Difficulties of finding the pill of immortality (4)

Metformin and other biguanides

(Continued. See the beginning of the article here.)

Metformin, an antiglycemic agent of the biguanide class for oral administration, is the most widely used drug in the treatment of metabolic syndrome and type 2 diabetes mellitus. The mechanism of action of metformin is not completely clear and it is most likely multifactorial. There is evidence that it reduces blood glucose by inhibiting the respiratory chain complex I in hepatocytes, which leads to a decrease in ATP production and subsequent activation of LKB1 and AMPK kinases, suppressing gluconeogenesis in the liver. The ability of metformin to activate AMPK in many other tissues, including adipose tissue, skeletal muscles, heart, pancreatic beta cells and hypothalamus, has been established, which is a potentially positive effect for patients with type 2 diabetes mellitus. However, metformin has an important effect independently of LKB1 and AMPK, for example by antagonizing the action of glucagon. Another AMPK-dependent mechanism of action of metformin has recently been discovered. The results of the study by Madiraju et al. metformin has been shown to uncompetitively inhibit the enzyme of the redox transporter of mitochondrial glycerophosphate dehydrogenase, increasing the redox status of the cytosol and reducing the redox status of mitochondria. This suppresses hepatic gluconeogenesis by suppressing the conversion of lactate and glycerol to glucose. Although metformin is currently approved as a therapy for type 2 diabetes mellitus, a large amount of literature data indicates the effectiveness of metformin against other conditions, especially cardiovascular diseases and cancer. In this regard, a recent study has demonstrated that metformin reduces oncogenesis by inhibiting mitochondrial complex I in cancer cells.

AMPK activation ensures the longevity of fruit flies and nematodes. The results of a number of studies indicate that metformin therapy can reproduce some of the effects of a low-calorie diet. In this context, several studies have analyzed the effect of metformin and other biguanides on life expectancy and demonstrated different results. Metformin and other biguanides dose-dependently increase the lifespan of C.elegans. An increase in the lifespan of these nematodes is mediated through inhibition of bacterial metabolism of folate and methionine, which in turn changes the metabolism of methionine in the body of worms, leads to a decrease in S-adenosylmethionine levels and an increase in S-adenosylhomocysteine levels. However, metformin does not increase the lifespan of fruit flies. In fact, despite the pronounced activation of AMPK, high doses of metformin even reduce the life expectancy of both female and male fruit flies, possibly due to a violation of the homeostasis of intestinal fluids. However, metformin therapy suppresses age-related phenotypes in the stem cells of the midgut, and also has a positive effect on the model of fly obesity. The results of a recent study have shown that metformin therapy provides a significant increase in the average and maximum life expectancy of female and male house crickets.

Several studies on the effect of metformin and other biguanides on life expectancy have been conducted on rodents. Their results varied depending on the genotype, gender, as well as the dose and duration of therapy. Chronic metformin therapy (100 mg/kg in drinking water) increased the average life expectancy of cancer-prone transgenic HER-2/neu, outbred SHR and inbred 129/Sv female mice by 8% (p<0.05), 37.8% (p<0.01) and 4.4% (p<0.05), respectively. Metformin therapy also increased the maximum lifespan of transgenic HER-2/neu, outbred SHR female mice by 9% and 10.3%, respectively, while the maximum lifespan of inbred 129/Sv female mice did not change. On the contrary, therapy using a similar dose of metformin reduced the average life expectancy of inbred 129/Sv male mice by 13.4%. At the same time, metformin therapy (2 mg/ml in drinking water) in a transgenic mouse model of Huntington's disease increased the average life expectancy of males by 20.1% (p=0.017), but did not affect the survival of females. It was also shown that metformin therapy initiated at 3 months of age (100 mg/kg in drinking water) provided a tendency to increase the life expectancy of female outbred SHR mice. Metformin therapy also delayed the formation of detectable tumors during initiation in the middle, but not in old age. Neonatal therapy with metformin 129/Sv mice (100 mg/kg in the form of subcutaneous injections) provided an increase in the average life expectancy of males by 20% (p<0.001), and also slightly increased the maximum life expectancy (by 3.5%). However, the average and maximum life expectancy of females decreased by 9.1% and 3.8%, respectively. In a recent study by Martin-Montalvo et al., male mice of the C57BL/6 line receiving 0.1% metformin in feed showed an increase in average life expectancy by 5.8% (p=0.02), whereas at a concentration of 1% metformin had a toxic effect and reduced average life expectancy by 14.4%. At the same time, the addition of 0.1% metformin to the feed of males of the B6C3F1 line provided an increase in life expectancy by only 4.2% (p=0.064). Therapy with another biguanide, phenformin, (2 mg/mouse in 0.2 ml of drinking water) significantly reduced the frequency of spontaneous tumor formation in C3H/Sn mice themselves and increased their average life expectancy by at least 21% (p<0.05), and the maximum life expectancy by 26%. Currently, the ITP consortium is evaluating the effect of metformin on the lifespan of mice, the results should soon be available.

In experiments on rats, therapy with buformin (5 mg/rat in 1 ml of drinking water) led to an insignificant (7.3%) increase in the average life expectancy of LIO females, while phenformin (5 mg/rat in 1 ml of drinking water) had no effect. However, the use of buformin and phenformin increased the maximum life expectancy of female line by 5.5% and 98%, respectively. Metformin therapy (300 mg/kg/day) did not increase either the average or maximum life expectancy of female F344 rats. However, the same publication contained data according to which, in a parallel group of males of the F344 line, kept on a low-calorie diet, there was also no increase in life expectancy, which makes the results of experiments with metformin unproven. It has been suggested that metformin therapy reproduces a number of effects of a low-calorie diet, especially by increasing AMPK activity, as well as activating antioxidant reactions, which simultaneously leads to a decrease in the severity of accumulation of oxidative damage and chronic inflammation.

Despite the fact that the effect of metformin on the life expectancy of healthy people has not been officially analyzed in any study, randomized clinical trials have demonstrated positive effects of the drug on the health and survival of overweight/obese patients suffering from type 2 diabetes mellitus. These conclusions were made on the basis of a decrease in the incidence of diseases of the cardiovascular system and cancer, as well as a decrease in overall mortality. However, in combination with sulfonylurea, metformin increased the risk of diabetes-associated death and mortality from all causes in a mixed group of people with normal body weight, as well as overweight/obese with a diagnosis of type 2 diabetes mellitus. Consistent with these observations, in a recent study by Bannister et al. metformin-treated patients with type 2 diabetes had improved survival compared to the control group, which included specially selected people without diabetes, while patients treated with sulfonylurea had a decrease in survival.

Given the relatively promising results of experiments on rodents, evidence that metformin can suppress the development of cancer and other age-related human pathologies, as well as the relatively harmless safety profile of this drug, there is great interest in the official testing of the ability of this drug to delay age-related diseases in humans. The U.S. Food and Drug Administration (FDA) recently approved the study "The effects of metformin on aging" (Targeting Aging With Metformin, TAME), dedicated to the evaluation of metformin as a drug to slow aging. The TAME project will involve approximately 3,000 people aged 70-80 years who already have one, two or of the following pathologies: cancer, heart disease or cognitive impairment; or are at risk for the development of these pathologies. The study will be conducted in approximately 15 centers in the United States for 5-7 years and it is planned to spend approximately $ 50 million on its implementation. The aim of the study is to determine the ability of metformin to prevent the development of age-related diseases. This key work will be the first study to conduct clinical testing of a potential anti-aging drug.

Continued: Resveratrol and other sirtuin-activating compounds

Portal "Eternal youth" http://vechnayamolodost.ru  08.09.2016