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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The paradox of overnutrition in aging and cognition
Roger A. Fielding,John Gunstad,Deborah Gustafson,Deborah Gustafson,Steven B. Heymsfield,John G. Kral,Lenore J. Launer,Josef M. Penninger,David I. W. Phillips,Nikolaos Scarmeas,Nikolaos Scarmeas +10 more
TL;DR: Clinical and causal links between diseases of overnutrition and diseases of aging and cognition are explored and Alzheimer's disease, cerebrovascular dementia, and sarcopenia are explored.
Journal ArticleDOI
Acetate metabolism does not reflect astrocytic activity, contributes directly to GABA synthesis, and is increased by silent information regulator 1 activation.
TL;DR: Control of acetate metabolism and the degree to which it reflects astrocytic activity are investigated and it is found that acetate is a poor substrate for metabolism and will inhibit metabolism of itself and of glucose at concentrations in excess of 2 mmol/L.
Journal ArticleDOI
Stabilization of Resveratrol in Blood Circulation by Conjugation to mPEG and mPEG-PLA Polymers: Investigation of Conjugate Linker and Polymer Composition on Stability, Metabolism, Antioxidant Activity and Pharmacokinetic Profile
TL;DR: Polymer conjugates irrespective of linker chemistry protected resveratrol against metabolism in vitro and displayed improved pharmacokinetic profiles with significantly higher plasma area under curve (AUC), slower clearance and smaller volume of distribution, compared to resver atrol.
Journal ArticleDOI
Sirtuin 1 Is a Negative Regulator of Parathyroid Hormone Stimulation of Matrix Metalloproteinase 13 Expression in Osteoblastic Cells: ROLE OF SIRTUIN 1 IN THE ACTION OF PTH ON OSTEOBLASTS
TL;DR: Significance: Activation of SIRT1 and suppression of MMP13 may prolong the anabolic bone-forming period of PTH treatment in osteoporotic patients, and this regulation is mediated by Sirt1 association with c-Jun at the AP-1 site of the Mmp13 promoter.
Journal ArticleDOI
PACS-2 mediates the ATM and NF-κB-dependent induction of anti-apoptotic Bcl-xL in response to DNA damage.
Jonathan Barroso-González,Sylvain Auclair,Shan Luan,Laura L. Thomas,K M Atkins,Joseph E. Aslan,Laurel Thomas,J Zhao,Y Zhao,Gary Thomas +9 more
TL;DR: PACS-2 is identified as an in vivo mediator of the ATM and NF-κB-dependent induction of Bcl-xL that promotes cell survival in response to DNA damage.
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.
Journal ArticleDOI
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.
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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.