Nusirt Sciences, Inc.

A review.This article discusses on the dairy foods, calcium, and weight management.Retrospective and prospective epidemiol. and observational studies, secondary anal. of past clin. trials originally conducted with other primary endpoints (e.g., skeletal, cardiovascular), and prospective clin. trials are discussed.The role of dairy components in suppressing oxidative and inflammatory stress and thereby reducing the risk of obesity-associated comorbidities and metabolic syndrome are discussed.

The AMPK-Sirt1 pathway is an important regulator of energy metabolism and therefore a potential target for prevention and therapy of metabolic diseases. We recently demonstrated leucine and its metabolite β-hydroxy-β-methylbutyrate (HMB) to synergize with low-dose resveratrol (200 nM) to activate sirtuin signaling and stimulate energy metabolism. Here we show that leucine exerts a direct effect on Sirt1 kinetics, reducing its Km for NAD(+) by >50% and enabling low doses of resveratrol to further activate the enzyme (p = 0.012). To test which structure elements of resveratrol are necessary for synergy, we assessed potential synergy of structurally similar and dissimilar polyphenols as well as other compounds converging on the same pathways with leucine using fatty acid oxidation (FAO) as screening tool. Dose-response curves for FAO were constructed and the highest non-effective dose (typically 1-10 nM) was used with either leucine (0.5 mM) or HMB (5 µM) to treat adipocytes and myotubes for 24 h. Significant synergy was detected for stilbenes with FAO increase in adipocytes by 60-70% (p<0.05) and in myotubes >2000% (p<0.01). Sirt1 and AMPK activities were stimulated by ∼65% (p<0.001) and ∼50% (p<0.03), respectively. Similarly, hydroxycinnamic acids and derivatives (chlorogenic, cinnamic, and ferulic acids) combined with leucine/HMB increased FAO (300-1300%, p<0.01), AMPK activity (50-150%, p<0.01), and Sirt1 activity (∼70%, p<0.001). In contrast, more complex polyphenol structures, such as ellagic acid and epigallocatechin gallate required higher concentrations (>1 µM) and exhibited little or no synergy. Thus, the six-carbon ring structure bound to a carboxylic group seems to be a necessary element for leucine/HMB synergy with other stilbenes and hydroxycinnamic acids to stimulate AMPK/Sirt1 dependent FAO; these effects occur at concentrations that produce no independent effects and are readily achievable via oral administration.

Caloric deficit from fasting and/or exercise increases NAD⁺ and AMP levels, resulting in activation of Sirt1 and AMPK, resp.These two energy-sensing systems work cooperatively in a finely tuned network to stimulate mitochondrial biogenesis and fuel metabolism, and mediate, in part, the salutary effects of caloric restriction on lifespan and healthspan.We have shown that leucine activates Sirt1 by lowering the activation energy for NAD⁺, thereby serving as a partial mimetic of caloric restriction and enabling synergy with sirtuin co-activators.Resveratrol is a widely recognized activator of Sirt1; however, poor bioavailability and rapid metabolism limit effective translation of the high concentrations (>50 mM) in pre-clin. models.We found that combining low resveratrol doses (200 nM) which exerted no independent effects on any measured parameter synergized with leucine (0.5 mM) to increase median lifespan ∼50% in C. elegans (p=0.0095), increase murine skeletal muscle and adipocyte Sirt1 activity, mitochondrial biogenesis and fatty acid oxidation ∼50%, and markedly reduced insulin resistance by 55%, inflammatory markers ∼50%, and weight and visceral adiposity 31% (all p<0.01) in diet-induced obese mice.To translate these data from mice to humans, we assessed the effects of resveratrol (50 mg)/leucine (1.11 g; sufficient to achieve 0.5 mM plasma concentration) on glucose dynamics in a 4-wk placebo-controlled trial of 36 pre-diabetic subjects.Leucine-resveratrol reduced insulin resistance (HOMA_IR) 33% with corresponding reductions in glucose and insulin area under the curve (p<0.01) in oral glucose tolerance test.We have extended these concepts in preclin. studies using other direct Sirt1 activators (NAD⁺ precursors) and Sirt1 pathway activators.Low-dose (10 nM) NAD⁺ precursors (nicotinic acid, NMN, nicotinamide riboside) synergized with leucine to increase Sirt1 activity in adipocytes, hepatocytes and muscle cells (30-100%, p<0.01) and median and maximal lifespan in C. elegans (25%, p=0.025) and to reduce circulating lipids and significantly regress atherosclerotic lesion size and macrophage infiltration in a mouse model of atherosclerosis (LDL-receptor knockout).Thus, synergistic activation of Sirt1 using leucine and a co-activator exerts pleiotropic effects impacting cardiometabolic endpoints; further, these data provide evidence of successful clin. translation of this concept.