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
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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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Larval crowding accelerates C. elegans development and reduces lifespan.
Andreas H. Ludewig,Andreas H. Ludewig,Clotilde Gimond,Joshua C. Judkins,Staci Thornton,Dania C. Pulido,Robert J. Micikas,Frank Döring,Adam Antebi,Christian Braendle,Frank C. Schroeder +10 more
TL;DR: It is shown that in the model organism C. elegans developmental rate and adult lifespan depend on larval population density, and that this effect is mediated by excreted small molecules, which demonstrates how inter-organismal signaling during development regulates reproductive maturation and longevity.
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Nicotinamide mononucleotide (NMN) supplementation ameliorates the impact of maternal obesity in mice: comparison with exercise
Golam M. Uddin,Neil A. Youngson,Bronte M. Doyle,David A. Sinclair,David A. Sinclair,Margaret J. Morris +5 more
TL;DR: Both interventions reduced adiposity, and showed a modest improvement in glucose tolerance and improved markers of mitochondrial function, and the interventions appeared to exert the most global benefit in mice that were most metabolically challenged (HFD-consuming offspring of obese mothers).
Journal ArticleDOI
1,4-Dihydropyridines Active on the SIRT1/AMPK Pathway Ameliorate Skin Repair and Mitochondrial Function and Exhibit Inhibition of Proliferation in Cancer Cells.
Sergio Valente,Paolo Mellini,Francesco Spallotta,Vincenzo Carafa,Angela Nebbioso,Lucia Polletta,Ilaria Carnevale,Serena Saladini,Daniela Trisciuoglio,Chiara Gabellini,Maria Tardugno,Clemens Zwergel,Chiara Cencioni,Sandra Atlante,Sébastien Moniot,Clemens Steegborn,Roberta Budriesi,Marco Tafani,Donatella Del Bufalo,Lucia Altucci,Carlo Gaetano,Antonello Mai +21 more
TL;DR: New 1,4-dihydropyridines bearing changes at the C2/C6, C3/C5, C4, or N1 position displayed antiproliferative effects in the range of 8-35 μM and increased H4K16 deacetylation, suggesting a possible role for SIRT1 activators in cancer therapy.
Journal ArticleDOI
Loss of sirtuin 1 and mitofusin 2 contributes to enhanced ischemia/reperfusion injury in aged livers
Sung Kook Chun,Sung Kook Chun,Sooyeon Lee,Joseph Flores-Toro,Rebecca Y. U,Ming-Jim Yang,Kristina L. Go,Thomas G. Biel,Catherine E. Miney,Schiley Pierre Louis,Brian K. Law,Mary E. Law,Elizabeth Thomas,Kevin E. Behrns,Kevin E. Behrns,Christiaan Leeuwenburgh,Jae-Sung Kim +16 more
TL;DR: The SIRT1‐MFN2 axis is pivotal during I/R recovery and may be a novel therapeutic target to reduce I/ R injury in aged livers.
Journal ArticleDOI
The N-Terminal Domain of SIRT1 Is a Positive Regulator of Endogenous SIRT1-Dependent Deacetylation and Transcriptional Outputs.
Fiorella Ghisays,Cynthia S. Brace,Shawn M. Yackly,Hyock Joo Kwon,Kathryn F. Mills,Elena A. Kashentseva,Igor P. Dmitriev,David T. Curiel,Shin-ichiro Imai,Tom Ellenberger +9 more
TL;DR: It is demonstrated that the N-terminal domain of SIRT1 (NTERM) can trans-activate deacetylation activity by physically interacting with endogenous Sirt1 and promoting its association with the deacetolation substrate NF-κB p65.
References
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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.
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.
Journal ArticleDOI
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.