Nicotinic acid synergizes with leucine to stimulate AMPK/Sirt1 signaling and regulates lipid accumulation and lifespan in C. elegans (269.7)

Previous data demonstrate the BCAA leucine (Leu) to stimulate AMPK and Sirt1 signaling in vitro and in vivo. Nicotinic acid (NA) has been used as a highly effective treatment of dislipidemias; however, its poorly tolerated side effects (severe vasodilation and flushing at high doses) limits its use as a drug. Since it increases NAD+ and thereby activates Sirt1, we tested the synergistic effects of leucine (0.5 mM) and low dose NA (10 nM) on AMPK/Sirt1 signaling and downstream effects in cell culture and C. elegans. The NA‐Leucine combination increased P‐AMPK by 80%, P‐AMPK/AMPK ratio by 114% (p<0.001) and Sirt1 by 25% (p=0.04) in adipocytes and myotubes, while the individual components exerted no independent effect. In C. elegans, NA‐Leu increased P‐AMPK and DAF‐16 (FOXO) signaling by 66% (p=0.018) and 105% (p=0.004), respectively. This was associated with a reduction in lipid accumulation by 49% (p=0.017) and a 28% increase in median survival (p=0.0001) under mild oxidative stress conditions (0.2 mM paraquat). These data indicate that low concentrations of NA synergize with leucine to modulate sirtuin signaling and lipid metabolism, and may therefore be a potential therapeutic for treatment of metabolic diseases. Grant Funding Source : NuSirt Sciences Inc.