The Final Common Pathway that Controls Aging and Chronic Illness: Use Your Knowledge
Growth Factors (insulin, mTOR, and AMPK
One of my readers Made this comment last week. “I've been trying to gather some of this information, but I am not the right person to do it. This list could be updated monthly and sent to paying subscribers. Whichever fields changed from the prior month could be highlighted. Perhaps with a few notes on your thought about the change.
This one monthly post would easily be worth the subscription cost to anyone who is interested in health span extension. To get to up to date info on several of the leading researchers would take hours for most of us. That is easily worth paying for and I think you would have a big target audience.” I am taking on that request and that is what this series is all about.
My reader was talking about identifying the leading aging scientists and updating their recommendations. Most scientists like David Sinclair are working on a very narrow part of the story like NAD. David Sabatinin works on mTOR and rapamycin. Cythia Kenyon works on the pathway. There are many things like this that impact aging. I will tie it all together, explain how it works in terms you can understand, and give you practical steps to a longer youthspan. Tell your friends.
In our last post you learned that insulin, a growth factor, activates mTOR and deactivates AMPK to makes you age faster, get sick sooner, and die prematurely. In middle aged and older adults, mTOR is the death switch and AMPK is the survival switch. Now lets look at the practical implications of your new knowledge.
Most of you understand that the way you live makes a huge difference in how healthy you are and AMPK plays a central role in this piece of the puzzle. AMPK is really an energy sensor. We already discussed how AMPK helps a child survive when there is no food. When there is no food to provide the energy to run the heart and brain, mTOR becomes much less active and AMPK becomes much more active. AMPK mobilizes calories from fat and muscle so that the vital organs survive and we can do just enough to make it.
Diet
You all know that caloric restriction increases lifespan and healthspan. Not eating as many calories activates AMPK to pull calories from your fat stores, but if you really starve yourself, that pulls calories from muscle and that is no good. Losing one to three pounds a month is a much better way to lose fat and save muscle. In the studies of caloric restriction, the study animals received all their daily calories at one time and they ate them pretty quickly. Part of the benefit in those studies, probably came from intermittent fasting. The link takes you to a great review of intermittent fasting in the New England Journal of Medicine that is edited by Dr. Dan Longo, another aging scientist. That means taking in all calories within a six-to-eight-hour window. When you do that, you activate AMPK and deactivate mTOR during the fasting periods when you are taking in no food. Many of you have also heard of the benefits of NAD from Dr. David Sinclair, FOXO from Dr. Cynthia Kenyon, and resveratrol found in grapes and red wine which is the most widely used sirtuin activator. These factors are all involved in the AMPK/mTOR relationship. There is a great diagram in the New England Journal article with an explanation of the relationships off to the side. That is how the diet piece of lifestyle makes you healthy and keeps you living longer.
Exercise
Now let’s turn to exercise. When you exercise you increase your energy needs even further and that switches on AMPK and switches off mTOR. Heavy aerobic exercise probably has the greatest effect there. Progressive resistance exercises with increasing weight as you can preserves muscle size and strength in the face of reduced food intake.
Medication
I hear people talk about maximizing the lifestyle piece so that they can get off their medicines all the time. If you really want to maximize your youth span and healthspan medication will help. There are very commonly used drugs that impact AMPK and mTOR directly. In fact, every medication that protects organs and cells more than it lowers the target risk factor works in this way. Metformin was developed to lower your blood sugar if you have type 2 diabetes. It does that but it also lowers your risk of heart attack by 39% and other diabetes complications by 32% compared with achieving the same blood sugar with another means. Now we know the reason for that tremendous benefit. Metformin directly inhibits mTOR by interfering with the amino acid sensing mechanism. It directly activates AMPK. Its impact on mTOR, and AMPK leads to lower glucose levels and that reduces the insulin level. It is a nearly perfect drugs for type 2 diabetes. It is generic. It only costs $10 for a 90 day supply at Walmart even if you don’t have insurance. If you have ever had diabetes, even if you lose weight and exercise, many of these abnormalities in gene expression that you had when you were diabetic persist. If you have ever had the diagnosis of diabetes, you should continue to take metformin. Your mTOR/AMPK balance is most likely still abnormal, and metformin pushes it in the right direction.
Medications in the same class as Jardiance also directly activate AMPK. That is the reason that those drugs reduce the progression of chronic kidney disease and hospitalization for congestive heart failure by 30% when compared to other drugs that achieve the same blood sugar. Dr Milton Packer, one of the foremost American experts on heart failure said this: “… it is now critical for physicians to reconceptualize SGLT2 inhibitors (Jardiance) as organ-protective agents rather than glucose-lowering drugs. The antihyperglycemic (glucose lowering) action of these drugs represents a tiny fraction of their broad portfolio of effects, which (when fully exercised) cause an adaptive reprogramming of stressed cells in a manner that promotes homeostasis and survival.” Said another way, drugs that activate AMPK protect every cell and organ in the body.
There are people that take rapamycin itself. Rapamycin directly inhibits mTOR just like metformin does but the dosing is less certain and there are more side effects. Some people take it to live longer because of the animal studies, but I think there are more certain ways to achieve the same thing in humans. The brand name of rapamycin is Sirolimus and there are other brands with the imus ending also. Rapamycin is used to avoid rejection in patients who have had an organ transplant. It is also used in chemotherapy.
The most interesting way that rapamycin is used is in the heart artery stents that are impregnated with that drug. The old stents without rapamycin often clogged up in about 6 months with scar tissue and inflammation. The Sirolimus eluting stents last much longer. But you should remember this. Rapamycin only protects the short segment of artery where the stent is. Metformin protects the entire arterial system. That is probably why stents don’t prevent heart attack in stable patients and metformin lowers the risk of heart attack by 39% in patients newly diagnosed with diabetes when the risk is much lower.
You have learned about a growth factor, insulin. You have learned how insulin and other factors switch on mTOR and switch off AMPK to make you age faster and get old and sick sooner. You have learned how diet, weight loss, intermittent fasting, NAD, resveratrol and other sirtuins impact the same signaling and you have learned about using rapamycin, metformin, and Jardiance to provide great benefit to patients, In the next post, I will discuss how other growth factors besides insulin make us age and get sick faster.
Awesome! Learning this information vaults a practitioner forward massively! Mind-opening. Thank you so much!
“If you have ever had the diagnosis of diabetes, you should continue to take mTOR.” I think you meant keep taking your metformin.