Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank

Background: Metformin, a first-line medication for type 2 diabetes, might also have a protective effect against ageing-related diseases, but so far little experimental evidence is available. We sought to assess the target-specific effect of metformin on biomarkers of ageing in the UK Biobank. Methods: In this drug target mendelian randomisation study, we assessed the target-specific effect of four putative targets of metformin (AMPK, ETFDH, GPD1, and PEN2), involving ten genes. Genetic variants with evidence of causation of gene expression, glycated haemoglobin A_1c (HbA_1c), and colocalisation were used as instruments mimicking the target-specific effect of metformin via HbA_1c lowering. The biomarkers of ageing considered were phenotypic age (PhenoAge) and leukocyte telomere length. To triangulate the evidence, we also assessed the effect of HbA_1c on the outcomes using a polygenic mendelian randomisation design and assessed the effect of metformin use on these outcomes using a cross-sectional observational design. Findings: GPD1-induced HbA_1c lowering was associated with younger PhenoAge (β –5·26, 95% CI –6·69 to –3·83) and longer leukocyte telomere length (β 0·28, 0·03 to 0·53), and AMPKγ2 (PRKAG2)-induced HbA_1c lowering was associated with younger PhenoAge (β –4·88, –7·14 to –2·62) but not with longer leukocyte telomere length. Genetically predicted HbA_1c lowering was associated with younger PhenoAge (β –0·96 per SD lowering of HbA_1c, 95% CI –1·19 to –0·74) but not associated with leukocyte telomere length. In the propensity score matched analysis, metformin use was associated with younger PhenoAge (β –0·36, 95% CI –0·59 to –0·13) but not with leukocyte telomere length. Interpretation: This study provides genetic validation evidence that metformin might promote healthy ageing via targets GPD1 and AMPKγ2 (PRKAG2), and the effect could be in part due to its glycaemic property. Our findings support further clinical research into metformin and longevity. Funding: Healthy Longevity Catalyst Award, National Academy of Medicine, and Seed Fund for Basic Research, The University of Hong Kong.