Researchers give new insights into metformin’s life-extending effects, but is it just drugs for the boys?

Life expectancy has increased in the past few years and the ultimate goal is to target aging to produce both healthier and longer lives. Numerous compounds are under investigation as potential drugs to counteract the aging process. A promising candidate to reach healthy aging is the antidiabetic drug metformin, which has shown to prolong the lifespan in several species [1,2] and in diabetic people in their 60s [3]. However, its use in the longevity field is still controversial.

Aging is often accompanied by a decline in cardiac function [4] characterised by proinflammatory microenvironment and low mitochondrial function [5]. Metformin has shown to reduce cardiovascular mortality and morbidity [6] as well as to improve lifespan in male mice [7], whereas its life-extending effects in female mice has not been documented.

Longevity.Technology: A recent study by a team led by researchers at the Institute of Ageing Research at Hangzhou University School of Medicine investigated whether metformin exerts protective effects in myocardial metabolism and longevity in female mice. With pressure coming to bear on researchers to be more aware of differences in the sexes when formulating clinical trials and models, this study shows that gender bias isn’t consigned to history, just yet.

Zhu et al. found that 20-month-old female mice showed degenerative cardiac phenotypes, such as reduced ejection fraction, more cardiac collagen deposition, an increased heart weight-to-body weight ratio and augmented inflammatory gene expression. Metformin failed to extend lifespan of the female mice, instead displaying toxic effects, and despite lowered reactive oxygen species production, long-term metformin treatment did not improve cardiac function in the aged female mice [8].

The researchers further explored the underlying mechanisms of metformin toxicity through RNA-sequencing analysis, revealing an increase of extracellular matrix (ECM)-related genes and a lower oxidative phosphorylation-related gene expression following metformin treatment [8].

Metformin failed to extend lifespan of the female mice, instead displaying toxic effects.

Moreover, metformin treatment was found to induce metabolic reprogramming that suppressed mitochondrial respiration but activated glycolysis in cultured primary cardiomyocytes and macrophages from aged females, thereby sustaining an inflammatory status and lowering ATP production [8]. Together, these findings indicate unexpected detrimental effects of metformin on the regulation of cardiac homeostasis and longevity in female mice, thus making the role of metformin in longevity even more puzzling.

Would this imply that metformin can be used as a longevity drug in men and not in women? It must be noted that Zhu et al. [8] used a limited number of aging mice cohort, and they only tested one dosage at a one-time window. The methods of metformin delivery, dosage, intervention time point, and age factors have to be taken under consideration as they may affect the study outcomes. Due to the limitations of the study and the marginal benefit of metformin treatment observed in a myocardial infarction (MI) swine model [9], clinical trials will be needed to extrapolate animal-based findings to human cardiovascular aging/diseases.

A recent study [10], provides new evidence for metformin in improving cognitive function in old age. Indeed, metformin treatment started in late middle age improved cognitive function in old male mice [10]. Although the role of metformin in longevity has not been fully established, these findings suggest that taking metformin could be beneficial in maintaining cognitive abilities and memory in old age, thus delaying brain degeneration and contributing to healthy lifespan. However, further studies will be needed to confirm the data in female mice and clinical trials to translate animal-based findings to human scenario.

Although approved for safety, metformin is a “dirty drug”, meaning it can bind to different receptors, thus having effects on several molecular targets. Therefore, its use as a longevity drug should be carefully evaluated, in order to avoid off-targets effects that could be dangerous to patient’s life.

[1] https://link.springer.com/article/10.1007%2Fs11357-019-00146-3
[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060268/
[3] https://pubmed.ncbi.nlm.nih.gov/25041462/
[4] https://pubmed.ncbi.nlm.nih.gov/30054574/
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6146930/
[6] https://pubmed.ncbi.nlm.nih.gov/25552600/
[7] https://pubmed.ncbi.nlm.nih.gov/23900241/
[8] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877555/
[9] https://pubmed.ncbi.nlm.nih.gov/30355033/
[10] https://onlinelibrary.wiley.com/doi/10.1111/acel.1327