Metformin Beyond Diabetes: Mechanisms underlying its health benefits in aging and longevity
Metformin is a drug currently on the World Health Organization (WHO) model list of essential medicines and is the most widely used medicine globally for the management of non-insulin dependent diabetes mellitus (NIDDM, Type 2 diabetes – T2DM). Guanidine, the parent compound from which metformin was developed, is a plant chemical; the plant commonly known as French Lilac or goat’s rue (Galega officinalis is the scientific name) has a long history of medicinal use in medieval Europe. Metformin was one of the many chemicals that were structurally similar to guanidine that were synthesized and tested for their anti-diabetic effects. Metformin was introduced for clinical use to treat diabetes first in Europe in the 1960’s and was approved by the FDA for use in the United States of America in 1995.
Chemical synthesis of metformin dates back to 1922. Since then, scientific exploration of its medicinal properties have provided unique insights into its mechanistic ability to influence many key biological pathways from glucose lowering effects to its potential use an anti-malarial agent, treatment of influenza infection (the flu) and most recently in COVID19, cancers and as a potential drug for slowing down aging process. The scale of its use in humans over the past sixty plus years, understanding its safety profile and low cost of use makes it a potential wonder drug for the management of metabolic dysfunction, maintenance of good health and overall well-being.
Let’s dive into what makes metformin unique and why it’s capturing the imagination of scientists and the public alike.
How Metformin Works
At its core, metformin is a metabolic regulator. It decreases the liver’s production of glucose, increases the muscle tissue's uptake of glucose, and improves insulin sensitivity. These actions help stabilize blood sugar levels, making metformin a cornerstone in managing type 2 diabetes. Interestingly, its mechanism of action doesn’t involve directly stimulating insulin production, making it less likely to cause hypoglycemia—a common concern with some other diabetes medications.
In recent years, research has shown that glucose lowering effects of metformin goes beyond its effects on the liver and skeletal muscle. Metformin influences cells and tissues of the gut lining to improve glucose handling, a mechanism that appears to be synergistic (additive) to the anti-diabetic mechanism of GLP-1 therapies. Metformin also exerts effect on the gut microbiome, altering the composition to promote an overall beneficial effect.
Many mechanisms have been attributed to metformin’s benefits in human health highlighting continued interest in scientific community and health practitioners to continue leveraging its utility in various health conditions.
Beyond Diabetes: A Potential Fountain of Youth?
What truly sets metformin apart is its emerging role in biology beyond metabolic dysfunction and diabetes. While it may not necessarily be a "magic pill," there is growing evidence that it could slow the onset of many age-related biological changes that lead to organ dysfunctions and diseases.
1. Cardiovascular Health
Studies suggest that metformin reduces cardiovascular risk, even in individuals without diabetes. By lowering inflammation and improving lipid profiles, it may protect against heart disease, a leading cause of death worldwide.
Metformin -
Decreases “AGE” (advanced glycation end products)
Decreases “ROS” (reactive oxygen species)
Improves lipid profiles
Influences energy metabolism in heart muscle cells, reduces overall muscle dysfunction
Protects against vascular endothelial (cells lining the walls of blood vessels) dysfunction
Benefits of metformin has been observed in lowering incidence of coronary artery disease (CAD) and congestive heart failure (CHF), two of the major cardiovascular diseases associated with diabetes and aging.
2. Cancer Prevention
The ability of cancer cells to keep growing unchecked requires access to continuous supply of nutrients, growth factors and energy. The evidence of metformin’s anti-cancer potential was identified from human and animal studies comparing diabetes versus non-diabetes groups. Several studies have reported evidence of metformin’s anti-cancer effects in organs like the breast, brain, endometrium, lung, ovary and kidneys. Metformin has been reported to influence key metabolic and cell cycle signaling pathways in cancer cells to elicit its anti-cancer effect. Some of the important signaling pathways influenced by metformin to elicit its anti-cancer effects include:
Inhibits activity of mitochondrial complex 1
Activation of AMPK – energy metabolism pathway
Inhibitors mTOR (mammalian target of rapamycin)
Modulates proteins regulating cell cycle (process of cell division and growth characteristic of cancer) including cyclins, p21, p27, p53, Akt and others
Inhibition of cell cycle
Although metformin does not appear to have significant single agent anti-cancer activity (i.e. cannot be used for treatment of cancer on its own), it has the potential to add benefits when combined with standard of care anti-cancer treatments for multiple cancers including bladder cancer, lung cancer, colorectal cancer, multiple myeloma, melanoma, thyroid cancer, liver cancer and some rare cancers of the bone. As of December 2024, the clinical trials website lists over 400 clinical trials (www.clinicaltrials.gov) testing metformin in combination with other anti-cancer treatments for various cancers.
3. Cognitive Benefits
Age related cognitive decline (slow progressive impairment in memory functions) is an hallmark of the aging process and associated with onset of mild cognitive impairment, dementia and Alzheimer’s disease. Can metformin help our brains age better? Some studies hint at a reduced risk of dementia and Alzheimer’s disease among metformin users, although the data isn’t conclusive yet. Some evidence of potential mechanisms of metformin with potential to influence and improve brain function include:
Metformin crosses the blood brain barrier (it can get access to the brain cells)
Lowers expression of a-synuclein (protein that forms aggregates or clumps in Parkinson’s Disease, potential benefit for patients with disease)
Effects on dementia observed in non-human model testing
Minimizes risk of cognitive impairment in diabetic patients in clinical studies
Improved metabolic fitness with metformin use, reduced ROS production and influence on key metabolic signaling are potential mechanisms involved in metformin associated improvement in brain function
4. Aging
Most recently, metformin has gained significant attention for its potential to slow down the cellular processes associated with aging. In human studies, a comprehensive review and analysis provides evidence of metformin use was associated with a reduction in all-cause mortality (death due to all causes). Numerous metabolic and growth factor signaling pathways, that incidentally also influenced by metformin, have been subject of active investigations as potential targets for anti-aging therapeutics.
The significant contributions from scientific research supporting the impact of metformin on various biological mechanisms has been critical for recent investments in the clinical investigation of its utility as an anti-aging therapy.
The TAME Trial: Targeting Aging with Metformin
The most ambitious study in this area is the TAME trial, led by Dr. Nir Barzilai. This is a nationwide clinical trial that aims to determine (proof of concept) whether metformin can be used to treat aging by delaying the onset of chronic diseases associated with aging, such as heart disease, diabetes, cancer, and cognitive decline. The study is to be conducted at 14 leading research institutions and is expected to involve an estimated 3000 individuals between the ages of 65 – 79. If successful, it could redefine how we approach aging as a modifiable process.
Should Everyone Take Metformin?
While metformin is generally well-tolerated, it isn’t without side effects. Common complaints include gastrointestinal upset, and in rare cases, lactic acidosis. Moreover, its off-label use for aging is not yet FDA-approved, and the long-term effects in non-diabetic individuals remain uncertain.
For now, metformin is a promising tool in the growing toolkit of longevity science, but it’s not a substitute for a healthy lifestyle. Eating well, exercising regularly, and managing stress remain the gold standards for promoting a long and healthy life.
The Future of Metformin
Metformin’s journey from a plant-derived remedy to a potential anti-aging drug is a testament to the evolving landscape of medicine. As research unfolds, it may pave the way for broader acceptance of therapies targeting the aging process itself.
In the meantime, this modest medication continues to transform lives by doing what it does best—helping millions manage diabetes while quietly opening the door to a healthier, longer future.
Have you heard of or used metformin for non-diabetic purposes? Share your thoughts in the comments below!
Select References
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2. Marshall, S.M. 60 years of metformin use: a glance at the past and a look to the future. Diabetologia (2017) 60, 1561–1565. https://doi.org/10.1007/s00125-017-4343-y. Summary description of metformin from discovery to clinical utility.
3. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):854-65. Erratum in: Lancet 1998 Nov 7;352(9139):1558. PMID: 9742977. Demonstrated the benefits of metformin in reducing complications in type 2 diabetes patients.
4. Dutta S, Shah RB, Singhal S, Dutta SB, Bansal S, Sinha S, Haque M. Metformin: A Review of Potential Mechanism and Therapeutic Utility Beyond Diabetes. Drug Des Devel Ther. (2023) 17:1907-1932. https://doi.org/10.2147/DDDT.S409373. A comprehensive review of mechanisms and use of metformin beyond diabetes.
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6. Foretz, M., Guigas, B. & Viollet, B. Metformin: update on mechanisms of action and repurposing potential. Nat Rev Endocrinol. 19, 460–476 (2023). https://doi.org/10.1038/s41574-023-00833-4. Updated information on the biochemical mechanisms underlying metformin effects on various signaling pathways and relationship to clinical utility.
7. Campbell JM, Stephenson MD, de Courten B, Chapman I, Bellman SM, Aromataris E. Metformin Use Associated with Reduced Risk of Dementia in Patients with Diabetes: A Systematic Review and Meta-Analysis. J Alzheimers Dis. 2018;65(4):1225-1236. doi: 10.3233/JAD-180263. PMID: 30149446; PMCID: PMC6218120. Suggests a link between metformin use and cognitive benefits.
8. Mohammed I, Hollenberg MD, Ding H, Triggle CR. A critical review of the evidence that metformin is a putative anti-aging drug that enhances healthspan and extends lifespan. Front Endocrinol (20221) 12:718942. https://doi.org/10.3389/fendo.2021.718942. A comprehensive review of scientific evidence supporting role for metformin in aging and longevity.
