Metformin

Metformin

Metformin is used primarily to decrease possible side effect of Rapamycin, to lower insulin resistance and help prevent diabetes. 


In "From Rapalogs to anti-aging formula", Blagosklonny advocated combined use of Rapamycin and metformin and noted, "Two agents may even cancel each other's potential side effects. For example, wheras metformin can increase lactate production, rapamycin decreases it." ..."Metformin is expected to reduce manifestations of benevolent glucose-intolerance, if rapamycin will cause these manifestations, in a minority of individuals."  Also rapamycin increases hepatic gluconeogenesis and metformin decreases hepatic gluconeogenesis. (44)


Rapamycin inhibits mTOR directly. Metformin indirectly inhibits mTOR by activating AMPK which activates TSC2/1 pathway which inhibits mTOR. 


A clinical trial called TAME (Targeting Aging with Metformin) was recently begun in which metformin will be given to thousands of people to see if metformin decreases risk of heart disease, cancer or cognitive impairment. While study not complete, this shows many consider metformin of value regarding these conditions.


Since 1972, Russian scientists, ... demonstrated that metformin slows aging, decrease obesity, prevents cancer and extend lifespan in rodents.


In editorial, "Metformin in the diabetic brain: friend or foe?', 2014, (69) various studies are discussed and no conclusion is reached. In studies involving transgenic mice, metformin was shown to induce PP2A (38) activity which is very important enzyme to prevent Tau hyperphosphorylation. However, metformin was shown to promote Tau aggregation in a mouse model. Another study showed metformin could increase beta-amyloid by up-regulating BACE1 (beta-secretase). Likewise,in various clinical studies of whether treatment with metformin caused an increase or decrease in dementia and AD, the results were mixed. Based upon these studies Metformin is not included to prevent AD directly.


In study entitled, "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, 3 year follow-up; metformin had 31% reduction compared to 58% reduction for lifestyle which consisted of weight loss and exercise. (70). This shows metformin is of value , although lifestyle was twice as effective. 


A remarkable 2014 paper (Bannister) (71) stated in conclusion, "Patients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls. In this UK study of 78,000 subjects on metformin, the adjusted survival was 15% greater for diabetics treated with metformin than individuals without diabetes.