Review Article
Seven sirtuins for seven deadly diseases ofaging

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Abstract

Sirtuins are a class of NAD+-dependent deacetylases having beneficial health effects. This extensive review describes the numerous intracellular actions of the seven mammalian sirtuins, their protein targets, intracellular localization, the pathways they modulate, and their role in common diseases of aging. Selective pharmacological targeting of sirtuins is of current interest in helping to alleviate global disease burden. Since all sirtuins are activated by NAD+, strategies that boost NAD+ in cells are of interest. While most is known about SIRT1, the functions of the six other sirtuins are now emerging. Best known is the involvement of sirtuins in helping cells adapt energy output to match energy requirements. SIRT1 and some of the other sirtuins enhance fat metabolism and modulate mitochondrial respiration to optimize energy harvesting. The AMP kinase/SIRT1–PGC-1α–PPAR axis and mitochondrial sirtuins appear pivotal to maintaining mitochondrial function. Downregulation with aging explains much of the pathophysiology that accumulates with aging. Posttranslational modifications of sirtuins and their substrates affect specificity. Although SIRT1 activation seems not to affect life span, activation of some of the other sirtuins might. Since sirtuins are crucial to pathways that counter the decline in health that accompanies aging, pharmacological agents that boost sirtuin activity have clinical potential in treatment of diabetes, cardiovascular disease, dementia, osteoporosis, arthritis, and other conditions. In cancer, however, SIRT1 inhibitors could have therapeutic value. Nutraceuticals such as resveratrol have a multiplicity of actions besides sirtuin activation. Their net health benefit and relative safety may have originated from the ability of animals to survive environmental changes by utilizing these stress resistance chemicals in the diet during evolution. Each sirtuin forms a key hub to the intracellular pathways affected.

Highlights

► The 7mammalian sirtuins and their intracellular actions are now well understood. ► Their actions in diseases of aging seem beneficial, but in cancer may be detrimental. ► Drugs that stimulate or inhibit different sirtuins have great potential as therapeutics.

Introduction

The “Seven Deadly Sins” of old (sloth, gluttony, wrath, greed, pride, lust, and envy) have overlapping counterparts in modern society (sloth, gluttony, junk food, smoking, alcoholism, drug abuse, and psychosocial stress). These “sins” contribute to the seven deadly conditions that increase in prevalence with aging (obesity, type 2diabetes, cardiovascular disease, cancer, dementia, arthritis, and osteoporosis).

The sirtuins are a class of NAD+-dependent deacetylases comprising seven members in humans and other mammals[1]. These enzymes have attracted major interest because of their apparent roles as protectors, and controversially, as contributors to all or some of the life-threatening conditions of aging. More specifically, the sirtuins are important in the transduction pathways emanating from energy sensing. Their ability to regulate systems that control the redox environment has the potential to help counteract oxidative damage that is associated with common diseases of aging and that contributes to aging itself[2]. Because sirtuin malfunction likely has pathophysiological consequences in common clinical conditions of aging pharmaceutical agents targeting sirtuins have been developed[3].

The history leading up to the explosion in research on sirtuins stems from the finding that calorie restriction can extend rat life span [4], [5] and later evidence that the natural flavanoid resveratrol might mimic this effect in lower organisms [6], [7], [8]. The gain in life expectancy achieved by calorie restriction was suggested to exceed that achieved by curing cardiovascular disease, cancer, and type 2diabetes combined[9]. Since population level calorie restriction is unrealistic, many therefore asked whether sirtuin activation might mimic calorie restriction [10] or at least delay onset of age-related diseases by “compression of morbidity” [11].

Although the first sirtuin was discovered in 1984 in yeast [12], interest did not really take off until an effect on life span was noted, first in yeast in 1997 [13], then in higher eukaryotes such as the nematode worm Caenorhabditis elegans in 2001 [14] and the fruit fly Drosophila melanogaster in 2004 [15]. The nature of sirtuins as NAD+-dependent deacetylases was recognized in 2000 [16] and immediately implicated them in the metabolic state of the cell [17]. Once their enzymatic actions in the cell started to be elucidated it was soon realized that their apparent ability to extend life span involved similar pathways as utilized by calorie restriction.

A role for the most-studied sirtuin, SIRT1, in life span has now been refuted, however. Manipulation of SIRT1 expression or activity has little or no effect on mammalian life span [18], [19]. And subsequent studies in model organisms using better controls showed that SIRT1 activation or deletion had little [20], [21] or no [22] effect on their life span. So too calorie restriction it seems, at least in primates, with the 25-year study of rhesus monkeys having found no effect on life span [23], in contrast to earlier findings by others that did [24]. The earlier study involved ad libitum feeding of controls with a different diet that notably included 28% (as opposed to 4%) sucrose, leading to overweight and diabetes. So earlier death of controls may partly explain the discrepancy. Disease onset was later and health markers were nevertheless more favorable in the calorie-restricted group of each cohort of monkeys.

Overexpression of SIRT6, however, extended the life span of male mice by 15%, in effect extinguishing the sex difference in mouse longevity [25]. This effect was seen in mice with different genetic backgrounds. While SIRT1 deacetylates numerous targets, the best-known substrates for SIRT6 are two histones (H3K9 and HK56); the targeting of these explains SIRT6’s role in DNA damage response, especially during oxidative stress, and in telomere maintenance [26], [27], [28]. While SIRT1 is more similar structurally to the single sirtuin present in yeast, SIRT6 is more similar functionally to yeast sirtuin [29]. Male SIRT6 transgenic mice exhibit a female metabolic profile, most notably in fat tissue, in which changes seem linked to life span [29]. The liver of male mice showed the biggest changes in gene expression [25], which overlapped those seen in calorie-restricted mice [30], [31]. Serum IGF-1 level was reduced modestly in male mice, as was IGF-1 signaling in adipose tissue [25]. Thus SIRT6 has partial feminizing effects in male mice. Loss of SIRT6 causes severe metabolic defects, rapid aging, and death at 4weeks of age [32].

The seven mammalian sirtuins all appear to be important in suppression of such common diseases of aging as cardiovascular disease, type 2diabetes and dementia [33], [34], [35]. Effects involving mitochondrial function are crucial tothis.

Here I provide the most extensive review of sirtuins to date. This describes their function and roles in disease processes. Because there are over 2500 publications on sirtuins, only a selective overview is provided. Moreover, for simplicity, this review will use the human nomenclature “SIRT” rather than “Sirt” or “SirT” to refer to both the human and rodent sirtuin proteins and genes. All abbreviations are shown in the footnote on the previous page.

Section snippets

Intracellular localization

SIRT1 is localized in the nucleus [36] (Table 1), but it shuttles to the cytoplasm when required to act on cytoplasmic targets, such as during inhibition of insulin signaling [37]. During pro-metaphase, levels increase and SIRT1 associates with mitotic chromatin until telophase [38]. It mediates loading of histone H1 and the condensing I complex to chromatin, thus contributing to chromosomal condensation [38].

In contrast, SIRT2 is cytoplasmic (Table 1). It deacetylates tubulin microtubules [39]

Enzymatic activity of each sirtuin

Each sirtuin has a characteristic enzymatic activity [47], [48], [49] (Table 1). SIRTs 1, 2, 3, 5, and 6have NAD+-dependent deacetylase activity [16], [50]. Whether SIRT7 is [51] or is not [36] a deacetylase [3] has now been clarified by recent evidence pointing to an important role for SIRT7 in deacetylation of acetylated histone H3K18 [52]. Deacetylation is the most prominent activity of SIRT1 [16] and SIRT2 [39]. In contrast, SIRT4 [53] and SIRT6 [54] possess mostly mono-ADP-ribosyl

Actions of nuclear sirtuins (SIRT1 and SIRT6)

These are crucial in adaptation of metabolic processes to redoxstate.

Actions of mitochondrial sirtuins (SIRT3, SIRT4, and SIRT5)

These sirtuins help the cell adapt to reduced energy consumption [45].

Actions of the cytosolic sirtuin (SIRT2)

SIRT2 deacetylates FOXO1 [142] and FOXO3 [143], [144], thus implicating it in the diversity of processes that these key transcription factors regulate.

SIRT2 overexpression delays cell cycle progression [41]. It colocalizes with microtubles in the cytoplasm, where it deacetylates α-tubulin [39], [145]. During mitosis SIRT2 increases [41]. It migrates transiently into the nucleus during G2/M transition [39], where it deacetylates histone H4 to modulate chromatin condensation during metaphase [43]

Actions of the nucleolar sirtuin (SIRT7)

SIRT7 associates with active ribosomal RNA genes and binds to histones and RNA polymerase I to stimulate transcription [157]. A proteomic analysis using HEK293 kidney cells identified 462 proteins bound by SIRT7, including 257 in the nucleus, 189 of which were nucleolar [158]. Its interaction with RNA polymerase I and upstream binding factor was confirmed, and new associations included 150 proteins involved in transcriptional processes involving both RNA polymerase I and II, as well as 32

Transcriptional regulation of sirtuin genes

Most is known about SIRT1, whose expression is induced during low energy states such as nutrient or calorie deprivation [159], and repressed during energy excess, such as high-fat feeding [160].

Fig. 2 shows transcription factors and targets in the SIRT1 promoter. Activators include FOXO1 [159], PPAR-α [161] and PPAR-β (also known as PPAR-δ) [162], CREB [163], and the cell-cycle and apoptosis regulator E2F1 [164]. Repressors include PPARγ [165], ChREBP [163], HIC1 [166] (via CTBP [167]), and

Posttranscriptional regulation

The well-known posttranscriptional regulator HuR binds to the 3′UTR of mRNA for many different genes and enhances mRNA stability. HuR increases SIRT1 mRNA and protein levels [169]. Under oxidative stress the cell-cycle checkpoint kinase CHK2 phosphorylates HuR causing it to dissociate from SIRT1 mRNA causing HuR to decay [169].

Micro (mi) RNAs target specific sequences in the 3′UTR of mRNAs to cause mRNA decay [170]. Sixteen microRNAs can bind to the SIRT1 3′UTR [171]. The miRNAs miR-34a [172]

Posttranslational regulation

Various posttranslational modifications of sirtuins 1to 6take place [174]. These direct sirtuins to specific targets. They can also increase activity, as occurs after phosphorylation of SIRT1 [175]. The pattern of SIRT1 phosphorylation by the cyclin B–CDK-1 complex affects the cell cycle and cell proliferation [175]. JNK1-mediated phosphorylation during oxidative stress increases nuclear localization of SIRT1 and orients SIRT1 to substrates such as histone H3, although not p53 [176]. Curiously,

Formation of complexes with other proteins

Sirtuin action is modulated SIRT1-binding proteins. Binding of the cell-cycle apoptosis regulator E2F1 inhibits SIRT1 activity [164]. This effect may regulate the induction of apoptosis in response to DNA damage.

The protein AROS binds to the N-terminus of SIRT1, but not other sirtuins, to double its activity and inhibit p53 [182]. AROS reduction increases apoptosis [182]. In contrast, SENP-1 inactivates SIRT1 by binding to the C-terminus and desumoylating it, thus increasing p53 activity [181].

Roles for sirtuins in tissue functions

Sirtuins have a multiplicity of different actions in most tissues in the body. Those involving SIRT1 are summarized in Fig. 4.

Sirtuins in metabolism

Mice with whole-body overexpression of SIRT1 are leaner, more metabolically active, and glucose tolerant [240], [241]. This phenotype resembles calorie restriction. The mice were moreover resistant to diet-induced hyperglycemia, metabolic syndrome, and fatty liver [242], [243]. Although they were protected against diseases of aging such as metabolic syndrome and cancer, there was no significant increase in their life span [19]. The higher SIRT1 activity achieved by its overexpression confirmed

Chemical compounds that activate sirtuins

Given the health benefits of sirtuins, it makes sense that chemicals that activate sirtuin activity might prove useful in pharmacotherapy [3], [35], [254], [255], [256]. The natural polyphenol, resveratrol, has long been known to confer health benefits. The first demonstration of this was its ability to prevent skin cancer in mice [257]. Then a decade ago, screening an array of chemical compounds for the ability to activate SIRT1 and extend C. elegans life span led to the identification of not

Obesity

In obesity SIRT1 activity is low, consistent with a causative role. The mechanism of SIRT1’s effect could, in part, involve hypothalamic control of food intake [229]. Genetic deletion of SIRT1 in orexigenic Ag-RP neurons of the hypothalamus and administration of the SIRT1 inhibitor EX527 reduce food intake and body weight via the melanocortin pathway [320], [321], whereas knockout of SIRT1 in anorexigenic POMC neurons of the hypothalamus leads to obesity [322]. Perhaps SIRT1 is required for

Type 2diabetes

Sirtuins have important roles in diabetes. Transgenic overexpression of SIRT1 prevents diabetes in various mouse models of this condition, as well as diabetes that occurs during normal aging [240], [242]. Similarly, chemical activation of SIRT1 has antidiabetic and other beneficial effects. SRT1720 is one chemical being examined in clinical trials. The key NAD+ intermediate NMN, in part via activation of SIRT1, ameliorates type 2diabetes seen with aging and caused by a high-fat diet in mice [69]

Cardiovascular disease

By various means the actions of SIRT1 protect against cardiovascular disease processes [352], [353]. Humans who restrict their caloric intake exhibit a very favorable cardiovascular risk profile [354]. Calorie restriction, by increasing SIRT1, leads to deacetylation and thereby activation of eNOS [355]. The ensuing rise in NO causes vasodilatation and vascular protection. This may contribute to the ability of resveratrol (150 mg/day for 30 days) to reduce systolic blood pressure by 5mm Hg [279].

Neurodegenerative diseases

A functional deficit in sirtuin activity appears to be involved in a variety of neurological diseases that increase in frequency during aging. The cognitive decline that occurs with aging may be countered by sirtuin activation.

SIRT1 improves learning and memory in mice [403], [404]. Its expression in the hippocampus is crucial to such actions. This involves effects on dendritic branching, branch length, complexity of neuronal dendritic arbors, ERK1/2 phosphorylation, and its ability to alter

Cancer

There seems to be little doubt that sirtuins are involved in carcinogenesis. But owing to the complexity and diversity of their effects, the mechanisms remain elusive and there is as yet no consensus on precisely what the role of each is in cancer [435]. Overall, however, it would appear that SIRT2 and SIRT6 may be tumor suppressors, whereas, depending on the context, SIRT1 seems to be either a tumor suppressor or an oncogenic factor [435].

Inflammatory arthropathies

While a role for sirtuins in inflammatory diseases has been known for a while, only more recently has it become apparent that sirtuins are involved in the acute inflammatory response as well. This involves a switch from increased glycolysis to increased fatty acid oxidation as early inflammation converts to late inflammation. SIRT6 reduces glycolysis, while SIRT1 increases fatty acid oxidation [529]. Mediators include PPAR-γ coactivators PGC-1α and PGC-1β that increase CD36 in the external

Osteoporosis

Activation of SIRT1 by resveratrol produces expression in mesenchymal stem cells of the bone-specific transcription factor RUNX2 [540], [541]. Osteocalcin is also upregulated [540], whereas genes for adipo-lineage proteins PPAR-γ [540], [541] and leptin [540] are downregulated. This leads to spontaneous osteogenesis, mediated by an increase in SIRT1/FOXO3A complex formation and increased FOXO3A-dependent transcriptional activity, which includes binding of FOXO3A to a site in the RNX2 promoter

Reproductive function

SIRT1 affects fertility. A point mutation that disrupts SIRT1 activity, but with no effect on SIRT1 gene transcription, produces a milder phenotype than that seen in SIRT1 knockout mice [544]. Female mice were fertile rather than sterile, although male mice lacking either SIRT1 activity or transcription were sterile and hypermetabolic [544]. In human ovarian tissue the ability of resveratrol to increase mRNAs for SIRT1, lutenizing hormone receptor, steroidogenic acute regulatory protein, and

Other medical conditions

The critical role of CD8 T-cells in protection against viral infections involves SIRT1-mediated regulation of epigenetic remodeling and energy metabolism during promotion, by BATF, of CD8 T-cell differentiation [547].

In the lung, SIRT1 activation by SRT172 or elevated SIRT1 gene expression protects against emphysema via a FOXO3A-dependent mechanism [548]. In response to air pollution, SIRT1 prevents Kruppel-like factor 2-mediated expression of the thrombomodulin gene, thus lowering lung

Aging

Sirtuins protect against many of the various aging-associated conditions discussed above [19]. These conditions are often interrelated. For example, liver cancers can be induced by inflammation associated with the metabolic syndrome [19]. The role of SIRT1 during aging seems to involve the orchestration of different stress response pathways [558]. This involves targeting of multiple transcriptional regulators, such as p53, FOXO, andHSF1.

SIRT1 activity is modulated by nutrient availability and

Clinical molecular genetics

Several SNPs in the SIRT1 gene have shown associations with a variety of factors and disease conditions. These include associations with SIRT1 gene expression [597], energy expenditure [244], body fat [598], body mass index [597], [599], [600], obesity [597], blood pressure [598], metabolic syndrome (which involves a coding variant) [124], a reduction in acute response in insulin to a glucose load [601], risk of type 2diabetes [601], anxiety disorders [224], major depressive disorder [602],

Conclusion

It can be seen from this extensive detailed review that sirtuins exert a wide repertoire of actions on intracellular processes. Apart from roles in adapting cellular physiology to changes in nutrient conditions, there is now compelling evidence for their role in common diseases of aging. The potential therefore exists for development of drugs that target one or other of the seven sirtuins, either directly or indirectly, for treatment of the seven deadly chronic conditions of aging that plague

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