ADMA: One Explanation for the Difference in Heart Artery Disease Between Women and Men
Look at the graph which shows ADMA levels by age in healthy women and men. ADMA is the abbreviation for asymmetric dimethyarginine. Men and women at age 20 have ADMA levels that are roughly equal. ADMA levels in men increase with age in a linear fashion. Women have a very different pattern. Their ADMA levels stay about the same until menopause, then they increase sharply and by 75 women have substantially higher ADMA levels than men. ADMA is a small molecule of intense interest in cardiovascular disease. ADMA levels are increased in all cardiovascular risk factors including obesity. The pattern of ADMA increase fits the time difference in heart attack rates between women and men by age. Almost no women have a heart attack before menopause, but ultimately more women than men die of a heart attack. The graph below shows that the death rate from heart disease follows the rough pattern of ADMA increase and exceeds that of all cancers. Ten times as many women die of heart disease as breast cancer.
So, what is ADMA? ADMA is a marker for epigenetic activity or gene regulation. Increased ADMA levels mean more genes are being switched on. Arginine is an amino acid. ADMA is produced when arginine components of proteins surrounding the genes have two methyl groups added which loosens the protein to unravel the gene to switch it on. After the gene is switched on, these histone proteins break down releasing free ADMA into the circulation which switches on additional genes. ADMA is itself a signaling molecule. Small changes in ADMA have significant effects to switch on genes involved in DNA repair, cell cycle regulation, cell proliferation, transcriptional regulation, and metabolism. ADMA reduces nitric oxide production, increases oxidant production, and reduces the ability of the artery to dilate (endothelial dysfunction.) Nitric oxide is the active ingredient in nitroglycerin. Viagra increases nitric oxide supply. As you can see from the diagram above, ADMA levels rise with age and increase oxidant production to accelerate aging and increase rates of chronic diseases including cardiovascular diseases. The pattern is different between men and women. The pattern in the photograph is very similar to the differences in heart attack rates between men and women. Heart attacks in women are often due to microvascular disease and endothelial dysfunction. ADMA increases after menopause and is associated with increased oxidative particle production.
Metformin and ADMA are structural analogues. Metformin blocks ADMA effects at the membrane level in intact cells. Metformin directly blocks the nutrient-sensing apparatus of the master metabolic switch mTOR and the metformin-ADMA antagonism likely occurs at the lysosomal membrane level. This is the most important part of the entire discussion. Metformin directly blocks the impact of ADMA. As with empagliflozin (Jardiance), the effect of metformin in reducing heart attack by 39% probably has little to do with diabetes or blood sugar control. It has little to do with risk factor control. It is blocking the very biology that causes cardiovascular disease, cancer, and accelerated aging. It is time to make optimal medical therapy widely available and treat chronic diseases very precisely. Treatment should be based on a working understanding of molecular biology and epigenetics. Are you ready to get started?