Activating the longevity gene to restore insulin sensitivity and immune reciprocity in patients with metabolic syndrome

Townsend Letter for Doctors and Patients, May, 2007 by Paul Yanick

Metabolic Syndrome due to insulin resistance and aberrations in visceral-abdominal fat generates a cluster of physiological abnormalities: high triglycerides, high blood pressure, high fasting blood sugar, and low HDL Cholesterol. While insulin injections help control diabetes, they are by no means a cure. Diabetics commonly have elevated risks of severe neurological and vascular complications, primarily due to autoimmune destruction of the insulin-producing beta cells. When the body lacks insulin, cells starve and glucose levels soar, causing blindness, kidney failure, and a wide spectrum of diseases. No treatment on the market has been proven to correct insulin resistance by addressing immune and genetic mechanisms underlying the death of pancreatic beta cells.

Recently SIRT1, also known as the longevity gene, has been shown to promote adaptation to caloric restriction (CR) by regulating the genetic programs for gluconeogenesis and glycolysis in the liver. (1) SIRT1 is a pivotal sensor of glucose and nutrient availability, a central metabolic regulator in the liver, muscle, and fat cells, and a regulator of cell proteins, apoptosis (cell death), and glucose metabolism. (1-4) Since insulin resistance causes a buildup of visceral-abdominal fat that induces unwanted inflammation and oxidative stress, we may need to ask if SIRT1 activation is necessary to reverse these processes. The answer, based on recent research, appears to be a resounding yes.

Excessive abdominal fat is a strong predictor of heart attacks in young men and chronic heart failure in older people and a predictor of high blood pressure. Excessive abdominal fat is even implemented in the development of Alzheimer's disease, colon cancer, gallstones, ovarian cystic disease, breast cancer, and sleep apnea. Unlike other kinds of body fat, visceral-abdominal fat can become dysfunctional and produce a stew of menacing molecules that can expand to the point of rupturing. Ruptured fat cells trigger immune cells (macrophages), interleukin-6 (IL-6), and tumor necrosis factor-alpha, which adhere to the endothelium of the blood vessels, causing atherosclerosis. Indeed, elevated levels of IL-6 and C-reactive protein (CRP) predict the development of type 2 diabetes and support the role for inflammation in diabetogenesis. Baseline levels of CRP and IL-6 were significantly higher in 188 diabetic women vs. 362 matched "normal" controls. And large-scale studies (the Physician's Health Study and the Women's Health Study) revealed high CRP levels to be a risk predictor of myocardial infarction or stroke in men, (5) cardiovascular events in women, (6) and cardiovascular events in patients with the metabolic syndrome. (7,8) A cross-sectional study revealed that CRP levels were related to insulin resistance, obesity, endothelial dysfunction, hypertension, and diabetes, (9-12) and excessive visceral-abdominal fat. (13,14) These studies raise the prospect that doctors might forestall autoimmune disease by restoring immune function.

In autoimmune disorders, immune reciprocity is lost, due to an insufficient population of commensal cells and a disruption of the pH gradients in the digestive tract. Besides diabetes, autoimmune disorders cause rheumatoid arthritis and more than forty other conditions. In these disorders, components of the body's immune system cause extensive damage to the energy-producing mitochondrion in commensal cells. Commensal cells account for 90% of the body's cells and possess a rich genetic diversity. With 235,000 more genes than human cells to express, they can activate huge amount of SIRT1 and mimic the positive health effects of caloric restriction. (15-16) In my February-March 2007 column, I defined how the use of synbiotic-prebiotic nourishment, rich in bipolar energies (polarities), provided the best way to nourish SIRT1-generating commensals. (17) In choosing nourishment for these cells, we need to consider avoiding man-made, synthetic "USP" vitamins or pharmaceuticals, as they all carry positive ionic charges that have the opposite effect on SIRT1.

Since maldigestion (gastro-duodenitis) causes constrictions in what I term the body's primary Excretion-Secretion Channel, it needs to be addressed clinically. Gastric acid production is regulated by reciprocity of the Autonomic Nervous System (ANS) and hormones. The vagus nerve is directly involved in this process, and stress depresses vagus function. The duodenal release of digestive fluids depends on the volume of fluids being secreted via the sphincter of oddi. Gastric acid is neutralized by pancreatic sodium bicarbonate-enzymes and alkaline bile. It is important to understand that low levels of gastric acids lead to a major reduction in hepatic cell production of bile, causing infectious gastritis. In these cases, the disinfecting properties of gastric acid can no longer act as a chemical barrier to food-borne infections as explained in Table 1.

When bile production is reduced, bile becomes toxic and acidic, burning the duodenum and increasing the body's toxic burden. An inflamed duodenum interferes with detoxification (excretion) and digestion (secretion). Toxic bile fractions cause extensive mucosal damage, breaching gut barrier functions even further. As Figure 1 illustrates, gastric-Biliary pH disorders cause insulin resistance and cause commensal cells to starve and die from a lack of synbiotic nutrients, because synbiotic nutrients cannot be produced in the gut when digestive fluids are diminished or gastric or bile pH is abnormal.