellular protection during oxidative stress [180].

Other work suggests that inhibition of FoxO protein activity during SIRT1 activation can increase cell survival. As a histone deacetylase, SIRT1 reversibly deacetylates FoxO proteins [62] and maintains tissue function during periods of starvation through pathways involving autophagy [181]. Through the deacetylation of FoxOs, SIRT1 leads to increased cortical bone formation with osteoblast progenitors by blocking FoxO protein binding to β-catenin that would inhibit Wnt signaling [182]. SIRT1 activity can foster cell survival in the nervous system through the blockade of FoxO protein activity [62,77,79,183,184]. For example, promotion of SIRT1 nuclear translocation increases neuronal survival [150]. If SIRT1 activity is lost, increased FoxO1 expression during high glucose exposure can lead to endothelial cell dysfunction [185]. The degree of SIRT1 activity can be a critical modulator of cell survival. Exercise training in rodents can limit age-related impairments though the increase in antioxidant pathways and the increase of SIRT1 activity and FoxO3a expression [186]. Yet it appears that antioxidant activity, such as through catalase expression and FoxO protein dependent pathways, requires SIRT1 activity that increases less than 7.5-fold [187]. Levels of SIRT1 activity that exceed 12.5-fold can lead to apoptosis and cardiac dysfunction [187].

Through SIRT1, trophic factors that involve EPO are tied to additional cell protective pathways that involve both FoxOs and Wnt signaling (Table 1.1). Wnt proteins are cysteine-rich glycosylated proteins that are proliferative in nature and control vascular cells, stem cells, immune function, tumorigenesis, and neuronal survival [188–196]. Pathways that involve Wnt signaling can block the degradation of SIRT1, maintain its activity, and prevent apoptotic caspase activation [150,162,197,198]. EPO protects vascular cells during exposure to elevated glucose by maintaining the expression of Wnt1 signaling [199]. EPO also increases Wnt signaling to maintain the survival of mesenchymal stem cells [200], prevent Aβ toxicity in microglial cells [201], and foster microglial cell integrity during oxidative stress [202]. With FoxO proteins, EPO uses Wnt signaling to limit FoxO activity and increase cell survival [66,104,157]. EPO relies upon Wnt1 to inhibit FoxO3a activity and maintain endothelial cell survival during elevated glucose exposure [157]. In addition, other pathways of Wnt signaling are dependent upon SIRT1 and FoxOs. As an example, Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4) is a target of Wnt1 signaling that oversees apoptosis and autophagy, extracellular matrix production, tumorigenesis, cellular migration, fibrosis, inflammation, and mitosis [54,203–210]. Similar to Wnt1 signaling, WISP1 promotes SIRT1 activity and trafficking to the cell nucleus [150]. WISP1 through SIRT1 activation protects neurons through the phosphorylation of FoxO3a, by sequestering FoxO3a in the cytoplasm with protein 14-3-3, and by limiting deacytelation of FoxO3a [150].

1.6 SIRT1 and the mechanistic target of rapamycin

SIRT1 pathways are intimately tied to the mTOR. mTOR is a 289-kDa serine/threonine protein kinase that is encoded by a single gene FRAP1 [18,25,211,212]. mTOR also is known as the mammalian target of rapamycin and the FK506-binding protein 12-rapamycin complex-associated protein 1 [34,58,69]. The target of rapamycin (TOR) was initially described in Saccharomyces cerevisiae with the genes TOR1 and TOR2 [34]. Using rapamycin-resistant TOR mutants, TOR1 and TOR2 were found to encode the Tor1 and Tor2 isoforms in yeast [213]. Rapamycin is a macrolide antibiotic in Streptomyces hygroscopicus that inhibits TOR and mTOR activity [214]. mTOR serves as the principal component of the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) [119,215,216]. Rapamycin blocks 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 [69]. 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 [212,217].

mTORC1 and mTORC2 are divided into subcomponents. 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) [18,69]. 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 [218]. The inability to phosphorylate serine⁸⁶³ limits mTORC1 activity, as illustrated using a site-direct mutation of serine⁸⁶³ [219]. mTOR can control Raptor activity and this activity can be blocked by rapamycin [219]. 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 diminished, Akt, mTORC1, and mTORC2 activities are increased [220]. PRAS40 prevents mTORC1 activity by blocking the association of p70 ribosomal S6 kinase (p70S6K) and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) with Raptor [18,69,221,222]. Akt also is active 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 [142,223–225]. In contrast to Deptor and PRAS40, mLST8 fosters the activity of mTOR. This requires the binding of p70S6K and 4EBP1 to Raptor [226]. mLST8 also oversees insulin signaling through the transcription factor FoxO3 [104,227], is necessary for Akt and protein kinase C-α (PKCα) phosphorylation, and is required for Rictor to associate with mTOR [227].

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) [18,69]. 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 [228]. mTORC2 promotes 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, results in SGK1 activity [229,230]. mSin1 is important for the assembly of mTORC2 and for mTORC2 to phosphorylate Akt [231]. Rictor and mSIN1 phosphorylate Akt at serine⁴⁷³ and promote threonine³⁰⁸ phosphorylation through phosphoinositide-dependent kinase 1 (PDK1) to increase cell survival.

mTOR has an active role with neurodegenerative disease and SIRT1 [20,38,58,232,233] (Table 1.1). Activation of mTOR may prevent cognitive loss [18,38,69,233–235], block diabetic neuropathy [236], and limit ischemic stroke injury in conjunction with circadian clock genes [11,18,237–239]. mTOR activation also can prevent microglial injury during oxidative stress and prevent Aß injury in neurons [38,201,224,240]. Vascular cell survival during mTOR activation is increased [69,235,241,242] and neuroplasticity is fostered [243]. SIRT1 has an inverse relationship with mTOR [18,33,69,114,117,208,217,244,245]. SIRT1 activity results in neurite outgrowth and increased neuronal survival during nutrient-limiting conditions with the inhibition of mTOR [246]. SIRT1 can promote tumor cell growth with autophagy activity that requires mTOR inhibition, suggesting that both SIRT1 and autophagy pathways can be targets to control tumor cell growth [114]. During oxidative stress, SIRT1 can promote autophagy induction and the inhibition of mTOR to prevent mitochondrial dysfunction in embryonic stem cells [115] and other cells [247]. During periods of hyperglycemia, SIRT1 blocks vascular cell injury during inhibition of mTOR activity [245]. Inhibition of mTOR with SIRT1 activation can increase cell survival for photoreceptor cells [72] and prevent cell senescence [117]. However, under some conditions that may involve dopaminergic neuronal cell loss a balance in activities of SIRT1, mTOR, and forkhead transcription factors is required to achieve neuroprotection [107].

1.7 SIRT1 and the circadian clock genes

Circadian rhythm clock genes have a prominent role during neurodegenerative disorders [11,70,248–250]. The mammalian circadian clock is in the suprachiasmatic nucleus (SCN). This region of the brain is located above the optic chiasm and receives light input from photosensitive ganglion cells in the retina. The SCN depends upon the pineal gland, hypothalamic nuclei, and vasoactive intestinal peptide to control several processes that involve the release of the hormones cortisol and melatonin, oxidative stress responses [251], and the regulation of body temperature [249]. Members of the clock gene family include the basic helix-loop-helix-PAS (Period-Arnt-Single-minded) transcription factor family, such as CLOCK and brain and muscle ARNT-Like 1 (BMAL1) [252]. These transcription factors control the expression of the genes Cryptochrome (Cry1 and Cry2) and Period (Per1, Per2, and Per3). Feedback of these pathways is provided by PER:CRY heterodimers that can translocate to the nucleus to inhibit and block the transcription of CLOCK:BMAL1 complexes. Other regulatory loops consist of retinoic acid-related orphan nuclear receptors REV-ERBα, also known as NR1D1 (nuclear receptor subfamily 1, group D, member 1), and RORα that are activated by CLOCK:BMAL1 heterodimers. The REV-ERBα and RORα receptors bind retinoic acid-related orphan receptor response elements (ROREs) present in the BMAL1 promoter to control transcription with RORs that can foster transcription and REV-ERBs that can inhibit transcription to lead to circadian oscillation of BMAL1 [253,254].

Rhythmic methylation of BMAL1 may impact several neurodegenerative diseases. For example, rhythmic methylation of BMAL1 is changed in the brains of patients with AD, illustrating that alterations in the DNA methylation of clock genes may contribute to cognitive loss and behavior changes [255]. Animal models of PD with 6-hydroxydopamine (6-OHDA) have shown decreased BMAL1 and RORα can persist with levodopa treatment, suggesting that long-term levodopa treatment may affect circadian rhythm function [256]. Clock genes can impact life span that are related to neurodegeneration and even tumorigenesis [257]. In studies with D. melanogaster, life span was found to be reduced in three arrhythmic mutants involving ClkAR, cyc0, and tim0. ClkAR mutants expressed faster age-related locomotor deficits and restoring Clk function rescued Drosophila from the locomotor deficits. Although increased oxidative stress was present with the mutant phenotypes, deficits appeared to correlate best with loss of dopaminergic neurons rather than directly to the presence of oxidative stress [258].

Circadian rhythm dysfunction during cognitive loss and aging can be associated with autophagy induction as well as SIRT1 [11,70,251] (Table 1.1). In animal models of AD, a basal circadian rhythm that controls macroautophagy appears to be necessary to prevent cognitive decline and Aβ deposition [259]. Chronic sleep fragmentation also has been shown to affect autophagy proteins in the hippocampus [260] that may impair cognition [33,67,261–263]. Autophagy in the hippocampus is depressed during the absence of the PER1 circadian clock protein that may worsen the pathology of cerebral ischemia [264]. In regard to SIRT1, SIRT1 has been associated with altered circadian rhythm function that affects the development of disorders such as AD [248]. SIRT1 control of circadian rhythm and melatonin can affect glucose tolerance and DM [249], as well as inflammation during obesity [265]. Increased SIRT1 activity with a disruption in circadian rhythm also affects tumor growth, such as increased susceptibility to mammary carcinogenesis [266]. Given the inverse relationship with mTOR, SIRT1 can control clock gene pathways through mTOR. For example, during SIRT1 activity and mTOR inhibition, loss of mTOR activity can lead to altered circadian rhythm and cognitive decline during prolonged space flight [267]. Ischemic stroke also be influenced by changes in circadian rhythm genes and fluctuations in mTOR activity [237,264].

1.8 SIRT1 and noncoding RNAs

Small noncoding RNAs, termed microRNAs (miRNAs), have recently become the focus for the treatment of neurodegenerative disorders [244,268–278]. MiRNAs are composed of 19–25 nucleotides and control gene expression by silencing targeted messenger RNAs (mRNAs) translated by specific genes. These small noncoding RNAs may play an important role to influence stem cell proliferation and cellular differentiation [244]. For example, overexpression of miR-381 can lead to neural stem cell proliferation and prevent differentiation into astrocytes [273]. MiR-134, miR-296, and miR-470 can serve to target Oct4, Sox2, and Nanog coding regions to lead to stem cell differentiation [279]. In relation to SIRT1, inhibition of miR-34a can increase the expression of SIRT1 and prevent the loss of angiogenesis in vascular cells during hyperglycemia [103] (Table 1.1). In contrast, loss of SIRT1 activity through miR34a expression can accelerate retinal vascular dysfunction [92,280] and through miR-204 expression lead to vascular cell dysfunction [281]. Cochlear hair cell loss through the presence of miR-29b occurs as a result of downregulation of SIRT1 activity [282]. Inhibition of other miRNAs, such miR-22, can block the proliferation, motility, and invasion of human glioblastoma cells by directly targeting SIRT1 [283].

Circular ribonucleic acids (circRNAs) also appear to be increasingly recognized as having a role in the nervous system [42,56,68,207,244,276,284,285]. CircRNAs are noncoding RNAs of approximately 100 nucleotides in length that were initially identified as being circular in nature [276,286,287]. CircRNAs have covalent bonds that maintain their circular structure, have both cis and trans regulation, control gene expression through the sponging of miRNAs [288], function as biomarkers [48,56,285,289–291], and control apoptotic pathways [45,46,276]. During vascular disease, circular antisense noncoding RNA in the INK4 locus (circANRIL) in vascular smooth muscle cells and macrophages prevents exonuclease-mediated preribosomal RNA processing, ribosome biogenesis, and proliferation of cells that lead to atherosclerosis through the onset of apoptosis [292]. In the nervous system, circRNAs may be beneficial for the treatment of AD. The circRNA HDAC9 (circHDAC9) has been shown to function as a miR-138 sponge, decrease miR-138 expression, and promote SIRT1 activity to limit Aβ production by miR-138. CircHDAC9 was found to be decreased in the serum of both AD patients and individuals with mild cognitive impairment, suggesting a clinical role for this circRNA with SIRT1 [293] (Table 1.1). In a similar manner, circERCC2 was shown to decrease miR-182-5p, block apoptosis, and decrease intervertebral disc degeneration in the spine through the activation of SIRT1 [294]. Yet, it is important to note that circRNAs may not always be protective against cell death and apoptosis. Upregulation of specific circRNAs may foster apoptotic cell injury during cell models of ischemic-reperfusion injury [295].

1.9 Future considerations

Although life expectancy was temporarily decreasing in the United States over a recent 4-year period, life expectancy has now increased again in the United States with prior reductions in opioid overdoses. In addition, life expectancy continues to increase throughout the world with large countries expected to observe an increase in elderly populations from 5% to 10% over multiple decades. The increase in global life expectancy corresponds to an increased prevalence of NCDs, and in particular, neurodegenerative diseases (Fig. 1.1). Nervous system diseases comprise over 600 disorders that lead to death and disability with at least 15% of the world’s population succumbing to neurodegenerative diseases. This increase in neurodegenerative disorders also yields severe financial burdens for countries around the world that consume significant portions of the GDP to care for individuals with neurodegenerative disorders.

Figure 1.1 Innovative SIRT1 therapeutic strategies for neurodegenerative disease.

With a rise in life span observed throughout the globe, noncommunicable diseases, and in particular, neurodegenerative diseases have increased in prevalence resulting in both disability and death for individuals and leading to severe financial burdens for countries around the world. The SIRT1 and its integrated pathways with mammalian forkhead transcription factors (FoxOs), the mechanistic target of rapamycin (mTOR), circadian clock genes, and noncoding ribonucleic acids (RNAs) provide innovative strategies for the development of new treatments for neurodegenerative disorders. Through growth factors, such as erythropoietin (EPO), SIRT1 can maintain cellular metabolism and prevent cellular demise in the nervous system. EPO also can use Wnt signaling to block FoxO activity and increase cell survival. As part of an autofeedback mechanism, FoxO proteins oversee the transcription and expression of SIRT1. Yet SIRT1 also can limit FoxO activity through Wnt signaling and Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4). SIRT1 also has a critical relationship with circadian clock genes and noncoding RNAs and can interface with mTOR to prevent vascular cell degeneration and cognitive decline. Ultimately, SIRT1 can prevent apoptotic cell death and promote the induction of autophagy to increase cell survival in the nervous system.

Several challenges for addressing neurodegenerative disorders exist that include obtaining an accurate diagnosis, effective treatment, and strategies to hopefully limit the progression of disease. Yet, due to the complexity of neurodegenerative disorders, present care for neurodegenerative diseases is limited and does not effectively target critical underlying pathways. As a result of these challenges, innovative treatment pathways that involve SIRT1, FoxOs, mTOR, circadian clock genes, and noncoding RNAs offer exciting prospects to develop therapeutic strategies for neurodegenerative diseases (Table 1.1). SIRT1 can prevent memory loss, block neurofibrillary degeneration, maintain mitochondrial integrity, limit oxidative stress, and reduce Aβ and tau toxicity in models of AD. In addition, SIRT1 can foster vascular and neuronal protection in the brain that would be relevant for ischemic-mediated dementia.

SIRT1 functions through pathways that rely upon the inhibition of apoptosis and the induction of autophagy that can enhance cell survival and limit cell senescence. Growth factors, that involve EPO, maintain cellular metabolic homeostasis in cells, prevent mitochondrial depolarization, and block apoptotic cytochrome c release, Bad, and caspase activation by promoting the activity of SIRT1. Even in the presence of toxic chemotherapy agents, EPO can protect human cells against mitochondrial dysfunction through SIRT1 activation. SIRT1 also can function synergistically with FoxOs. In studies examining the protective effects of hydrogen-rich water to prevent Aβ toxicity in the brain, SIRT1 and FoxO3a can prevent Aβ injury that limits the toxicity of oxidative stress. Yet, under other conditions, SIRT1 activity can foster cell survival in the nervous system through the blockade of FoxO protein activity. If SIRT1 activity is absent, increased FoxO expression can lead to cell demise. These observations suggest that the degree of SIRT1 activity can be a critical modulator of cell survival. Furthermore, FoxOs have been shown to function through autofeedback mechanisms that can control SIRT1 activity since FoxO proteins have been shown to oversee the transcription and expression of SIRT1. In addition to SIRT1, Wnt signaling proteins also limit FoxO activity to increase cell survival. WISP1 through SIRT1 activation protects neurons through the phosphorylation of FoxO3a and by limiting deacytelation of FoxO3a. SIRT1 also maintains a close but inverse relationship with mTOR. For example, SIRT1 can promote neurite outgrowth and increase neuronal survival during nutrient-limiting conditions by reducing mTOR activity. Inhibition of mTOR with SIRT1 activation can also increase cell survival for photoreceptor cells and block cell senescence. However, under some conditions that may involve dopaminergic neuronal cell loss, a fine balance in activities of SIRT1, mTOR, and forkhead transcription factors is required for neuroprotection.

SIRT1 also has a critical relationship with circadian clock genes and noncoding RNAs. SIRT1 can oversee circadian rhythm and melatonin release that can affect glucose homeostasis, DM, and inflammation. The impact of SIRT1 on circadian rhythm is dependent upon mTOR. As an example, during SIRT1 activity and mTOR inhibition, loss of mTOR activity can lead to altered circadian rhythm and cognitive decline. With miRNAs, loss of SIRT1 activity can lead to vascular cell degeneration and cochlear hair loss. On the flip side, control of SIRT1 activity through miRNAs can be useful to control tumorigenesis in the brain with glioblastoma cells. SIRT1 and circRN As also play an important role for neurodegenerative disorders. CircRNA HDAC9 was shown to function as a miR-138 sponge, to decrease miR-138 expression, and to foster SIRT1 activity to block Aβ production by miR-138. Given the complexity of SIRT1 and its intricate relationship with FoxOs, mTOR, trophic factors, circadian clock genes, and noncoding RNAs, future work is warranted to provide further understanding for the fine interplay among these pathways to ensure robust development of innovative, effective, and safe therapeutic strategies for neurodegenerative diseases.

Acknowledgments

This research was supported by the following grants to Kenneth Maiese: American Diabetes Association, American Heart Association, NIH NIEHS, NIH NIA, NIH NINDS, and NIH ARRA.

References

1. National Center for Health Statistics. National vital statisitcs system. National Center for Health Statistics Fact Sheet; February 2019, p. 1–2.

2. Maiese K. Cutting through the complexities of mTOR for the treatment of stroke. Curr Neurovasc Res. 2014;11(2):177–186.

3. Minino AM. Death in the United States, 2011. NCHS Data Brief 2013;(115):1–8.

4. Hayutin A. Global demographic shifts create challenges and opportunities. PREA Q 2007;46–53.

5. Maiese K. SIRT1 and stem cells: in the forefront with cardiovascular disease, neurodegeneration and cancer. World J Stem Cell. 2015;7(2):235–242.

6. Maiese K. Programming apoptosis and autophagy with novel approaches for diabetes mellitus. Curr Neurovasc Res. 2015;12(2):173–188.

7. Maiese K. New insights for nicotinamide: metabolic disease, autophagy, and mTOR. Front Biosci (Landmark Ed). 2020;25:1925–1973.

8. Diamanti-Kandarakis E, Datillo M, Macut D, et al. Mechanisms in endocrinology: aging and anti-aging endocrinology: a combo - endocrinology overview. Eur J Endocrinol. 2017;176(6):R283–R308.

9. Fann DY, Ng GY, Poh L, Arumugam TV. Positive effects of intermittent fasting in ischemic stroke. Exp Gerontol. 2017;89:93–102.

10. Lushchak O, Strilbytska O, Piskovatska V, Storey KB, Koliada A, Vaiserman A. The role of the TOR pathway in mediating the link between nutrition and longevity. Mech Ageing Dev. 2017;164:127–138.

11. Maiese K. Moving to the rhythm with clock (circadian) genes, autophagy, mTOR, and SIRT1 in degenerative disease and cancer. Curr Neurovasc Res. 2017;14(3):299–304.

12. Stefanatos R, Sanz A. The role of mitochondrial ROS in the aging brain. FEBS Lett. 2018;592(5):743–758.

13. Quesada I, de Paola M, Torres-Palazzolo C, et al. Effect of garlic’s active constituents in inflammation, obesity and cardiovascular disease. Curr Hypertens Rep. 2020;22(1):6.

14. Ali T, Rahman SU, Hao Q, et al. Melatonin prevents neuroinflammation and relieves depression by attenuating autophagy impairment through FOXO3a regulation. J Pineal Res. 2020;69(2):e12667.

15. Doroftei B, Ilie OD, Cojocariu RO, et al. Minireview exploring the biological cycle of vitamin B3 and its influence on oxidative stress: further molecular and clinical aspects. Molecules. 2020;25(15):3323.

16. Speer H, D’Cunha NM, Alexopoulos NI, McKune AJ, Naumovski N. Anthocyanins and human health—a focus on oxidative stress, inflammation and disease. Antioxid (Basel, Switz). 2020;9(5):366.

17. Hu Z, Jiao R, Wang P, et al. Shared causal paths underlying Alzheimer’s dementia and type 2 diabetes. Sci Rep. 2020;10(1):4107.

18. Maiese K. Cognitive impairment with diabetes mellitus and metabolic disease: innovative insights with the mechanistic target of rapamycin and circadian clock gene pathways. Expert Rev Clin Pharmacol. 2020;13(1):23–34.

19. Schiano C, Benincasa G, Franzese M, et al. Epigenetic-sensitive pathways in personalized therapy of major cardiovascular diseases. Pharmacol Ther. 2020;210:10754.

20. Maiese K. Targeting the core of neurodegeneration: FoxO, mTOR, and SIRT1. Neural Reg Res. 2021;16(3):448–455.

21. World Health Organization. Global action plan on the public health response to dementia 2017–2025. 2017:1–44.

22. World Health Organization. Description of the global burden of NCDs, their risk factors and determinants. Glob Status Rep Noncommunicable Dis 2010 2011;1–176.

23. Castro-Portuguez R, Sutphin GL. Kynurenine pathway, NAD(+) synthesis, and mitochondrial function: targeting tryptophan metabolism to promote longevity and healthspan. Exp Gerontol. 2020;132:110841.

24. Cheng X, Song C, Du Y, Gaur U, Yang M. Pharmacological treatment of Alzheimer’s disease: insights from Drosophila melanogaster. Int J Mol Sci. 2020;21(13):4621.

25. Xu F, Na L, Li Y, Chen L. Roles of the PI3K/AKT/mTOR signalling pathways in neurodegenerative diseases and tumours. Cell Biosci. 2020;10:54.

26. Corti O, Blomgren K, Poletti A, Beart PM. Autophagy in neurodegeneration: new insights underpinning therapy for neurological diseases. J Neurochem. 2020;154:354–371.

27. Maiese K. Impacting dementia and cognitive loss with innovative strategies: mechanistic target of rapamycin, clock genes, circular non-coding ribonucleic acids, and Rho/Rock. Neural Regen Res. 2019;14(5):773–774.

28. Borjini N, Sivilia S, Giuliani A, et al. Potential biomarkers for neuroinflammation and neurodegeneration at short and long term after neonatal hypoxic-ischemic insult in rat. J Neuroinflamm. 2019;16(1):194.

29. Handa JT, Bowes Rickman C, Dick AD, et al. A systems biology approach towards understanding and treating non-neovascular age-related macular degeneration. Nat Commun. 2019;10(1):3347.

30. Su M, Naderi K, Samson N, et al. Mechanisms associated with type 2 diabetes as a risk factor for Alzheimer-related pathology. Mol Neurobiol 2019.

31. World Health Organization. Dementia: a public health priority Geneva: World Health Organization; 2012;1–4.

32. Chong ZZ, Li F, Maiese K. Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol. 2005;75(3):207–246.

33. Maiese K. Taking aim at Alzheimer’s disease through the mammalian target of rapamycin. Ann Med. 2014;46(8):587–596.

34. Maiese K, Chong ZZ, Shang YC, Wang S. mTOR: on target for novel therapeutic strategies in the nervous system. Trends Mol Med. 2013;19(1):51–60.

35. Song DY, Wang XW, Wang S, et al. Jidong cognitive impairment cohort study: objectives, design, and baseline screening. Neural Regen Res. 2020;15(6):1111–1119.

36. Prokopenko D, Hecker J, Kirchner R, et al. Identification of novel Alzheimer’s disease loci using sex-specific family-based association analysis of whole-genome sequence data. Sci Rep. 2020;10(1):5029.

37. Fan X, Zhao Z, Wang D, Xiao J. Glycogen synthase kinase-3 as a key regulator of cognitive function. Acta Biochim Biophys Sin 2020.

38. Wang H, Li Q, Sun S, Chen S. Neuroprotective effects of salidroside in a mouse model of Alzheimer’s disease. Cell Mol Neurobiol. 2020;40:1133–1142.

39. De Vecchis D, Brandner A, Baaden M, Cohen MM, Taly A. A molecular perspective on mitochondrial membrane fusion: from the key players to oligomerization and tethering of mitofusin. J Membr Biol. 2019;252(4–5):293–306.

40. Kotrys AV, Szczesny RJ. Mitochondrial gene expression and beyond-novel aspects of cellular physiology. Cells. 2019;9(1):17.

41. Caberlotto L, Nguyen TP, Lauria M, et al. Cross-disease analysis of Alzheimer’s disease and type-2 diabetes highlights the role of autophagy in the pathophysiology of two highly comorbid diseases. Sci Rep. 2019;9(1):3965.

42. Cai H, Li Y, Niringiyumukiza JD, Su P, Xiang W. Circular RNA involvement in aging: an emerging player with great potential. Mech Ageing Dev. 2019;178:16–24.

43. Kowalska M, Piekut T, Prendecki M, Sodel A, Kozubski W, Dorszewska J. Mitochondrial and nuclear DNA oxidative damage in physiological and pathological aging. DNA Cell Biol 2020.

44. Maiese K. The mechanistic target of rapamycin (mTOR): novel considerations as an antiviral treatment. Curr Neurovasc Res. 2020;17:332–333.

45. Klionsky DJ, Abdelmohsen K, Abe A, et al. Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy. 2016;12(1):1–222.

46. Maiese K, Chong ZZ, Shang YC, Wang S. Targeting disease through novel pathways of apoptosis and autophagy. Expert Opin Ther Targets. 2012;16(12):1203–1214.

47. Ruhal P, Dhingra D. Inosine improves cognitive function and decreases aging-induced oxidative stress and neuroinflammation in aged female rats. Inflammopharmacology. 2018;26(5):1317–1329.

48. Ding S, Zhu Y, Liang Y, Huang H, Xu Y, Zhong C. Circular RNAs in vascular functions and diseases. Adv Exp Med Biol. 2018;1087:287–297.

49. Wang F, Cao Y, Ma L, Pei H, Rausch WD, Li H. Dysfunction of cerebrovascular endothelial cells: prelude to vascular dementia. Front Aging Neurosci. 2018;10:376.

50. Mehta J, Rayalam S, Wang X. Cytoprotective effects of natural compounds against oxidative stress. Antioxid (Basel, Switz). 2018;7(10):147.

51. Centers for Disease Control and Prevention. National diabetes statistics report, 2020. 2020;CS 314227-A:1–30.

52. Blagosklonny MV. From causes of aging to death from COVID-19. Aging (Albany, NY). 2020;12(11):10004–10021.

53. Mahmoudi N, Kiasalari Z, Rahmani T, et al. Diosgenin attenuates cognitive impairment in streptozotocin-induced diabetic rats: underlying mechanisms. Neuropsychobiology. 2020;11:1–11.

54. Maiese K. Prospects and perspectives for WISP1 (CCN4) in diabetes mellitus. Curr Neurovasc Res. 2020;17:327–331.

55. Yamashima T, Ota T, Mizukoshi E, et al. Intake of ω-6 polyunsaturated fatty acid-rich vegetable oils and risk of lifestyle diseases. Adv Nutr 2020.

56. Zaiou M. circRNAs signature as potential diagnostic and prognostic biomarker for diabetes mellitus and related cardiovascular complications. Cells. 2020;9(3):659.

57. Coca SG, Ismail-Beigi F, Haq N, Krumholz HM, Parikh CR. Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus: systematic review and meta-analysis intensive glucose control in type 2 diabetes. Arch Intern Med. 2012;172(10):761–769.

58. Maiese K. Dysregulation of metabolic flexibility: the impact of mTOR on autophagy in neurodegenerative disease. Int Rev Neurobiol. 2020;155:1–35.

59. Potthast AB, Nebl J, Wasserfurth P, et al. Impact of nutrition on short-term exercise-induced sirtuin regulation: vegans differ from omnivores and lacto-ovo vegetarians. Nutrients. 2020;12(4):1004.

60. Lee JH, Lee JH, Jin M, et al. Diet control to achieve euglycemia induces significant loss of heart and liver weight via increased autophagy compared with ad libitum diet in diabetic rats. Exp Mol Med. 2014;46:e111.

61. Charles S, Raj V, Arokiaraj J, Mala K. Caveolin1/protein arginine methyltransferase1/sirtuin1 axis as a potential target against endothelial dysfunction. Pharmacol Res. 2017;119:1–11.

62. Chong ZZ, Shang YC, Wang S, Maiese K. SIRT1: new avenues of discovery for disorders of oxidative stress. Expert Opin Ther Targets.