Combining a High Dose of Metformin With the SIRT1 Activator, SRT1720, Reduces Life Span in Aged Mice Fed a High-Fat Diet.

SRT1720, a sirtuin1-activator, and metformin (MET), an antidiabetic drug, confer health and life-span benefits when administered individually. It is unclear whether combination of the two compounds could lead to additional benefits. Groups of 56-week-old C57BL/6J male mice were fed a high-fat diet (HFD) alone or supplemented with either SRT1720 (2 g/kg food), a high dose of MET (1% wt/wt food), or a combination of both.

SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass.

Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density, and insulin sensitivity associated with higher mitochondrial content and decreased inflammation.

Identification of a SIRT1 mutation in a family with type 1 diabetes.

Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis.

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

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.

SRT1720 improves survival and healthspan of obese mice.

Sirt1 is an NAD(+)-dependent deacetylase that extends lifespan in lower organisms and improves metabolism and delays the onset of age-related diseases in mammals. Here we show that SRT1720, a synthetic compound that was identified for its ability to activate Sirt1 in vitro, extends both mean and maximum lifespan of adult mice fed a high-fat diet. This lifespan extension is accompanied by health benefits including reduced liver steatosis, increased insulin sensitivity, enhanced locomotor activity and normalization of gene expression profiles and markers of inflammation and apoptosis, all in the absence of any observable toxicity.

Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase.

Notch signalling is a key intercellular communication mechanism that is essential for cell specification and tissue patterning, and which coordinates critical steps of blood vessel growth. Although subtle alterations in Notch activity suffice to elicit profound differences in endothelial behaviour and blood vessel formation, little is known about the regulation and adaptation of endothelial Notch responses. Here we report that the NAD(+)-dependent deacetylase SIRT1 acts as an intrinsic negative modulator of Notch signalling in endothelial cells.

Sirt1 inhibition promotes in vivo arterial thrombosis and tissue factor expression in stimulated cells.

Aims: The mammalian silent information regulator-two 1 (Sirt1) blunts the noxious effects of cardiovascular risk factors such as type 2 diabetes mellitus and obesity. Nevertheless, the role of Sirt1 in regulating the expression of tissue factor (TF), the key trigger of coagulation, and arterial thrombus formation remains unknown.

Methods And Results: Human as well as mouse cell lines were used for in vitro experiments, and C57Bl/6 mice for in vivo procedures.

Conserved role of SIRT1 orthologs in fasting-dependent inhibition of the lipid/cholesterol regulator SREBP.

The sterol regulatory element-binding protein (SREBP) transcription factor family is a critical regulator of lipid and sterol homeostasis in eukaryotes. In mammals, SREBPs are highly active in the fed state to promote the expression of lipogenic and cholesterogenic genes and facilitate fat storage. During fasting, SREBP-dependent lipid/cholesterol synthesis is rapidly diminished in the mouse liver; however, the mechanism has remained incompletely understood.

SIRT1 mRNA expression may be associated with energy expenditure and insulin sensitivity.

Objective: Sirtuin 1 (SIRT1) is implicated in the regulation of mitochondrial function, energy metabolism, and insulin sensitivity in rodents. No studies are available in humans to demonstrate that SIRT1 expression in insulin-sensitive tissues is associated with energy expenditure and insulin sensitivity.

Research Design And Methods: Energy expenditure (EE), insulin sensitivity, and SIRT1 mRNA adipose tissue expression (n = 81) were measured by indirect calorimetry, hyperinsulinemic-euglycemic clamp, and quantitative RT-PCR in 247 nondiabetic offspring of type 2 diabetic patients.

SIRT1 inhibits inflammatory pathways in macrophages and modulates insulin sensitivity.

Chronic inflammation is an important etiology underlying obesity-related disorders such as insulin resistance and type 2 diabetes, and recent findings indicate that the macrophage can be the initiating cell type responsible for this chronic inflammatory state. The mammalian silent information regulator 2 homolog SIRT1 modulates several physiological processes important for life span, and a potential role of SIRT1 in the regulation of insulin sensitivity has been shown. However, with respect to inflammation, the role of SIRT1 in regulating the proinflammatory pathway within macrophages is poorly understood.

Crystal structures of human SIRT3 displaying substrate-induced conformational changes.

SIRT3 is a major mitochondrial NAD(+)-dependent protein deacetylase playing important roles in regulating mitochondrial metabolism and energy production and has been linked to the beneficial effects of exercise and caloric restriction. SIRT3 is emerging as a potential therapeutic target to treat metabolic and neurological diseases. We report the first sets of crystal structures of human SIRT3, an apo-structure with no substrate, a structure with a peptide containing acetyl lysine of its natural substrate acetyl-CoA synthetase 2, a reaction intermediate structure trapped by a thioacetyl peptide, and a structure with the dethioacetylated peptide bound.

Biochemical characterization, localization, and tissue distribution of the longer form of mouse SIRT3.

SIRT3 is a key mitochondrial protein deacetylase proposed to play key roles in regulating mitochondrial metabolism but there has been considerable debate about its actual size, the sequences required for activity, and its subcellular localization. A previously cloned mouse SIRT3 has high sequence similarity with the C-terminus of human SIRT3 but lacks an N-terminal mitochondrial targeting sequence and has no detectable deacetylation activity in vitro. Using 5' rapid amplification of cDNA ends, we cloned the entire sequence of mouse SIRT3, as well as rat and rabbit SIRT3.

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

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.

Fracture resistance of endodontically treated maxillary premolars restored with CAD/CAM ceramic inlays.

Statement Of Problem: Endodontically treated posterior teeth are more likely to fracture compared to posterior teeth with vital pulps. Reinforcement with an extracoronal restoration that covers the cusps is the most commonly recommended method for reducing the risk of fracture. It is not known whether bonded intracoronal restorations without cuspal coverage will reduce the risk of fracture.

Ataxia telangiectasia mutated expression and activation in the testis.

Ionizing radiation (IR) and consequent induction of DNA double-strand breaks (DSBs) causes activation of the protein ataxia telangiectasia mutated (ATM). Normally, ATM is present as inactive dimers; however, in response to DSBs, the ATM dimer partners cross-phosphorylate each other on serine 1981, and kinase active ATM monomers are subsequently released. We have studied the presence of both nonphosphorylated as well as active serine 1981 phosphorylated ATM (pS1981-ATM) in the mouse testis.