“Happy Accidents”: Repurposing Metformin

A recent article on the multiple uses of metformin brings up the important topic of repurposing medications.¹ Repurposing has been around since the advent of modern medicine. One prominent example is the use of chlorpromazine (CPZ) as an antipsychotic.² Chlorpromazine was first synthesized in 1951 as a potentiator of general anesthesia.² The psychiatric benefits were found later by Henri Laborit, a surgeon in the French army, who was doing research with artificial hibernation in the prevention of surgical shock. Laborit employed CPZ as an adjunct to anesthetics. He observed that CPZ at doses of 50 mg to 100 mg produced a lowering of body temperature, sedation, and disinterest without loss of consciousness. He was able to persuade his colleagues in the military hospital in Paris, France, to try CPZ in the treatment of a patient who was experiencing psychotic agitation. The mechanism of action was not fully known, and it was thought that it worked in controlling agitation because of its cooling effect and induction of artificial hibernation in patients.² The pharmacological mechanism was not fully understood until many years later, and the way it has impacted the practice of psychiatry needs no introduction.

These happy accidents in medicine have played a vital role in getting where we are right now in patient care compared with just 50 years ago. This begs the question, are we onto another happy accident with metformin? There is an accumulating body of evidence that metformin may have benefits in aging beyond its effect on glycemic control.³

Repurposing Metformin

Metformin is endorsed by the American Diabetes Association and the European Association for the Study of Diabetes as initial therapy for patients with type 2 diabetes (T2D), and it is one of the most prescribed antidiabetic medications worldwide.⁴ It is widely recognized that metformin improves hyperglycemia and insulin sensitivity.⁴ Recently, the observation that metformin decreased the development of certain age-associated pathology in individuals with and without diabetes has garnered attention.³ Aging refers to the time-dependent physiological loss of cellular integrity⁵ and is associated with T2D, dementia, cancer, and cardiovascular disease.⁶ The United Kingdom Prospective Diabetes Study has shown that metformin is associated with a lower all-cause mortality rate in patients with diabetes.⁷ This study was a 20-year randomized multicenter longitudinal study, and researchers found cardiovascular benefits of metformin in patients with diabetes.⁷ Similarly, a systematic review of 53 studies showed that metformin use resulted in a decrease in all-cause mortality linked with aging-related diseases such as cancer and cardiovascular disease.⁸ As the aging population grows and life expectancy increases, we are searching for ways to maintain quality of life for as long as possible.

In the US, advances in health care and public health have afforded increases in life expectancy.⁵ Unfortunately, this longevity has been accompanied by an increase in the incidence of age-related diseases, which leads to a decreased quality of life.⁵ Health span refers to the life period in which one is healthy and free from chronic illness and aging-related dysfunction; it serves as a proxy for quality of life during the older years.⁶ There is a pressing need for interventions that can delay age-associated diseases and improve health span. Preclinical data indicate that metformin may influence cellular mechanisms associated with aging, including inflammation, oxidative stress, cell senescence, and autophagy.^3,5 Of note, metformin mimics the metabolic actions of caloric restriction, which is a recognized strategy to prolong health and life span in mammals.⁹ Metformin may also mimic the geroprotective effects of exercise.⁵ Since metformin is inexpensive and offers a good tolerability and safety profile, it is attractive as a focus of antiaging research.³

Reducing Inflammation

As early as 1907, Élie Metchnikoff theorized that cell senescence resulted from chronic systemic inflammation due to increased permeability in the colon, and the escape of bacteria and their toxic metabolites into the systemic circulation.10 Accordingly, these toxic bacterial products activated phagocytes and an inflammatory response that led to death of adjacent tissues.¹¹ Interestingly, more than a century later, aging is thought to be associated with a persistent low-grade inflammation, referred to as inflammaging, that originates in the gut.¹¹ We now know that the intestinal mucosal layer is a key modulator of inflammatory responses, protecting against invasion of dietary and microbial antigens and lumen contents. With aging there is a reduction in thickness of this mucus layer, resulting in weakened intestinal barrier function. The term leaky gut refers to excessive bacterial translocation from the intestinal lumen into the systemic circulation, which triggers inflammatory cascades and low-grade chronic inflammation. Results of recent research in mice lend support to the hypothesis that metformin may decrease inflammation by maintaining the integrity of the intestinal barrier.¹²

In one study, metformin significantly decreased bacterial translocation in older mice and the expression of inflammatory markers such as interleukins (ILs) and tumor necrosis factor α.¹² In addition to low-grade inflammation, contemporary views of aging suggest a decline in several mediators of cell maintenance.⁵ For example, autophagy (a cellular recycling program that removes dysfunctional organelles from the cytoplasm) deteriorates with aging.⁵ Of interest, metformin has been implicated in improving autophagy and slowing several cellular mechanisms of aging.⁵ It has been posited that metformin’s anti-inflammatory effects modulate cellular integrity by maintenance of cell-to-cell communication, leading to a reduction in proinflammatory cytokines.³

In addition to chronic inflammation and dysregulation of cell-cell connectivity, other hallmarks of aging include mitochondrial dysfunction, genomic instability, and oxidative stress.³ Although knowledge of metformin’s effects on these aging processes remains elusive, there is increasing interest in this field. One example is the Metformin in Longevity Study (MILES; NCT02432287), a double-blind, placebo-controlled clinical study that included 14 patients. Researchers sought to establish associations between 6-week metformin intake and youthful gene expression in older persons with impaired glucose tolerance.¹³ Preliminary results indicate that in older individuals, metformin is implicated in metabolic changes, including DNA repair in the muscle tissue and mitochondrial fatty acid oxidation in the adipose tissue.^6,13

Early on, the antidiabetic benefits of metformin were deemed to occur via decreased lipogenesis and gluconeogenesis in the liver because of its impact on molecular signaling and mitochondrial function.³ The end result was a decrease in plasma glucose and decreased insulin resistance.³ Metformin also exerts action in extrahepatic sites such as the gut. After oral administration, metformin concentrations in the intestinal lumen are significantly higher than in the systemic circulation.¹⁴ Metformin exerts many actions within the gut, such as an increase in lactate production and intestinal glucose uptake, an increase in glucagon-like peptide-1 (GLP-1), and advantageous changes in the gut microbiota.¹⁴ The gut microbiota is an ecosystem that interacts in a symbiotic fashion with the host to promote health.¹⁵ The microbiota impacts vitamin and short-chain fatty acid production, digestion, immunity, and the permeability of the intestinal barrier.¹⁵ With aging, there are changes in the gut microbiome leading to increased inflammation, gut permeability, and release of proinflammatory cytokines.¹¹ Metformin may improve the gut microbe composition by increasing the ratio of bacteria that produce anti-inflammatory short chain fatty acids (SFCAs).¹⁶ These bacteria ferment dietary carbohydrates that humans cannot digest.¹⁶ SCFAs are widely known for enhancing glucose homeostasis in adipose tissue, liver, and muscles.¹⁶ Metformin also reduces the abundance of proinflammatory bacterial species supporting the integrity of the intestinal barrier.¹² In animal studies, metformin expanded the gut population of Akkermansia spp, a producer of short-chain fatty acids that is correlated with a decrease in adipose tissue inflammation.16 Although human studies are yet to uncover a metformin signature on the gut microbiome, this is an area that merits further examination.¹⁶

Anticancer Effects

In terms of aging-related diseases, there has been interest in exploring the putative anticancer actions of metformin. Preclinical evidence has shown that metformin inhibits tumor growth and metastasis in mouse models for head and neck squamous cell carcinoma, hepatocellular carcinoma, and breast cancer.⁹ Observational studies have also revealed that metformin exerts beneficial effects on individuals with diabetes who also have comorbid cancer.⁹ Recent attempts to explore whether metformin decreases the incidence of age-related disease in humans have yielded variable results. Notably, the largest randomized trial of metformin as adjuvant treatment for breast cancer (N = 3649 women, 5-year follow-up) found no advantage of metformin in measures of disease-free survival or overall survival.⁹ Whether metformin can delay the onset of other age-associated cancer and pathology remains unclear.

Neuroprotective Effects

Finally, a neuroprotective effect of metformin has also been proposed. Aging and neurodegenerative disease share similar cellular dysfunction patterns, including inflammation, oxidative stress, and mitochondrial dysfunction. It is possible that regulation of glucose metabolism and insulin sensitivity may counter some of these cellular processes. In 5528 patients with diabetes with a median follow-up of 5.2 years, prolonged metformin use (> 2 years) significantly decreased the risk of developing neurodegenerative disorders.¹⁷ However, in a subsequent meta-analysis, metformin did not decrease the risk of developing Alzheimer disease.17 Doubts about the neurocognitive effects of metformin persist. Does long-term metformin treatment alter the risk of cognitive decline?

Major efforts to clarify these putative effects include the Targeting Aging With Metformin (TAME) trial, which is a large double-blind, placebo-controlled study that seeks to establish antiaging properties of metformin.¹⁸ Specifically, the TAME trial aims to examine whether giving metformin to healthy individuals delays the onset of aging-associated diseases.18 It will include 3000 participants aged 65 to 79 years, and it is the first large trial for geroprotective medications.¹⁸

Concluding Thoughts

In sum, the repurposing of metformin has been of research and clinical interest worldwide. Interest in metformin’s potential benefits in aging-related diseases has been renewed given the increase in human life span and the need to extend quality of life in geriatric populations. Despite promising data from preclinical and observational studies, the use of metformin for antiaging continues to be investigational. Whether geroprotection will become another avatar of metformin remains to be seen.

Dr Modesto-Lowe is medical director at Hartford Behavioral Health and community faculty at the University of Connecticut. Dr León-Barriera is an assistant professor of psychiatry at the University of Pittsburgh School of Medicine in Pennsylvania. Dr Kaur is a principal psychiatrist at the Connecticut Valley Hospital in Middletown.

References

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