A research team from the School of Public Health, LKS Faculty of Medicine of the University of Hong Kong (HKUMed), has provided genetic evidence that metformin might promote healthy aging using a cohort study of more than 300,000 participants of European descent (UK Biobank). 

The proof-of-concept work supports further clinical research into the drug repositioning of metformin in healthy longevity. The findings were published in The Lancet Healthy Longevity.

Background

Metformin is a first-line medication for type 2 diabetes. Increasing evidence suggests metformin’s benefits extend far beyond diabetes and may promote healthy aging. However, earlier observational studies can be biased, whilst clinical trials of metformin in longevity are underway and some genetic studies suggested metformin may have protective effects against other aging-related diseases such as cancer and Alzheimer’s disease. 

To address the role of metformin in healthy longevity, the research team set out to investigate this research question by exploring the target-specific effect of metformin on biomarkers of aging using genetics (i.e. drug-target Mendelian randomization) in a large cohort study. Since genetic variants are randomly allocated at conception, this provides a potentially less biased assessment in whether metformin may promote healthy longevity in comparison to conventional pharmaco-epidemiologic studies.

Research methods and findings

The study included 321,412 white British participants from the UK Biobank with valid genomic and phenotypic data. The researchers derived aging metrics of interest, including phenotypic age derived from chronological age and nine clinical markers, and leukocyte telomere length (LTL).

To assess the target-specific effect of metformin in biomarkers of aging, the researchers identified variants in the protein-encoding genes related to metformin using data from the Genotype-Tissue Expression (GTEx) project and UK Biobank, with relevant statistical approaches (i.e. Mendelian randomization and co-localization). The researchers also used a conventional observational design to compare biomarkers of aging by metformin users only with users of other antidiabetic drugs via propensity score matching in UK Biobank.

The research team found that glycated hemoglobin (HbA1c) lowering induced by the metformin target GPD1 were associated with younger phenotypic age and longer LTL, while AMPKγ2 (PRKAG2) was associated with younger phenotypic age only. Such effects might be in part due to the glycaemic property of metformin. These findings from genetic analyses were corroborated by the propensity score matching analyses.

Study significance

Metformin is a highly affordable medicine with a known safety profile and has long been on the WHO Model Lists of Essential Medicines. This drug-target Mendelian randomization provides genetic evidence that encourages further exploration of this safe and affordable medication to be repurposed for the promotion of healthy aging. 

“Increasing evidence suggests metformin may also exert its effect via glycaemic-independent pathways. Better understanding of mechanisms of metformin action using big data approaches and different omics is warranted and improve evaluation of its repositioning potential,” said Luo Shan, research assistant professor, School of Public Health, HKUMed.

The findings may foreshadow results from the TAME (Targeting Ageing with Metformin) trial, the first-ever anti-aging study approved by the U.S. Food and Drug Administration, to evaluate the role of metformin in longevity, which is in its preparatory stage. 

“Our work has demonstrated the utility of using large-scale epidemiologic studies and genomic data in evaluating drug reposition opportunities. Genetic validation studies, such as this study, shall help improve the success rate of subsequent clinical trials,” said Ryan Au Yeung Shiu-lun, assistant professor, School of Public Health, HKUMed.