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

Shan Luo; Ian Chi Kei Wong; Celine Sze Ling Chui; Jie Zheng; Yuan Huang; Catherine Mary Schooling; Shiu Lun Au Yeung

doi:10.1016/S2666-7568(23)00085-5

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

Lancet Healthy Longev. 2023 Jul;4(7):e337-e344. doi: 10.1016/S2666-7568(23)00085-5.

Authors

Shan Luo¹, Ian Chi Kei Wong², Celine Sze Ling Chui³, Jie Zheng⁴, Yuan Huang⁵, Catherine Mary Schooling⁶, Shiu Lun Au Yeung⁷

Affiliations

¹ School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China. Electronic address: aprilluo@hku.hk.
² Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; Research Department of Practice and Policy, School of Pharmacy, University College London, London, UK.
³ School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; School of Nursing, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; Laboratory of Data Discovery for Health, Hong Kong Science and Technology Park, Hong Kong Special Administrative Region, China.
⁴ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Medical Research Council Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, UK.
⁵ Hong Kong Quantum AI Lab, The University of Hong Kong, Hong Kong Special Administrative Region, China.
⁶ School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China; School of Public Health and Health Policy, City University of New York, New York, NY, USA.
⁷ School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.

PMID: 37421961
DOI: 10.1016/S2666-7568(23)00085-5

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biological Specimen Banks
Biomarkers
Cross-Sectional Studies
Diabetes Mellitus, Type 2* / drug therapy
Diabetes Mellitus, Type 2* / genetics
Diabetes Mellitus, Type 2* / metabolism
Hemoglobin A / genetics
Humans
Metformin* / pharmacology
Metformin* / therapeutic use
Telomere / genetics
Telomere / metabolism
Transcription Factors / genetics
Transcription Factors / therapeutic use
United Kingdom

Substances

Metformin
Biomarkers
Hemoglobin A
Transcription Factors