A research team from the University of Hong Kong’s School of Public Health has presented compelling genetic evidence that metformin, a drug commonly used to treat type 2 diabetes, may contribute to healthy aging.
Their findings, based on a cohort study of over 300,000 participants from the UK Biobank of European descent, support the potential of metformin for promoting longevity and healthy aging. The study’s results were published in The Lancet Healthy Longevity.
Metformin is a widely recognized first-line medication for managing type 2 diabetes. However, emerging evidence has suggested its broader benefits, potentially reaching beyond diabetes treatment to foster healthy aging. Although earlier observational studies hinted at these effects, biases could have influenced their outcomes.
To address this concern, the research team adopted a novel approach called drug-target Mendelian randomization, utilizing genetics to gain insights into metformin’s impact on biomarkers of aging with minimal bias.
The study encompassed 321,412 white British participants from the UK Biobank, all possessing valid genomic and phenotypic data. The researchers meticulously analyzed aging metrics, including phenotypic age derived from chronological age and nine clinical markers, along with leukocyte telomere length (LTL).
Using data from the Genotype-Tissue Expression (GTEx) project and the UK Biobank, the scientists pinpointed genetic variants associated with metformin and deployed Mendelian randomization and co-localization techniques to assess the drug’s target-specific effects on aging biomarkers.
Additionally, they utilized a conventional observational design, employing propensity score matching in the UK Biobank, to compare aging biomarkers among metformin users and users of other antidiabetic medications.
The team’s findings revealed that the metformin target GPD1, which reduces glycated hemoglobin (HbA1c) levels, was linked to a younger phenotypic age and longer LTL. Moreover, AMPKγ2 (PRKAG2), another metformin target, showed an association with a younger phenotypic age alone. These effects could be partially attributed to metformin’s glycaemic properties. Importantly, the genetic analyses concurred with the results from propensity score matching analyses.
Metformin is valued for its cost-effectiveness, established safety profile, and long-standing inclusion on the WHO Model Lists of Essential Medicines. The genetic evidence presented in this study highlights its potential as a candidate for repurposing in the pursuit of healthy aging.
Luo Shan, a research assistant professor at the School of Public Health, HKUMed, emphasized that metformin might exert its effects through glycaemic-independent pathways. To gain a more comprehensive understanding of metformin’s mechanisms, Shan proposed delving into big data approaches and various omics to further evaluate its potential as a drug for healthy aging.
Additionally, this study’s findings hold promise for the ongoing TAME (Targeting Ageing with Metformin) trial, the first anti-aging study approved by the U.S. Food and Drug Administration. The TAME trial aims to investigate metformin’s role in promoting longevity, and these genetic insights could provide valuable guidance.
Ryan Au Yeung Shiu-lun, an assistant professor at the School of Public Health, HKUMed, expressed optimism about the utility of large-scale epidemiologic studies and genomic data in assessing drug repositioning opportunities.