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Dive into the research topics where Siva Lavu is active.

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Featured researches published by Siva Lavu.


Nature | 2003

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

In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD+-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that 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. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.


Nature | 2004

Sirtuin activators mimic caloric restriction and delay ageing in metazoans.

Jason G. Wood; Blanka Rogina; Siva Lavu; Konrad T. Howitz; Stephen L. Helfand; Marc Tatar; David A. Sinclair

Caloric restriction extends lifespan in numerous species. In the budding yeast Saccharomyces cerevisiae this effect requires Sir2 (ref. 1), a member of the sirtuin family of NAD+-dependent deacetylases. Sirtuin activating compounds (STACs) can promote the survival of human cells and extend the replicative lifespan of yeast. Here we show that resveratrol and other STACs activate sirtuins from Caenorhabditis elegans and Drosophila melanogaster, and extend the lifespan of these animals without reducing fecundity. Lifespan extension is dependent on functional Sir2, and is not observed when nutrients are restricted. Together these data indicate that STACs slow metazoan ageing by mechanisms that may be related to caloric restriction.


Nature | 2007

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes.

Jill Milne; Philip D. Lambert; Simon Schenk; David Carney; Jesse J. Smith; David J. Gagne; Lei Jin; Olivier Boss; Robert B. Perni; Chi B. Vu; Jean E. Bemis; Roger Xie; Jeremy S. Disch; Pui Yee Ng; Joseph J. Nunes; Amy V. Lynch; Hongying Yang; Heidi Galonek; Kristine Israelian; Wendy Choy; Andre Iffland; Siva Lavu; Oliver Medvedik; David A. Sinclair; Jerrold M. Olefsky; Michael R. Jirousek; Peter J. Elliott; Christoph H. Westphal

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme–peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.


Molecular Cell | 2004

Acetylation of the C terminus of Ku70 by CBP and PCAF controls bax-mediated apoptosis

Haim Y. Cohen; Siva Lavu; Kevin J. Bitterman; Brian Hekking; Thomas A Imahiyerobo; Christine M. Miller; Roy A. Frye; Hidde L. Ploegh; Benedikt M. Kessler; David A. Sinclair

Apoptosis is a key tumor suppression mechanism that can be initiated by activation of the proapoptotic factor Bax. The Ku70 DNA end-joining protein has recently been shown to suppress apoptosis by sequestering Bax from mitochondria. The mechanism by which Bax is regulated remains unknown. Here, we identify eight lysines in Ku70 that are targets for acetylation in vivo. Five of these, K539, K542, K544, K533, and K556, lie in the C-terminal linker domain of Ku70 adjacent to the Bax interaction domain. We show that CBP and PCAF efficiently acetylate K542 in vitro and associate with Ku70 in vivo. Mimicking acetylation of K539 or K542 or treating cells with deacetylase inhibitors abolishes the ability of Ku70 to suppress Bax-mediated apoptosis. We demonstrate that increased acetylation of Ku70 disrupts the Ku70-Bax interaction and coincides with cytoplasmic accumulation of CBP. These results shed light on the role of acetyltransferases as tumor suppressors.


Nature Reviews Drug Discovery | 2008

Sirtuins — novel therapeutic targets to treat age-associated diseases

Siva Lavu; Olivier Boss; Peter J. Elliott; Philip D. Lambert

Sirtuins post-translationally modulate the function of many cellular proteins that undergo reversible acetylation–deacetylation cycles, affecting physiological responses that have implications for treating diseases of ageing. Potent small-molecule modulators of sirtuins have shown efficacy in preclinical models of metabolic, neurodegenerative and inflammatory diseases, and so hold promise for drug discovery efforts in multiple therapeutic areas. Here, we discuss current knowledge and data that strengthens sirtuins as a druggable set of enzymes for the treatment of age-associated diseases, including activation of SIRT1 in type 2 diabetes.


BMC Systems Biology | 2009

Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo.

Jesse J. Smith; Renée Deehan Kenney; David J. Gagne; Brian P. Frushour; William M. Ladd; Heidi Galonek; Kristine Israelian; Jeffrey Song; Giedre Razvadauskaite; Amy V. Lynch; David Carney; Robin J Johnson; Siva Lavu; Andre Iffland; Peter J. Elliott; Philip D. Lambert; Keith O. Elliston; Michael R. Jirousek; Jill Milne; Olivier Boss

BackgroundCalorie restriction (CR) produces a number of health benefits and ameliorates diseases of aging such as type 2 diabetes. The components of the pathways downstream of CR may provide intervention points for developing therapeutics for treating diseases of aging. The NAD+-dependent protein deacetylase SIRT1 has been implicated as one of the key downstream regulators of CR in yeast, rodents, and humans. Small molecule activators of SIRT1 have been identified that exhibit efficacy in animal models of diseases typically associated with aging including type 2 diabetes. To identify molecular processes induced in the liver of mice treated with two structurally distinct SIRT1 activators, SIRT501 (formulated resveratrol) and SRT1720, for three days, we utilized a systems biology approach and applied Causal Network Modeling (CNM) on gene expression data to elucidate downstream effects of SIRT1 activation.ResultsHere we demonstrate that SIRT1 activators recapitulate many of the molecular events downstream of CR in vivo, such as enhancing mitochondrial biogenesis, improving metabolic signaling pathways, and blunting pro-inflammatory pathways in mice fed a high fat, high calorie diet.ConclusionCNM of gene expression data from mice treated with SRT501 or SRT1720 in combination with supporting in vitro and in vivo data demonstrates that SRT501 and SRT1720 produce a signaling profile that mirrors CR, improves glucose and insulin homeostasis, and acts via SIRT1 activation in vivo. Taken together these results are encouraging regarding the use of small molecule activators of SIRT1 for therapeutic intervention into type 2 diabetes, a strategy which is currently being investigated in multiple clinical trials.


Science | 2003

Yeast life-span extension by calorie restriction is independent of NAD fluctuation

Rozalyn M. Anderson; Magda Latorre-Esteves; Ana Rute Neves; Siva Lavu; Oliver Medvedik; Christopher M. Taylor; Konrad T. Howitz; Helena Santos; David A. Sinclair

Calorie restriction (CR) slows aging in numerous species. In the yeast Saccharomyces cerevisiae, this effect requires Sir2, a conserved NAD+-dependent deacetylase. We report that CR reduces nuclear NAD+ levels in vivo. Moreover, the activity of Sir2 and its human homologue SIRT1 are not affected by physiological alterations in the NAD+:NADH ratio. These data implicate alternate mechanisms of Sir2 regulation by CR.


Journal of Medicinal Chemistry | 2013

Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3.

Jeremy S. Disch; Ghotas Evindar; Cynthia H. Chiu; Charles A. Blum; Han Dai; Lei Jin; Kenneth Lind; Svetlana L. Belyanskaya; Jianghe Deng; Frank T. Coppo; Leah Aquilani; Todd L. Graybill; John W. Cuozzo; Siva Lavu; Cheney Mao; George P. Vlasuk; Robert B. Perni

The sirtuins SIRT1, SIRT2, and SIRT3 are NAD(+) dependent deacetylases that are considered potential targets for metabolic, inflammatory, oncologic, and neurodegenerative disorders. Encoded library technology (ELT) was used to affinity screen a 1.2 million heterocycle enriched library of DNA encoded small molecules, which identified pan-inhibitors of SIRT1/2/3 with nanomolar potency (e.g., 11c: IC50 = 3.6, 2.7, and 4.0 nM for SIRT1, SIRT2, and SIRT3, respectively). Subsequent SAR studies to improve physiochemical properties identified the potent drug like analogues 28 and 31. Crystallographic studies of 11c, 28, and 31 bound in the SIRT3 active site revealed that the common carboxamide binds in the nicotinamide C-pocket and the aliphatic portions of the inhibitors extend through the substrate channel, explaining the observable SAR. These pan SIRT1/2/3 inhibitors, representing a novel chemotype, are significantly more potent than currently available inhibitors, which makes them valuable tools for sirtuin research.


Journal of Medicinal Chemistry | 2009

Discovery of Imidazo[1,2-b]thiazole Derivatives as Novel SIRT1 Activators

Chi B. Vu; Jean E. Bemis; Jeremy S. Disch; Pui Yee Ng; Joseph J. Nunes; Jill Milne; David Carney; Amy V. Lynch; Jesse J. Smith; Siva Lavu; Philip D. Lambert; David J. Gagne; Michael R. Jirousek; Simon Schenk; Jerrold M. Olefsky; Robert B. Perni

A series of imidazo[1,2-b]thiazole derivatives is shown to activate the NAD(+)-dependent deacetylase SIRT1, a potential new therapeutic target to treat various metabolic disorders. This series of compounds was derived from a high throughput screening hit bearing an oxazolopyridine core. Water-solubilizing groups could be installed conveniently at either the C-2 or C-3 position of the imidazo[1,2-b]thiazole ring. The SIRT1 enzyme activity could be adjusted by modifying the amide portion of these imidazo[1,2-b]thiazole derivatives. The most potent analogue within this series, namely, compound 29, has demonstrated oral antidiabetic activity in the ob/ob mouse model, the diet-induced obesity (DIO) mouse model, and the Zucker fa/fa rat model.


British Journal of Clinical Pharmacology | 2013

Pharmacokinetics and tolerability of SRT2104, a first‐in‐class small molecule activator of SIRT1, after single and repeated oral administration in man

Ethan Hoffmann; Jeff Wald; Siva Lavu; John Roberts; Claire Beaumont; Jon Haddad; Peter J. Elliott; Christoph H. Westphal; Eric W. Jacobson

AIM SRT2104 is a novel, first-in-class, highly selective small molecule activator of the NAD + dependent deacetylase SIRT1. SRT2104 was dosed to healthy male and female volunteers in a series of phase 1 clinical studies that were designed to elucidate tolerability and pharmacokinetics associated with oral dosing to aid in dose selection for subsequent clinical trials. METHODS In the first-in-human study, there was both a single dose phase and 7 day repeat dose phase. Doses used ranged from 0.03 to 3.0 g. A radioactive microtracer study was subsequently conducted to determine systemic clearance, bioavailability and preliminary metabolism, and a crossover study was conducted to determine the effect of gender, formulation and feeding state on SRT2104 pharmacokinetics. RESULTS SRT2104 was well tolerated in all of these studies, with no serious adverse reactions observed. SRT2104 displayed a dose-dependent, but sub-proportional increase in exposure following single dose and repeated dose administration. Accumulation of three-fold or less occurs after 7 days of repeat dosing. The mean bioavailability was circa 14% and the mean clearance was circa 400 ml min(-1). Although there were no substantial effects on exposure resulting from gender or formulation differences, a notable food effect was observed, manifested as up to four-fold increase in exposure parameters. CONCLUSIONS In the absence of an optimized formulation of SRT2104, the food effect can be used to maximize exposure in future clinical studies. Combined with the good tolerability of all doses demonstrated in these studies, the favourable selectivity profile of SRT2104 allows for the use of this SIRT1 modulator for target validation in the clinic.

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Olivier Boss

Beth Israel Deaconess Medical Center

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