Metformin is here again

Among the many hypoglycemic drugs, metformin has been tested for more than 50 years and is the second-generation “star” in hypoglycemic drugs, the first choice for the treatment of “type 2 diabetes” and the entire course, and the first choice for combined treatment of type 2 diabetes. In this way, after the US FDA approved it to be marketed in 1994, it has gradually improved, and new effects will be discovered by researchers every once in a while. At present, metformin has been found to have more than 20 effects. In addition to lowering blood sugar, there are anti-cancer, anti-aging, weight loss, promote hair growth, assist in smoking cessation, cardiovascular protection, and reverse pulmonary fibrosis. In China, the overall scale of metformin medication in 2018 exceeded 5 billion yuan, which is an out-and-out large variety of medicine.
However, in the elderly Caenorhabditis elegans, the loss of metabolic plasticity is the basis of metformin toxicity. It was found that in nematodes and human primary cells, when metformin is provided later in its life, metformin shortens the life span, which is similar to metformin. The positive effect of acid in young organisms is opposite.

In nematodes and human primary cells, when metformin is provided late in their lifespan, metformin prolongs lifespan, which is contrary to the positive effect of metformin in young organisms.

In order to further develop the efficacy of metformin, current clinical trials are exploring the life-prolonging effect of metformin in healthy individuals without diabetes. However, the metabolic response to metformin in non-diabetic people has not been studied. In the article, researchers in C. elegans and human primary cells showed that when metformin is used in the later stages of life, it will be accompanied by positive effects in young organisms and shorten lifespan. We found that dimethyl double blends aggravated mitochondrial dysfunction associated with aging, leading to respiratory failure. The failure of glycolysis is similar to the unfortunate failure of mobilization to activate dietary restriction, and the boots cause deadly ATP failure in senile nematodes treated with dimethyl dinucleotide and advanced human cells. The toxicity of metformin is alleviated in worms with interrupted receptor signaling. These worms, in short, our data indicate that metformin can cause harmful changes in the conservative metabolic pathways in old age, and this fact may make it possible for metformin to let The benefit of the elderly without diabetes is a big question mark.

The author’s research shows that the treatment of dimethyl dioxin in later life can cause metabolic failure, and ultimately lead to fatal ATP reduction and cell death. Mitochondrial dysfunction and mitochondrial volume reduction associated with aging are the main causes of metformin toxicity. The study also found that similar protective mechanisms exist in aging animal models and cell mitochondria. Through genetic manipulation, direct ATP supplementation or co-treatment with rapamycin in the body, stabilize the ATP content in old animals and cells, thereby bringing similar protective effects. The adverse effects of metformin on respiration will be exacerbated by the lack of adaptive up-regulation of glycolysis and metabolic disorders in aging mitochondria. In addition to the loss of metabolic plasticity, elderly animals also exhibited metformin-induced deterioration of longevity guarantees, and this damage caused a complete reversal of metformin’s ability to survive.
At the same time, the authors should observe that the toxicity of metformin will be delayed by the insulin receptor mutations caused by diabetes-like DAF-16/FOXO. Between nematodes and humans, there was a negative correlation between FOXO transcription factor activity and the signal, and enhanced FOXO activity was detected in diabetic mice. Moreover, the consequences of increased FOXO activity in diabetes are not fully understood, but the gene expression program induced by FOXO is comparable between different types. Researchers believe that it is very likely that FOXO protection will need to be further studied in mammals and humans. Individuals who overcome resistance are indeed not susceptible to the toxicity of metformin.

The metabolic effects of metformin in certain age groups may limit its treatment complications in elderly people who do not have diabetes

In general, the metabolic effects of metformin in certain age groups may limit its treatment complications in elderly people without diabetes. In fact, there have been some recent studies and reports in mice and humans that there will be observations related to the reversal of dimethyl double-strand free radicals, and the effects of dimethyl double-strand exposure on microscopic adaptation, exercise and cognitive abilities . The research in this article focuses on the detailed molecular mechanism of action.
Through this study, the researchers remind everyone that it is not advisable to take metformin blindly in order to prolong life. Obviously, more research is needed to determine the feasibility of providing metformin to people without diabetes.
references:
Lake Espada, Dakovnik, A. Chowdhury, sports etc. The loss of metabolic plasticity is the basis of metformin toxicity in senile C. elegans. Nat Metab (2020).https://doi.org/10.1038/s42255-020-00307-1