Age-related Obesity

A hyper mTOR disease

Age-related obesity is a hyper mTOR disease. An old proverb is "Waste not, Want not". mTOR puts that proverb into practice. High levels of mTOR drive excess calories to be stored as adipose tissue. Older people have increase levels of mTOR and the most common sign of elevated mTOR in older persons is a dramatic change in body shape. We are all very familiar  with the typical silhouette of a 25 year old man versus a 75 year man. The change is a dramatic increase in waist line. Increase waist line reflects an increase in both visceral fat and increase in subcutaneous waist line fat. 

Obesity and age-related diseases

The incidence of obesity is rapidly increasing in many Western countries. Older persons are much less able to tolerate overweight and obesity without development of age-related and obesity related diseases. Elevated mTOR is at the core of these diseases. Obesity is associated with increased risk of cardiovascular disease, type 2 diabetes, cancer, Alzheimer's disease, non-alcoholic fatty liver disease (NAFLD and osteoarthritis. All these age-related diseases have increased risk caused by a hyper mTOR state. 


Obesity and overweight leads to numerous metabolic disorders including dyslipidemia including reduced HDL cholesterol, elevated LDL cholesterol, and insulin resistance.  


Elevated insulin resistance sets in motion a vicious circle. Obesity increases insulin resistance, which increases insulin levels, which increases mTOR levels. Higher mTOR levels promote obesity and the entire litany of obesity, age-related, high mTOR diseases.

Waist/hip ratio

Obesity is about your shape, not your weight. Obesity is diagnosed with a tape measure, not the scale. BMI can be very misleading as includes all body mass which includes muscle mass which is good. Obesity is primarily visceral fat and subcutaneous fat on waist line. 


Overweight and obesity is best determined by waist/hip ratio.  The proper waist/hip ratio is 0.9 for men and 0.75 for women. A waist hip ratio of more than 0.8 for women and and 1.0 for men is associated with increased health risk. A waist circumference of over 35 inches in women and 40 inches in men puts you in obese category, and increases your risk of all age-related diseases due to hyper mTOR.

Rapamycin, mTOR, Obesity

Rapamycin and Obesity

This is summary from In Blagosklonny paper, "Koschei the Immortal".


Rapamycin prevents Obesity:  


1. mTOR decreases lipolysis (hydrolysis of triglycerides) (fatty acids); rapamycin increases lipolysis, releasing fatty acids from the fat tissues.


2. mTOR increases lipogenesis (synthesis of triglycerides; rapamycin blocks lipogenesis. 


3. mTOR promotes adipocyte differentiation and hypertrophy; rapamycin prevents adipocyte differentiation. 


4. Nutrients such as glucose, amino acids, and fats activate mTOR and increase insulin; rapamycin blocks mTOR and decreases insulin secretion and insulin-induced obesity. In a vicious cycle, obesity activates mTOR. 


5. Rapamycin prevents entry of lipoproteins into tissues. This can lead to elevated lipids. This is benign as rapamycin prevents atherosclerosis. However, the elevation of lipids can be blocked by using statins, part of the Koschei formula. 






Clinical studies and personal experience

In studies involving mice, rats and humans, rapamycin can decrease excess weight gain. Rapamycin prevented weight gain with rats on a high fat diet.


My experience is rapamycin does not cause automatic weight loss in humans. Rapamycin is very helpful to stabilize weight. It at a desired weight, easy to maintain that weight with rapamycin without tendency to put on excess fat.


Trying to loose weight on rapamycin is still hard work; but very much easier than if not on rapamycin. 


For myself, I spent 50 years trying to lose weight and could never get my weight below 170 pounds. When I started on rapamycin, in a few months I was 150 pounds, a weight I had not seen since a young teenager.  My impression is that on rapamycin, a person could actually pick any weight they think is best for them and then with a great deal of effort, achieve that weight and then maintain that weight.



Adipokines

Adipokines are a very big and important topic. In recent years it has been recognized that adipose tissue is a very active endocrine organ and secretes a large number of hormone-like substances. Central (belly fat) and visceral adipose tissue are most active in secretion adipokines. Most adipokine levels increase with increase amount of visceral fat. Their most common effect of adipokines is promoting chronic inflammation, which promote various diseases including atherosclerosis.


Adiponectin, another very important adipokine, has beneficial effects. However, the level of adiponectin goes down with increase in adipose tissue.


While belly fat is bad, adipose tissue on the buttocks is neutral. This is reason for common statement that pear shape is good, while apple shape is bad. This appears to be true from medical perspective. 


Creating a better adipokine pattern, in addition to main goal of reduction of mTOR signaling, are medical benefits obtained from reduction of visceral fat and obesity

Obesity, mTOR, Autophagy

Obesity causes high mTOR and high mTOR inhibits Autophagy.


A decrease in autophagy is a very common factor for many age-related disease including Non-alcoholic fatty liver disease, Neurodegeneration [Alzheimer, Parkinson disease], Osteoarthritis.


For a complete discussion of Autophagy, see section on fatty liver [NAFLD, NASH]