The more I study rapamycin, the more fascinating the story becomes. We have discussed the critical role of this medication throughout this series. Rapamycin is the active ingredient in heart artery stents which slowly leaks out to block scar formation and inflammation so that the stent stays open longer. Stents are tubular wire cages that are placed over a balloon in a catheter. Cardiologists thread a stent catheter through a heart artery until the balloon is within the blocked arterial segment. Then they blow up the balloon up to open the blockage and the stent also expands to keep the artery open. Of course, opening the artery creates a wound and that kicks off the healing process. Scar formation and inflammation are part of the healing process. If you cut your arm, healing is great. If you have just put in a stent, healing is horrible. Scar tissue cells grow and block the stent within months if it does not contain rapamycin. Once the artery is wounded it just keeps making scar tissue. Rapamycin shuts down scar formation and the stent stays open for years. You can easily see how important that is. Prior to rapamycin, repeated procedures were needed to keep the artery open.
The heart artery story was the first place rapamycin became important, but now there are many applications and scientists understand very precisely how this medication works. YOU can easily understand it. All you need to know is this. Rapamycin inhibits a master metabolic genetic switch appropriately named the mechanistic target of rapamycin (mTOR). mTOR regulates many other genes and another equally important master metabolic switch named AMPK. These two master metabolic switches evolved to regulate dozens of genes that coordinate food supply with growth in children.
It seems mTOR is involved in regulation virtually all growth in humans. Scar formation is a problem in many other medical settings as well. A cut on the face must activate scar tissue growth to heal. But we have all seen facial cuts where the extent of the scar detracts from appearance. Some people form very excessive amount of scar leading to keloid formation. Topical rapamycin application inhibits mTOR locally and reduces scar formation from cuts and burns. That may also be important for arm and leg function. Scarring can be so extensive that it limits mobility. Applying rapamycin can stop the excessive scar formation once the essential healing is done.
mTOR is critical to beneficial healing in the skin. It is also critical in human organ regeneration. The liver, intestines, kidney, muscles, and skin have extensive regenerative capacity in young people. mTOR plays a central role in this healthy organ regeneration after injury.
Scar formation doesn’t just affect the skin. Most organs scar with aging. Scar formation in the abdomen after surgery results in bowel obstructions and makes operations in that same area later much more difficult. Radiation treatments do the same thing. Aging and heart attacks lead to heart enlargement, heart muscle cell death, and scar tissue formation. Increased mTOR activity is central to that increased heart size and decreased function. Caloric restriction and rapamycin which inhibit mTOR slow these effects. Scar tissue formation and functional cell death seem to be a feature of disease of other organs as well and mTOR activity is critical in these diseases. Cirrhosis of the liver is a good example. Alcohol repeatedly kills the working liver cells, and they are replaced by scar tissue. The same factors are activated in chronic kidney disease. mTOR activity is generally higher in these organs with aging. Organs can functionally regenerate when we are younger. Later in life, increased oxidative particles and excessive mTOR signaling leads to functional cell loss, scar formation, and organ failure. Inhibiting mTOR slows these processes. Those are the fundamental issues with aging and chronic disease.
The last two videos I posted by Cynthia Kenyon tell a new story of aging biology. We are learning the pathways that control aging and chronic diseases and these can be modified. Dr. Kenyon talked about mutations. Of course, we cannot control that. The practical treatment potential is not in mutations but in epigenetics. Genes that are essential to normal childhood growth and wound healing cause disease and accelerated aging when activated by overeating and tobacco smoke. Cynthia has shown high insulin levels (and insulin related growth factor 1 IGF-1) accelerate aging and shorten lives. Eating sugar and carbohydrate raises insulin levels in real time and the more you eat the higher the insulin level goes. Insulin and IGF-1 are both growth factors that activate mTOR and that increases resistance to insulin effects. Insulin resistance and insulin levels increase until insulin levels are persistently three times normal in some overweight patients. Increased insulin levels persistently activate mTOR and inhibit AMPK and that accelerates aging and chronic disease development.
Cynthia and others have worked out how this causes chronic disease very precisely. Excess fast food and increased abdominal weight increase angiotensin II production which increases oxidant production. Oxidants activate a growth factor receptor which in turn activates mTOR and inactivates AMPK. Lisinopril and losartan block that signaling like a laser. Extra weight and overeating also activates the HMG CoA reductase enzyme which leads to more oxidant production and mTOR activation. Statins block that signaling very precisely. It also leads to increased aldosterone levels which add still more oxidant production and mTOR actively. Spironolactone and eplerenone block that effect exactly. Each puff of cigarette smoke contains 1015 oxidative particles, which persistently activate growth factor signaling and mTOR. Stopping smoking is a very powerful step to slow aging and chronic disease development. Overeating itself activates this master metabolic switch mTOR in real time. Excess sugar intake actives mTOR and cholesterol synthesis. Eating less and intermittent fasting deactivate it. Exercise deactivates it. Finally, it becomes clear how these seemingly unrelated factors combine to accelerate aging and chronic disease development. It is also clear how we can interfere with this biology
Metformin directly inhibits mTOR and activates AMPK just like rapamycin. Medications like empagliflozin for diabetes directly activates AMPK which deactivates mTOR. Every single intervention that improves health more than it lowers the target risk factor inhibits mTOR and activates AMPK.
This understanding of chronic disease has been extensively studied in a real-world setting. Combining lisinopril, atorvastatin, metformin, aspirin, and lifestyle measures in high-risk patients with diabetes over 21 years extended life by 8 years compared with usual care—the care that most diabetics receive. This is not some future fantasy. A longer healthier life has already been produced in humans. We can improve on these results from 20 years ago. Now we understand the mechanisms involved. We did not understand the critical benefits of spironolactone and eplerenone then. We did not have medications like empagliflozin. We did not understand sugar and carbohydrate restriction as well—nor the benefits of intermittent fasting. Adding these interventions to optimal medical treatment should produce much better results. More effective chronic disease management and longer, healthier lives can be a reality today.
Cynthia Kenyon deserves the Nobel Prize in medicine. She and others like her have worked out major parts of the biology of chronic disease and aging. That science has practical application now—today. The biology of chronic diseases, aging, and their relationships should become a major function of new research efforts. We are not doing nearly enough translational research on this very promising science . Help spread the word. Help make optimal medical treatment a universal standard of care so you can have these benefits. If you want to keep up with this information, please subscribe. Let’s press forward to a better health system together.
Excellent article Bill!