Caloric deficit from fasting and/or exercise increases NAD+ and AMP levels, resulting in activation of Sirt1 and AMPK, respectively. 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 (&gt;50 mM) in pre-clinical 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&lt;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-week placebo-controlled trial of 36 pre-diabetic subjects. Leucine-resveratrol reduced insulin resistance (HOMAIR) 33% with corresponding reductions in glucose and insulin area under the curve (p&lt;0.01) in oral glucose tolerance test. We have extended these concepts in preclinical studies using other direct Sirt1 activators (NAD+ precursors) and Sirt1 pathway activators. Low-dose (10 nM) NAD+ precursors (nicotinic acid, nicotinamide mononucleotide, nicotinamide riboside) synergized with leucine to increase Sirt1 activity in adipocytes, hepatocytes and muscle cells (30-100%, p&lt;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 clinical translation of this concept.

Modulation of energy sensing targets by natural products: Effects on health span

2019 Fall National Meeting

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