Metformin, Inflammation, the Gut Microbiome, and Health Span: Connecting the Dots

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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. He was doing research with artificial hibernation in prevention of surgical shock.² Laborit employed the drug as an adjunct to anesthetics.² 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.² He was able to persuade his colleagues in the military hospital in Paris to try CPZ in the treatment of one of their patients who was experiencing psychotic agitation.² Laborit hypothesized that since cooling with water had been used to treat agitation in France, the drug would have a similar effect.² 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 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 that are beyond its effect on glycemic control.³

Metformin is endorsed by the American Diabetes Association and the European Association for the Study of Diabetes as initial therapy of type 2 diabetes mellitus (DM2) and is one of the most prescribed antidiabetic medications worldwide.⁴ It is widely recognized that metformin improves hyperglycemiaand insulin sensitivity.⁴ Recently, the observation that metformin decreased the development of certain age-associated pathology in diabetics and nondiabetics has garnered attention.³ Aging refers to the time-dependent physiological loss of cellular integrity⁵ and is associated with DM2, dementia, cancer, and cardiovascular disease.⁶ The United Kingdom Prospective Diabetes Study (UKPDS) 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 found cardiovascular benefits of metformin in diabetic patients.⁷ Similarly, one 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 With a growing aging population and longer life expectancy, how can we 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, free from chronic illness and aging-related dysfunction, and serves as a proxy for quality of life during the older years.⁶ There is a pressing need for interventions that can delay the 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 lifespan 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

As early as the 1900s, 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 todeath of adjacent tissues.¹¹ Interestingly, even many years later, aging is thought to be associated with a persistent low-grade inflammation, referred to as “inflammageing” 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.¹² With aging there is a reduction in thickness of this mucus layer, resulting in weakened intestinal barrier function.¹² “Leaky gut” refers to excessive bacterial translocation from the intestinal lumen into the systemic circulation triggering inflammatory cascades and low-grade chronic inflammation.¹² Recent research in mice lends some 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 old mice and the expression of inflammatory markers such as interleukins (ILs) and tumor necrosis factor alpha (TNF-a).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 pro-inflammatory cytokines.³ In addition to chronic inflammation and dysregulation of cell-cell connectivity, other hall marks of aging include mitochondrial dysfunction, genomic instability, and oxidative stress.³ While metformin effects on these aging processes remain elusive, there is increasing interest in this field. One example is the Metformin in Longevity Study (MILES), a double-blind, placebo-controlled clinical study including 14 patients.¹³ The study 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 on mitochondrial function.³ The end-result was a decrease in plasma glucose and decreasedinsulin resistance.³ Metformin also exerts action in extra-hepatic sites, such as the gut.¹⁴ 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, 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 pro-inflammatory cytokines release.¹¹ Metformin may improve the gut microbe composition by increasing the ratio of bacteria that produces anti-inflammatory short chain fatty acids (SFCA).¹⁶ These bacteria ferment dietary carbohydrates that humans cannot digest.¹⁶ SCFA’s are widely known for enhancing glucose homeostasis in adipose tissue, liver, and muscles.¹⁶ Metformin also reduces the abundance of pro-inflammatory bacterial species supporting the integrity of the intestinal barrier.¹² In animal studies, metformin expanded the gut population of Akkermansia spp, which is a producer of short-chain fatty acids and is correlated with a decrease in adipose tissue inflammation.¹⁶ While human studies are yet to uncover a “metformin signature” on the gut microbiome, this is an area that merits further examination.¹⁶

In terms of aging-related diseases, there has been interest in exploring the putative anticancer actions of metformin.⁹ Preclinical evidence has shown that metformin inhibits tumor growth, and metastasis in mouse models for head and neck squamous cell carcinoma, hepatocellular carcinoma, as well as breast cancer.⁹ Observational studies have also revealed that metformin exerts beneficial effects on individuals with diabetes suffering from cancer.⁹ Recent attempts to explore if 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) with a 5-year follow-up, found no advantage of metformin in measures of disease-free survival or overall survival.⁹ Whether or not metformin can delay the onset of other age-associated cancer and pathology remains unclear.

Finally, a neuroprotective effect of metformin has also been proposed.¹⁷ Aging and neurodegenerative disease share similar cellular dysfunction patterns including inflammation, oxidative stress, and mitochondrial dysfunction.¹⁷ It is possible that regulation of glucose metabolism and insulin sensitivity may counter some of these cellular processes.¹⁷ In 5528 diabetic patients, prolonged metformin use (> 2 years) significantly decreased the risk of developing neurodegenerative disorders with a median follow-up of 5.2 years.¹⁷

However, in a subsequent meta-analysis, metformin did not decrease the risk of Alzheimer disease development.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 which seeks to establish anti-aging properties of metformin.¹⁸ Specifically, the TAME trial aims to examine if giving metformin in healthy persons delays the onset of aging-associated diseases.¹⁸ It will include 3000 participants, aged 65 to 79 and is the first large trial for geroprotective medications.¹⁸

In sum, the repurposing of metformin has been of research and clinical interest worldwide. Interest in potential benefits of metformin in aging-related diseases have been renewed given increase in human lifespan and the need to extend quality of life in geriatric populations. Despite promising data from preclinical and observational studies, the use of metformin for anti-aging 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. Dr Kaur is a principal psychiatrist at the

Connecticut Valley Hospital.

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