Beyond Diabetes: Unveiling Metformin's Potential for Healthy Aging
Metformin, the diabetes medication, has been suggested to support healthy aging, revealed The Lancet Healthy Longevity ().
Role of Metformin in Longevity
Metformin is a first-line medication for type 2 diabetes. Increasing evidence suggests metformin's benefits extend far beyond diabetes and may promote healthy ageing. However, earlier observational studies can be biased, whilst clinical trials of metformin in longevity are underway and some genetic studies suggested metformin may have protective effects against other ageing-related diseases such as cancer and Alzheimer's disease. ()
To address the role of metformin in healthy longevity, the research team set out to investigate this research question by exploring the target-specific effect of metformin on biomarkers of ageing using genetics (i.e. drug-target Mendelian randomization) in a large cohort study. Since genetic variants are randomly allocated at conception, this provides a potentially less biased assessment in whether metformin may promote healthy longevity in comparison to conventional pharmacoepidemiologic studies.
‘Lowering of glycated hemoglobin (HbA1c) achieved through metformin is linked to a younger phenotypic age and longer leukocyte telomere length. #healthyaging #longevity #diabetesdrug #metformin’
The study included 321,412 white British participants from the UK Biobank with valid genomic and phenotypic data. The researchers derived ageing metrics of interest, including phenotypic age derived from chronological age and nine clinical markers, and leukocyte telomere length (LTL).
To assess the target-specific effect of metformin in biomarkers of ageing, the researchers identified variants in the protein-encoding genes related to metformin using data from the Genotype-Tissue Expression (GTEx) project and UK Biobank, with relevant statistical approaches (i.e. Mendelian randomisation and colocalisation).
The researchers also used a conventional observational design to compare biomarkers of ageing by metformin users only with users of other antidiabetic drugs via propensity score matching in UK Biobank.
Such effects might be in part due to the glycemic property of metformin. These findings from genetic analyses were corroborated by the propensity score matching analyses.
Metformin is a highly affordable medicine with a known safety profile and has long been on the WHO Model Lists of Essential Medicines. This drug-target Mendelian randomization provides genetic evidence that encourages further exploration of this safe and affordable medication to be repurposed for the promotion of healthy ageing. �Increasing evidence suggests metformin may also exert its effect via glycaemic-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 may foreshadow results from the TAME (Targeting Ageing with Metformin) trial, the first-ever anti-ageing study approved by the U.S. Food and Drug Administration, to evaluate the role of metformin in longevity, which is in its preparatory stage. �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.
References:
- Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank - (https:www.thelancet.com/journals/lanhl/article/PIIS2666-7568(23)00085-5/fulltext)
- Evaluating the efficacy and mechanism of metformin targets on reducing Alzheimer's disease risk in the general population - (https:pubmed.ncbi.nlm.nih.gov/35902387/)