With the aging of the global population, many age-related chronic diseases have become the first cause of death. At present, many foods, drugs and gene therapy can prolong life. These interventions involve a core network of nutrition receptors, namely, AMPK. The current research shows that metformin may be the first cause of death and metformin activates the same signal path as the heat limitation and produces some independent effects. Let's look at how does Metformin HCL to prolong life?
1. Activate AMPK
AMPK is a serine / threonine protein kinase that related to energy metabolism, which is an essential function to maintain cell energy level in all eukaryotes. AMPK can be activated by increased intracellular amp. ATP ratio caused by metabolic stress, disruption of ATP production or acceleration of ATP consumption. The biochemical activity of AMPK is regulated by upstream kinase and phosphatase. When the total energy level in the cell decreases, AMPK is activated by phosphorylation of upstream kinase and AMP and ADP. The activated AMPK regulates the energy synthesis process that consumes ATP and up regulates the catabolism process that produces ATP. AMPK can directly inhibit the catalytic activity of many enzymes through phosphorylation. Metformin HCL can activate AMPK pathway to enhance glycolysis, fatty acid oxidation ,mitochondrial biosynthesis and activate autophagy.
2. Metformin HCL inhibits MTO
MTOR is an immunosuppressant with antitumor activity. It can block mTOR in yeast, worms, flies and mice to prolong life. Blocking mTOR signaling in mice and humans can improve age-related diseases, such as cognitive decline, cancer and so on. Metformin HCL can inhibit mTOR by activating AMPK. Metformin can also inhibit the activation of transcription co activator (TORC1) in a way independent of AMPK. One lung cancer study showed that metformin inhibited mTOR by a pathway independent of AMPK. Metformin can prevent cell aging and prolong life by inhibiting mTOR.
3. Regulation the growth factor of insulin-like
Experimental studies on mammalian animals show that hyperglycemia and hyperinsulinemia are important factors of aging. Metformin is a clinical drug for diabetes, but it involves many aging related mechanisms, some of which are related to glucose metabolism. Metformin HCL can reduce insulin level, reduce insulin-like growth factor-1 signal level, and prolong life.
4. Reduce the production of ROS
Another mechanism of metformin HCL prolonging life span may be to reduce the production of ROS. Metformin reduces the number of transferred electrons and the production of ROS by inhibiting electron transfer chain complex to reduce the number of transferred electrons and prevent electron transfer. Metformin HCL could reduce the endogenous ROS induced by paraquat, but not the exogenous ROS induced by hydrogen peroxide. The basic action site of Metformin HCL activity is respiratory chain complex 1, which can inhibit oxidative phosphorylation.
5. Regulated sirts expression
SIRT pathway was first regulated by regulated sirts expression. It was found that a variety of sirts can regulate the function of mitochondria and affect the life span. SIRT family is a kind of NAD( + ) dependent enzymes, which plays an important role in the protection of age-related diseases. SIRT 2 plays an important role in metabolism and aging. Mutations of sirt2, SIRT3 and sirt4 genes in yeast indirectly lead to DNA mutation and shorten the life of yeast.
In conclusion, the existing studies preliminarily show that metformin can activate AMPK, inhibit mTOR and its downstream related molecules to play its anti-inflammatory, cardiovascular disease protection, anti-tumor and anti-aging role through the way related to heat restriction, which makes metformin a promising anti-aging drug.