Metformin is an Anti-Aging Drug

Metformin and Metabolism

Before discussing the role of metformin (trade name: Glucophage) as an anti-aging drug it is useful to review its effects on overall glucose homeostasis which justify its use an a drug to treat the persistent hyperglycemia associated with type 2 diabetes. Indeed, metformin (trade name: Glucophage) is one of the most widely prescribed drugs for the treatment of the chronic hyperglycemia associated with type 2 diabetes.

Metformin is a drug in the biguanide class. The biguanides function to lower serum glucose levels by enhancing insulin-mediated suppression of hepatic glucose production (gluconeogenesis and glycogen breakdown) and enhancing insulin-stimulated glucose uptake by skeletal muscle.

Metformin administration does not lead to increased insulin release from the pancreas and as such the risk of hypoglycemia is minimal. Because the major site of action for metformin is the liver its use can be contraindicated in patients with liver dysfunction. The drug is ideal for obese patients and for younger type 2 diabetics.

Evidence on the mode of action of metformin shows that it improves insulin sensitivity by increasing insulin receptor tyrosine kinase activity and enhancing glycogen synthesis in hepatocytes, and by increasing recruitment and transport of the GLUT4 glucose transporters to the plasma membrane in adipose tissue. Additionally, it has been shown that metformin affects mitochondrial activities dependent upon the model system studied. Metformin exerts an inhibitory effect on complex I (most commonly called NADH dehydrogenase but also known as NADH:CoQ oxidoreductase or NADH-ubiquinone oxidoreductase) of oxidative phosphorylation, has antioxidant properties, and activates both glucose-6-phosphate dehydrogenase (G6PD; also identified as G6PDH) and AMP-activated protein kinase (AMPK). The inhibition of mitochondrial oxidative phosphorylation results in numerous downstream effects that alter the metabolic and non-metabolic processes of aging.

The importance of AMPK in the actions of metformin stems from the role of AMPK in the regulation of both lipid and carbohydrate metabolism. In adipose tissue, metformin inhibits lipolysis while enhancing re-esterification of fatty acids to be stored as treiglycerides.

The activation of AMPK by metformin occurs, in part, through the inhibitory effects of the drug on complex I of oxidative phosphorylation. This would lead to a reduction in ATP production and, therefore, an increase in the level of AMP and as a result activation of AMPK. In fact, since the cells of the gut will see the highest doses of metformin they will experience the greatest level of inhibited complex I which may explain the gastrointestinal side effects (nausea, diarrhea, anorexia) of the drug that limit its utility in many patients.

Recent research has demonstrated that metformin directly activates AMPK in both a dose- and time-dependent manner which in turn inhibits the mechanistic target of rapamycin complex 1 (mTORC1). The mTORC1 is a key regulator of protein synthesis, cellular responses to energy depletion, and control of autophagy (the normal process by which cells break down and destroy old, damaged, or abnormal proteins and other substances present in the cytoplasmic compartment (essentially the liquid, non-organelle compartment of cells).

Within hepatocytes the metformin-mediated activation of AMPK results in suppression of both glycogenolysis and gluconeogenesis, effects that limit glucose output by the liver. These effects of AMPK are, in part, due to the phosphorylation and activation of the enzyme (a phosphodiesterase) that degrades an activator (cyclic AMP, cAMP) of the kinase known as cAMP-dependent protein kinase (PKA). When PKA is activated it will phosphorylate and activate phosphorylase kinase (encoded by the PHK gene). Phosphorylase kinase predominantly phosphorylates and activates glycogen phosphorylase, the enzyme responsible for removal of glucose from glycogen. In addition, phosphorylase kinase is one of the enzymes that phosphorylates and inhibits glycogen synthase. Therefore, at the level of hepatic glycogen homeostasis, metformin promotes glucose storage in glycogen and reduces glucose release from glycogen.

Other key substrates for PKA that regulate hepatic glucose homeostasis include PFK-2 and pyruvate kinase (PK). Phosphorylation of PFK-2 by PKA results in the stimulation of gluconeogenesis while phosphorylation of PK by PKA results in inhibition of glycolysis. Thus, at the level of overall glucose homeostasis the AMPK-mediated activation of phosphodiesterase will counter all of the cAMP-PKA-mediated effects in hepatocytes that are stimulated by the pancreatic hormone, glucagon, as well as those exerted by the stress hormone, epinephrine.

In addition to its effects on hepatic glucose and lipid homeostasis and adipose tissue lipid homeostasis, metformin exerts effects in the pancreas, vascular endothelial cells, and in cancer cells. The latter effects of metformin were recognized in epidemiological studies of diabetic patients taking metformin versus those who were taking another anti-hyperglycemia drug.

Metformin as an Anti-Aging Drug

Excellent review on the role of metformin as an anti-aging drug can be found in the journal, Cell Metabolism:

Benefits of Metformin in Attenuating the Hallmarks of Aging

One major anti-aging process that is activated by metformin centers on its effects on the activity of AMPK. AMPK exerts numerous metabolic effects within cells. Indeed, AMPK is considered a master metabolic regulator that limits energy consumption and promotes energy storage. Activation of AMPK suppresses the formation of advanced-glycation end products (AGE) such as hemoglobin A1c (HbA1c) that are known to stimulate the production of inflammatory cytokines, proteins that stimulate inflammation. Inflammation within the vasculature is known to directly contribute to cardiovascular diseases such as atherosclerosis (vessel plaque formation) a significant contributor to aging processes in the vascular system.

Within the liver metformin also suppresses inflammatory processes of aging. These include suppression of the release of inflammatory cytokines such as TNFα, IL-1β, and IL-6. These anti-inflammatory effect, coupled with reduced release of glucose dramatically contribute to reductions in age-related processes that occur within the vasculature.

Within the gastrointestinal system metformin exerts effects that lower age-related alterations in gut bacteria (microbiota). During aging the changes in gut microbiota promote inflammation, gut permeability, and pro-inflammatory cytokine release. Healthy gut bacteria are known to be associated with optimal healthy immune function within the gastrointestinal system. The glucose regulatory properties exerted by metformin result in increased levels of "good" (healthy) gut bacteria such as strains of Lactobacilli and Bacteroides.

Overall, the metabolic effects exerted by metformin reduce the aging process by numerous interacting pathways well beyond the scope of metabolism and inflammation. Metformin action decreases age-related mitochondrial dysfunction, cellular senescence (the process of cellular deterioration associated aging), genomic instability and telomere loss (telomeres are the specialized nucleic acid sequences at the ends of all the chromosomes), stem cell exhaustion, and epigenetic changes. Epigenetics refers to the processes of gene expression control that do not involve changes to the actual DNA sequences of genes.