Should I Take Metformin for Longevity?

What is Metformin? 

Metformin is a common medication prescribed to manage type 2 diabetes. It lowers blood sugar levels by improving insulin sensitivity, helping the body use glucose more effectively, and reducing the amount of glucose the liver produces. 

French researchers first synthesized metformin in the 1920s based on an old folk remedy—the use of French lilac for treating diabetes. They discovered the chemical compound galegine, the precursor to metformin, and named it after the Latin name for the flower (Galega officinalis). However, it wasn’t until the 1950s that metformin was officially introduced as a diabetes treatment. 

Since then, it has become a cornerstone in managing type 2 diabetes due to its ability to regulate blood sugar without causing significant drops in glucose levels, which is a common side effect with other medications. Today, it is used by over 150 million people around the world.

Metformin’s effectiveness in treating diabetes is well-established. However, early research suggests that it could also have health benefits for people who don’t have diabetes. In particular, its effects on cellular processes and metabolism could potentially improve longevity—in other words, help people live longer (1).

Metformin and Longevity: The Research 

The idea of using metformin to combat aging is a new one, so there is still much research to be done. But early studies show promising signs that metformin may have exceptional anti-aging properties.

Animal Studies 

Metformin has shown significant benefits in animal studies, particularly in mice. Female mice have consistently responded better to metformin, with some studies showing an 8-9% increase in lifespan. For example, in cancer-prone mice, metformin extended both mean and maximum lifespan while reducing the size and frequency of mammary tumors. 

Long-term metformin use in another study resulted in a 37.9% increase in average lifespan without altering body weight or food intake. Animal studies have demonstrated that metformin slows down cellular aging processes, though the exact mechanisms remain unclear (1)(2).

Human Studies 

One of the most anticipated studies into metformin’s potential role in aging is the TAME (Targeting Aging with Metformin) trial. This six-year study, involving over 3,000 individuals aged 65-79, will examine whether metformin increases longevity by delaying the onset of age-related diseases like cancer, heart disease, and dementia. 

Though the trial has been designed, it’s not yet running. The main issue is that metformin is a generic drug, meaning that there is potentially little profit for pharmaceutical companies in funding the study (3)(4).

In the meantime, observational studies like the UK Prospective Diabetes Study (UKPDS) are filling the research gap. This 20-year study showed that metformin not only controls blood sugar but also reduces cardiovascular disease and overall mortality in diabetic patients. The findings revealed that patients using metformin had better longevity due to lower rates of heart attacks and strokes compared to those on other diabetes medications (1).

Mechanisms of Action 

There are several potential ways in which metformin may work to help improve longevity:

• AMPK activation: Metformin activates an enzyme called AMPK, which is linked to improved metabolic function and longer lifespan, particularly when combined with calorie restriction. AMPK sensitivity decreases with age, so this mechanism of action may be even stronger in older populations.

• Reducing inflammation: Inflammation is closely linked to aging and age-related diseases—so much so that the term “inflammaging” was recently coined to describe the link. Metformin causes an anti-inflammatory response both through AMPK activation and the mTOR signaling pathway, which helps regulate cellular health and plays a key role in anti-aging and disease prevention.

• Hormone regulation: By improving insulin sensitivity, metformin helps to balance a hormone called insulin-like growth factor 1 (IGF-1). Excess IGF-1 has been linked with a higher risk of mortality and various age-related diseases, like cancer and heart disease. 

• Influence on the gut microbiome: Research suggests that metformin changes the composition of gut bacteria in ways that may promote a longer lifespan, with animal studies showing extended lifespans when metformin is introduced into their diet (1).

Though more research is still needed to pinpoint its exact mechanisms of action, especially in humans, it’s clear that metformin has exciting potential as an anti-aging drug.

Potential Benefits Beyond Longevity 

Beyond its impact on longevity, metformin also seems to have significant health benefits that could extend healthspan—the period of life a person spends free of illness or disease. This means that as well as helping you live longer, it could also help you stay healthier for longer (5).

Cardiovascular Health 

Research demonstrates that metformin can help improve cardiovascular health by protecting the lining of blood vessels from damage caused by high blood sugar. This protection prevents premature cellular aging and reduces the risk of cardiovascular disease. 

It does this by increasing levels of sirtuin-1, a protein that regulates angiogenesis (the formation of new blood vessels) and provides protection against oxidative stress. Metformin also reduces reactive oxygen species (ROS), which are harmful molecules that damage blood vessel cells (1).

Cancer Prevention

Initial studies suggest that metformin may help prevent certain cancers by boosting cellular health. It helps regulate cell metabolism, encouraging cells to recycle old and damaged cell parts, reducing the risk of cancer-causing mutations.

Numerous studies have demonstrated this protective role, although not all findings are consistent, so more research is needed to understand precisely how, why, and whether metformin can help prevent cancer. As of 2021, ongoing clinical trials are exploring metformin's potential to prevent breast, head and neck, endometrial, ovarian, leukemia, and thyroid cancers (1).

Cognitive Function 

Metformin can also help prevent various root causes of cognitive decline, like diabetes-related hyperglycemia (high blood glucose) and vascular disease.

The evidence base for metformin’s beneficial effects on the brain is robust. The Singapore Longitudinal Aging Study, which monitored 2,365 diabetic individuals aged 55 and older for four years, found a substantial relationship between higher metformin levels and the prevention of cognitive impairment. Another study showed that people taking metformin showed cognitive improvements compared to a placebo group. 

At the molecular level, metformin encourages the growth of certain brain cells and targets monoacylglycerol lipase in the brain, both of which stave off cognitive decline. Its abilities to reduce inflammation and strengthen blood vessels may also play a role here (1).

Weight Management

Finally, metformin can help people manage their weight. It does this by affecting the part of the brain that regulates feelings of fullness, the hypothalamus. As a result, people taking metformin feel fuller after meals, and don’t get as hungry as quickly as they otherwise would.

Metformin can also normalize the body's metabolism. It promotes fat oxidation, which helps the body use fat as an energy source, and improves insulin sensitivity, allowing for better blood sugar control. These factors collectively help you lose weight and maintain a healthy body weight over time (2).

Risks and Side Effects

Metformin is generally regarded as a safe and effective medication. However, there are potential risks and side effects that users should be aware of, and which can impact its ability to improve lifespan:

• Gastrointestinal issues: About 20-30% of people experience gastrointestinal side effects, such as abdominal pain, bloating, diarrhea, nausea, and vomiting. Around 5% of those prescribed metformin need to switch diabetes management medications due to severe GI symptoms, which may be linked to metformin's accumulation in the gut cells over time, and the changes it causes to gut bacteria.

• Vitamin B12 deficiency: Long-term use of metformin can lead to vitamin B12 deficiency in 6% to 30% of users, making it important to monitor B12 levels.

• Lactic acidosis: While rare, some people who take metformin can develop a serious and sometimes fatal complication called lactic acidosis. The risk is higher in people with kidney or liver dysfunction.

• Drug interactions: Metformin can interact with certain other medications, potentially altering its effectiveness or increasing the risk of adverse effects.

Some of these issues can be serious, and may have the potential to reduce lifespan if not addressed. Talk with a medical professional if you’re unsure about taking metformin (1).

Who Might Benefit from Metformin?

The health and longevity benefits of metformin are most strongly established for people with type 2 and gestational diabetes, especially those who struggle to control their blood sugar through diet and exercise. It can also be useful for delaying or preventing the onset of diabetes in people with prediabetes (6).

Due to its wide range of health implications, however, metformin may also help improve longevity for:

• Older adults with (or at higher risk of) age-related diseases, such as cardiovascular disease, dementia, or cancer.

• People with polycystic ovary syndrome (PCOS), by helping to regulate blood sugar and hormones. If untreated, PCOS can lead to serious health conditions such as cardiovascular issues, leading to a 47% higher risk of overall mortality (7)(8).

• People taking medications that can cause weight gain, such as antipsychotics, to help prevent obesity. Obesity is strongly linked with reduced healthspan and life expectancy (9). 

The long-term effects of metformin in non-diabetic individuals—as well as its efficacy in treating other conditions—are still under investigation, however. 

Ethical and Regulatory Considerations

In the US, metformin is only currently approved by the FDA as a treatment for type 2 diabetes. It’s therefore not approved for preventing or treating any other health conditions, or for use as a general anti-aging medication. This may change in future depending on the outcome of the TAME study (4).

That being said, because there is scientific evidence of metformin’s health and longevity benefits beyond diabetes treatment, it may be prescribed off-label (i.e. for a use not endorsed by the FDA). Off-label prescribing is legal provided the drug itself is FDA-approved, which metformin is.

Prescribing metformin requires a thorough individual health assessment which takes into account the potential benefits as well as any risks or contraindications. If you are interested in possibly taking metformin for longevity or any other reason, speak to your healthcare provider (1).

Expert Opinions

Metformin’s potential as a longevity treatment has sparked varying perspectives among researchers. 

Steven Austad, a senior scientific advisor at the American Federation for Aging Research, acknowledges the uncertainty but remains cautiously optimistic: "I don't know if metformin increases lifespan in people, but the evidence that exists suggests that it very well might."

Dr. Nir Barzilai, who leads the TAME trial effort, sees metformin as a breakthrough in preventative medicine: "If you could help prevent multiple problems at the same time, like we think metformin may do, then that's almost the ultimate in preventative medicine” (4).

Opinions do vary, however. A study by the Oklahoma Medical Research Foundation cautions that metformin might interfere with some benefits of exercise in healthy older adults. Dr. Benjamin Miller noted that "metformin and exercise did not seem to play together very well" (10). This highlights how more research is needed before any conclusions about taking metformin for longevity can be drawn.

Alternatives to Metformin for Longevity

If you are unable to take metformin for longevity, there are many other ways you can improve your chances of living a long, healthy life. For example:

• Quit smoking and drinking. Many studies have demonstrated a clear inverse relationship between smoking and alcohol consumption and longevity.

• Improve your diet. By eating plenty of vegetables, fruits, and whole grains, and limiting sugary drinks and processed meats, you could live up to 10 years longer (11).

• Get enough sleep. Sleeping for less than 6 hours per night has been linked with a 12% increased risk of death (12). 

• Exercise regularly. Regular physical activity can help prevent many health issues associated with mortality, and can increase life expectancy by up to 7 years (13). 

You could also consider taking research-backed longevity and anti-aging supplements as an alternative to metformin. Spermidine supplements, for example, may help improve longevity by promoting autophagy, the body’s way of recycling old and damaged cells. Meanwhile, NMN and resveratrol help boost NAD+ levels; declining NAD+ has been linked with aging and age-related conditions.

Conclusion

In summary, metformin—a widely-used diabetes medication—shows promising potential for extending lifespan and improving overall health. Its positive effects on metabolic function, hormone and blood sugar regulation may help prevent various health conditions that can impact longevity, from obesity and cardiovascular disease to cancer.

But while the evidence so far is encouraging, more research is needed to fully understand metformin's anti-aging and health benefits, especially in non-diabetic individuals. It’s important to remember that metformin is not a longevity supplement, but a prescription medication that may not be suitable or effective for everyone. Always consult with a healthcare professional before considering taking metformin for longevity or any other reason.

FAQs 

Can I take metformin without a prescription?

Metformin is a prescription-only medication, and unavailable over the counter or as a supplement.

How long does it take to see potential longevity benefits?

Studies have demonstrated long-term rather than short-term benefits, although anecdotal evidence suggests that people feel better in the short-term for taking it. More research is needed for a definitive answer.

Are there natural alternatives to metformin?

There are several lifestyle modifications and natural compounds that may offer similar lifespan-improving benefits to metformin. These include dietary changes, regular physical activity, adequate sleep, and maintaining a healthy weight. Some supplements, like NAD+ boosters and spermidine, have shown promising results through similar cellular pathways. Consult a doctor for natural alternatives to managing diabetes.

Can metformin be combined with other anti-aging interventions?

Yes, potentially. Metformin and spermidine, for example, work in a similar way: by promoting good cellular health. Combining them could strengthen their effects, although no research has yet been conducted on doing so.

What age should one consider taking metformin for longevity?

Metformin would be most useful for people at higher risk of age-related disease. However, people of any age could benefit from improved cellular health.