The last post was aimed at helping you understand that you can really slow down the aging process and extend your youth span. Dr. Kenyon showed how the normal Daf-2 gene makes the little worms die faster. A mutated gene that does not function as well may double the lifespan. The closest thing that we have to the Daf-2 gene is the genes that make up our insulin system. In fact, Dr. Kenyon went on from her study described in the TED talk, to do other studies that prove that high insulin levels make us age faster.
I think that is a great coincidence, because everyone reading this knows about insulin. You know that if you don’t have enough insulin, you become diabetic. You know that you can control the blood sugar in diabetes by injecting insulin. Right? Everything you know about insulin today is positive. We must have it. That is true, but there is another, even more important, reality. Genes and hormones are like dimmer switches. It cannot be too bright or too dim. They are also like Goldilocks’ porridge. It can’t be too hot. It can’t be too cold. It must be just right. Having no insulin will kill you pretty quickly. Massive overdoses of insulin will kill you quickly too. Sugar is like oxygen. If you eliminate it from the bloodstream with very high insulin doses, you will die in minutes. For optimum health, your insulin level must be just right. Not too much. Not too little. Just right. It is like the Chinese concept of yin and yang, light and dark, balance.
That part of insulin’s function is not the part that makes you age faster. Insulin has a completely different function. It is also a growth factor. It is that part of insulin function that can make us age faster and the following diagram can help you understand that. Don’t panic. You can easily understand this. It is really very simple and if you want to increase your youthspan it is important.
Insulin in the top box in the diagram is a three-dimensional protein that is produced by a gene. Insulin produces its effects by activating other proteins. It works like dominoes. If you knock over the first domino, it knocks down a line of dominoes to produce an effect at the end of the line. In molecular biology we call that a signaling cascade. In this diagram, the arrow underneath the box means the domino above knocks over the domino below. So insulin knocks over the insulin receptor domino. It is like insulin is the ball and the insulin receptor is a catcher’s mitt on the surface of the cell. When the mitt catches the ball that activates other steps. It activates the boxes below just like knocking over a row of dominoes.
Now if you look at this diagram, you can see that it splits into two branches. The left branch with PI3K involves sugar lowering. The right branch is the growth promoting branch and then both branches end up at mTOR. Activating mTOR deactivates AMPK. That is what the symbol between mTOR and AMPK means. mTOR is a master metabolic genetic switch is linked directly to AMPK. When mTOR is more active, AMPK is less active and vice-versa.
mTOR is a very important part of the youthspan story. The letters stand for the mechanistic target of rapamycin. Rapamycin is a naturally occurring antibiotic that was found in a bacteria growing on Easter Island or Rapa Nui in 1964. That is 60 years ago. Dr. David Sabatini learned that rapamycin blocked mTOR in 1994 and that is why we call it the mechanistic target of rapamycin. If you give a mouse rapamycin to dim the mTOR switch directly the mouse lives longer. It is not just more insulin activity that makes us age faster, it is also more mTOR. Finally, if the AMPK dimmer switch is less bright or active, that also makes us age faster. There are many other things that impact the relationship between mTOR and AMPK but this is the final central common pathway that controls aging and chronic illnesses. There are many other influences, but that is where the story ends.
Insulin switches on mTOR and switches off AMPK. That is a central relationship that tells you that too much insulin makes you age faster and devolop chronic disease earlier. Early in life, in the fetus and child, mTOR is absolutely essential. It coordinates growth with the food supply. When there is plenty of food mTOR is switched on and AMPK is switched off. Food is another way to activate mTOR besides insulin.
Every time we eat, mTOR is switched on and it is not just the insulin increase from eating starch and sugar that does it. The amino acids in protein also activate mTOR directly. When there is no food, mTOR is deactivated and AMPK is activated and it mobilizes calories from fat and muscle to provide enough energy to keep the child alive until there is food again. mTOR is the growth switch and AMPK is the survival switch.
Once the child is a healthy young adult, mTOR becomes less active if they are slender and eating only when they are hungry, but most young American are not like that. They are overweight and eating all day. Every time they eat, they increase the mTOR signal and decrease the AMPK signal. They are making themselves age faster and develop chronic diseases sooner. If you go back to the signaling diagram, you can see that there is a line on the left showing that mTOR activation degrades the IRS-1 protein to interfere with the insulin signaling cascade. Insulin and eating activate mTOR and that makes us resistant to insulin effects almost in real time. If we are resistant to the effects of insulin, then we need higher insulin levels to maintain a normal blood sugar and that is in fact what happens. Americans who are overweight and eating all day may have insulin levels that are three times normal in order to maintain a normal blood sugar and then higher insulin levels increase the appetites and favor depositing excess calories into fat. It is a vicious cycle that makes us older and sicker faster.
Taken together, these facts have profound implications for your health. Eating sugar and processed carbs immediately raises your insulin level. Those calories are absorbed right away, and they don’t satisfy you long. Most people want more food in an hour or two after eating these foods producing another sugar and insulin spike. Even whole grain carbs raise the sugar and insulin level. They just do it more slowly. Eating real whole food minimizes this effect— Lean meat, eggs, fruits, vegetables, beans, peas, and nuts. Intermittent fasting helps. Take in all calories in a six-to-eight-hour period. The more abdominal fat you have, the more resistant you are to the effects of insulin. Many overweight people have insulin levels that are three times normal, and they are persistently elevated. That means mTOR is persistently elevated as well.
These facts should also influence treatment. Everything that I have said means that higher insulin levels make you older and sicker faster. Our current diabetes treatment paradigm is like all risk factor management. Almost the entire focus is on lowering the target risk factor. In this case lower blood sugar that is all that matters. I have heard leading diabetologists say that you can always get the sugar down if you give enough insulin. That is a deadly error. The first study that was designed to show the benefit of lowering blood sugar using tolbutamide in 1961 was stopped early because the more people died who were taking tolbutamide. Tolbutamide, like glyburide and glipizide today, increases the insulin level. That is how it works. The ACCORD trial was designed to show that lowering the sugar to near normal would reduce deaths and heart attacks. Again, more people died in the aggressive treatment arm and the study had to be stopped early. This confirms that your insulin level must be just right. The medications for type 2 diabetes that reduce heart attack and deaths all lower the insulin requirement. The lesson? Lowering the sugar to near normal is not dangerous. It is how you lower it. That is why avoiding carbs and sugar when you are overweight is so important. The more carbs and sugar you eat, the more insulin you need. It is just that simple.
That is an easy introduction to molecular biology and signaling pathways. All you need to know is that insulin increases mTOR activity and decreases AMPK activity. AMPK is the survival switch and it protects your cells and organs your entire life. mTOR is the growth switch and it perfectly coordinates food availability with growth in children. In adults, mTOR continues to promote growth, but it makes your heart bigger and your arteries thicker. It causes heart and artery disease. It makes cancer cells grow wildly without food even when the cancer victim is too far gone to eat. In older adults, mTOR becomes the aging and death switch. In the next post we will build on that story. You already know more than most people about aging and chronic illness.
I have always wondered why diabetes and heart disease were closely associated, your explanation hit it out of the park for me. Thank you so much!
Yup! The entire “Insulin pushers industrial complex” needs to be held accountable and tried for crimes against humanity.