Scientists have confirmed yet another positive effect of metformin: its prolonged use by people with diabetes lowers the risk of cognitive impairment and cerebral small vessel disease .
Metformin is one of the top candidate geroprotective (life-prolonging) drugs for several reasons. First, it has been shown to extend lifespan and healthspan in animal models and to improve health in humans. Second, it is dirt cheap and not patented anymore, so it can be easily and widely distributed. Third, we know metformin is safe, since it has been used to treat diabetes for decades.
A major human trial of metformin as an anti-aging agent is currently underway. It is called Treating Aging with Metformin (TAME) and is aimed at proving that metformin can delay the onset of several age-related diseases at once.
Metformin works mostly as a caloric restriction mimetic . It increases insulin sensitivity, which is why it is used against diabetes, and activates the enzyme AMPK, which triggers the “survival mode” in cells as if energy levels were low. This “less growth, more conservation” mode turns out to be beneficial for our health, especially later in life. You can read a more thorough summary of metformin here.
While we will be waiting breathlessly for TAME’s results to come in so we can understand whether metformin does prolong lifespan and healthspan in humans, some beneficial effects of metformin have already been well-documented, though mainly in diabetes patients.
Metformin and brain health
In this new study, the researchers wanted to see whether metformin can alleviate cognitive impairment (CI) and cerebral small vessel disease (CSVD) in elderly patients that suffer from type 2 diabetes, which is a known risk factor both for CI and CSVD. The researchers recruited 234 patients with type 2 diabetes from the memory clinic in Hebei General Hospital in China. The participants were divided into two groups by duration of metformin use: one group had taken it for less than six years, and the other had taken it for more. MRI scans were used to study brain morphology, and Mini-Mental State Examination (MMSE) tests were used to assess cognitive status.
CSVD itself is a major cause of cognitive impairment . Research shows that it accounts for about half of dementia cases worldwide, and that’s not all: by affecting small blood vessels in the brain, CSVD can trigger stroke and psychiatric disorders. While several studies have already shown that metformin alleviates CI, this one is novel in that it also accounts for CSVD.
Long-term metformin treatment turned out to be highly negatively correlated with CI and CSVD. The correlation remained statistically significant even after correcting for various possible confounders, such as age, hypertension, history of stroke, body mass index, etc. Since diabetes patients sometimes switch drugs, the researchers were able to include other anti-diabetes drugs in their analysis, and none of those showed any significant effect on CI and CSVD. This echoes previous research that singled out metformin as having clear beneficial effects outside its primary use.
Moreover, among all the factors measured, metformin had the strongest correlation with CI, even stronger than the history of stroke. For CSVD, history of stroke and hypertension were stronger predictors. Since CSVD burden correlated with both metformin use and CI, the researchers looked for the mediation effect – that is, to what extent CI is impacted by CSVD rather than by metformin. They found the effect to be a bit less than 30%. This means that metformin is solely responsible for more than two-thirds of the impact.
The authors also propose a possible mechanism for this effect. AMPK, which is constantly activated by metformin, is highly expressed in brain cells – neurons, astroglia, and astrocytes. There is evidence that AMPK promotes the integrity of the blood-brain barrier (BBB) and improves endothelial health (endothelium is the inner layer of blood vessels, and its degradation is age-related). Both BBB dysfunction and endothelial cell dysfunction are major factors of CSVD pathogenesis. Other possible mechanisms include lowering inflammation and oxidative stress, for which metformin has been credited by previous research.
It is worth noting that a couple of other studies failed to demonstrate a positive effect of metformin on CI, and one even showed an opposing relationship . There are some factors that might explain this, such as the duration of treatment. Short-term metformin treatment might not be enough; in this new study, the effect was observed in the over six-year group.
This is not the biggest nor the most robust metformin study to date, but it illuminates an important new aspect of metformin’s action by showing that prolonged use of metformin can alleviate cerebral small vessel disease and cognitive impairment. This reinforces metformin’s reputation as a multi-action drug that affects some underlying mechanisms of aging rather than the symptoms of a specific disease.
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 Teng, Z., Feng, J., Qi, Q., Dong, Y., Xiao, Y., Xie, X., … & Lv, P. (2021). Long-Term Use of Metformin Is Associated With Reduced Risk of Cognitive Impairment With Alleviation of Cerebral Small Vessel Disease Burden in Patients With Type 2 Diabetes. Frontiers in Aging Neuroscience, 13.
 Lee, S. H., & Min, K. J. (2013). Caloric restriction and its mimetics. BMB reports, 46(4), 181.
 Li, Q., Yang, Y., Reis, C., Tao, T., Li, W., Li, X., & Zhang, J. H. (2018). Cerebral small vessel disease. Cell transplantation, 27(12), 1711-1722.
 Porter, K. M., Ward, M., Hughes, C. F., O’Kane, M., Hoey, L., McCann, A., … & McNulty, H. (2019). Hyperglycemia and metformin use are associated with B vitamin deficiency and cognitive dysfunction in older adults. The Journal of Clinical Endocrinology & Metabolism, 104(10), 4837-4847.