The Link Between Aging, Longevity, and the Biology of Alzheimer’s Disease

mTOR is Persistently Switched on in Alzheimer’s Disease

The Left Image is an MRI in Alzheimer’s Disease. The Black Spaces Without Brain Tissue are Larger.

In the last post, we discussed how long a healthy human life could be. As I said there, there is good evidence that we can be healthy substantially longer and of course that is the goal. Everyone in my family knows that I want no life prolonging measures if I have lost my mental capacity. Alzheimer’s disease is one of the conditions that terrifies me the most.

One of the things that happens in aging is the housekeeping function of the cells progressively breaks down. It is like living with a hoarder who has so many boxes of stuff that you can’t even get around. When we are young and healthy, proteins that have served their purpose are broken down and recycled. As we age, the ability to break those proteins down progressively declines and they accumulate in the cell. The boxes build up and interfere with cell function. That is a factor that causes the general decline of aging and specifically Alzheimer's disease. Two proteins accumulate and clump together and this housekeeping function is a root cause of the impaired thinking in that disease.

Type 2 diabetes and Alzheimer’s disease are both risk factors for one another. That brings us back to our paired master genetic metabolic switches mTOR and AMPK that we discussed in the last post. As you remember mTOR coordinates food supply with growth in the fetus and child. It is the growth switch. When there is no food, AMPK is switched on to mobilize calories from fat and muscle so that the child survives. Even in prediabetes mTOR is persistently switched on by overeating and high insulin levels. That continues when prediabetes becomes diabetes. As expected, when mTOR is switched on, AMPK is switched off.

Switching on mTOR shuts down the housekeeping function of cells. mTOR is all about making new proteins, not recycling old ones. AMPK, on the other hand, is all about survival. It increases housekeeping in the cells and protein recycling. AMPK throws out the boxes. That is the common denominator in Alzheimer's disease and diabetes. They have a common root cause. Because mTOR is switched on and AMPK is switched off in Alzheimer’s disease patients, amyloid-B and tau proteins accumulate and the brain cells can no longer function appropriately. Amyloid-B proteins also switch on mTOR and contribute to a vicious cycle.

These facts have important clinical implications, and they help us understand what we see in practice. Metformin directly switches off mTOR and switches on AMPK. That is the core way in which it works to provide much better outcomes patients with diabetes compared to other drugs that achieve the same glucose level. Metformin slows the progression to Alzheimer’s disease. Here is a quote from the medical journal Diabetes Care. “Type 2 diabetes (diabetes) is associated with increased risk of cognitive deficit and dementia. Midlife hypertension, obesity, and smoking increase risk of dementia by 30–65%; however, a staggering 60% of people with type 2 diabetes develop dementia. Cognitive dysfunction is considered an important comorbidity of diabetes, reflecting metabolic disease, cardiovascular disease, and frequently shared risk factors.” The same risk factors that cause diabetes and related conditions increase the risk of dementia. There was a five-fold difference in new onset dementia between patients on and off metformin. Another article shows that metformin activates the housekeeping function in cells by switching off mTOR and switching on AMPK. That all seems pretty tight to me. It is all tied together.

That is one of the ways that optimal medical therapy prolongs healthy life. Calorie restriction, intermittent fasting, exercise, lisinopril or losartan and spironolactone or eplerenone for hypertension, statins for cholesterol, and metformin or Jardiance for diabetes all switch off mTOR and switch on AMPK. OMT in type 2 diabetes should protect against Alzheimer’s disease. It needs to be a preventive strategy. Once the cells are too far gone, there is no going back.