Metformin Could Help To Promote Healthy Aging

A study has found genetic evidence that the diabetes drug metformin may help to promote healthy aging, according to data from 300,000 people from the United Kingdom (UK) Biobank. The research is published in The Lancet Healthy Longevity.

Understanding metformin

Metformin is a drug used to treat type 2 diabetes and also helps to prevent diabetes in those at risk of developing the condition. It works in several different ways, including helping to reduce glucose production in the liver and increasing the effects of insulin. For example, metformin lowers levels of hemoglobin A1c (HbA1c), an indicator of blood sugar levels.

Metformin is a cost-effective, readily available drug that has been included in the World Health Organization’s Model Lists of Essential Medicines for many years.

Previous studies have suggested that metformin could have far-reaching effects aside from the treatment of diabetes – in 2017, a meta-analysis of 53 studies showed that metformin could reduce all-cause mortality and aging-related diseases.

However, some of these early observational studies can be biased, and randomized controlled trials aiming to explore the role of metformin in longevity are still in their early stages.

With this lack of experimental data, researchers in the current study used genetics-based approaches to investigate the effects of metformin on aging-related disease using specific markers of aging.

Lowering aging markers

The team, led by researchers from The University of Hong Kong Faculty of Medicine, assessed data from over 300,000 participants in the UK Biobank – a large database of anonymized genetic, lifestyle and health information from UK volunteers of European descent. The resource includes data from blood samples, heart and brain scans and genetic analysis, and is globally accessible to approved researchers. They looked at 4 targets of metformin – AMP-activated protein kinase (AMPK), electron transfer flavoprotein dehydrogenase (ETFDH), glycerol-3-phosphate dehydrogenase 1 (GPD1) and presenilin enhancer 2 (PEN2), and their associated genes, and how they might influence aging.

As there is no gold-standard biomarker for aging, the researchers assessed participants’ phenotypic age (a measure of 10 variables, including their chronological age) as well as leukocyte telomere length (LTL) – the lengths of the ends of chromosomes (telomeres) in white blood cells, which typically decrease with age.

The research team found that HbA1c lowering – induced by the metformin target GPD1 – was associated with younger phenotypic age and longer LTL, while AMPKγ2 – a variant of AMPK – was associated only with younger phenotypic age.

The researchers state that this could, at least in part, be due to metformin’s effects on blood sugar: “The beneficial effects of metformin on aging could involve HbA1c lowering via GPD1 and AMPKγ2 targets, indicating that the glycemic property of metformin could be one of its mechanistic pathways,” the authors write in the study. “Future studies of specific downstream targets and signatures (e.g., proteomics and lipidomics) would improve understanding of the underlying mechanisms by which metformin could affect longevity.”

Supporting further research

This proof-of-concept work suggests that metformin might promote healthy aging via targets GPD1 and AMPKγ2 and supports further clinical research into the repurposing of metformin in healthy longevity. The findings may foreshadow results from the TAME (Targeting Aging with Metformin) trial, the first anti-aging study approved by the US Food and Drug Administration to evaluate the role of metformin in longevity.

“Our work has demonstrated the utility of using large-scale epidemiologic studies and genomic data in evaluating drug reposition opportunities,” said Dr. Ryan Au Yeung Shiu-lun, senior author of the study and assistant professor at the University of Hong Kong’s School of Public Health. “Genetic validation studies, such as this study, shall help improve the success rate of subsequent clinical trials.”

Reference: Luo S, Wong ICK, Chui CSL, et al. Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomization study using data from the UK Biobank. Lancet Healthy Longev. 2023;4(7):e337-e344. doi: 10.1016/S2666-7568(23)00085-5

This article is a rework of a press release issued by the University of Hong Kong. Material has been edited for length and content.