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Article: Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank
| Title | Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank |
|---|---|
| Authors | |
| Issue Date | 6-Jul-2023 |
| Publisher | Elsevier |
| Citation | The Lancet Healthy Longevity, 2023, v. 4, n. 7, p. 337-344 How to Cite? |
| Abstract | BackgroundMetformin, 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. MethodsIn 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 A1c (HbA1c), and colocalisation were used as instruments mimicking the target-specific effect of metformin via HbA1c lowering. The biomarkers of ageing considered were phenotypic age (PhenoAge) and leukocyte telomere length. To triangulate the evidence, we also assessed the effect of HbA1c 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. FindingsGPD1-induced HbA1c 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 HbA1c lowering was associated with younger PhenoAge (β –4·88, –7·14 to –2·62) but not with longer leukocyte telomere length. Genetically predicted HbA1c lowering was associated with younger PhenoAge (β –0·96 per SD lowering of HbA1c, 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. InterpretationThis 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. |
| Persistent Identifier | http://hdl.handle.net/10722/329180 |
| ISSN | 2023 Impact Factor: 13.4 2023 SCImago Journal Rankings: 4.324 |
| DC Field | Value | Language |
|---|---|---|
| dc.contributor.author | Luo, Shan | - |
| dc.contributor.author | Wong, Ian Chi Kei | - |
| dc.contributor.author | Chui, Celine Sze Ling | - |
| dc.contributor.author | Zheng, Jie | - |
| dc.contributor.author | Huang, Yuan | - |
| dc.contributor.author | Schooling, Catherine Mary | - |
| dc.contributor.author | Au Yeung, Shiu Lun | - |
| dc.date.accessioned | 2023-08-05T07:55:53Z | - |
| dc.date.available | 2023-08-05T07:55:53Z | - |
| dc.date.issued | 2023-07-06 | - |
| dc.identifier.citation | The Lancet Healthy Longevity, 2023, v. 4, n. 7, p. 337-344 | - |
| dc.identifier.issn | 2666-7568 | - |
| dc.identifier.uri | http://hdl.handle.net/10722/329180 | - |
| dc.description.abstract | <h3>Background</h3><p><a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/glycon" title="Learn more about Metformin from ScienceDirect's AI-generated Topic Pages">Metformin</a>, a first-line medication for type 2 diabetes, might also have a protective effect against ageing-related <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/disease" title="Learn more about diseases from ScienceDirect's AI-generated Topic Pages">diseases</a>, 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.</p><h3>Methods</h3><p>In this <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/chemotherapeutic-agent" title="Learn more about drug from ScienceDirect's AI-generated Topic Pages">drug</a> target <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/mendelian-randomization-analysis" title="Learn more about mendelian randomisation from ScienceDirect's AI-generated Topic Pages">mendelian randomisation</a> 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<sub>1c</sub> (HbA<sub>1c</sub>), and colocalisation were used as instruments mimicking the target-specific effect of metformin via HbA<sub>1c</sub> lowering. The biomarkers of ageing considered were phenotypic age (PhenoAge) and leukocyte <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/telomere" title="Learn more about telomere from ScienceDirect's AI-generated Topic Pages">telomere</a> length. To triangulate the evidence, we also assessed the effect of HbA<sub>1c</sub> 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.</p><h3>Findings</h3><p>GPD1-induced HbA<sub>1c</sub> 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 (<em>PRKAG2</em>)-induced HbA<sub>1c</sub> lowering was associated with younger PhenoAge (β –4·88, –7·14 to –2·62) but not with longer leukocyte telomere length. Genetically predicted HbA<sub>1c</sub> lowering was associated with younger PhenoAge (β –0·96 per SD lowering of HbA<sub>1c</sub>, 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.</p><h3>Interpretation</h3><p>This study provides genetic validation evidence that metformin might promote healthy ageing via targets GPD1 and AMPKγ2 (<em>PRKAG2</em>), and the effect could be in part due to its <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/glycemic" title="Learn more about glycaemic from ScienceDirect's AI-generated Topic Pages">glycaemic</a> property. Our findings support further <a href="https://www.sciencedirect.com/topics/medicine-and-dentistry/clinical-research" title="Learn more about clinical research from ScienceDirect's AI-generated Topic Pages">clinical research</a> into metformin and longevity.</p> | - |
| dc.language | eng | - |
| dc.publisher | Elsevier | - |
| dc.relation.ispartof | The Lancet Healthy Longevity | - |
| dc.rights | This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. | - |
| dc.title | Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank | - |
| dc.type | Article | - |
| dc.description.nature | published_or_final_version | - |
| dc.identifier.doi | 10.1016/S2666-7568(23)00085-5 | - |
| dc.identifier.scopus | eid_2-s2.0-85164254669 | - |
| dc.identifier.volume | 4 | - |
| dc.identifier.issue | 7 | - |
| dc.identifier.spage | 337 | - |
| dc.identifier.epage | 344 | - |
| dc.identifier.eissn | 2666-7568 | - |
| dc.identifier.issnl | 2666-7568 | - |