Open Access
Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators
Basil P. Hubbard,Ana P. Gomes,Han Dai,Jun Li,April Case,Thomas Considine,Thomas V. Riera,Jessica E. Lee,E. Sook Yen,Dudley W. Lamming,Eli Schuman,Linda Stevens,Alvin J. Y. Ling,Sean M. Armour,Shaday Michan,Huizhen Zhao,Yong Jiang,Sharon Sweitzer,Charles A. Blum,Jeremy S. Disch,Pui Yee Ng,Konrad T. Howitz,Anabela P. Rolo,Yoshitomo Hamuro,Joel Moss,Robert B. Perni,James L. Ellis,George P. Vlasuk,David A. Sinclair,Bradley L. Pentelute +29 more
TLDR
Yuan et al. as mentioned in this paper found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT 1 activation by STACs.Abstract:
It's a SIRT Intense attention has focused on the SIRT1 deacetylase as a possible target for anti-aging drugs. But unexpected complications in assays of SIRT1 activity have made it unclear whether compounds thought to be sirtuin-activating compounds (STACs) are really direct regulators of the enzyme. Further exploration of these effects by Hubbard et al. (p. 1216; see the Perspective by Yuan and Marmorstein) revealed that interaction of SIRT1 with certain substrates allows activation of SIRT1 by STACs and identified critical amino acids in SIRT1 required for these effects. Mouse myoblasts reconstituted with SIRT1 mutated at this amino acid lost their responsiveness to STACs. An interaction of the deacetylase SIRT1 with its substrate offers a possible explanation for some effects on aging. [Also see Perspective by Yuan and Marmorstein] A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu230, located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.read more
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Nutraceuticals and Their Potential to Treat Duchenne Muscular Dystrophy: Separating the Credible from the Conjecture
Keryn G. Woodman,Keryn G. Woodman,Chantal A. Coles,Shireen R. Lamandé,Shireen R. Lamandé,Jason D. White +5 more
TL;DR: This review gathers and evaluates the peer-reviewed scientific studies that have used nutraceuticals in clinical or pre-clinical trials for DMD and thus separates the credible from the conjecture.
Journal ArticleDOI
Obesity Weighs down Memory through a Mechanism Involving the Neuroepigenetic Dysregulation of Sirt1
Frankie D. Heyward,Gilliam D,Coleman Ma,Cristin F. Gavin,Jing Wang,Garrett A. Kaas,Trieu R,John W. Lewis,Moulden J,J. D. Sweatt +9 more
TL;DR: Evidence of epigenetic dysregulation (i.e., altered DNA methylation and hydroxymethylation) of memory-related genes, including Sirt1, within the hippocampus of obese mice is presented, suggesting that the memory-impairing effects of diet-induced obesity may potentially be mediated by neuroepigenetic Dysregulation of SIRT1Within the hippocampus.
Journal ArticleDOI
Nicotinamide mononucleotide (NMN) supplementation promotes neurovascular rejuvenation in aged mice: transcriptional footprint of SIRT1 activation, mitochondrial protection, anti-inflammatory, and anti-apoptotic effects.
Tamas Kiss,Ádám Nyúl-Tóth,Ádám Nyúl-Tóth,Priya Balasubramanian,Stefano Tarantini,Stefano Tarantini,Chetan Ahire,Andriy Yabluchanskiy,Tamas Csipo,Tamas Csipo,Tamas Csipo,Eszter Farkas,Jonathan D. Wren,Jonathan D. Wren,Lori Garman,Anna Csiszar,Anna Csiszar,Anna Csiszar,Zoltan Ungvari +18 more
TL;DR: The present findings taken together with the results of recent studies using mitochondria-targeted interventions suggest that mitochondrial rejuvenation is a critical mechanism to restore neurovascular health and improve cerebral blood flow in aging.
Journal ArticleDOI
Resveratrol-Induced AMP-Activated Protein Kinase Activation Is Cell-Type Dependent: Lessons from Basic Research for Clinical Application
TL;DR: It is shown that resveratrol-induced activation of AMPK requires the presence of functional LKB1, and that AMPK-mediated increases in NAD+ in the second mechanism require several ATPs, which may not be available in many pathological conditions.
Journal ArticleDOI
Mitochondria, the NLRP3 Inflammasome, and Sirtuins in Type 2 Diabetes: New Therapeutic Targets.
Susana Rovira-Llopis,Nadezda Apostolova,Celia Bañuls,Jordi Muntané,Milagros Rocha,Victor M. Victor +5 more
TL;DR: An overview of the existing literature concerning the crosstalk between mitochondrial impairment and the inflammasome is provided, with particular attention to cellular and mitochondrial redox metabolism and the potential role of the NLRP3 inflammaome and sirtuins in the pathogenesis of type 2 diabetes.
References
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疟原虫var基因转换速率变化导致抗原变异[英]/Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
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Resveratrol improves health and survival of mice on a high-calorie diet
Joseph A. Baur,Kevin J. Pearson,Nathaniel O Price,Hamish A. Jamieson,Carles Lerin,Avash Kalra,Vinayakumar Prabhu,Joanne S. Allard,Guillermo López-Lluch,Kaitlyn N. Lewis,Paul J. Pistell,Suresh Poosala,Kevin G. Becker,Olivier Boss,Dana M. Gwinn,Mingyi Wang,Sharan Ramaswamy,Kenneth W. Fishbein,Richard G. Spencer,Edward G. Lakatta,David G. Le Couteur,Reuben J. Shaw,Plácido Navas,Pere Puigserver,Donald K. Ingram,Rafael de Cabo,David A. Sinclair +26 more
TL;DR: It is shown that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice onA standard diet and significantly increases their survival and point to new approaches for treating obesity-related disorders and diseases of ageing.
Journal ArticleDOI
Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan
Konrad T. Howitz,Kevin J. Bitterman,Haim Y. Cohen,Dudley W. Lamming,Siva Lavu,Jason G. Wood,Robert E. Zipkin,Phuong Chung,Anne Kisielewski,Li-Li Zhang,Brandy Scherer,David A. Sinclair +11 more
TL;DR: The potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD+, and increases cell survival by stimulating Sirt1-dependent deacetylation of p53.
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Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase
Anne Brunet,Lora B. Sweeney,J. Fitzhugh Sturgill,Katrin F. Chua,Paul L. Greer,Yingxi Lin,Hien Tran,Sarah E. Ross,Raul Mostoslavsky,Haim Y. Cohen,Linda Hu,Hwei-Ling Cheng,Mark P. Jedrychowski,Steven P. Gygi,David A. Sinclair,Frederick W. Alt,Michael E. Greenberg +16 more
TL;DR: One way in which members of the Sir2 family of proteins may increase organismal longevity is by tipping FOXO-dependent responses away from apoptosis and toward stress resistance.
Journal ArticleDOI
Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.
Joseph T. Rodgers,Carlos Lerin,Wilhelm Haas,Steven P. Gygi,Bruce M. Spiegelman,Pere Puigserver +5 more
TL;DR: It is shown that the Sir2 homologue, SIRT1 controls the gluconeogenic/glycolytic pathways in liver in response to fasting signals through the transcriptional coactivator PGC-1α, and this findings have strong implications for the basic pathways of energy homeostasis, diabetes and lifespan.