Metformin is an FDA-approved synthetic biguanide widely used for its anti-hyperglycemic effects as first-line treatment for diabetes mellitus type 2. It is the most preferred anti-hyperglycemic drug due to its safety, low cost, ability to reduce blood glucose levels and restore insulin sensitivity in diabetic patients. So in simpler terms, Metformin is a great drug to lower the sugar levels in your blood if you have type 2 diabetes.
Although for over 60 years Metformin has been widely known for its hypoglycemic properties, many studies have been designed to look into its non-anti-diabetic effects and amazing results have been achieved suggesting that Metformin could be the answer to the question of how can we delay the aging process.
Mechanism of action of Metformin
Metformin regulates blood glucose levels by inhibiting the production of glucose in the liver, by decreasing absorption of glucose in the intestines and also by promoting insulin sensitivity by facilitating glucose intake into the various types of cells and its ultimate utilization.
Metformin works by stimulating and inhibiting different pathways, but the most remarkable effect is Metformin’s ability to activate a pathway that is responsible for both hypoglycemic and non-hypoglycemic effects of Metformin called the AMPK pathway, the short form for AMP-Protein Kinase pathway. Metformin does this by inhibiting complex 1 of the mitochondrial respiratory chain which in turn prevents mitochondrial ATP production and thus leads to an activation of AMPK. Activated AMPK is a metabolic regulator that favors the fat and sugar burning in our bodies. It plays a role in the regulation of glucose and ATP metabolism. This pathway also reduces the effects of chronic inflammation and oxidative stress in our bodies while improving the rate of elimination of damaged cells in our body, cells which when not effectively removed can be a huge risk factor for cancer and autoimmune disorders.
Metformin inhibits one of the nutritional sensing pathways called mTOR pathway, which regulates growth in animals and controls most anabolic and catabolic processes in response to nutrients and nutrient-induced signals, like insulin.
Is Metformin an anti-aging drug?
Before we even dwell on whether Metformin is an anti-aging drug, we first have to understand the definition of an anti-aging drug. An anti-aging drug is any drug that has the potential or the ability to prevent and/or treat diseases that are related to aging such as cancer, cardiovascular diseases and neurodegenerative disorders thereby positively affecting the healthspan (the period of life spent in good health and free of these disabling diseases) of an individual. A simple way of answering the question above is by saying that only time will tell, but a complex answer would be: “Yes, in animal models it definitely seems to be an anti-aging drug, in people taking it to treat type 2 diabetes, it shows some non-hypoglycemic effects that may prolong their life span but a considerable amount of scientific research still has to be done to see how effective it is in delaying aging in non-diabetic patients”.
So how does metformin help delay aging?
Metformin’s target signaling pathways associated with anti-aging benefits have been extensively investigated over the past years. These pathways mainly include AMPK and mTOR pathways and their associations with cell cycle, immunity, nutrient signaling, mitochondria and DNA repair. The main aim of some investigations is to establish how Metformin acts on these pathways to exert its anti-aging effects.
Metformin is said to reduce the incidence of age-related diseases like dementia, Alzheimer’s, cancer, and it also reduces the risk of cardiovascular events. How it does this, is the main question in the minds of many researchers.
The well-known mechanism of Metformin on insulin sensitivity is the one that normalizes insulin growth factor levels which also leads to the activation of AMPK and inhibition of mTOR pathway. Activation of AMPK has hypoglycemic effects and inhibition of mTOR pathway prevents progression of cancer, diabetes mellitus type 2, neurological and inflammatory diseases.
The dilemma may be how effective are other means of prolongation of a life span compared to Metformin’s anti-aging properties. Several mechanisms have been shown to delay the process of aging, which in turn results in improved healthspan in animal models, including mammals. These include caloric restriction, alteration in GH/IGF1 pathways, as well as the use of several drugs such as Resveratrol (SIRT1 activator) and Rapamycin (mTOR inhibitor).
Now let us look at individual effects of Metformin on diseases related to aging.
Diabetes mellitus type 2 is a metabolic disorder and also a type of age-related disease. Metformin reduces levels of glycated hemoglobin, facilitates weight reduction and prevents diabetes in pre-diabetic patients. Other well-known effects are that Metformin decreases blood glucose levels and increases insulin sensitivity to upregulate its intake by cells.
Cardiovascular diseases are the main leading cause of death worldwide and the main risk factor predisposing to cardiovascular diseases is age. It has been said that Metformin can reduce mortality and diseases that accelerate the aging of the cardiovascular system.
The cardiovascular effects of Metformin were published based on the United Kingdom’s prospective diabetes study in 1998. It was reported that Metformin promotes myocardial preconditioning, alters the metabolism of cardiomyocytes and reduces apoptosis of cardiac cells during ischemic events like heart attack. Metformin has also been reported to protect the endothelial layer of the blood vessels from the burden of atherosclerosis by lowering LDL-cholesterol and triglycerides.
As mentioned already, inhibition of mTOR pathway plays a role in the prevention of certain cancers by stimulating the increase in AMP which then leads to reduced tumor growth. Metformin also decreases levels of circulating insulin and many cancer cells express insulin receptors on their surfaces. Insulin receptors on cancer cells stimulate a pathway that is responsible for cellular proliferation (PI3K pathway). So a decrease in insulin levels reduces PI3K pathway activation and thus inhibits tumor growth. There is also a direct relationship between AMPK pathway activation and cancer. Its activation blocks the expression of cancer-promoting genes and thus inhibiting tumor growth.
The neuroprotective effects of Metformin have been reported due to its ability to increase neurotrophic derived factors from the brain and glial cells which in turn alleviates symptoms associated with Parkinsons. An increase in the neurotrophic factors also leads to protection of mitochondria, reduction of inflammation and the preservation of neurons. Metformin has also been said to improve cognitive function in Alzheimer’s patients but the mechanism behind this is still not well understood.
So, does Metformin increase lifespan?
Pre-clinical data studies which have been designed on different animals prompted investigations into whether Metformin has therapeutic utility as an anti-aging drug that may also extend life span and it was found that Metformin decreases the incidence of age-related diseases as mentioned above and this improves longevity.
Clinical trials like MILES (Metformin in Longevity Study) and TAME (Targeting Aging with Metformin) have been designed to assess the potential benefits of Metformin as an anti-aging drug. However regardless of evidence supporting the anti-aging benefits of Metformin, the fact that it increases lifespan is controversial, but we can say it improves healthspan by extending the period of life without disabling age-related diseases like diabetes, cancer, neurodegenerative disorders and cardiovascular diseases.
AMPK is a key regulator of many cellular pathways linked to healthspan and lifespan, and its sensitivity declines with aging thus promoting activation of AMPK delays aging, improves life span and healthspan. Based on many reviews done on the studies that looked at the effects of Metformin on aging we can conclude or give a report that Metformin improves the health span of individuals and not necessarily the lifespan of individuals - meaning that it improves the number of years that a person spends in good health.
Dosage for anti-aging
A dose of 250 mg to 850 mg twice a day with meals is recommended for anti-aging purposes. For healthy non-diabetic patients dosage of 500mg twice a day is recommended but its long-term effects in healthy patients are not well known yet. It is important to keep in mind that Metformin has not been FDA approved yet as an anti-aging drug.
In a nutshell, Metformin currently shows promising effects against factors that promote aging, such as decreased methylation, insulin insensitivity, cardiovascular diseases in obese patients and chronic inflammatory and oxidative stress. So with this said, Metformin is seen to be having an indirect effect on the aging process and the reason this is like this is because the FDA still hasn’t recognized aging as a single disease or a direct indication for treatment. This unfortunately has made studies for the isolated anti-aging effects of Metformin in non-diabetic human models to be challenging, even though they have been extensively studied on animal models.
(Article by Dr. Thiago Freire, Nthinya Mankokomohi Mafusi Valentia, and Matsunyane Serame Simon).
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