The last post discussed the key role of metabolic memory and chronic diseases, and how we can use that new information to prolong healthy life. Many of you know about oxidants as a cause of faster aging and more rapid chronic disease development. Some of you took vitamin E, a known antioxidant, but later studies proved that vitamin E was not helpful. You were on the right track. Medications like lisinopril or losartan for hypertension, spironolactone for high blood pressure, statins for cholesterol, and metformin for type 2 diabetes are powerful antioxidants that prolong your healthy life. Metformin directly blocks the effects of ADMA which increases oxidant production. When they are combined in a protocol for type 2 diabetes people with that illness live 8 years longer free of heart attack or stroke. They have one fourth as many heart attacks and one fifth as many strokes. Medications with powerful antioxidant effects are much more effective than other medications that achieve the same blood pressure or blood sugar levels because they interfere with the epigenetics and molecular biology that cause more rapid aging and chronic illness. Risk factor levels are less important than attacking the fundamental mechanisms of chronic disease to protect cells and organs.
The new science gives us a deep understanding of the mechanisms of chronic disease and aging. We all get older and die. Many of us develop chronic illness along the way, but the new science makes it possible to slow down aging and chronic disease development. We can be healthier longer.
Let’s take a deeper look at the fundamental mechanisms of heart artery disease and related conditions like diabetes and high blood pressure. These conditions are all related and the most common driver is poor diet leading to too much abdominal fat. The number of people with diabetes, high blood pressure, heart artery disease, chronic kidney disease and heart failure are all increasing as our population gets heavier and older. Increased belly fat, high triglycerides, low good (HDL) cholesterol, high blood pressure, and resistance to insulin effects all come together to form what is called the metabolic syndrome. Increased levels of aldosterone lead to insulin resistance and high blood pressure that is more resistant to treatment. High levels of aldosterone lead to increased oxidant production which directly increases inflammation while make arteries thicker and the heart larger. Oxidants damage cells and organs. They worsen insulin resistance. It is all tied together. High aldosterone levels lead to less insulin production and more resistance to insulin effects to increase sugar levels in the blood. Angiotensin II is another molecule that is made by abdominal fat to cause diabetes and vascular disease.
There are more than a dozen genes in the system that produces increased levels aldosterone and angiotensin II in abdominal fat. These are normal and essential genes in the fetus that are responsible for forming the urinary system. If we block angiotensin II with losartan or lisinopril in the fetus the kidney does not develop normally. These genes become inactive in healthy slender young adults. They are inappropriately reactivated later in life by increased abdominal fat to make us age and become ill more rapidly. These genes activate other genes in the vessel that cause vascular disease. This is a perfect example of a general principle. Most chronic disease is not caused by inherited abnormal genes. It is caused by normal genes that are inappropriately switched on later in life. It is not genetic. It is a matter of gene regulation and inappropriately switched on genes. It is epigenetic.
ADMA (asymmetric dimethyarginine) is one of the most fascinating molecules in all of biology. Metformin blocks the effect of ADMA. That is how metformin really works and that is very important to understand its dramatic benefits. ADMA levels are a marker of gene activation. There are histone proteins that are tightly wound around genes to keep them inactive. Arginine is a key amino acid in those proteins. A methyl group is a central carbon atom with three hydrogen atoms attached. ADMA is formed when two methyl groups are added to arginine to form asymmetric dimethyarginine. That causes the proteins around the gene to loosen up so that the gene can unravel and do its work. ADMA is thus part of the machinery of gene activation. “Oxidative stress has been shown to increase the activity of arginine methylating and ADMA degrading enzymes leading to increased ADMA concentrations.” After the histone protein has switched on the gene, its work is done and it is broken down to release free ADMA into the system where it switches on other genes. Therefore, this is a vicious cycle.
Abdominal fat makes mediators that increase oxidant production and then increased oxidants increase ADMA levels. ADMA increases oxidant production directly and thus the vicious cycle occurs. That is the reason blocking this epigenetic increase in oxidant production with the medications in our protocol lead to much better clinical and financial outcomes.
ADMA levels vary with age. The graph is a U shape. Levels are very high in the fetus and infant. ADMA levels correlate with growth rates in children. The lowest ADMA levels are found in slender healthy young adults when the work of growth and development is done. ADMA levels begin to rise again as we get older, and it increases faster when we develop increased abdominal fat.
ADMA levels are finely coordinated during growth and development but later in life they can rise acutely when you simply drink a milkshake. Arginine also is the amino acid that is converted to nitric oxide in your arteries. Nitric oxide is the active ingredient in nitroglycerin that dilates the arteries and relieves pain in patients who have angina due to heart artery disease. Nitric oxide supports arterial health. Simply drinking a milk shake increases ADMA levels enough to impair arterial dilatation within hours. It changes arterial health within hours.
When ADMA levels are increased, it shifts arginine conversion from nitric oxide which preserves arterial health to oxidant (peroxynitrate) production that damages the artery leading to more rapid aging and heart attacks. That was thought to be the main way that increased ADMA caused artery disease. Researchers at Stanford called ADMA an “Uber Marker.” Here is a translated version of what they said. “We and others have provided evidence for a universal mechanism of arterial disease shared by all risk factors and vascular risk markers examined to date. This mechanism of arterial disease is mediated by an inhibitor of nitric oxide formation, a molecule known as asymmetrical dimethylarginine (ADMA). Risk factors produce arterial disease by causing the accumulation of ADMA.” There are increased levels of ADMA with many risk factors for heart attack such as age, high blood pressure, diabetes, insulin resistance, high cholesterol, high triglycerides, and high homocystine. They are saying that ADMA blocks the conversion of arginine to nitric oxide and that is a major causative factor in all vascular disease.
It would make sense, then, that you could overcome the effects of ADMA with arginine supplements. The Stanford people tried that and it did not work. Then we also learned that metformin blocks the effects of ADMA. But wait. That can’t be right. If ADMA is producing arterial disease by inhibiting conversion of arginine to nitric oxide, blocking ADMA effects with metformin would not work. You can’t block the effect of an inhibitor with another inhibitor. And indeed, that is not the way metformin works. This next piece of the story ties it all together.
There is a master metabolic genetic switch called mTOR (mechanistic target of rapamycin). Let’s call it the growth switch because it coordinates growth in the fetus and child with food availability. Remember the key role of the amino acid arginine in gene activation and nitric oxide formation. When we break down the proteins in the food that we eat into amino acids, free arginine enters the circulation, and it switches on mTOR to support growth in the fetus and child. That is a critical function. ADMA is arginine with two methyl groups. It is enough like arginine to also switch on mTOR. This is where metformin works. It blocks the amino acid sensing mechanism that switches on the growth switch. The growth switch is essential for the fetus, infant, and child. When it is reactivated later in life by overeating and belly fat, it causes growth again except that this time it makes the heart bigger and the artery thick. It kills the cells lining the artery and increases inflammation. The new heart artery stents all contain rapamycin that inhibits mTOR to reduce inflammation and scar formation so that the stent stays open longer. Rapamycin keeps that tiny segment of artery with the stent open. Metformin makes the entire arterial system healthier by inhibiting mTOR everywhere.
There is another master metabolic genetic switch that is tied to mTOR. When food switches on mTOR, it switches off AMPK. When there is no food, mTOR is switched off, and AMPK is switched on. AMPK is a survival switch. When food is scarce, AMPK mobilizes calories and energy from fat and muscle to enable survival until food is available again. It promotes survival in the child and fetus. Later in life switching on AMPK promotes a longer healthier life and switching on mTOR favors more rapid chronic disease development and earlier death.
As you can easily see from this diagram, the top three red boxes are molecules produced by genes that have been switched on by overeating and too much belly fat. Those red boxes increase oxidant production which switches on mTOR and switches off AMPK. Every medication in a green box blocks the effect of switching on genes that should be switched off. Jardiance also directly switches on AMPK. The most effective medications and lifestyle measure switch off mTOR and switch off AMPK. Calorie restricted diets, intermittent fasting, and exercise do the same thing. Pressure switches on EGFR. Smoking persistently switches on EGFR. This is how chronic diseases and aging are all tied together. It helps us understand how overeating, belly fat, and smoking all come together to cause heart attack, stroke, and cancer. Now we understand how to interfere precisely to assist you in staying healthier longer.
While this is an absolute excellent post , the vitamin E research I believe you are citing was extremely flawed . The researchers use only alpha -tocopherol , which lowers the delta and gamma tocipherols , which are cardio protective . The results of this research have deprived many of an important anti-oxidant. Let’s hope they are getting some lipoic acid somewhere to help recycle their available e ( and c).
Thank you for all the effort in above article . I will print and study .
I use NAC at times (4800) short term to help control mTor .
Where does insulin fit in all this complexity? What about fasting and exercise? Stress reduction?