When the SIRT1 gene is activated, it produces proteins that protect cells from inflammation and oxidative stress, two of the primary causes of premature aging and many degenerative diseases. Almost all organisms have a gene that is equivalent to SIRT1. The gene is a defense mechanism, activated by low calorie consumption, that gives cells an extra level of protection during periods of time when they need it the most. The gene is believed to have a profound affect on lifespan, as studies have shown that animals on calorie-restricted diets live, on average, as much as 40 percent longer than those whose calories are not limited.
Several studies since 2003 have shown that resveratrol can mimic many of the positive effects of calorie restriction. High SIRT1 levels appear to be the key to slowing the aging process and living a healthier life, and calorie restriction and resveratrol are the two primary SIRT1 activators.
The Power of Resveratrol
Unlike pharmaceutical drugs that are specifically targeted to prevent or treat specific illnesses and symptoms, resveratrol can offer protection on a cellular level from two of the primary, underlying causes of premature aging and many age-related diseases. Inflammation and oxidative stress result from two natural body processes, the immune response and oxygen metabolism, but nonetheless are harmful and disruptive to healthy cellular activity. SIRT1 protects cells from free radical damage, inhibits inflammatory substances such as NF-kappa B, and lowers nitrotyrosine, tumor necrosis factor-alpha, and other measures of inflammation and oxidative stress. With its remarkable anti-inflammatory and anti-oxidative effects, SIRT1 can slow the aging process, extend lifespan, and reduce the risk of many degenerative diseases.
Resveratrol improves insulin sensitivity and lowers hepatic glucose production (HGP) in rat models of obesity and diabetes1, 2, 3, 4, 5, but the underlying mechanisms for these antidiabetic effects remain elusive. One process that is considered a key feature of resveratrol action is the activation of the nicotinamide adenine dinucleotide (NAD+)–dependent deacetylase sirtuin 1 (SIRT1) in various tissues1, 3, 6, 7, 8. However, the low bioavailability of resveratrol raises questions about whether the antidiabetic effects of oral resveratrol can act directly on these tissues9, 10. We show here that acute intraduodenal infusion of resveratrol reversed a 3 d high fat diet (HFD)–induced reduction in duodenal–mucosal Sirt1 protein levels while also enhancing insulin sensitivity and lowering HGP. Further, we found that duodenum-specific knockdown of Sirt1 expression for 14 d was sufficient to induce hepatic insulin resistance in rats fed normal chow. We also found that the glucoregulatory role of duodenally acting resveratrol required activation of Sirt1 and AMP-activated protein kinase (Ampk) in this tissue to initiate a gut–brain–liver neuronal axis that improved hypothalamic insulin sensitivity and in turn, reduced HGP. In addition to the effects of duodenally acting resveratrol in an acute 3 d HFD–fed model of insulin resistance, we also found that short-term infusion of resveratrol into the duodenum lowered HGP in two other rat models of insulin resistance—a 28 d HFD–induced model of obesity and a nicotinamide (NA)–streptozotocin (STZ)–HFD-induced model of mild type 2 diabetes. Together, these studies highlight the therapeutic relevance of targeting duodenal SIRT1 to reverse insulin resistance and improve glucose homeostasis in obesity and diabetes.
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