Brief
Early aggressive management of cardiovascular and related conditions provides better results even years later when both groups are on the same intensity of care
We know how metabolic memory works at least in part. Asymmetric dimethylarginine (ADMA) is an amino acid that is elevated in all risk factors for heart disease and related conditions. Specifically, ADMA levels are increased in people with high cholesterol, atherosclerotic vascular disease, high blood pressure, chronic heart failure, diabetes, and chronic kidney disease. A common denominator of vascular risk factors is they increase ADMA levels and that diminishes nitric oxide production which is essential to vascular health. Nitric oxide is the active ingredient in nitroglycerin which relieves chest pain in patients with heart artery disease. Decreased nitric oxide production is a common denominator of all vascular disease and vascular risk factors. ADMA switches the system from healthy nitric oxide production to increased oxidant release which is a double hit to vascular health. Several studies have found that ADMA levels increase with aging and antioxidant defenses become weaker as we grow older.ADMA levels are not just elevated in obesity, diabetes, and heart disease, they are also elevated in lung diseases including asthma, pulmonary arterial hypertension and pulmonary fibrosis or scarring of the lung.
The increased oxidant and reduced nitric oxide production due to increased ADMA are part of the cause of many chronic illnesses and aging. But now this gets to be a very strange story, because ADMA is part of the normal epigenetic regulation that produces a normal infant from a fertilized egg. In fact, if a fetus does not have the gene that adds two methyl groups (CH3) to arginine to open up DNA and switch on genes at just the right time in just the right place, the fetus dies. Oddly, ADMA correlates tightly with growth rate in healthy children. In the embryo, oxidants are vital signaling molecules necessary for development and they are precisely controlled. Later in life, ADMA levels are a marker produced by genes that are inappropriately and chaotically switched on by factors like excess abdominal fat. ADMA levels may go up quickly after drinking a milkshake and cause an impaired ability of arteries to dilate. ADMA levels are increased in the elderly and they are a strong independent predictor of mortality.
That leads us to another crazy fact. Metformin and ADMA look alike when you examine their clinical structure. Look at the left side of the picture and you see two CH3 or methyl groups that have been substituted for hydrogen (H) on arginine, a key amino acid in humans. That is what makes it dimethyl-arginine. Now look at metformin. The left side of the compound is identical, but the right side of the molecule is completely different. That is very common with precision medications. Losartan controls lowers high blood pressure and reduces oxidant production because it is enough like angiotensin II to engage its receptor and block its effects to increase pressure. Metformin looks enough like ADMA to block its effect at a cellular membrane. Metformin also directly switches off mTOR and switches on AMPK via an amino acid sensing mechanism. ADMA is an amino acid that activates mTOR and this is the likely location of metformin’s ability to block the effects of ADMA.
If you read about metformin, you will usually find that its mechanism of action described as reducing insulin resistance in the liver. But that is yet another major anomaly in the old science. Reducing insulin resistance doesn’t prolong life and provide benefit in many chronic diseases. Metformin has those effects because the blocks the effect of ADMA to switch off mTOR and switch on AMPK and that influences dozens of genes. ADMA itself changes the activity of more than 50 genes when added to one cell type. Sure, metformin reduces insulin resistance in the liver, but that is like saying Tom Brady plays football. It is true, but it falls far short of explaining his impact on the game. ADMA is a critical part of the machinery that regulates genes. Metformin blocks the effect of ADMA precisely. That is why metformin slows aging and delays chronic illness. Patients on a protocol containing metformin designed to treat patients with type 2 diabetes and chronic kidney disease live eight years longer than patients in usual care treated under the old science. That is proof that we can slow aging and delay chronic illness now.
I did not understand (in my quick reading) all the details. But the conclusion is very easy to understand:
Patients on a protocol containing metformin designed to treat patients with type 2 diabetes and chronic kidney disease live eight years longer than patients in usual care treated under the old science. That is proof that we can slow aging and delay chronic illness now.
YES.
Now, what about those of us who are among the "super healthy" - no pills, no doctor visits, no aches and pains. What's right for us?