what are sirtuin activators

2021/05/21

Wang and colleagues have previously shown that in vivo SIRT1+/; p53+/ mice xenograft models with different malignancy types (i.e. Therefore there may be interest in combining chemotherapy with sirtuin inhibitors to prevent the cancer cells from responding to DNA damage and other stresses induced by chemotherapy for treatment of cancers. HDACs also play a major role in pancreatic beta cell differentiation, preservation, and proliferation, as well as improving insulin resistance and inhibiting adipogenesis [102]. Dietary restriction, which induces SIRT1, acts via mTOR signaling and nicotine amide dinucleotide (NAD)dependent pathways accompanied by a shift toward oxidative metabolism,88 both representing novel modes of rejuvenation therapy. These compounds are presently undergoing clinical trials. An interesting question is how much of the carcinogenic effect of these exposures is conferred by the theoretical reduced sirtuin activity. Expression of SIRT1 was suppressed in these two cancer cell lines due to hypoxic stress, thus promoting EMT. Firstly regarding activators, the study of resveratrol sensitivity of cancer cell lines found a marked degree of variability based on cell type. Synthetic STACS have also been demonstrated to exert beneficial cardiovascular effects on healthy cigarettes smokers (Venkatasubramanian et al., 2013). These compounds include biguanides such as metformin, which targets the AMPK and insulin signaling pathways; resveratrol, which partially affects sirtuin activity; and rapamycin, which interacts with mTOR signaling. A number of clinical trials involving resveratrol showed benefits in glucose metabolism and cardiovascular disease risk factors [263,264], but many others have shown little to no benefits [265]. ScienceDirect is a registered trademark of Elsevier B.V. ScienceDirect is a registered trademark of Elsevier B.V. Complementary and Alternative Therapies and the Aging Population, Pharmacological Approaches for Modulating Sirtuins, Introductory Review on Sirtuins in Biology, Aging, and Disease, The bifunctional roles of sirtuins and their therapeutic potential in cancer, Sirtuin Biology in Cancer and Metabolic Disease, Sirtuins, Healthspan, and Longevity in Mammals, Handbook of the Biology of Aging (Eighth Edition), High-throughput screens have been conducted to identify small molecule, Baur and Sinclair, 2006; Kaeberlein et al., 2005; Pacholec et al., 2010; Park et al., 2012, Barger et al., 2008a,b; Pearson et al., 2008, Miller et al., 2011; Pearson et al., 2008, Baur and Sinclair, 2006; Kaeberlein et al., 2005; Pacholec et al., 2010, Metabolic Alterations at the Crossroad of Aging and Oncogenesis, International Review of Cell and Molecular Biology. Regarding sirtuin inhibitors in hematologic malignancies, sirtinol induces growth arrest, senescence, and apoptosis of human breast cancer cells, lung cancer cells, and leukemia cells, and enhances sensitivity to chemotherapy drugs of cancer cell lines [254,255]. For example, in a mouse model of T2D, NMN supplementation mitigates negative metabolic effectsinsulin insensitivity, glucose intolerance, and inflammationof age-related or diet-induced diabetes, potentially due to the activation of SIRT1 and other sirtuins, and their downstream target pathways (Yoshino et al., 2011). William Giblin, David B. Lombard, in Handbook of the Biology of Aging (Eighth Edition), 2016. Pharmacologically increasing cellular NAD+ levels by supplementation with NAD+ precursors such as NR and NMN, or inducing expression of NAMPT to convert NAM to NAD+ more efficiently, have recently provided alternative means of promoting sirtuin function (Canto et al., 2012; Yoshino et al., 2011) (Figure 3.6). SRT2104 has shown benefit in psoriasis [261] and metabolic syndrome [262]. In response to moderate RSV doses, SIRT1 activates AMPK in the skeletal muscle, which results in an increase in NAD+ levels through an unknown mechanism to generate a positive feedback loop to maintain mitochondrial function in energetically active tissues. However, clinical trials to date have been less promising than the preclinical studies. Among various candidates for CR mimetics, Epigenetics in Human Disease (Second Edition), . STACs have been reported to interact with a specific region on the SIRT1 protein (Hubbard et al., 2013). One STAC, SRT1720, extends mean mouse lifespan in response to a HFD by 18% (Minor et al., 2011) and by 8.8% in mice fed a standard diet (Mitchell et al., 2014). In this study, antioxidants such as NAC or Trolox were reported to completely counteract UBCS039-induced autophagy, indicating that increased ROS had a key role in upstream events that commit the cells to autophagy. Interestingly, daratumumab, an anti-CD38 antibody, is FDA-approved for the treatment of multiple myeloma. One caveat in interpreting any findings involving NAD+ modulation is that increased NAD+ levels may activate not only sirtuins, but also additional NAD+-dependent enzymes, such as PARP1. Although resveratrol and these compounds represent several differing chemotypes, biochemical and structural studies suggest that they all employ a common activation mechanism.29,30 Sirt1/STAC complex structures revealed a Sirt1-specific STAC binding domain (SBD) N-terminal from the catalytic core, which provides a rather hydrophobic and flat depression as a STAC docking site, leaving the second activator surface solvent accessible (Fig. Interestingly, U937 and MOLT-4 leukemia cell lines are the most sensitive to resveratrol, and treatment is associated with increased BAX expression [253]. Michael S. Goligorsky, in Kidney Transplantation, Bioengineering and Regeneration, 2017, The more traditional therapeutics acting on EPCs and endothelial cells belong to categories of ACE inhibitors, aldosterone inhibitors and statins, as has been exhaustively described in the past.46. Allosteric sirtuin activation with small molecules, with the goal of promoting healthspan and longevity, has been an area of intense investigation. Other treatments targeting CD38 are in development. NMN, NR supplementation, CR or physical activity increases cellular NAD+ levels. NAD+ bioavailability is reduced in disease states and aging.65 A precursor of NAD+, nicotinamide, is paving ways as a therapy to correct NAD+ deficiency. Besides, RSV has been shown to alleviate EMT processes in lung and ovarian cancer in vitro and in vivo [279,280]. In contrast, two more recent meta-analysis on randomized controlled clinical studies failed to show beneficial effects on cardiovascular risk factors [91,92]. In mouse studies, flavonoids (e.g., quercetin, apigenin, and luteolindin) and thiazoloquin(az)olinones inhibit CD38 and cause an increase in NAD+ levels [266268]. Pharmacological sirtuin activation. In comparison, these drugs were poorly active in healthy PBMCs [52]. Thus, human clinical studies using NAD+ precursors are currently ongoing. Therefore the combination of PARP inhibitors and sirtuin inhibitors represents a potentially interesting therapeutic strategy to treat cancer. Thus further evaluation of STACs activity in a cancer-specific manner is required. Ken Shinmura, in Nutritional Epigenomics, 2019. Moreover, such studies might suggest ways to modulate sirtuin signaling to enhance treatment efficacy. PARPs are another major utilizer of NAD+ in humans. These compounds include biguanides such as metformin, which targets the AMPK and insulin signaling pathways; resveratrol, which partially affects sirtuin activity; and rapamycin, which interacts with mTOR signaling. Whether RSV and other STACs actually activate mammalian SIRT1 or its paralogs in vivo, and if so whether they function via direct mechanisms, or through upstream mediators such as AMPK, has been hotly debated (Baur and Sinclair, 2006; Kaeberlein et al., 2005; Pacholec et al., 2010). 5.2B).30 However, in the presence of FdL substrate, resveratrol was found to interact with the SBD but to rotate with this domain on top of the active site (Fig. SRT1720 has been shown to reduce cancer cell viability and sensitize cancer cells to chemotherapy drugs. It will be interesting to see how newer, more potent, and more orally bioavailable sirtuin modulators evolve. Although increased evidence indicates RSV to be an effective SIRT1 activator with anticancer properties, its poor solubility, low bioavailability, rapid elimination, and unwanted toxicity effects are the major factors that limit its development as a cancer drug candidate [281]. RSV regulates SIRT1 through the AMP-dependent kinase (AMPK) pathway which activates SIRT1 by increasing the intracellular concentration of NAD+ [273,276]. The mechanism underlying the beneficial effects of resveratrol is controversial since it has been proposed that the direct activation of sirtuin 1 by resveratrol is an in vitro artifact (Beher et al., 2009; Kaeberlein et al., 2005; Pacholec et al., 2010) and that resveratrol works primarily by activating AMPK (Canto et al., 2009), potentially by inhibition of phosphodiesterases (PDE). NBMs supply precursors for NAD+ synthesis. This study also reported that RSV treatment induces autophagy through SIRT1/S6K pathways and inhibits the incidence of precursor lesions of prostate cancer through the Akt/mTOR signaling pathway [277]. Acetyl peptide (beige) and NAD+ (yellow) were modeled to indicate their binding sites. NAD+ is a cofactor for activation of several sirtuins. The use of CR mimetics would be much easier to incorporate into clinical practice than lifelong CR [4]. In mice and nonhuman primates fed a high-fat diet, resveratrol protects against the effects of obesity and age-related metabolic decline, increases insulin sensitivity and mitochondrial functions, and prevents liver steatosis (Baur et al., 2006; Fiori et al., 2013; Jimenez-Gomez et al., 2013). Thus, spermidine is a promising CR mimetic and has the potential to be safe for testing the epigenomic-dependent and independent effects on human healthy lifespan. Drug design approaches and high-throughput screening have since identified thousands of both naturally occurring and synthesized STACs.4 STACs of a variety of chemotypes, including oxazolo[4,5-b]pyridine, thiazolopyridine, and bridged urea have been developed with improved activation potency, physiochemical properties, and therapeutic potential.5,6 Another unrelated class of 1,4-dihydropyridine-based compounds bearing a benzyl group at the N1 position are reported to activate SIRT1, SIRT2, and SIRT3.7 Molecules such as SRT1720 and SRT2104 (from the third generation) have improved bioavailability and up to 1000 times the potency of resveratrol, and have been extensively tested in animals8,9 (Fig. Using public database resources, Soda etal. Promising CR mimetics with properties of cardiovascular protection include compounds that intersect with the critical signaling pathways identified above. However, RSV treatment does not extend longevity in mice fed a standard diet (Miller et al., 2011; Pearson et al., 2008). Another venue for rejuvenation therapy is based on the series of findings implicating mTOR activation and the resulting defect in autophagy in senescence. Despite the apparent beneficial effects of RSV and other STACs in multiple systems, in human patients with nonalcoholic fatty liver disease, RSV treatment appeared to exert toxic effects on hepatocytes, and did not ameliorate liver steatosis or insulin resistance (Chachay et al., 2014). Alternatively, synthetic STACs such as SRT2170 and SIRT1460 have been synthesized to overcome the RSV limitation. Inhibition of NAD+-consuming enzymes, PARPs or CD38, also enlarges the cellular NAD+ pool. Figure 5.2. It is noteworthy that SRT501 is an improved formulation of RSV possessing improved bioavailability [270,273]. However, SRT2104 has been limited by poor and variable pharmacokinetics after oral intake. This was also seen with pharmacologic PARP inhibition in vitro and in vivo [269]. Interestingly, SRT1720 improves insulin sensitivity, lowers plasma glucose, and increases mitochondrial capacity in experimental diabetes models, thus representing a promising new therapeutic approach for treating age-related diseases such as type 2 diabetes (Milne et al., 2007). These mice are highly resistant to weight gain in response to a HFD relative to controls. The more commonly known synthetic STACs which are commercially available and reported to target cancer include SRT1720, SRT3025, SRT1460, SRT2183, and UBCS039 [235,267270]. NMN is then converted to NAD+ by nicotinamide mononucleotide adenylyltransfereases (NMNATs). Activator development for the other isoforms, which lack Sirt1s SBD, has lagged behind, but promising compounds are now emerging. Resveratrol also shows benefit in improving insulin sensitivity in nonhuman primates [259]. SRT2104 protects against experimentally induced muscle atrophy in wild-type mice, and muscle-specific Sirt1 knockdown in vivo accelerates muscle loss. (A) Targets of NAD-boosting molecules or NBMs. NAD+ is synthesized de novo from tryptophan via a series of enzymatic reactions, including the initial conversion of tryptophan to kynurenine by the enzyme indoleamine 2,3-dioxygenase (IDO). Concordantly, Parp knockout mice show increased SIRT1 activity, mitochondrial metabolism, and biomass [269]. SRT1720 induced apoptosis in multiple cancer cells including breast and myeloma [283,284] through the increase in SIRT1 deacetylase activity.

(A) Crystal structure of Sirt5 in complex with FdL peptide (blue) and resveratrol (gray; PDB entry 4HDA). It will also be critical to assess how PARP inhibitors affect the activity of the other sirtuins. Activation of Sirt6-dependent deacetylation can be achieved with fatty acids, and competition experiments implicated the enzymes long acyl-binding channel as a binding site.35 This activating effect required several hundred M fatty acid concentrations, however, and only more recently, pyrrolo[1,2-a]quinoxaline-derived compounds were discovered as first potent Sirt6 activators.36 These compounds increase Sirt6-dependent deacetylation of peptide substrates, histone proteins, and complete nucleosomes. Going through each of the seven sirtuins above, I have tried to highlight potential therapeutic opportunities. In addition, calorie restriction diet, which possibly induces SIRT1, acts via mTOR signaling and nicotine amide dinucleotide (NAD)-dependent pathways,64 both representing novel venues of rejuvenation therapy. To date, several epigenetic modifiers are in the market or currently under clinical trial, including HDAC inhibitors (HDACi), HAT inhibitors (HATi), protein arginine methyltransferase inhibitors (PRMTis), DNA methyltransferase inhibitors (DNMTis), histone demethylating inhibitors (HDMis), and. Further, searching for predictive biomarkers for sensitivity to sirtuin modulators will be a critical next step. Huang et al. Synthetic activators such as SRT1720 and SRT2104 improve the metabolic profile and extend life span and health span of mice under a high-fat and normal diet (Mitchell et al., 2014; Minor et al., 2011). PARP inhibitors increase NAD+ levels, which in theory could activate sirtuins.

Bone marrow transplant (BMT) is a treatment often employed in hematologic malignancies. Reduced NAD+ levels induced by advanced age, caloric excess, or a sedentary lifestyle would impair activity of sirtuins and other NAD+-dependent cellular processes. Interestingly, the resveratrol effect on Sirt5 also depends on the acyl modification, since resveratrol activated Sirt5-dependent FdL deacetylation but inhibited Sirt5-dependent FdL desuccinylation.32. From: Complementary and Alternative Therapies and the Aging Population, 2009, Alice E. Kane, David A. Sinclair, in Introductory Review on Sirtuins in Biology, Aging, and Disease, 2018, The first generation of STACs were discovered in a high-throughput screen using a so-called Fluor de Lys peptide substrate.2 Several classes of plant polyphenols were shown to activate recombinant SIRT1 and to extend the lifespan of Saccharomyces cerevisiae.2 The most effective of these, activating SIRT1 by more than 10-fold, was resveratrol (3,5,4-trihydroxystilbene),2 a natural product found in grapes. Evidence suggests that the inhibition of HDAC3 protects -cells from cytokine-induced apoptosis, improves insulin production and insulin sensitivity, and reduces the expression of proinflammatory cytokines such as IL-1b [104]. This section will summarize preclinical and clinical studies of sirtuin modulators and discuss some of the most impactful future avenues of investigation. Hubbard and Sinclair, 2014; Pearson et al., 2008, Mitchell et al., 2014; Minor et al., 2011, Baur et al., 2006; Fiori et al., 2013; Jimenez-Gomez et al., 2013, Beher et al., 2009; Kaeberlein et al., 2005; Pacholec et al., 2010, Sirtuin signaling in hematologic malignancies, Chronic Kidney Disease and the Vascular Endothelium, Endothelial Progenitor Cells in Kidney Disease, Kidney Transplantation, Bioengineering and Regeneration, Structural and Mechanistic Insights in Sirtuin Catalysis and Pharmacological Modulation, Dietary restriction in the epigenomic regulation of cardiovascular diseases. Iachettini and colleagues reported that UBCS039-mediated activation of autophagy was strictly dependent on SIRT6 deacetylating activity. Two opposing models have been proposed to account for STAC activity: (1) direct allosteric activation of SIRTs through the lowering of peptide substrate Km, and/or (2) indirect activation resulting from off-target effects [258261]. Among these epigenetic modifiers, valproic acid, sodium phenylbutyrate, vorinostat, givinostat, and curcumin are HDACi; resveratrol is a STACs; AMI-1 is a PRMTis; tranylcypromine is part of HDMis; and hydralazine, procainamide, RG108, and MG98 belong to DNMTis [98]. Furthermore, a significant inhibition of growth and induction of apoptosis were demonstrated in malignant lymphoid cell lines when these compounds were used in adjunct with panobinostat [275]. An emerging branch of rejuvenation pharmacology seeks to interfere with one of three major pathways of cell aging: sirtuins, target of rapamycin (mTOR), and insulin-like growth factor, all involved in EPC senescence and dysfunction. Phenotypes resulting from increased NAD+ levels must be rigorously elucidated in model organisms before use of these non-allosteric approaches can be attempted in humans. Although no difference in body weight, caloric intake or physical activity was observed, SRT2104-supplemented mice exhibit a lower percentage of fat mass, decreased fasting blood glucose and insulin levels, and increased skeletal muscle endurance. Michael S. Goligorsky, in Chronic Renal Disease (Second Edition), 2020. Another strategy to modulate sirtuin activity in hematologic malignancies is by inhibiting endogenous breakdown of NAD+. An increase in the cellular NAD+/NADH ratio will increase sirtuin activity. Among them, resveratrol, the most popular and evaluated STAC, exhibited mixed efficiency including anti-oxidant, anti-inflammatory, and anti-tumor properties [94]. Alternatively, resveratrol may first activate sirtuin 1 in vivo, leading to AMPK activation via deacetylation and activation of the AMPK kinase LKB1 (Hou et al., 2008; Lan et al., 2008). In this way, STACs bind to an allosteric site of SIRT1 and increase the enzymes affinity for target substrates.6 Extensive research has identified the specific amino acid residues of the STAC binding domain and determined that they activate SIRT1 via a bend-at-the-elbow model in which the binding of an STAC exposes the substrate binding site of SIRT1.6. Moreover, in rhesus monkeys, under a high-fat and high-sugar diet, resveratrol exerts antiinflammatory effects in visceral white adipose tissue (Jimenez-Gomez et al., 2013). Clinical trials aimed at increasing the intake of this polyamine seems feasible for the purpose of suppressing cardiovascular aging in humans. The first activator identified, the plant polyphenol resveratrol that is found, e.g., in red wine, extends yeast lifespan in a sirtuin-dependent manner and promotes human cell survival by stimulating Sirt1.26 Direct Sirt1 activation was initially debated, since resveratrol appeared to increase peptide substrate affinity but only in the presence of the artificial fluorophore label of the FdL substrate used.27 Moreover, indirect mechanisms were suggested to cause the in vivo effects of resveratrol on sirtuins as the compound affects a variety of cellular targets.28 However, direct sirtuin binding and activation by resveratrol and synthetic STACs was validated later through biophysical methods and crystal structure analyses, and testing the resveratrol effect on ~6500 mammalian acetylation sites in peptide microarrays identified physiological substrate sites whose deacetylation can be activated.2931 Interestingly, this study revealed a dramatic influence of the substrate sequence on resveratrol effects, ranging from strong activation to significant inhibition,31 and the relevance of the substrate sequence was confirmed independently.29 The molecular basis of resveratrol activation was first studied with Sirt5, whose deacetylase activity against FdL and a substrate protein could also be stimulated.32 A crystal structure of Sirt5 in complex with FdL peptide and resveratrol revealed activator binding between two loops and through extensive hydrophobic interactions to the artificial substrate fluorophore (Fig. However, SRT1720 has also been reported to promote breast cancer metastasis [274], suggesting that the effects of STACs may function in the opposite manner. Treatment of lymphoma cell lines and a lymphoma cell line xenograft in mice with cambinol (a SIRT1 inhibitor) causes apoptosis [53]. sarcomas, lymphomas, teratomas, and carcinomas) exhibited SIRT1 activation after treatment with RSV, which in turns effectively inhibited the tumorigenesis of SIRT1+/; p53+/ mice [60].

To elucidate the effects of SIRT1 activation more specifically, structurally unrelated synthetic STACs have been evaluated, though off-target effects, if any, of these molecules have not yet been determined. -cell destruction found in diabetic pancreatic islets, caused by hyperacetylation of the proinflammatory NF-B promoter gene, can be counteracted by HATi, as garcinol [99]. HDACi can also improve insulin signaling through trichostatin, which increases glucose transporter GLUT4 content and its translocation in muscle cells, lung, liver, kidney, and preadipocytes, providing long-term elevation of GLUT4 in insulin target tissues [105,106]. Non-allosteric methods to activate sirtuins have also received intense scrutiny as an alternative to STACs. Modulating sirtuin activities could also be an area of prevention of hematologic malignancies. Specific to hematologic malignancies, mice xenografted with human plasmacytoma to model human multiple myeloma were treated with the SIRT1-specific activator SRT1720 on 5 consecutive days per week for 4 weeks, finding that this SIRT1 agonist synergized with bortezomib or dexamethasone to reduce tumor growth [238]. (D) Crystal structure of Sirt6 in complex with UBCS039 (cyan) and the product fragment ADP-ribose (yellow; PDB entry 5MF6). Three generations of STACs include, in addition to resveratrol, quercetin and butein (first generation), SRT 1720, 1460, and 2183 (second generation), and STAC-5, -9, and -10 (third generation), all extending lifespan and/or health-span in preclinical settings. (C) Crystal structure of Sirt1 in complex with FdL peptide (beige) and three resveratrol molecules (cyan) around its fluorophore (PDB entry 4BTR). Administration of NMN mimicked CR-induced cardioprotection against ischemia/reperfusion in mice [42]. Based on earlier studies of sirtuin 1 activation by resveratrol, a number of small-molecule SIRT1 activators have been synthesized and are being currently tested.87 Sirtuin-activating compounds (STACs) exert their effect by allosteric activation of this deacetylase. In the setting of DNA damage, PARPs consume NAD+ to help repair DNA, but this probably reduces sirtuin activity. RSV treatment in high-proliferative SIRT1 knockdown prostate cancer cells have a reverse effect by inhibiting cancer cells growth and proliferation [277]. sirtfood happier scientifically proven Figure 6.1. Lifelong SRT2104 supplementation, beginning at 6 months of age, extends mean lifespan of male C57BL/6J mice fed a standard diet by 9.7% and increases the maximal lifespan by 4.9% (Mercken et al., 2014b).