Are SIRT1 activators another indirect method to increase AMPK for beneficial effects on aging and the metabolic syndrome?

The discovery that caloric restriction enhances lifespan and that sirtuins 1 (Sirt1) may mediate these effects ushered in a renaissance of research into the development of novel small molecule activators targeting this highly conserved family of deacetylases (Sinclair and Guarente, 2014Sinclair D.A. Guarente L. Small-molecule allosteric activators of sirtuins.Annu. Rev. Pharmacol. Toxicol. 2014; 54: 363-380Crossref PubMed Scopus (171) Google Scholar). Subsequent findings that the polyphenol resveratrol, a substance enriched in the skin of red and purple fruits and most notably red wine, was a potent Sirt1 activator created further excitement around developing more specific agonists towards this new molecular target for anti-aging therapies (Sinclair and Guarente, 2014Sinclair D.A. Guarente L. Small-molecule allosteric activators of sirtuins.Annu. Rev. Pharmacol. Toxicol. 2014; 54: 363-380Crossref PubMed Scopus (171) Google Scholar). It has now been over a decade since the first synthesis and characterization of potent, novel, small molecule, Sirt1 activating compounds (STACs) and their reported ability to improve glucose tolerance and insulin sensitivity in rodent models of obesity and type 2 diabetes (T2D) (Sinclair and Guarente, 2014Sinclair D.A. Guarente L. Small-molecule allosteric activators of sirtuins.Annu. Rev. Pharmacol. Toxicol. 2014; 54: 363-380Crossref PubMed Scopus (171) Google Scholar). Since this time, STACs (i.e., SRT501, SRT1720, SRT2104) have been shown to improve lipid profiles, glucose tolerance, lifespan and healthspan in rodents (Mitchell et al., 2014Mitchell S.J. Martin-Montalvo A. Mercken E.M. Palacios H.H. Ward T.M. Abulwerdi G. Minor R.K. Vlasuk G.P. Ellis J.L. Sinclair D.A. Dawson J. Allison D.B. Zhang Y. Becker K.G. Bernier M. De Cabo R. The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet.Cell Rep. 2014; 6: 836-843Summary Full Text Full Text PDF PubMed Scopus (275) Google Scholar). Clinical trials with these activators for a variety of conditions are currently underway or completed (i.e. NCT00938275, NCT00933062, NCT00964340, NCT01018017, NCT01018628, NCT00933530, NCT00937326). However, the development of STACs for clinical use has not been without controversy, and a major question regarding their use has centered on their specificity for Sirt1. These concerns were initially raised when the utility of the fluorescent cell-free assays used to identify direct Sirt1 activation was questioned (Sinclair and Guarente, 2014Sinclair D.A. Guarente L. Small-molecule allosteric activators of sirtuins.Annu. Rev. Pharmacol. Toxicol. 2014; 54: 363-380Crossref PubMed Scopus (171) Google Scholar). Further questions were raised by findings that Sirt1 was dispensable for the beneficial metabolic effects of resveratrol, and that these activities were mediated by adenosine monophosphate (AMP)-activated protein kinase (AMPK) in some (Park et al., 2012Park S.J. Ahmad F. Philp A. Baar K. Williams T. Luo H. Ke H. Rehmann H. Taussig R. Brown A.L. Kim M.K. Beaven M.A. Burgin A.B. Manganiello V. Chung J.H. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases.Cell. 2012; 148: 421-433Summary Full Text Full Text PDF PubMed Scopus (1048) Google Scholar, Um et al., 2010Um J.H. Park S.J. Kang H. Yang S. Foretz M. Mcburney M.W. Kim M.K. Viollet B. Chung J.H. AMP-activated protein kinase-deficient mice are resistant to the metabolic effects of resveratrol.Diabetes. 2010; 59: 554-563Crossref PubMed Scopus (537) Google Scholar), but not all studies (Price et al., 2012Price N.L. Gomes A.P. Ling A.J. Duarte F.V. Martin-Montalvo A. North B.J. Agarwal B. Ye L. Ramadori G. Teodoro J.S. Hubbard B.P. Varela A.T. Davis J.G. Varamini B. Hafner A. Moaddel R. Rolo A.P. Coppari R. Palmeira C.M. De Cabo R. Baur J.A. Sinclair D.A. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function.Cell Metab. 2012; 15: 675-690Summary Full Text Full Text PDF PubMed Scopus (1109) Google Scholar). Like Sirt1, AMPK is a highly conserved protein that has evolved to sense cellular energy status. Activation of AMPK in response to alterations in adenine nucleotides leads to the inhibition of energy consuming and actuating energy producing processes. Activation of AMPK holds exciting potential as a therapeutic target, as evidenced by the clinical effectiveness of metformin and salsalate, which activate AMPK indirectly by inhibiting mitochondrial function (Smith and Steinberg, 2017Smith B.K. Steinberg G.R. AMP-activated protein kinase, fatty acid metabolism, and insulin sensitivity.Curr. Opin. Clin. Nutr. Metab. Care. 2017; (in press)https://doi.org/10.1016/j.ebiom.2017.03.019Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar). This potential has sparked significant interest and progress in developing new, direct AMPK activators. Notably, AMPK activation produces many of the same effects as those observed with STACs, such as improved glucose homeostasis (Smith and Steinberg, 2017Smith B.K. Steinberg G.R. AMP-activated protein kinase, fatty acid metabolism, and insulin sensitivity.Curr. Opin. Clin. Nutr. Metab. Care. 2017; (in press)https://doi.org/10.1016/j.ebiom.2017.03.019Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar), increased mitochondrial biogenesis (Smith and Steinberg, 2017Smith B.K. Steinberg G.R. AMP-activated protein kinase, fatty acid metabolism, and insulin sensitivity.Curr. Opin. Clin. Nutr. Metab. Care. 2017; (in press)https://doi.org/10.1016/j.ebiom.2017.03.019Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar) and, at least in the case of metformin, improved healthspan and lifespan (Martin-Montalvo et al., 2013Martin-Montalvo A. Mercken E.M. Mitchell S.J. Palacios H.H. Mote P.L. Scheibye-Knudsen M. Gomes A.P. Ward T.M. Minor R.K. Blouin M.J. Schwab M. Pollak M. Zhang Y. Yu Y. Becker K.G. Bohr V.A. Ingram D.K. Sinclair D.A. Wolf N.S. Spindler S.R. Bernier M. De Cabo R. Metformin improves healthspan and lifespan in mice.Nat. Commun. 2013; 4: 2192Crossref PubMed Scopus (892) Google Scholar). In the April 2017 issue of EBioMedicine, Park et al., 2017Park S.J. Ahmad F. Um J.H. Brown A.L. Xu X. Kang H. Ke H. Feng X. Ryall J. Philp A. Schenk S. Kim M.K. Sartorelli V. Chung J.H. Specific Sirt1 activator-mediated improvement in glucose homeostasis requires Sirt1-independent activation of AMPK.EBioMedicine. 2017; 18: 128-138Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar present evidence that, similar to resveratrol, the beneficial metabolic effects of STACs may also require AMPK. The authors show that AMPK activation by SRT1720 does not require Sirt1 in C2C12 muscle cells and Sirt1 knockout (KO) animals. Assays in mouse embryonic fibroblasts (MEFs) in vitro or in skeletal muscle of muscle-specific Sirt1 KO mice in vivo indicate that SRT1720 competes with cyclic AMP (cAMP); this competition inhibits recombinant cAMP-degrading phosphodiesterases in vitro. Using pharmacological inhibitors and siRNA gene manipulation in C2C12 and HeLa cells, the authors find that SRT1720-mediated activation of AMPK occurs through cAMP-Epac1 signaling involving the release of sarcoplasmic reticulum calcium and subsequent activation of calcium/calmodulin-dependent protein kinase kinase β (CaMKKβ) and protein kinase A (PKA). This mechanism of action is very similar to that previously demonstrated for resveratrol by the same authors (Park et al., 2012Park S.J. Ahmad F. Philp A. Baar K. Williams T. Luo H. Ke H. Rehmann H. Taussig R. Brown A.L. Kim M.K. Beaven M.A. Burgin A.B. Manganiello V. Chung J.H. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases.Cell. 2012; 148: 421-433Summary Full Text Full Text PDF PubMed Scopus (1048) Google Scholar). Interestingly, the authors find using MEFs lacking AMPKα1/α2 or Sirt1 that AMPK appears to be the predominant regulator of mitochondrial biogenesis. Importantly and consistent with changes in mitochondrial biogenesis, the authors show that in the absence of AMPKα2 (the primary AMPK subunit expressed in skeletal muscle) SRT1720-induced improvements in glucose tolerance and insulin sensitivity are markedly blunted. Collectively, these data suggest that SRT1720 activates AMPK independently of SIRT1 and that AMPK is essential for the beneficial metabolic effects of this compound on mitochondrial biogenesis and glucose homeostasis. Despite these interesting findings several limitations should be noted. The in vivo mouse experiments conducted here use a germline whole body deletion of the AMPK α2 isoform and a muscle-specific Sirt1 deletion, which leaves room for compensatory activity of AMPK α1 or parallel pathways that do not reflect normal biology. Specifically, AMPK α2 KO mice have elevated catecholamines (which would increase cAMP) due to hyperactivation of the autonomic nervous system, and this could be an important factor contributing to in vivo insulin resistance and hypoinsulinemia (Viollet et al., 2003Viollet B. Andreelli F. Jorgensen S.B. Perrin C. Geloen A. Flamez D. Mu J. Lenzner C. Baud O. Bennoun M. Gomas E. Nicolas G. Wojtaszewski J.F. Kahn A. Carling D. Schuit F.C. Birnbaum M.J. Richter E.A. Burcelin R. Vaulont S. The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity.J. Clin. Invest. 2003; 111: 91-98Crossref PubMed Scopus (441) Google Scholar). In addition, the importance of CaMKKβ in regulating AMPK activity in muscle has been questioned given that liver kinase B1 (LKB1) accounts for nearly all detectable AMPK activity (Sakamoto et al., 2005Sakamoto K. Mccarthy A. Smith D. Green K.A. Grahame Hardie D. Ashworth A. Alessi D.R. Deficiency of LKB1 in skeletal muscle prevents AMPK activation and glucose uptake during contraction.EMBO J. 2005; 24: 1810-1820Crossref PubMed Scopus (443) Google Scholar). Lastly, experiments assessing glucose tolerance and insulin sensitivity were not performed in Sirt1 KO mice to rule out potential co-dependency of AMPK and Sirt1 in vivo. Considering the limitations noted above, experiments using inducible muscle-specific CaMKKβ, AMPK and Sirt 1 null mice are still required to clarify the inter-relationship/contribution of AMPK and Sirt1 to the physiological effects of STACs. In conclusion, the study by Park and colleagues (Park et al., 2017Park S.J. Ahmad F. Um J.H. Brown A.L. Xu X. Kang H. Ke H. Feng X. Ryall J. Philp A. Schenk S. Kim M.K. Sartorelli V. Chung J.H. Specific Sirt1 activator-mediated improvement in glucose homeostasis requires Sirt1-independent activation of AMPK.EBioMedicine. 2017; 18: 128-138Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar) suggest it may be important to re-evaluate whether activation of AMPK is required for the metabolic benefits of STACs. Given the recent development of more specific AMPK activators (Smith and Steinberg, 2017Smith B.K. Steinberg G.R. AMP-activated protein kinase, fatty acid metabolism, and insulin sensitivity.Curr. Opin. Clin. Nutr. Metab. Care. 2017; (in press)https://doi.org/10.1016/j.ebiom.2017.03.019Summary Full Text Full Text PDF PubMed Scopus (22) Google Scholar), these data raise the question of whether therapeutic interventions indirectly targeting Sirt1 via multifaceted upstream signaling is the best approach, or whether direct activation of AMPK would be a more efficient means to elicit beneficial metabolic effects. Lastly, given the widespread clinical use of metformin and salsalate, which are safe, well-tolerated and effective activators of AMPK, it is currently unclear whether STACs may provide additional therapeutic benefit for improving insulin resistance and healthspan. However, given the STACs' distinct mechanism of action, investigating whether there may additive or synergistic benefits by combining them with direct and indirect AMPK activators will be an interesting area of future study. The authors declare no conflicts of interests. G.R.S. is a Canada Research Chair in Metabolism and Obesity and the J. Bruce Duncan Chair in Metabolic Diseases at McMaster University. Specific Sirt1 Activator-mediated Improvement in Glucose Homeostasis Requires Sirt1-Independent Activation of AMPKThe specific Sirt1 activator SRT1720 increases mitochondrial function in skeletal muscle, presumably by activating Sirt1. However, Sirt1 gain of function does not increase mitochondrial function, which raises a question about the central role of Sirt1 in SRT1720 action. Moreover, it is believed that the metabolic effects of SRT1720 occur independently of AMP-activated protein kinase (AMPK), an important metabolic regulator that increases mitochondrial function. Here, we show that SRT1720 activates AMPK in a Sirt1-independent manner and SRT1720 activates AMPK by inhibiting a cAMP degrading phosphodiesterase (PDE) in a competitive manner. Full-Text PDF Open Access

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