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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Sirtuin-1 inhibits endothelin-2 expression in human granulosa-lutein cells via hypoxia inducible factor 1 alpha and epigenetic modifications†.
Magdalena Szymanska,Sarah Manthe,Ketan Shrestha,Eliezer Girsh,Avi Harlev,Tatiana Kisliouk,Rina Meidan +6 more
TL;DR: Findings propose novel, physiologically relevant roles for SIRT1 in downregulating EDN2 and survival of hGLCs and via deacetylation of histone H3 at the EDn2 promoter, inducing a repressive histone configuration.
Journal ArticleDOI
Anti-diabetic activity of fused PPARγ-SIRT1 ligands with limited body-weight gain by mimicking calorie restriction and decreasing SGK1 expression.
Celine Pirat,Catherine Dacquet,Veronique Leclerc,Nathalie Hennuyer,Monique Beucher-Gaudin,Ghislaine Zanirato,Anne Géant,Bart Staels,Alain Ktorza,Amaury Farce,Daniel-Henri Caignard,Pascal Berthelot,Nicolas Lebegue +12 more
TL;DR: Compound 14d showed high efficacy in an ob/ob mice model with significant decreases in serum triglyceride, glucose and insulin levels but mostly with limited body-weight gain by mimicking calorie restriction (CR) and inhibiting SGK1 expression.
Journal ArticleDOI
Healthspan and longevity in mammals: a family game for cellular organelles?
Enzo Nisoli,Alessandra Valerio +1 more
TL;DR: The evidence that mitochondrial biogenesis and quality control, as well as the complex interplay among cellular organelles, may be affected by the aging process(es), with negative consequences for the well being of elderly individuals is considered.
Journal ArticleDOI
KDAC8 with High Basal Velocity Is Not Activated by N-Acetylthioureas.
Tasha B. Toro,Subramanya R. K. Pingali,Thao P. Nguyen,Destane Garrett,Kyra A. Dodson,Kyara A. Nichols,Rashad A. Haynes,Florastina Payton-Stewart,Terry J. Watt +8 more
TL;DR: This article showed that N-acetylthioureas are not true activators of KDAC8 and only increase activity if the enzyme preparation is below the maximal basal activity.
Journal ArticleDOI
Dietary Supplements and Natural Products: An Update on Their Clinical Effectiveness and Molecular Mechanisms of Action During Accelerated Biological Aging
Ye Chen,Sherif Hamidu,Xintong Yang,Yiqi Yan,Qilong Wang,Lin Li,Patrick Kwabena Oduro,Yuhong Li +7 more
TL;DR: It is suggested that dietary/natural products increase healthspan—rather than lifespan—effectively minimizing the period of frailty at the end of life, but real-world setting clinical trials and basic studies on dietary supplements and natural products are further required to decisively demonstrate whether dietary/ natural products could promote human lifespan.
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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.
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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.
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.