The Mechanistic Target of Rapamycin (mTOR): A Major Driver of Normal Growth, Aging, Chronic Diseases, and Death
mTOR at the nexus of nutrition, growth, ageing and disease
nex·us
· the central and most important point or place.
"the nexus of all this activity was the disco"
The link above goes to a summary article on mTOR from the lab of Dr. David M Sabatini. His articles were the first that I saw on this master genetic metabolic switch. He is the world’s leading authority on the topic. Rapamycin is a natural product purified in 1975 from bacteria found in soil collected on Easter Island. It has extraordinary anticancer, antifungal, and immunosuppressive effects. The mechanistic target of rapamycin (mTOR) gets its name from the fact that rapamycin directly and precisely blocks the epigenetic and biochemical effects of this switch. Rapamycin (Sirolimus) is the compound in the drug-eluting heart artery stent that reduces inflammation and scar tissue formation to keep the stent open longer. Most remarkably, rapamycin prolongs lifespan in multiple species. Even more remarkably, it does not merely prolong lifespan, it prolongs health span, the time that our cells and organs are healthy and fully functional, free of disability or disease.
How can that be? Well, you have heard that eating less—caloric restriction—leads to a longer, healthier life. Remember that mTOR coordinates food availability with healthy growth in children. That is an essential part of normal development, but persistent mTOR activation in middle aged adults from eating too much makes our cells and organs age more rapidly leading to chronic illnesses and death. mTOR is central to the regulation of nutrition, growth, ageing and disease. Rapamycin mimics caloric restriction which switches off mTOR. That is the way rapamycin prolongs healthspan. Caloric restriction added to rapamycin treatment fails to prolong lifespan any further. mTOR inhibition also reduces oxidant production with further benefit on cellular health.
Healthy cells can break down obsolete or damaged cellular parts and recycle them. This built-in maintenance program clears damaged proteins and cellular organelles to repair and regrow cells and organs. This ability to maintain and renew the cell declines with aging leading to cardiovascular and neurodegenerative diseases. Rapamycin restores this capacity. Persistent mTOR signaling leads to reduced availability of stem cells that renew tissues as we age. Cells also become senescent, meaning that they can no longer grow and divide, which is another feature of cellular aging. These old cells make molecules that increase inflammation further contributing to more rapid aging and disease development.
Rapamycin and its derivatives are used clinically in cancer therapy and organ transplantation. You may ask why this miracle drug is not used more broadly. For reasons that are not clear to me, rapamycin increases insulin resistance and is a powerful immunosuppressant in cancer and transplant patients using intense, high-dose regimens. That makes dangerous infections more likely. The doses needed to slow aging and delay chronic illness are much smaller and less likely to cause side effects.
Dr. Sabatini sums it up this way: “the unique spectrum of mTOR dependent processes is also one of its most powerful advantages as a therapeutic target. More so than other strategies to delay ageing or counter disease, mTOR inhibition disrupts a wide variety of degenerative processes with a single intervention.” That is why optimal medical therapy for chronic diseases is much so much more effective than usual care. That is why it protects cells and organs beyond its effects on the target risk factor. That is why treatments for high blood pressure can reduce the risk of diabetes and treatments for diabetes can lower the blood pressure. The Mediterranean diet, intermittent fasting, metformin, and empagliflozin all directly deactivate mTOR (and activate AMPK). Losartan and lisinopril for hypertension, statins for cholesterol, and spironolactone all indirectly inactivate mTOR by reducing oxidant production and growth factor signaling. mTOR is at the nexus of chronic disease and aging and we can effectively manipulate it now with inexpensive generic medications with very few side effects to achieve much better clinical and financial outcomes.
Wow! Fascinating. I look forward to more on this.