The Role of Other Growth Factors in Aging
Since last Wednesday, Jan 17, we have been reviewing very practical ways to increase your healthspan and youthspan. You know about the growth factor insulin, and that insulin activates mTOR and inactivates AMPK. You know how diet, exercise, and certain medications play into that story.
Now we are going to expand that tale a bit more. Insulin is not the only growth factor that makes you age faster and get sick sooner. The diagram above is superficially like the insulin diagram but it is different. Take a good look. The point of the picture is to show that cigarette smoke switches on mTOR and switches off AMPK just like insulin and other growth factors. This is the fundamental mechanism through which cigarettes cause arterial disease and cancer. They lead to emphysema and lung cancer. They kill the functional cells in the lung and cause other cells to multiple wildly in lung cancer.
Cigarettes also make you age faster. Many of you have heard that oxidants are bad, and antioxidants are good. Many of you took vitamin E to help you stay healthy. Vitamin E did not work, but oxidants are still important and an imbalance between oxidant exposure and antioxidant capacity is part of the aging and chronic disease story. That imbalance is called oxidative stress and if you become really interested in this topic, you will see that term a lot in your reading.
Each puff of cigarette smoke contains ten to the fifteenth power oxidative particles. I think that is a quadrillion. In any case, it is a huge oxidative load. This huge oxidative particle bombardment in the lungs activates the epidermal growth factor receptor (EGFR) in the lung tissue persistently. Insulin is a growth factor also as we previously discussed. Insulin activated the insulin receptor. That makes perfect sense. There is also an epidermal growth factor. The epidermal growth factor activates the epidermal growth factor receptor in fetal skin. There it works just like insulin and the insulin receptor. In the case of cigarette smoke, oxidative particles activate the EGFR without any growth factor involvement. Oxidants activate the receptor directly without involving a growth factor like the epidermal growth factor or insulin. That is one of the most important relationships in human biology. The epidermal growth factor and EGFR are persistently elevated in many cancers including lung, brain, breast, and skins cancers. The HER2 test in breast cancer is looking for one of the four variants of the epidermal growth factor receptor.
Look at the boxes in the right-hand side of the diagram— Ras/Raf/Erk1/2. When any one of these boxes are persistently activated, that persistently and maximally activates mTOR while disengaging AMPK. In melanoma, the hepatocyte growth factor is persistently activated as well as a variant of Raf. That activates mTOR and deactivates AMPK. There are a wide variety of growth factors involved in cancer formation. This link talks about the ways these boxes in the diagram are related in melanoma.
Once again, this is really simple. We started in the first post in this series with the critical relationship between insulin, mTOR, and AMPK. We explained how diet, exercise, and intermittent fasting benefits all participate in that key relationship. Now we have moved on to show that it is not just insulin and the insulin receptor that are important in this final common pathway. Other growth factors like the epidermal growth factor and its receptor are critical in the development of the skin and other organs in the fetus, but persistent EGFR activity is critical as a key part of the cause of artery disease and many cancers later in life. EGFR is perfectly programmed and coordinated to form a perfect fetus. Later in life, EGFR signaling is chaotic and it leads to disease.
EGFR can also be activated persistently by the increased oxidants in cigarette smoke. That causes the functional gas exchanging cells in the lung to die, leading to emphysema. It causes the supporting cells to grow wildly leading to cancer. The same stimulus can lead to cell death (emphysema) or unregulated cell growth in lung cancer. It is not just the oxidants in cigarette smoke. This is the mechanism by which second hand smoke and the smoke from wildfires damages your health.
Have you even noticed that a baby’s skin is smooth and unblemished but older skin has more bumps and blemishes. The picture above is a benign growth called a seborrheic keratosis that is very common as we age. Even these benign growths have mutations of 3 genes you can see in the diagram including Ras, Akt, and EGFR. That is what causes their abnormal growth.
Cigarette smoke is not the only source of oxidants as we get older. The are other important sources upstream, and that will be the topic of our next post. And one more reminder. We are not just talking about extending lifespan. We are talking about extending healthspan and even youth span. Remember Cynthia Kenyon’s remarkable TED talk!