Metformin Longevity Potential: What do we know?

Imagine a scenario straight out of Death Becomes Her, where Meryl Streep discovers a potion that halts the aging process. The quest for such a “fountain of youth” has been a perennial pursuit in the longevity community, and recent developments suggest that they may be on the brink of a breakthrough.

Often, the most profound solutions emerge from the most unexpected places. Could the elusive elixir of youth be neither exorbitantly priced nor shrouded in exclusivity? Researchers are now considering the possibility that the key to extending both lifespan and healthspan might be concealed within a common antidiabetic medication. This drug, metformin, is not only globally recognized for its safety and efficacy but is also remarkably affordable. It’s time to shine a spotlight on metformin, the emerging star in the anti-aging arena.

The potential of metformin to promote longevity is currently under intense scientific scrutiny. While its efficacy for individuals with impaired glucose metabolism is well-established, the question of whether it can offer similar benefits to healthy individuals remains. Preliminary evidence is promising, fueling excitement and anticipation within the scientific community. Engage with the unfolding narrative of metformin and its connection to anti-aging, and stay tuned for future developments. 

What is Metformin?

Metformin (dimethylbiguanide) is a cheap, effective, and safe drug used primarily in the treatment of type 2 diabetes. It has been around for a long time: first in the form of Galega officinalis (also known as goat’s rue), a traditional European herbal medicine rich in guanidine, a substance that was found to lower blood sugar levels in 1918.1

In the 1920s and 1930s, other guanidine derivatives were synthesized for diabetes treatment. This era coincided with the groundbreaking discovery of insulin, which overshadowed these derivatives due to its efficacy. Consequently, all guanidine-based medications, except for metformin, were eventually phased out over toxicity concerns.1

Metformin was rediscovered in the 1940s during clinical trials evaluating potential drugs for malaria treatment. It has been used ever since all over the world. 

How Does Metformin Work?

As a first-line anti-diabetic treatment, metformin orchestrates a series of physiological changes to regulate sugar levels in the body. It curtails the liver’s glucose production (glycogenolysis) and blocks excess glucose absorption in the intestines. Metformin also sensitizes cells to insulin, facilitating the passage of sugar molecules through cell membranes to be converted into vital energy.2,3

Beyond its primary role, metformin is believed to wield additional anti-aging powers: 

• It may reduce oxidative damage to the cells and proteins. Metformin may have anti-oxidative effects and thus protect cells from genetic damage.4,5
• It may fight inflammation. Metformin appears to reduce the production of molecules that promote inflammation and enhance the release of molecules that reduce inflammation.4,5
• It may slow down cellular senescence, or cellular aging. This is one of the hallmarks of aging. As we age, cells stop functioning correctly and stop dividing, which is often linked to many age-related diseases.5
• It may promote adaptive cellular responses. Not all stress is bad. Sometimes, proper stress adaptation can help our cells remain healthy. Exercise and certain dietary interventions have the same effect on our bodies, something known as “hormesis.”6
• It may support cellular autophagy and apoptosis. The body removes damaged and aging cells through tightly regulated processes such as autophagy (breaking down and removing proteins, large molecules, cell parts, or foreign invaders.) and apoptosis (programmed cell death). While this happens regularly in young people,  these processes decline as we age.5

How does metformin achieve all of these remarkable effects? The exact pathways are still under investigation. What we do know is that metformin alters several molecular mechanisms, such as AMPK, mGPDH, and mTORC1 signaling.7

Metformin likely exerts other effects on the human body. This remains a subject of ongoing research, as scientists strive to demystify its mechanisms and potential health benefits.

Use Cases of Metformin 

Metformin is a well-known anti-diabetic drug, but that is scratching the surface. Its beneficial effects may extend far beyond that. Keep reading to learn more about the different clinical uses of metformin.

• Treatment of type 2 diabetes and insulin resistance, also known as pre-diabetes. In 1994, metformin was approved by the U.S. Food and Drug Administration (FDA) for the treatment of type 2 diabetes. It is the first-line treatment for diabetes in both adults and children over 10 years old. As a single agent or in combination with other antidiabetic drugs, metformin effectively manages glucose levels, especially when paired with lifestyle interventions. It is currently the only American Diabetes Association (ADA)-recommended antidiabetic medication used for prediabetes.2
• Treatment of polycystic ovary syndrome (PCOS). Metformin’s ability to lower blood glucose and insulin levels can positively influence hormonal balance. This, in turn, may reduce luteinizing hormone and androgen levels, helping to restore ovulation and normalize the menstrual cycle in women with PCOS.2
• Treatment of drug-induced weight gain. Some drugs, like antipsychotics, may trigger weight gain. Metformin is used to promote mild weight loss and prevent additional weight gain in these patients.2
• Treatment of gestational diabetes. Gestational diabetes is a type of diabetes that develops during pregnancy in previously non-diabetic women. To address any health concerns for the mother and the child, doctors may prescribe insulin and metformin. Metformin is sometimes the only option if compliance with insulin treatment is poor.2 

Beyond its established and off-label uses, ongoing research is exploring metformin’s potential in treating neurological disorders, certain cancer types, and as a component of anti-aging strategies.8 

Metformin for Anti-Aging and Longevity? 

The discovery that metformin-treated diabetic patients had a survival advantage over non-diabetic individuals sparked a surge of interest in the drug’s potential for enhancing longevity.7 This revelation has led to a significant body of research dedicated to uncovering the anti-aging properties of metformin. 

Typically, people with diabetes have a higher risk for many chronic conditions that contribute to mortality. Metformin may reduce the rates of atherosclerosis (blood vessel narrowing) and overall cardiovascular disease, as well as the risk of cancer and the general decline associated with aging.7,9 

Metformin has shown promise when studied in aging model organisms, such as the invertebrate Caenorhabditis elegans or mice. It appears to suppress the markers of aging and decrease the risk of aging-related conditions, including neurodegenerative disease and cancer.7,8 In some organisms, metformin slows aging by altering the microbiome. 

But what about humans? The Metformin in Longevity Study (MILES), a double-blind, placebo-controlled clinical trial enrolled 14 elderly human participants with type 2 diabetes. They were treated with 1700 mg of metformin per day. The findings suggest that metformin may influence gene expression linked to aging processes.10 

The question remains, could it be used in healthy people? A large, double-blind, placebo-controlled, multicenter clinical trial called Targeting Aging with Metformin (TAME)11 is underway to study this. It is set to enroll approximately 3000 elderly individuals without type 2 diabetes who will be treated with metformin and monitored for 6 years.10 This landmark study is expected to shed light on the full extent of metformin’s relationship with anti-aging mechanisms. 

Should You Use Metformin for Anti-Aging?

There is evidence suggesting that metformin may work for longevity optimization, but the data are not conclusive. Further research and well-designed clinical trials are needed to elucidate the real anti-aging effects of metformin on healthy people. 

For those dealing with impaired glucose metabolism, metformin offers a dual advantage: controlling diabetes and potentially extending lifespan. But caution is key—like any medication, metformin carries risks. It’s crucial to initiate treatment under the guidance of a healthcare professional, even at lower, generally safe doses.

How Should Metformin Be Taken? 

Metformin is administered orally, typically in capsule form. Upon ingestion, it is absorbed through the gastrointestinal tract before being distributed to the liver and subsequently throughout the body. The kidneys play a crucial role in excreting metformin, as it is primarily eliminated via the urine.2

There are two types of metformin: immediate-release, which you may take a few times per day, and extended-release, usually taken once per day. Doctors typically prescribe metformin at daily doses ranging between 500 and 2550 mg. To minimize side effects and modulate absorption, it is advisable to take it with food.2 

Who Should Not Use Metformin?

Metformin may be a widely prescribed medication, but it’s not suitable for everyone. A thorough health assessment by a physician is crucial before starting metformin due to potential contraindications:2,3 

• People with impaired kidney function. Metformin is eliminated through the urine. In cases of renal impairment, the drug can accumulate in the body, leading to adverse effects. Physicians assess kidney health using metrics like glomerular filtration rate (GFR) and creatinine levels before prescribing metformin. 
• People with impaired liver function. The liver’s role in glucose and fat metabolism is significant. Liver dysfunction can increase the risk of metformin-related side effects. 
• People with decompensated heart failure. Heart failure can compromise blood flow to organs. Patients with this condition should discontinue metformin and seek immediate medical attention.
• People who are overly sensitive to metformin. 

Even if you don’t fall into the above categories, exercise caution with metformin in the following scenarios:2 

• Drug interactions: Some medications and intravenous contrasts used in scans can adversely interact with metformin, especially if they affect kidney function.  
• Surgery: It is recommended to stop taking metformin before any surgery.
• Alcohol. If you are taking metformin, it’s important to limit alcohol consumption. Combining metformin with alcohol can lead to severe side effects. 
• Elderly people. As we age, kidney function declines. This means extra caution when initiating metformin. 
• Pregnant or breastfeeding women. Metformin requires careful monitoring to maintain appropriate levels when pregnant or breastfeeding.

What are the Side Effects of Metformin?

As with any other drug, metformin comes with potential risks. While these are typically mild and affect a minority of users, it’s important to be aware of them. You can reduce the likelihood of experiencing side effects by taking the drug exactly as prescribed. 

The most common side effects of metformin are gastrointestinal: diarrhea, nausea, flatulence, vomiting, poor digestion, and abdominal discomfort. Although metformin is generally a safe medication, these side effects happen to up to 30% of people who take it.2 On a positive note, these symptoms often subside over time. In some cases, a dose adjustment or discontinuation may be necessary. Tip: Consistently taking metformin with meals can help mitigate these effects.7 

Less common side effects may include headache, runny nose, weakness, sweating, hypoglycemia (low blood sugar levels), and chest discomfort.2 If you have used metformin for a very long time, you might want to check your vitamin B12 levels.7 Low levels of vitamin B12 can manifest as a particular type of anemia or damage to the nerves in your limbs, also known as peripheral neuropathy. Sometimes, supplementation is necessary.2

The most serious side effect of metformin treatment is low blood sugar along with lactic acidosis. Lactic acidosis refers to a buildup of lactic acid in the blood, which happens when energy production shifts and too much lactic acid is produced. As a result, blood pH levels drop. Luckily, it only happens to approximately 1 in 30,000 people who take metformin.2 

This severe complication manifests as exhaustion or extreme fatigue, weakness, headache, muscle cramps or pain, abdominal pain or discomfort, diarrhea, or respiratory distress. Lactic acidosis may trigger a decrease in blood pressure and body temperature, and even cause death.2 

Lactic acidosis is often a consequence of metformin overdose or or an interaction with other drugs or alcohol. People with liver, heart, or kidney dysfunction remain at a higher risk, which is why metformin is not recommended in this patient population. Treatment of lactic acidosis is immediate discontinuation of metformin and supportive care, and possibly, dialysis.2

How Should You Be Monitored?

Initiating metformin therapy requires consistent monitoring to ensure your body is responding favorably. Partnering with a qualified health professional is crucial for this process. 

• Before metformin initiation and every now and then, your physician should be monitoring your kidney function by assessing your glomerular filtration rate. If the rate is concerning, it warrants closer observation, typically every 3 months. In older patients, regular monitoring is essential because of the increased risk of lactic acidosis. 
• Every 3 to 6 months, your physicians should check your fasting glucose, glucose after meals, and hemoglobin A1C. 
• Regular monitoring of vitamin B12 levels is also recommended. It is necessary for patients with signs of anemia and peripheral neuropathy. 

The Bottom Line on Metformin Longevity Use 

Metformin is an effective, well-tolerated, and safe drug for the treatment of type 2 diabetes and a few other conditions. Its primary function is to lower blood sugar levels, yet it may also offer additional health benefits.

The scientific community is intrigued by the possibility that metformin could influence the genetic factors associated with aging and decrease inflammation, potentially reversing the aging process in healthy individuals. However, these hypotheses are yet to be substantiated by solid evidence. The comprehensive Targeting Aging with Metformin (TAME) trial is currently underway, examining the drug’s anti-aging effects on individuals without diabetes.11 The outcomes of this study are eagerly anticipated. 

Physicians are being cautious about prescribing the drug for longevity purposes. There is good reason for that: metformin is currently not recommended as an anti-aging treatment. If you have issues with high blood sugar, the idea is worth discussing with your doctor. 

Remember, when it comes to health optimization, one size does not fit all. The best approach to longevity is custom-made. It may include drugs, supplements, or simply, lifestyle interventions. In fact, the path to longevity is paved with optimal nutrition, good sleep, and regular exercise. 

At Opt Health, our team of medical experts is dedicated to personalized healthcare. We believe in a tailored approach to longevity, starting with a comprehensive health evaluation, thorough testing, and a careful consideration of risks and benefits to craft a bespoke longevity strategy for you. 

For guidance on enhancing your health and pursuing a vibrant, extended life, consider Opt Health as your partner. We are equipped with knowledge about the latest anti-aging interventions, effective strategies, and impactful methods. 

References 

1. Bailey CJ. Metformin: historical overview. Diabetologia. 2017;60(9):1566-1576. doi:10.1007/s00125-017-4318-z
2. Corcoran C, Jacobs TF. Metformin. In: StatPearls. StatPearls Publishing; 2024. Accessed April 16, 2024. http://www.ncbi.nlm.nih.gov/books/NBK518983/
3. Flory J, Lipska K. Metformin in 2019. JAMA. 2019;321(19):1926-1927. doi:10.1001/jama.2019.3805
4. Drzewoski J, Hanefeld M. The Current and Potential Therapeutic Use of Metformin-The Good Old Drug. Pharm Basel Switz. 2021;14(2):122. doi:10.3390/ph14020122
5. Kulkarni AS, Gubbi S, Barzilai N. Benefits of Metformin in Attenuating the Hallmarks of Aging. Cell Metab. 2020;32(1):15-30. doi:10.1016/j.cmet.2020.04.001
6. Calabrese EJ, Agathokleous E, Kapoor R, Dhawan G, Kozumbo WJ, Calabrese V. Metformin-enhances resilience via hormesis. Ageing Res Rev. 2021;71:101418. doi:10.1016/j.arr.2021.101418
7. Soukas AA, Hao H, Wu L. Metformin as Anti-Aging Therapy: Is It for Everyone? Trends Endocrinol Metab. 2019;30(10):745-755. doi:10.1016/j.tem.2019.07.015
8. Piskovatska V, Stefanyshyn N, Storey KB, Vaiserman AM, Lushchak O. Metformin as a geroprotector: experimental and clinical evidence. Biogerontology. 2019;20(1):33-48. doi:10.1007/s10522-018-9773-5
9. Campbell JM, Bellman SM, Stephenson MD, Lisy K. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: A systematic review and meta-analysis. Ageing Res Rev. 2017;40:31-44. doi:10.1016/j.arr.2017.08.003
10. 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. 2021;12:718942. doi:10.3389/fendo.2021.718942
11. TAME – Targeting Aging with Metformin. American Federation for Aging Research. Accessed April 19, 2024. https://www.afar.org/tame-trial