Metformin suggest an improvement to this article

Metformin is a drug commonly used to treat type 2 diabetes. It is the fourth most commonly prescribed medication in the United States, with more than 80 million prescriptions for the drug written yearly. Metformin is in a class of drugs called biguanides, which act by decreasing liver gluconeogenesis (the production of glucose in the liver), decreasing glucose uptake in the gut, and increasing overall glucose utilization by improving insulin sensitivity in skeletal muscle and fat tissue. Multiple studies demonstrate that metformin decreases fasting blood glucose levels by as much as 3.9 mmol/L, corresponding to a nearly 2 percent decrease in HbA1c (a measure of long-term blood glucose control).[1] Metformin is typically used in combination therapy that includes dietary modification and other anti-diabetes drugs. Brand names of metformin sold in the United States include Glucophage, Glucophage XR, Fortamet, and Glumetza.

In recent decades, extensive research has focused on characterizing the pathophysiology of aging and identifying strategies to prevent or delay the onset of age-related disease. A growing body of evidence indicates that metformin modulates the aging processes to improve healthspan and extend lifespan.

Metformin modulates the biology of aging

Aging, the progressive accumulation of damage that occurs to an organism over time, eventually leads to disease and death. High blood glucose and insulin levels and the signaling pathways they regulate play critical roles in aging and age-related diseases. Turning down the activity of these pathways improves lifespan in multiple organisms, including worms, fruit flies, and mice. The anti-aging properties of metformin appear to extend beyond glucose and insulin signaling pathways, however, to address the major hallmarks of disease and aging, including inflammation, altered cell signaling, mitochondrial dysfunction, epigenetic modification, telomere loss, genomic instability, and cellular senescence.[2]

Metformin's physiological and antiaging effects closely resemble those associated with caloric restriction, the practice of long-term restriction of dietary intake, typically characterized by a 20 to 50 percent reduction in energy intake below habitual levels. Caloric restriction extends lifespan and delays the onset of age-related chronic diseases in a variety of species, including rats, mice, fish, insects, worms, and yeast.[3] It alters the expression of a vast array of genes involved in metabolism, circadian rhythm, immune response, and others.[4] Interestingly, several studies indicate that metformin elicits similar gene expression profiles.[5]

Learn more about caloric restriction in this overview article.

Metformin's mechanisms and targets

The mechanisms by which metformin exerts its effects are not fully understood, but evidence suggests that pathways involved in cellular energy and antioxidant response may be responsible for the drug's actions.

AMPK activation and mitochondrial inhibition

Metformin activates adenosine monophosphate-activated protein kinase, or AMPK, an enzyme that serves as a master regulator of cellular energy homeostasis. Several in vitro studies in both human and animal cell lines indicate that AMPK activation is triggered when metformin alters aspects of mitochondrial performance via inhibition of complex 1 of the electron transport chain.[6][7][8][9][10] An in vivo study in which healthy and diabetic rats were treated with increasing doses of metformin (30, 100, or 300 milligrams per kilogram of bodyweight, mg/kg/bw) per day for two weeks found that at higher doses (100 mg/kg/bw and 300 mg/kg/bw) metformin decreased mitochondrial oxidative capacity by 21 percent and 48 percent, respectively, due to decreased activity of complex 1.[11]

Inhibition of complex 1 reduces the cellular AMP/ATP ratio, promoting glycolysis (the breakdown of glucose in the cytoplasm). This inhibition of mitochondrial metabolism may allow the mitochondria to "rest," thereby accumulating less oxidative damage. Some studies have demonstrated that metformin does not inhibit complex 1, however, highlighting issues regarding dose as well as study design and methodology.[12][13][14]

AMPK activation also influences gene expression. For example, one study in rats demonstrated that long-term activation of AMPK promoted muscle gene expression that mimicked that observed with endurance exercise training.[15]

Inhibition of mTOR

Metformin inhibits the mechanistic target of rapamycin, or mTOR.[16] mTOR is an enzyme that serves as a central regulator of mammalian metabolism and physiology. The mTOR network is a highly conserved signaling pathway that serves as a "hub," integrating input from the cellular environment about nutrient, oxygen, and energy levels, ultimately driving fundamental cellular responses such as growth, proliferation, apoptosis, and inflammation. Inhibition of mTOR via AMPK activation prevents chemical changes (the addition of a phosphate group, called phosphorylation) to various proteins downstream in the mTOR pathway. Metformin also inhibits mTOR via mechanisms that are independent of AMPK, however.[17][18][19]

Metformin elicits mixed effects on healthspan and longevity in multiple organisms

Metformin improves lifespan in worms

When a 50 millimolar (mM) dose of metformin was given to worms, their median lifespan increased by 40 percent.[20] This increase was driven by AMPK-related signaling and the transcription factor SKN-1, and it occurred on a magnitude similar to that observed when worms' diets are calorie-restricted. No improvements in lifespan were observed with lower (10 mM) or higher (100 mM) doses. In addition, the worms that received the intermediate (50 mM) dose also exhibited improvements in their locomotor activities. This finding was noteworthy because as worms age they exhibit muscle deterioration and subsequent poor locomotor activity similar to that observed with age-related sarcopenia (muscle loss) in humans.

Another study in worms demonstrated similar dose-dependent changes in mean lifespan with metformin. At doses of 25, 50, and 100 mM, the worms' mean lifespan increased by 18, 36, and 3 percent, respectively.[21]

Metformin does not improve lifespan in fruit flies

The lifespan-enhancing effects of metformin do not appear to extend to fruit flies, however. When adult fruit flies were fed increasing concentrations of metformin (0, 5, 10, 25, 50, and 100 mM) for seven days, they exhibited increased AMPK activity and lowered fat stores, but their lifespan was unchanged. At high concentrations, the drug was actually toxic to the flies.[22]

Metformin has variable effects on lifespan in rodents

When female mice were given 100 mg/kg/bw of metformin in their drinking water, they experienced improved metabolic markers, longer fertility, and 4 to 8 percent longer average lifespan than control mice. The average lifespan of the last 10 percent of surviving mice increased by 13 percent, and the overall maximum lifespan of the mice increased by one month.[23] In a similar study, long-term administration of metformin (100 mg/kg/bw) in the drinking water of female mice increased the average lifespan by 37.8 percent. The average lifespan of the last 10 percent of surviving mice was extended by nearly 21 percent, and the overall maximum lifespan of the mice was extended by 2.8 months – more than 10 percent – compared to control mice.

The age of initiation of treatment influenced the efficacy of metformin (100 mg/kg/bw) among female mice starting at the ages of 3, 9, or 15 months. Among mice started at 3 months, lifespan was increased by 14 percent, but among mice started at 9 months, lifespan increased by only 6 percent. When metformin was started at 15 months of age, no improvements in lifespan were observed.[24]

Some evidence suggests that metformin demonstrates sex-specific differences in mice. When male and female mice were administered metformin (100 mg/kg/bw) in drinking water, the average lifespan of the male mice decreased by 13.4 percent and the average lifespan of the female mice increased by 4.4 percent.[25]

Similarly, when male mice were given a 0.1 percent or 1 percent dose of metformin in their diets starting at the age of 54 weeks, the average lifespan of the mice treated with the lower dose was increased by 5.83 percent, compared to control mice. The higher dose was toxic, however, and reduced the average lifespan of the mice by 14.4 percent.[5] In a mouse model of Huntington's disease, 2 milligrams per milliliter of metformin in drinking water improved lifespan by 20 percent in male (but not female) mice. The mice also exhibited less hind-limb clasping, a marker of neurological damage.[26]

It is important to note that the methods used in these studies varied according to strain and sex of mouse used, time of initiation of the drug, and length of exposure.

Metformin modulates risk of age-related diseases in humans

Observational and clinical studies in humans suggest that metformin slows age-related cognitive decline, reduces the risk of cancer, and may reduce mortality among people who have type 2 diabetes.

Cognitive decline & mental health

Some evidence suggests that metformin may prevent cognitive losses or improve mental health status. For example, findings from a large, population-based study of 365 adults with diabetes who were 55 years of age and older demonstrated that those who took metformin were 51 percent less likely to experience cognitive impairment, even when considering vascular and non-vascular risk factors. The lowest risk was observed in those who had been taking metformin for longer than six years.[27] A similar study in which more than 67,000 people with diabetes were followed for five years demonstrated that metformin use was associated with lower rates of dementia compared to those who used other diabetes medications.[28] In one small clinical trial in which 58 adults who had both depression and type 2 diabetes were given either metformin or a placebo for 24 weeks, those who received the metformin demonstrated improved cognitive performance and reduced depressive symptoms.[29]

Cancer

Findings from many large, population-based studies involving several thousands of adults with type 2 diabetes indicate that metformin use is associated with reduced risk of developing or dying from several types of cancer, including those of the liver, pancreas, and colon.[30][31][32][33][34] In addition, a meta-analysis of 47 studies found that metformin use reduced overall cancer incidence by 31 percent and cancer death by 34 percent.[35] Mechanistic studies in rodent models and human cancer cell lines suggest that metformin's anti-cancer properties may be related to the drug's capacity to reduce insulin levels, improve insulin sensitivity, decrease IGF-1 signaling, and activate AMPK.[36][37][38][36][39][40][41]

Mortality among people with type 2 diabetes

The global prevalence of type 2 diabetes in adults is 8.5 percent. The two most common first-line treatments for diabetes are metformin or a class of drugs known as sulphonylureas. Taking a sulphonylurea is associated with an increased risk of cardiovascular-related complications and death. A retrospective observational study investigated this relationship. The study involved approximately 78,000 people with diabetes who were treated with metformin, 12,000 people with diabetes who were treated with a sulphonylurea, and 90,000 people without diabetes who took neither drug. Survival rates among people with diabetes who took metformin were 38 percent longer than among those who took sulphonylurea and 15 percent longer than those who did not have diabetes and took neither drug.[42]

Metformin may inhibit exercise-induced benefits

Metformin is not as effective as exercise in reducing the risk of developing diabetes, and it appears to counter some of the health benefits associated with exercise.

A large, randomized controlled trial conducted by the United States Diabetes Prevention Program compared the effectiveness of exercise versus metformin use in preventing the progression of prediabetes to type 2 diabetes. The study involved more than 3,200 healthy adults with elevated fasting blood glucose levels who were randomized to engage in 150 minutes of physical activity per week, take metformin (850 milligrams, twice daily), or take a placebo. Findings from the study demonstrated that engaging in 150 minutes of moderate-intensity exercise per week prevented the progression from prediabetes to type 2 diabetes by 58 percent whereas metformin prevented it by 31 percent, compared to placebo. These data suggest that exercise is roughly twice as effective as metformin in preventing the progression from prediabetes to type 2 diabetes.[43]

In a recent double-blind placebo-controlled trial involving 27 healthy older adults (average age, 62 years) with at least one risk factor for diabetes, each of the study participants engaged in three 45-minute aerobic exercise training sessions per week for 12 weeks using a treadmill, stationary cycle, or elliptical machine. In addition, each participant took either metformin or a placebo daily. The metformin dose was titrated over a four-week period, starting with 500 milligrams per day the first week and increasing by 500 milligrams each week until reaching 2,000 milligrams per day (1,000 milligrams twice daily) by the fourth week. Participants weighing less than 75 kilograms (165 lbs) took a maximum dose of 1,500 milligrams daily. Findings from the study demonstrated that metformin inhibited mitochondrial adaptations and improvements in cardiorespiratory fitness by 50 percent and diminished whole-body insulin sensitivity after aerobic exercise. Metformin did not diminish improvements in HbA1c, fasting insulin, blood glucose, fat mass, or skeletal muscle telomere length, however.[44]

Resistance training is the most effective means to increase muscle mass, fiber size, and strength. Muscle mass is directly related to mobility, frailty, and mortality. A randomized, double‐blind trial investigated whether metformin improved muscle response to resistance training in healthy adults (age 65 and older). Each of the study participants engaged in regular, supervised, progressive resistance training for 14 weeks and took either a placebo or 1,700 milligrams of metformin daily. Participants who took metformin gained less lean body mass and thigh muscle mass than those who took the placebo. The blunting effect of metformin on exercise-induced hypertrophy could be a consequence of mTOR inhibition. Muscle biopsies from participants given metformin showed lower levels of biomarkers that are activated by mTOR. Gains in strength were diminished with metformin use as well, but the findings were not significant.[45]

Metformin safety

Although metformin has an excellent safety profile, some mild side effects – primarily affecting the gut – have been observed with its use, including diarrhea, gas, and abdominal discomfort. Metformin is contraindicated in approximately five percent of people, however, due to severe gut-related effects. In addition, metformin interferes with gut absorption of vitamin B12 in about 30 percent of people, but the effects are mild and rarely lead to clinical deficiency.[46]

The greatest risk associated with metformin use is lactic acidosis, a life-threatening condition in which blood lactate levels rise, causing an imbalance in the body's pH levels. Lactic acidosis due to metformin use is extremely rare and is typically observed in people who have heart failure, poor kidney or lung function, or advanced age (greater than 80 years).[47][48]

Metformin bioavailability and dosing

Metformin has been described as a high dose, low potency, modest net efficacy drug.[7] At oral doses of 500 to 1,500 milligrams, metformin is 50 to 60 percent bioavailable.[49] It is readily taken up in the gut (which may contribute to the gut-related side effects) and excreted intact in the urine via the kidneys.[50][51] People with poor kidney function should not take metformin.[52]

Typical doses in the clinical setting for treatment of type 2 diabetes vary according to age, drug formulation, and individual response to the medication, ranging from 500 milligrams to 2,500 milligrams per day for adults. Evidence regarding dosing recommendations for slowing aging in humans is limited, however. Metformin doses used in animal studies lead to blood concentrations of the drug that are markedly higher than those used to treat diabetes in humans.[5] Future research will likely elucidate the appropriate dosing and long-term effects of metformin in humans.

Conclusion

Metformin is a drug commonly used to treat type 2 diabetes. Some evidence suggests that metformin may modulate the aging processes to improve healthspan and extend lifespan, in multiple species. However, human evidence is epidemiological and limited. The mechanisms by which metformin exerts its effects are not fully understood, but evidence suggests that pathways involved in cellular energy and antioxidant responses may be responsible. However, metformin may inhibit exercise-induced health benefits, especially with regard to muscle mitochondrial adaptations and muscle hypertrophy. Metformin is safe, even at high doses, and is readily bioavailable in humans. It is unclear if metformin is beneficial for healthy active adults.