A Unifying Hypothesis of Chronic Disease and Aging

The last post was about Dr. David Sinclair and his work on slowing and even reversing aging at Harvard. This video lasts just 6 short minutes, but it is very instructive regarding lifestyle measures that prolong healthy life. Most intriguingly to me, he mentions a unified hypothesis of aging. I would modify his assessment to broaden it to a unified hypothesis of aging and chronic disease. Chronic diseases and aging are related at the deepest level. The core of these challenges is epigenetics and related signaling that feed into the master metabolic switches mTOR and AMPK as Dr. Sinclair explained in the last post.

It is fascinating to me that he is a molecular geneticist who trained in Australia before coming to the United States. I am an internist who started down this path by trying to figure out why metformin reduces heart attacks and strokes better than other ways of achieving the same sugar level. These two completely different paths and backgrounds led us to the same conclusions and a unifying hypothesis of chronic disease and aging that I have written about previously in this space.

Dr. Sinclair is not diabetic and he takes metformin for reasons that he explains here.  Metformin is incredibly effective because it does exactly what you would want it to do with mTOR and AMPK. It switches off mTOR and switches on AMPK through the amino acid sensing mechanism. Jardiance for diabetes directly activates AMPK. It is a diabetic medication that lowers your risk of hospitalization from heart failure or chronic kidney disease whether you are diabetic or not!!!

The metformin story is especially fascinating. Metformin blocks epigenetic mechanisms by blocking the effect of asymmetric dimethylarginine (ADMA). ADMA is a methylated arginine that is formed by methylating histone proteins around DNA to open the gene and transcribe it. ADMA enters the circulation when those proteins are broken down. ADMA activates 26 genes. I think this methylated arginine activates the protein sensing mechanism of mTOR and AMPK and that is how metformin works. 

Lisinopril, losartan, spironolactone, and eplerenone for hypertension; statins for cholesterol, metformin and Jardiance for diabetes directly or indirectly switch off mTOR and switch off AMPK. So do diet, exercise, and intermittent fasting. That is why a protocol combining these drugs is so much more effective than the care that most people receive.