Sirtuin is an essential factor that delays cellular senescence and extends the organismal lifespan through the regulation of diverse cellular processes. Suppression of cellular senescence by Sirtuin is mainly mediated through delaying the age-related telomere attrition, sustaining genome integrity and promotion of DNA damage repair. In addition, Sirtuin modulates the organismal lifespan by interacting with several lifespan regulating signaling pathways including insulin/IGF-1 signaling pathway, AMP-activated protein kinase, and forkhead box O. Although still controversial, it is suggested that the prolongevity effect of Sirtuin is dependent with the level of and with the tissue expression of Sirtuin. Since Sirtuin is also believed to mediate the prolongevity effect of calorie restriction, activators of Sirtuin have attracted the attention of researchers to develop therapeutics for age-related diseases. Resveratrol, a phytochemical rich in the skin of red grapes and wine, has been actively investigated to activate Sirtuin activity with consequent beneficial effects on aging. This article reviews the evidences and controversies regarding the roles of Sirtuin on cellular senescence and lifespan extension, and summarizes the activators of Sirtuin including Sirtuin-activating compounds and compounds that increase the cellular level of nicotinamide dinucleotide.
The Sirtuin family is nicotinamide dinucleotide (NAD+)-dependent deacylases having remarkable properties in preventing diseases and reversing some aspects of ageing. Sirtuins are known to regulate diverse cellular processes including DNA repair, fat differentiation, glucose output, insulin sensitivity, fatty acid oxidation, neurogenesis, inflammation, and aging (1–3). Research interests increased after a report showed that extra copies of SIR2, a member of Sirtuin in budding yeast
Unlike budding yeast, multicellular organisms have more than one Sirtuin in their genome.
Cellular senescence is a physiological phenotype aimed at permanent cell cycle arrest, and is morphologically identified as flattening, increased size of nucleus and nucleoli, and the appearance of vacuoles in the cytoplasm (16). In addition, several biomarkers developed for cellular senescence are targeted towards the senescence-associated β-galactosidase (SA-β-gal), telomere attrition, senescence-associated heterochromatic foci, cell cycle arrest in the G1 phase, and accumulation of DNA damage with the high level of ATM, p53, p16, and p21 (17). Although cellular senescence is considered to be a beneficial process to suppress the accumulation of aberrant cells caused by stress in young organisms, it is detrimental in older organisms to induce age-related phenotypes. In addition, senescent cells are known to be increased by aging (18).
Although still under debate and not fully defined, growing evidences have shown that Sirtuin is an essential factor in delaying cellular senescence and extending organismal lifespan. Especially, the role of Sirtuin on the protection from cellular senescence has mainly been investigated with mammalian SIRT1 and SIRT6. The levels of Sirtuins, including SIRT1 and SIRT6 but not SIRT2, are reported to decrease in senescent cells of mouse embryonic fibroblasts, lung epithelial cells, human endothelial cells and macrophages exposed to oxidants (19–22). In addition, the reduction of SIRT1 and SIRT6 using pharmacological inhibitors, siRNA or miRNA, promotes premature senescence-like phenotypes in endothelial cells (23–25). Conversely, the overexpression of
The Sirtuin-related suppression of cellular senescence is mainly mediated through the prevention of telomere attrition and the promotion of DNA damage repair. Sirtuins play vital roles in sustaining genome integrity, by contributing in maintaining the normal chromatin condensation state, and responding to DNA damage and repair. Especially, the nuclear form of Sirtuins, such as SIRT1, SIRT6 and SIRT7, act as transcriptional regulators to suppress gene expression by stabilizing the chromatin structure (2). SIRT1 deacetylates histones H3, H4 and H1 and more than 50 non-histone proteins, including DNMT1, transcription factors and DNA repair proteins (29). Similar to mammalian Sirtuins,
In addition to the suppression of senescence of mitotic cells, Sirtuin also modulates the senescence of stem cells, and is required for the maintenance of stem cell self-renewal (44). The expression level of
In addition to the roles in cellular senescence, it is well established that Sirtuin regulates the organismal lifespan in several animal models. Increased expression levels of
Sirtuins other than SIRT1 are also reported to exert a prolongevity effect. The transgenic male mice overexpressing
The molecular targets of this longevity effect of Sirtuins have been actively investigated. Sirtuins are found to especially interact with all the major conserved longevity pathways, such as AMP-activated protein kinase (AMPK), insulin/IGF-1 signaling (IIS), target of rapamycin (TOR), and forkhead box O (FOXO). Of these, FOXO transcription factor is the most fascinating target of Sirtuin. In
Considering that FOXO is a major component in the IIS cascade to promote lifespan extension and stress resistance, several evidences have reported the association of the IIS pathway with the prolongevity effect of Sirtuin. In
AMPK signaling belongs to the protein kinase family and restores cellular energy levels. Increased AMPK activity is known to extend the lifespan of some model organisms. The mutation of AMPK (
Apart from these, several other molecules are also reported to mediate lifespan extension by Sirtuin overexpression, including 14-3-3,
Although numerous evidences indicate that overexpression of
These contradictory results concerning the effect of Sirtuin overexpression on lifespan might be explained by the extent of overexpression of Sirtuin. Whitaker
Calorie restriction (CR), also known as dietary restriction, is a proven intervention to extend lifespan in almost all animal models including non-human primate, which experimentally means a reduction in calorie intake by 10–50% compared to the
Numerous researches have also reported the requirement of Sirtuins in the lifespan-extension effect of CR in various organisms. In budding yeast, CR does not extend the lifespan of
The role of Sirtuins in lifespan extension by CR has long been challenged (71). Several reports asserted that Sirtuins are not required for lifespan extension by CR in yeast,
Since Sirtuin is commonly believed to mediate the beneficial effects of CR, the activators of Sirtuin are considered to mimic these beneficial effects and are hence attractive therapeutics for age-related diseases. Subsequently, high-throughput screening has identified over 14,000 Sirtuin-activating compounds (STACs).
In 2003, a screen for activators of the mammalian SIRT1 identified 15 small molecules including quercetin, butein, fisetin, and piceatannol (54). This study further revealed the most potent activator of SIRT1 to be resveratrol (3,5,4′-trihydroxystilbene), a polyphenol found in red wine, which extended the replicative lifespan of budding yeast by 70% at 10 μM (54). In addition, the lifespan-extension effect of resveratrol was abrogated by the
Other than resveratrol, natural compounds including cilostazol (106), paeonol (107), statins (108), hydrogen sulfide (109), Icariin (110), persimmon (111), melatonin (112), and curcumin (113) are also reported as potent STACs. Some of these STACs have exhibited a prolongevity effect on model animals. For example, pretreatment with curcumin or alkylresorcinols enhanced the SIRT1 activity (113, 114), and extended the lifespan of
Natural STACs are hydrophobic in nature with low solubility and low bioavailability. To overcome these weaknesses, synthetic STACs were developed by using drug design approaches. To date, more than 14,000 STACs have been synthesized up to the 5th generation, and dozens of these have been tested in animal disease models. Several STACs are also currently undergoing clinical trials (116). These synthetic STACs are reported to be beneficial for several age-related diseases, and have demonstrated protection from cancer, neurodegeneration, cardiovascular disease and diabetes, with some compounds exerting an extended lifespan. Of these, SRT1720, SRT2104, SRT1460, SRT2183, STAC-5, STAC-9, and STAC-10 have attracted attention due to their increased potency, solubility, and bioavailability as compared to resveratrol (117). Especially, SRT1720, a synthetic STACs structurally unrelated to resveratrol, has been reported to improve insulin sensitivity and mitochondrial capacity in obese rodents (118), and has extended the lifespan of mice fed a high-calorie diet, to a similar extent as resveratrol (119). In addition, SRT2104 mimics aspects of CR and extends the lifespan of male mice fed a standard diet (120). In addition to these STACs, several oxazolo(4,5-β)pyridine and imidazo(1,2-β)thiazole derivatives have also been identified as activators of SIRT1 (121, 122). Especially, 1,4-dihydropyridine derivatives activate several Sirtuins (SIRT1-SIRT3) in a dose-dependent manner (123), and synthetic iso-nicotinamide (iNAM) also acts as a Sirtuin-activator (124).
The requirement of SIR2 in the lifespan extension by these STACs is controversial, and several increasing evidences show that the lifespan extending effects of STACs are Sirtuin-independent. Predominantly, it is contentiously debated whether or not resveratrol and synthetic STACs directly activate SIRT1 (117). The original report reveals the activation of SIRT1 by resveratrol using a fluorescence-conjugated peptide substrate, Fluor-de-Lys (54). However, resveratrol and STACs showed no activation of Sirtuin using
An alternative approach to activating Sirtuins is regulating NAD+ levels by activating enzymes involved in biosynthesis of NAD. NAD is an essential cofactor for electron transfer and for regulating metabolic homeostasis, and its levels decrease with aging in the liver and muscle, as could partially be explained due to the decreased activity of Sirtuin upon aging (70). The supplementation of NAD extended the lifespan of
During deacetylation reaction by Sirtuin, NAD+ is converted to nicotinamide (NAM), and NAM is recycled into NAD or other nicotinic acid (NA) derivatives through the NAD salvage pathway. Thus, the administration of NAM increases the level of NAD with subsequent SIRT1 activation (133, 134). NAM is also methylated by nicotinamide N-methyltransferase (NNMT) to 1-methylnicotinamide (MNA). The treatment of NAM, NA, or MNA, and the overexpression of
An increase of NAD+ levels is also observed in energy deficient conditions, such as fasting, CR or low glucose feeding (83, 141, 142). Compounds that raise NAD levels, such as nicotinamide riboside and NMN, are potential candidates as CR mimetics that are shown to extend lifespan. Under conditions of starvation, AMPK is activated and alters the intracellular metabolism, resulting in an increase in NAD levels with a concomitant increase in SIRT1 activity (143). In yeast, the longevity effect of CR is reported to require PNC-1, a homologue of NAMPT (144). However, contrarily, several reports have revealed that the level of NAD does not increase in yeast exposed to CR (89, 145), and NAD supplementation further extended the lifespan of
For over 20 years, the Sirtuin family has been actively investigated for its function in delaying cellular senescence and extending longevity. In addition, based on the role of Sirtuin on the beneficial effect of CR, therapeutic trials using activators of Sirtuin have actively proceeded to protect age-related diseases. Growing evidences have principally supported that Sirtuin is an attractive anti-aging molecule involved in improving health through the target molecules participating in diverse biological processes; however, the role of Sirtuin on longevity, and the longevity effect of CR, are still controversial. In addition, numerous questions remain unresolved, such as the role of other Sirtuins in addition to SIRT1 and SIRT6 on aging, the redundancy of the Sirtuin family members to regulate lifespan, whether other enzymatic activities (apart from deacetylation activity) participate in the process of aging, and whether STACs could be promoted as drugs to treat aging or age-related diseases in humans. These questions will be answered in the near future, and Sirtuin may provide the effective approach to extend lifespan and improve our quality of life.
This work was supported by Inha University Research Grant.
The authors have no conflicting interests.
Properties and functions of Sirtuins related with senescence and aging
|Sirtuin||Cellular localization||Activity||Functions in cellular senescence and aging|
|Yeast||SIR2||Nucleus||Deacetylase||DNA damage repair|
|Replicative lifespan extension|
|Cell cycle arrest|
|sir-2.1||Nucleus and cytoplasm||Deacetylase||Lifespan extension|
|Sirt1 (dSir2)||Nucleus and cytoplasm||Deacetylase||Lifespan extension|
|Mammal||SIRT1||Nucleus and cytoplasm||Deacetylase||Lifespan extension|
|Cell cycle arrest|
|SIRT2||Cytoplasm||Deacetylase||Cell cycle regulation|
|SIRT4||Mitochondria||ADP-ribosyl-transferase||Fatty acid oxidation|
|SIRT5||Mitochondria||Demalonylase||Fatty acid oxidation|
|SIRT6||Nucleus (chromatin)||ADP-ribosyl-transferase||Lifespan extension|