Does Metformin Work as an Anti-Aging Drug?

Metformin is often the first line of therapy for managing type 2 diabetes. However, recent research has shown the benefits of metformin may extend beyond diabetes; longevity scientists believe metformin may have anti-aging properties.

Here’s where the research currently stands on metformin for anti-aging and longevity and why longevity scientists are interested in the possibility of metformin as an anti-aging drug.

What is metformin?

Metformin (brand name Glucophage) is an oral medication that reduces liver glucose production (hepatic gluconeogenesis) and intestinal glucose absorption. It promotes insulin secretion and signaling so more blood glucose is taken up by skeletal muscle. [1, 2] These mechanisms make it a go-to treatment for type 2 diabetes.

While blood sugar levels and metabolic health play a vital role in healthy aging, metformin’s effect on aging appears to impact numerous body systems and potentially offer a range of benefits beyond blood sugar control to people with and without type 2 diabetes.

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Does metformin slow aging and improve longevity?

Studies thus far hint that metformin may slow aging processes and promote longevity. This is where the research currently stands on metformin's link to measures of aging.

Type 2 diabetes is associated with Alzheimer’s disease, and it’s theorized that metformin may improve cognition. Researchers of a pilot study of individuals with mild cognitive impairment—who didn’t have diabetes—found that eight weeks of metformin use was associated with better executive functioning. Even more, the results indicated enhanced learning, memory, and attention. [3]

Another study noticed a 51% reduced risk of cognitive impairment with metformin use, with the lowest risk observed in participants who took metformin for more than six years. [4]

In a study of people with heart failure and type 2 diabetes, those who took metformin had a lower incidence of cardiac events, fewer deaths from cardiovascular disease, and reduced all-cause mortality. However, there was no effect of metformin on cardiac events in patients without diabetes. [5]

Pooled analysis of large studies In one meta-analysis, cancer diagnosis was reduced by 31% and deaths from cancer by 34% in people with diabetes taking metformin. [6]

One large systematic review found that people with diabetes taking metformin had lower all-cause mortality than people without diabetes. Diabetic metformin users had lower all-cause mortality than people with diabetes taking other non-metformin medications. Together, these results suggest that metformin may protect against aging. [7]

What are the potential anti-aging benefits of metformin?

Metformin influences multiple physiological processes related to aging. But how exactly metformin affects aging is not yet clear. Researchers are investigating whether metformin slows aging by acting on multiple pathways or one pathway with many downstream effects. [8]

Researchers think some ways metformin potentially slows aging include the following:

• Regulating metabolism and insulin sensitivity: Metformin activates the enzyme AMP-kinase, an energy sensor and regulator of glucose, fat, and protein metabolism. AMP-kinase alters liver glucose production to restore energy balance, improve insulin signaling and sensitivity, and encourage greater uptake of glucose in skeletal muscle. The root of many age-related disorders is inflammation, which is associated with glucose dysregulation and insulin resistance. [1, 2]
• Protecting against protein damage: Many age-related neurodegenerative diseases (Parkinson’s and Alzheimer’s) are associated with the build-up of damaged proteins. In mouse models, metformin appears to prevent protein damage. [2]
• Mediating inflammation: Metformin’s effect on inflammation is two-fold: it reduces pro-inflammatory and increases anti-inflammatory molecules. Moreover, metformin indirectly influences inflammation through its impact on body composition and insulin. [1, 2]
• Reducing oxidative damage: Chronic high blood sugar levels contribute to oxidative stress, which damages cells. Metformin may provide an antioxidative effect, but the exact mechanism has yet to be determined. [1]
• Slowing cellular senescence: Cellular senescence (when cells stop dividing and functioning correctly) contributes to the onset of age-related diseases. In cell studies, metformin delays cellular senescence, reducing the impact of senescent (“dead”) cells on aging. [2]
• Promoting positive stress: Some stress is actually beneficial for the body. Metformin may promote hormesis, the adaptive response of the cell to stress. Adapting to stress can benefit health, and hormesis is vital to normal physiological functioning. Hormesis can also occur in response to exercise or dietary restrictions. [9, 10]
• Encouraging cellular autophagy and apoptosis: Metformin may stimulate autophagy (the removal of damaged proteins and cells), potentially slowing aging. [2]

» Learn more about science behind supplements to slow aging

Dr. Nir Barzaili on genetics and lifestyle factors of centenarians

Through ongoing research, longevity scientists hope to understand how best to target aging to extend lifespan and improve healthspan. In particular, the ongoing TAME study by Dr. Nir Barzaili is evaluating the effect of metformin on aging in individuals without diabetes.

Can people without type 2 diabetes use metformin?

The Food and Drug Administration (FDA) approved metformin for off-label use, so technically people without type 2 diabetes can use this drug. However, a prescription from a physician is required to obtain metformin.

As mentioned earlier, researchers have discovered a lower risk of all-cause mortality in diabetes patients on metformin compared to those without diabetes. Similarly, a matched study between people with and without diabetes found increased survival rates in those with diabetes using metformin. And people on metformin had longer survival than those taking other diabetes medications. [7, 11]

Metformin does seem to positively affect processes related to aging. However, additional research is needed to determine if metformin can specifically target aging to increase lifespan and health span and whether and to what extent those benefits extend to all individuals or just those with type 2 diabetes. [12]

What are the side effects of metformin?

Generally, the side effects of metformin are isolated to gastrointestinal distress and are relatively mild. Side effects include: [13]

• Diarrhea, constipation, and stomach pain
• Bloating, gas, and indigestion
• Headache
• Unpleasant metallic mouth taste
• Heartburn
• Skin flushing

Metformin also increases the risk of lactic acidosis (the accumulation of lactic acid), which can cause severe consequences if untreated. Long-term use of metformin may result in vitamin B12 deficiency, so it’s important to monitor B12 levels while taking metformin. [14]

Dr. David Sinclair on learnings since Lifespan

Some longevity scientists like David Sinclair already take metformin to slow aging.

As an expert in longevity, Dr. David Sinclair—a longevity researcher and a board member of InsideTracker—takes metformin to extend his lifespan.

Dr. Sinclair takes metformin in the evening as insulin sensitivity decreases throughout the day. And Dr. Sinclair alternates days of taking metformin and exercising. [15]

Studies have shown that concurrent use of metformin and regular physical activity may affect physiological responses to exercise. In particular, when taken together, metformin may reduce some benefits of exercise, such as improved insulin sensitivity and muscle growth. [12]

What is InsideTracker’s stance on metformin for longevity?

As metformin is a prescription drug, it is up to you and your healthcare provider to decide whether you should consider metformin. InsideTracker will continue to monitor the research on metformin for longevity and can provide reliable educational information on the topic.

What other steps can you take to reverse aging and encourage longevity?

• Intermittent fasting: Intermittent fasting (IF) may increase cellular resilience, so cells adapt to stress, activating processes that may result in longevity. IF may slow aging and protect against aging-related diseases. [16]
• Strength-based exercise: Resistance training is associated with a 21% reduced risk of all-cause mortality. The benefits of strength-based exercise are extensive—regular physical activity results in changes to body composition and glucose metabolism, which influences the risk of aging-related diseases. [17]
• Manage stress: High stress levels negatively affect health, so managing stress can benefit longevity. Maintaining a joyful and optimistic outlook positively influences stress and can help extend lifespan. [18]
• Maintain good blood glucose levels: Persistently elevated blood sugar levels can contribute to whole-body inflammation. Research in diabetes patients showed that greater variations in blood sugar levels are associated with increased vascular issues and mortality. Regular exercise and opting for whole grains, foods with low glycemic indices, and healthy fats can help regulate blood glucose levels. [19]

References:

[1] https://pubmed.ncbi.nlm.nih.gov/33562458/

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347426/

[3] https://pubmed.ncbi.nlm.nih.gov/28538088/

[4] https://pubmed.ncbi.nlm.nih.gov/24577463/

[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6668189/

[6] https://pubmed.ncbi.nlm.nih.gov/24985407/

[7] https://pubmed.ncbi.nlm.nih.gov/28802803/

[8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5943638/

[9] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2248601/

[10] https://pubmed.ncbi.nlm.nih.gov/34365027/

[11] https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.12354

[12] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374068/

[13] https://medlineplus.gov/druginfo/meds/a696005.html

[14] https://pubmed.ncbi.nlm.nih.gov/31405774/

[15] David A. Sinclair. (2019); Lifespan: Why We Age—and Why We Don’t Have To; Atria Books

[16] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411330/

[17] https://pubmed.ncbi.nlm.nih.gov/31104484/

[18] https://pubmed.ncbi.nlm.nih.gov/28789793/

[19] https://cardiab.biomedcentral.com/articles/10.1186/s12933-020-01085-6