Diabetes drug could promote healthy aging

Researchers from the LKS Faculty of Medicine at The University of Hong Kong (HKUMed) have provided genetic evidence that metformin may promote healthy aging, using a cohort study of more than 300,000 participants of European descent. Published in The Lancet Healthy Longevity, the team’s proof-of-concept work supports further clinical research into repositioning metformin for healthy longevity.

Metformin is a first-line medication for type 2 diabetes, with evidence suggesting the drug may promote healthy aging. The research team set out to investigate this by exploring the target-specific effect of metformin on biomarkers of aging using genetics (ie, drug-target Mendelian randomisation) 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 pharmacoepidemiologic studies.

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 (ie, Mendelian randomisation and colocalisation). 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 team found that glycated haemoglobin (HbA1c) lowering induced by the metformin target GPD1 were associated with younger phenotypic age and longer LTL, whilst AMPKγ2 (PRKAG2) was associated with younger phenotypic age only; such effects might be in part due to the glycaemic property of metformin, the researchers suggested. Findings from genetic analyses were corroborated by the propensity score matching analyses.

“Increasing evidence suggests metformin may … exert its effect via glycaemic-independent pathways,” said HKUMed’s Dr Luo Shan. “Better understanding of mechanisms of metformin action using big data approaches and different omics is warranted.”

The drug-target Mendelian randomisation provides genetic evidence that encourages further exploration of metformin — an affordable medicine with a known safety profile — to be repurposed for healthy aging. Indeed, the findings may foreshadow the results of the US-based Targeting Aging with Metformin (TAME) trial, which is currently in its preparatory stage.

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

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