Metformin Promotes Healthy Aging Based on Genetics

Using a cohort analysis of more than 300,000 participants of European origin (UK Biobank), a research team from the University of Hong Kong’s School of Public Health, LKS Faculty of Medicine (HKUMed), presents genetic evidence that metformin may promote healthy aging.

This proof-of-concept study encourages more clinical research into metformin repositioning in healthy longevity. The study’s findings were published in the journal The Lancet Healthy Longevity.

Metformin is a first-line diabetes treatment. According to growing research, it’s effects extend far beyond diabetes and may promote healthy aging. However, early observational studies can be biased, and clinical trials of metformin in longevity are currently underway, as well as certain genetic studies suggesting metformin may have protective effects against other aging-related disorders such as cancer and Alzheimer’s disease.

To address the function of metformin in healthy longevity, the research team set out to investigate this research topic in a large cohort study by investigating the target-specific effect of metformin on biomarkers of aging using genetics (i.e. drug-target Mendelian randomization). In compared to traditional pharmacoepidemiologic research, this gives a potentially less biased assessment of whether metformin may enhance healthy longevity because genetic variants are randomly assigned at conception.

Methods and findings of research

The study comprised 321,412 white British participants with valid genomic and phenotypic data from the UK Biobank. The researchers created aging measures of interest, such as phenotypic age, which was calculated using chronological age and nine clinical markers, and leukocyte telomere length (LTL).

To assess metformin’s target-specific effect in aging biomarkers, the researchers used data from the Genotype-Tissue Expression (GTEx) project and UK Biobank to identify variants in metformin-related protein-encoding genes using relevant statistical approaches (i.e. Mendelian randomization and colocalization). The researchers also employed a traditional observational approach to compare indicators of aging in metformin users solely with users of other anti-diabetic medicines in the UK Biobank using propensity score matching.

The researchers discovered that metformin target GPD13-induced HbA1c reductions were linked with younger phenotypic age and longer LTL, but AMPK2 (PRKAG2)4 was associated with only younger phenotypic age. These effects could be attributed in part to metformin’s glycemic properties. The results of the genetic analysis were confirmed by the propensity score matching analyses.

Metformin is a low-cost drug with a well-established safety profile that has long been included on the WHO Model Lists of Essential Medicines. This drug-target Mendelian randomization provides genetic data that promotes additional research into this safe and inexpensive medication that could be repurposed to promote healthy aging.

“Increasing evidence suggests metformin may also exert its effect via glycemic-independent pathways. Better understanding of mechanisms of metformin action using big data approaches and different omics is warranted and improve evaluation of its repositioning potential,” said Dr. Luo Shan, Research Assistant Professor, School of Public Health, HKUMed.

The findings could predict the findings of the TAME (Targeting Aging with Metformin) experiment, the first anti-aging study licensed by the US Food and Drug Administration to assess the role of this drug in lifespan, which is now in the planning stages.

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

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