Metformin shows potential as a low-cost antiageing medication

Metformin may promote healthy ageing via targeting GPD1 and AMPKγ2, a Mendelian randomization study by the University of Hong Kong (HKU) has shown.

Increasing evidence suggests that metformin may provide benefits far beyond diabetes and may have a protective effect against age-related diseases such as cardiovascular disease, cancer, Alzheimer’s disease and osteoarthritis. [Sig Transduct Target Ther 2022;7:391; Lancet Healthy Longev 2023;4:e337-e344]

“However, observational studies can be biased, whereas the long-discussed randomized controlled TAME [Targeting Ageing with Metformin] trial is still at a preparatory stage,” said the researchers. Mendelian randomization study utilizes genetic variants randomly allocated at conception, which is less susceptible to confounding than observational studies. In the absence of data from large-scale randomized controlled trials, the use of genetic variants could provide another source of evidence on the potential antiageing effect of metformin. [Lancet Healthy Longev 2023;4:e337-e344]

“This is one of the first drug target Mendelian randomization studies to comprehensively explore the target-specific effect of metformin on ageing biomarkers [ie, phenotypic age and leukocyte telomere length],” highlighted the researchers.

The study included 321,412 individuals (mean age, 56.9 years; male, 46.4 percent) from the UK Biobank and assessed four putative metformin targets (AMPK, ETFDH, GPD1, and PEN2) and their corresponding 10 encoding genes.

GPD1 and AMPKγ2 were associated with young phenotypic age (GPD1: β, -5.26; 95 percent confidence interval [CI], -6.69 to -3.83) (AMPKγ2: β, -4.88; 95 percent CI, -7.14 to -2.62). Furthermore, GPD1, but not AMPKγ2, was associated with longer leukocyte telomere length (β, 0.28; 95 percent CI, 0.03–0.53).

To triangulate the putative findings from the Mendelian randomization study, the researchers further assessed the ageing biomarkers by comparing metformin users (n=3,075) with other antidiabetic drug users (n=17,981) in a propensity score analysis.

“Metformin use was associated with younger phenotypic age [β, -0.36; 95 percent CI, -0.59 to -0.13], but not with longer leukocyte telomere length [β, -0.04; 95 percent CI, -0.09 to 0.01] vs use of other antidiabetic drugs,” reported the researchers.

“The putative effects might be in part due to the [antiglycaemic] property of metformin,” they noted.

“Increasing evidence suggests metformin may also exert its effect via glycaemic-independent pathways,” said Dr Shan Luo of School of Public Health, HKU.

AMPK activation is a frequently proposed mechanism of action (MoA) of metformin, which leads to reduction of inflammatory responses and oxidative stress. [Biochimie 2018;154:62-68] “This proposed mechanism is consistent with studies showing reduced AMPK activity with ageing,” added the researchers. “A more recently proposed MoA of metformin is increased cytosolic redox state due to inhibition of mitochondrial GPD activity, which may also account for the potential biological ageing-related benefit of metformin.”

Metformin – a highly affordable medicine with a well-established safety profile – has long been on the WHO Model List of Essential Medicines. The current proof-of-concept study supports further clinical research on repositioning of metformin as an antiageing medication. [https://global.essentialmeds.org/dashboard/medicines; Lancet Healthy Longev 2023;4:e337-e344]