Metformin for Longevity? Benefits and Dosing Explained

Metformin, traditionally used for treating type 2 diabetes, has been found to have benefits beyond just controlling glucose levels. New research suggests metformin may have benefits for heart health, brain health, and even anti-cancer effects - all important for promoting longevity and health span.

What is Metformin?

Metformin was synthesized in 1922 from compounds discovered in 1918 from herbal preparations of goat's rue. Metformin acts all over the body, especially in the liver, to reduce glucose production and increase insulin sensitivity. Importantly, metformin activates a protein called AMPK (AMP-activated protein kinase), a "master regulator of cellular energy homeostasis." AMPK activation appears to support metformin's positive impact on longevity effects, including:

• Anti-inflammation
• Mitochondrial biogenesis
• Oxidative stress reduction
• Autophagy
• Metabolic health support

Indeed, a study from the UK found that patients with diabetes taking metformin lived longer than patients without diabetes. However, some studies show other results, and we are awaiting results from the ANTHEM and TAME trials to give us more definitive data on the longevity benefits of metformin.

Metformin's Effects on Aging: Epigenetics and Genetic Regulation

Emerging evidence indicates that metformin might slow the aging process as measured by epigenetic DNA markers. The slowed aging process may be from metformin's ability to stabilize DNA to protect against DNA damage and age-related diseases. Metformin also appears to protect stem cells from damage, especially in patients with kidney disease.

Cardiovascular Health and Metformin

Clinical evidence suggests metformin improves heart health even in patients without diabetes. Metformin's heart health benefits are likely from its correction of endothelial dysfunction, reduction of oxidative stress and improved inflammatory response. Specifically, metformin's anti-inflammatory effects can support cardiovascular health by reducing the neutrophil-to-lymphocyte ratio. However, some studies show that metformin might interfere with some heart health benefits of exercise, so you should always discuss the benefits and drawbacks of any intervention with your doctor.

Metformin and Neurological Health

Metformin may also protect against cognitive decline and neurodegenerative disorders. A recent study in patients over 59 years old demonstrated 66% reduction in dementia in patients with diabetes taking metformin. Importantly, the relationship was dose dependent, with greater protection with higher doses. This may be because of metformin's modulation of glucose metabolism, reduction in neuroinflammation, and enhancement of cholinergic activity - all of which are important for peak cognitive performance.

However, it is important to note that not all studies have shown associations with metformin and reductions in dementia. This may be because of failure to monitor vitamin B12 levels, which can affect cognitive performance on metformin therapy.

Also, metformin appears to have a more beneficial effect towards neurodegenerative disease in people with Asian ancestry.

ALS, FTD, and Metformin

ALS (amyotrophic lateral sclerosis, AKA Lou Gehrig's disease) is a devastating neurogenerative condition that has a curiously strong link with metformin use. Retrospective studies show that patients with diabetes taking metformin (or insulin) show a ~50% risk reduction in developing ALS. In mice, frontotemporal dementia (FTD) also appears conductive to metformin treatment. We do not yet know why metformin reduces these risks, though we believe it is through interfering with abnormal protein synthesis pathways.

Anti-Tumor and Cancer Effects of Metformin

Cancerous cells need glucose for energy to grow and multiply. Metformin directly inhibits this pathway by disrupting insulin signaling in cancerous cells. Indirectly, metformin can enter cancer cells and activate AMPK to slow down cancer cell growth. This is because AMPK is a general "slow down" signal for cells to enter autophagy and halt cell division.

Multiple studies demonstrate potential efficacy of combining metformin with traditional anti-cancer modalities for additive benefit.

Metformin, Gut Health, and Longevity

Metformin also appears to promote a more healthy gut microbiome. These changes appear to improve glucose tolerance, demonstrating metformin's metabolic support beyond just its effects on human cells.

Optimal Dosing for Longevity

Metformin studies for longevity typically use doses used in diabetes treatment (1500-2000mg/day). Metformin's half-life is roughly 6 hours, and can remain in cells and tissues for up to 24 hours. Some protocols will alternate exercise and metformin days to hypothetically minimize unwanted side effects (below).

Potential Concerns and Limitations

Metformin has decades of clinical use and is known to have an overall favorable side effect profile. Metformin has been associated with B12 deficiency and gastrointestinal discomfort. Our doctors at Clarus Health closely monitor blood tests to make sure B12 deficiency does not raise homocysteine levels or interfere with metabolism.

Metformin can block mitochondrial complex 1, reducing levels of ATP production, and lead to lactic acidosis. However, this side effect was much more common with historical medications in metformin's class than with metformin itself.

Despite its many benefits, metformin may blunt the physiological adaptations to exercise, such as muscle hypertrophy and VO2 max. Some of these effects appear very mild. It used to be thought that metformin attenuates the improvements in insulin sensitivity from physical activity, but this may not be the case. This suggests that its benefits for longevity must be carefully balanced against possible limitations, particularly in physically active populations.

Balancing Potential Benefits and Risks of Metformin

Given metformin's longstanding use, it is appealing to many patients, especially those with diabetes. Medical supervision is very important, and your longevity doctor should monitor your labs throughout treatment and tailor your protocol based on your individual health assessment. Speak with an expert at Clarus Health today to learn if metformin may be helpful for your longevity goals.