Metformin and Health Span

Metformin was first synthesized in 1922 and has an over 60-year history of use as an anti-diabetic drug for the treatment of type II diabetes.

The development was based on knowledge from folk medicine that the active, but toxic, constituent from Galega officinalis (French lilac) that could treat diabetes.

Many health benefits have been seen in individuals treated with metformin for type II diabetes.

Preclinical studies in animal models have generated conversation about and research into the use of metformin as an anti-aging medication.

Metformin is accepted as a comparatively safe and inexpensive medication.

The most prominent dose dependent side effects of metformin are gastrointestinal-related ,that occur in about 20-30% of individuals and can include abdominal pain, bloating, diarrhea, nausea and vomiting.

Metformin has actions independent of its antihyperglycemic actions that in can possibly slow cellular aging and enhance healthspan and lifespan.

Preclinical and clinical studies support the use of metformin to improve health span.

Metformin may have the ability to prevent diabetes, obesity, cardiovascular disease, cancer and dementia.

Metformin, via its direct protective effects on vascular function, may slow the aging process via improved blood flow and provide protection against age-related cognitive decline.

By lowering plasma glucose levels and body weight, metformin improves the metabolic profiles.

Clinical trials include the 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. Metformin is being investigated further into its ability to reduce early mortality associated with diabetes, cardiovascular disease, cognitive decline and cancer.

Although the evidence for lifespan expansion in mammalian species is not conclusive, a full analysis and follow-up of clinical trials, including MILES and TAME, may provide more definitive answers as to whether metformin should be promoted beyond its use to treat type II diabetes, as a drug that enhances both healthspan and lifespan.

Metformin may improve healthspan thereby extending the period of life spent in good health. Metformin impacts cellular metabolism and result from its anti-hyperglycemic action, enhancing insulin sensitivity, reduction of oxidative stress and protective effects on the endothelium and vascular function.

The anti-diabetic benefits of metformin are due to its hepatic-mediated actions and additional clinical benefits are secondary to its effects on glucose and lipid metabolism. Other sites of action of metformin include the gut, via modulating glucagon-like peptide 1 (GLP-1) levels by a duodenal AMPK-mediated pathway, as well as effects resulting from modulating the microbiota.

Based on a systematic review of 53 studies, it has been concluded that independent of its therapeutic efficacy as an anti-diabetic drug, the use of metformin results in a reduction of all-cause mortality associated with diseases that accelerate aging, including cancer and cardiovascular disease.

Potential clinical benefits of metformin include: repurposing for polycystic ovary syndrome (PCOS), preeclampsia, cancer, rheumatoid arthritis, malaria, and antibiotic and antiviral actions.

Cellular Targets for Metformin

Prior to absorption, metformin modulates the microbiome as well as enhances release of glucagon-like factor 1 (GLP-1).

Metformin moderates the cellular signaling pathways mediated by insulin, IGF-1, and cytokines.

Metformin also, inhibits the inflammatory pathway and increases AMPK activation, which inhibits mTOR, a primary target for cell aging modulation.

Inflammation, apoptosis, autophagy, cell survival, and protein synthesis are all affected by these mechanisms and are all linked to accelerated aging.

Transcriptional Changes

Metformin may induce anti-aging transcriptional changes.

Metformin, via its insulin sensitizing actions reduces insulin and thereby potentially normalize IGF-1 levels. The effects of metformin on IGF-1 are linked to metformin as an activator of AMP-activated kinase (AMPK) and inhibition of signaling through the mTOR pathway. mTOR is a highly conserved serine-threonine kinase that has important roles in the regulation of cell metabolism, including nutrient signaling and growth mediated by IGF-1. Signaling via mTOR is linked to accelerated aging and dysregulation of mTOR signaling is also linked to the progression of cancer, inflammatory and neurological diseases, as well as type II diabetes (T2DM).

AMPK is a key regulator of many cellular pathways that are linked to both healthspan and lifespan, including the benefits of calorie restriction. Thus, as an activator of AMP metformin has prompted interest as a potential anti-aging drug and its potential role as an anti-aging drug promoted.

AMPK functions as an energy sensor that coordinates multiple protective and energy-conserving signaling pathways including the pathways activated by caloric restriction.

AMPK is activated through metabolic stress and acts as a cellular regulator of lipid and glucose metabolism. Hepatic gluconeogenesis is inhibited by AMPK activation, which also enhances insulin sensitivity, muscle glucose absorption, and fatty acid oxidation.

Metformin inhibits the inflammatory response through nuclear factor κB (NFκB) inhibition via pathways involving AMPK.

An increase in the activity of AMPK would also explain the protective effects of metformin on endothelial function.

AMPK inhibits signaling via mTOR and through this action could contribute to the reduced incidence of some cancers that has been associated with the use of metformin.

The genes and cell signaling pathways related to the cell cycle, DNA repair cell death, mitochondria, immunity, nutrient signaling and the growth hormone Insulin Growth Factor-1 (IGF-1) mediated via the PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT (protein kinase B)/mammalian target for rapamycin) pathway have received extensive investigations as targets for anti-aging strategies.

Metformin and Mitochondrial Function

Mitochondria play a critical role in oxidative metabolism and a link has been made in patients between obesity, insulin resistance, and defective mitochondria oxidative processes that results in a buildup of toxic intermediate metabolites.

Metformin may play an important role in the ‘quality-control’ regulation of mitochondria and shift the cellular dynamics to a healthy population via mitophagy and eliminate damaged mitochondria.

AMPK has also been implicated in the regulation of mitochondrial biogenesis, thus providing another link between metformin, AMPK, and improved mitochondrial function.

Mitochondrial function declines with age due either to ROS and/or an accumulation of mutations in mitochondrial DNA.

Metformin may offset the decline in mitochondrial function and thus enhance healthspan and lifespan.

Metformin and the anti-oxidant, resveratrol, inhibit ROS-associated mitochondrial changes. Studies have also reported that resveratrol has anti-aging effects in several species with its effects, as also described for metformin, linked to the deacetylase, sirtuin-1.

Metformin and Autophagy

Autophagy is a process necessary for the removal of damaged proteins and organelles and plays an important role in the regulation of cell aging, providing a supply of nutrients to maintain cellular function during starvation,

Inhibition of autophagy mimics accelerated aging.

Calorie restriction is a strong inducer of autophagy and increases the lifespan in C. elegans.

A link has been reported between SIRT1, AMPK, and metformin-induced autophagy thereby supporting a synergistic relationship between the deacetylase, sirtuin-1, and metformin-mediated effects on aging.

Calorie Restriction and Nutrient Signaling Pathways

Caloric restriction of 10-15% without malnutrition has been suggested to have a role in increasing lifespan in humans. Furthermore, caloric restriction has been found to extend the life span of several organisms including S. cerevisiae (yeast), C. elegans, fish, rodents, and rhesus monkeys. Caloric restriction reduces the generation of growth hormone, insulin, IGF1, and other growth factors, all of which have been shown to hasten aging and increase mortality in a number of species.

A longitudinal study suggested that long-term calorie restriction of 30% significantly reduces age-related deaths in adult rhesus monkeys and a 50% lower incidence of cancer and cardiovascular disease as compared to control animals.

In addition to lifespan extension, caloric restriction also reduces the risk factors for major diseases including diabetes and cardiovascular disease in rodents.

Studies by the Calorie Restriction Society, a group of people who chose to limit their calorie consumption with the intention of extending their life span, included adult men and women (mean BMI, 19.6; mean age, 51 years; age range, 35-82 years) whose diet of nutrient-dense foods, consisted of approximately 1800 kcal/day for an average of 6.5 years and consumed 30% fewer calories than age and sex-matched adults on a standard Western diet. Those on the calorie-restricted diet demonstrated a number of metabolic improvements including body fat, lower blood pressure, and improved insulin sensitivity, and lipid profile. Meta-analysis has also demonstrated that dietary restrictions decreased levels of circulating IGF-1.

Collectively, these observations support the benefits of calorie restriction and heighten the interest in pharmacologic agents, such as metformin, as calorie restriction mimetics.

Calorie Restriction Mimetics

The National Institute on Aging Interventions Testing Program has investigated the effectiveness of a variety of pharmacologic agents, including aspirin, metformin, nordihydroguaiaretic acid (NDGA), and rapamycin to determine whether they prolong lifespan in animal models.

Metformin, like rapamycin, is known to inhibit mTOR signaling, and the inhibition of the mTOR signaling pathway with rapamycin has been shown to extend lifespan in animal models.

The lifespan-extending effects of metformin have been investigated in male mice, and indicate that long-term treatment with 0.1 percent metformin w/w supplemented in the diet and beginning in middle age, increased healthspan and lifespan.

The effects of metformin were reported to be similar to those of calorie restriction, including improved insulin sensitivity and lower cholesterol levels.

Metformin and Mortality in Diabetic Patients

A recent systematic review concluded that metformin significantly lowered all-cause mortality and cardiovascular events in patients with T2DM and mild/moderate chronic kidney disease.

Metformin and Endothelial Function and Cardiovascular Disease

The United Kingdom Prospective Diabetes Study, published in 1998, reported the cardiovascular (CV) benefits of the use of metformin for diabetes.

Retrospective studies have reported reduced cardiovascular morbidity and mortality benefits of metformin. Data have demonstrated that metformin can reduce both mortality and disease-accelerated aging of the cardiovascular system. Based on evidence from both clinical and pre-clinical studies metformin, independent of its anti-hyperglycemic actions, directly protects the endothelium.

AMPK is regulated by two upstream serine threonine AMPK kinases: LKB1, and Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) and is also positively regulated by the nicotinamide adenine dinucleotide (NAD+) deacetylase, sirtuin-1. Sirtuin-1 is the protein product of the putative anti-aging gene SIRT1, which targets lysine residues in proteins, including histones and the tumor-suppressors, LKB1 and p53. In endothelial cells, metformin has been shown to enhance phosphorylation and increase the activity of LKB1. Senescence is a major contributor to aging and the development of cardiovascular disease, and sirtuin-1 expression is required for metformin to protect endothelial cells against hyperglycemia-induced senescence. It has been suggested that metformin could directly activate SIRT1.

The endothelium plays a critical role in the regulation of cardiovascular function and not least as a source of the important signaling molecule, nitric oxide (NO).

Metformin improves endothelium-dependent, but not endothelium-independent vasodilation.

Metformin and a Decreased Incidence of Cancer

Diabetes has been associated with an enhanced risk for the development of various cancers. A retrospective study published in 2005 reported that patients with diabetes who had been treated with metformin for type II diabetes had a lower risk of cancer.

Metformin inhibits the electron transport chain of mitochondrial complex 1, which leads to a reduction in ATP levels, increasing the AMP/ATP ratio, thus increasing AMPK activation and also reduces the generation of reactive oxygen species (ROS).

AMPK activation leads to an inhibition of the mTOR pathway, which would contribute to the antitumor effects of metformin.

Metformin also has been shown to activate AMPK via the serine-threonine liver kinase B1 (LKB1) where phosphorylation (p) (activation) of AMPK occurs. The protein product of SIRT1, sirtuin1, is an upstream deacetylase, which activates LKB1 via deacetylation as indicated in the figure by loss of ac, at times of cellular stress and decreased cellular energy, when NAD+/NADH ratio is high and is also a putative site of action for metformin.

The link between metformin and the activation of AMPK has been emphasized as the basis for the anti-proliferative effects of metformin.

Extensive support for a protective effect of metformin against cancer has been provided by many but not all studies. There are a number of clinical trials investigating metformin and cancer risk.

A logical target whereby metformin could mediate its putative antiproliferative effects in cancer is via inhibition of mTOR and the serine-threonine kinase, ribosomal S6K (pS6K), either via activation of AMPK or via an AMPK-independent pathway. The metabolic changes that occur as a result of diabetes (hyperinsulinemia, hyperglycemia, and dyslipidemia) potentiate signaling pathways and may increase tumorigenesis.

These metabolic pathways, rather than a direct anti-proliferative action, may be the target as metformin decreases hepatic gluconeogenesis, improves insulin sensitivity, reduces insulin and blood glucose levels, and these effects, which also will reduce tumor growth, rather than a direct anti-proliferative action may be the primary target of metformin.

Beneficial effects of metformin are not seen in all cancers further studies are required to determine whether the anti-cancer actions are direct or are secondary to the positive effects of metformin on healthspan that are apparent in obese patients such as improved glucose homeostasis, enhanced insulin sensitivity and reduced signaling through the IGF-1–mTOR pathway.

Of significance and supporting a potential anti-cancer action of metformin is that LKB1 is a tumor suppressor and that mutations in LKB1 are observed in numerous cancers that result in the reduction of the inhibitory effect of the LKB1/AMPK pathway on the pro-proliferative signaling via mTOR. There is a link between metformin, AMPK, LKB1, sirtuin-1, and cellular mechanisms that could enhance both healthspan and lifespan by reducing both cellular senescence and the activation of pro-proliferative pathways.

The Connection Between Metformin and Improved Neurological Function

Diabetes-associated hyperglycemia, hyperinsulinemia, elevated oxidative stress, vascular disease, and inflammation are all linked to cognitive decline and, as reflected by a meta-analysis, it was concluded that metformin reduces cognitive decline and dementia in individuals with type II diabetes (T2DM)

In a large observational study, 67,731 participants, who had no evidence of dementia, were non-diabetic, and aged ≥ 65 were followed from January 2004 to December 2009, to observe the onset of T2DM and compare the risk of the incidence of dementia associated with the use of anti-diabetic drugs and reported that metformin reduced the risk of developing dementia. In another clinical trial, 58 participants who had both depression and T2DM received either metformin or placebo for 24 weeks concluded that metformin improved cognitive performance.

A molecular basis for the effects of metformin on cognitive function is suggested by data using adult murine neural stem cells in culture that shows metformin in the concentration range 500 nM to 1 μM enhanced proliferation and self renewal dependent on the transcription factor, Tap73, and enhanced neuronal differentiation via the AMPK-atypical protein kinase C (aPKC)-CREB-binding protein (CBP) pathway.

Metformin and the Gut

Metformin use in humans will change the microbiome. This action is an important determinant for the anti-hyperglycemic therapeutic effects, the gastrointestinal side effects and possibly the anti-aging effects of metformin. Metformin has a bioavailability of approximately 50% with the unabsorbed drug exiting in the stool. In addition, and also via gut-mediated action, metformin enhances the release of glucagon-like peptide-1 (GLP-1). It is the release of GLP-1 that contributes substantially to the antihyperglycemic effects of metformin.

Clinical Trials to Assess Effects of Metformin on Aging, Healthspan, and Lifespan

Designed as a crossover study, the Metformin in Longevity Study (MILES) is a double-blinded study where the subjects act as their own placebo control group MILES (https://clinicaltrials.gov/ct2/show/NCT02432287) commenced October 2014 and was conducted on 14 elderly participants with impaired glucose tolerance to determine whether metformin (1700 mg/day) can cause physiological and transcriptomic changes in muscle and adipose tissues after 6 weeks of treatment and also to determine which pathways are affected by metformin and outline possible molecular intermediates involved in metformin’s mechanism of action. Data from the MILES trial indicate that metformin modified multiple pathways associated with aging including metabolic pathways, collagen trimerization and extracellular matrix (ECM) remodeling, adipose tissue and fatty acid metabolism, mitochondria, and the MutS genes, MSH2 and MSH3, which play a role in DNA mismatch repair, a process that declines with age.

Dysregulation of adipose tissue metabolism has been previously linked to an age‐related process of ECM deposition and the effects of metformin on fatty acid metabolism have been previously shown to mimic those of other interventions that increase lifespan in model organisms. The results of the MILES study underscore metformin’s targeting of multiple mechanisms of aging.

Targeting Aging with Metformin (TAME) trial is a double-blinded, placebo-controlled, multicenter trial that is planned to involve 14 research centers in the USA, and subject to funding and approval, will enroll 3000 ethnically diverse, non-diabetic subjects aged 65–80. The objectives of TAME are: 1. Clinical outcomes as measured by the appearance of new age-related chronic diseases; 2. Functional outcomes such as changes in mobility as well as measures of cognitive impairment; 3. Biomarkers of aging such as for inflammation and senescence. The study plan for TAME is that patients will be given a daily dose of metformin (1500 mg) for 6 years, with an estimated follow-up period of more than 3.5 years. The TAME trial outcomes will give more insight on whether metformin decreases the risk of developing age-dependent diseases, excluding diabetes, in non-diabetic individuals, and potentially provide a tool to target aging itself and not related diseases individually.