The Impact of Metformin on Placental Ageing in Humans and Mice

Hattersley GJ, et al. J Physiol. 2025 Jun;603(11):3463-3477. Epub 2025 May 31. PMID: 40448705; PMCID: PMC12148204.

This study investigated whether metformin influences placental ageing in pregnancies affected by maternal obesity. Placental ageing, characterized by telomere shortening, fibrosis, calcification, and transcriptomic changes, is accelerated in adverse pregnancy outcomes such as pre-eclampsia and fetal growth restriction. Given metformin’s proposed anti-ageing properties in other contexts, the authors examined its potential to modulate placental ageing.

The researchers used three complementary models: human placentas from the EMPOWaR randomized controlled trial (n=105), where obese pregnant women received metformin or placebo; in vitro human trophoblast cultures treated with metformin; and an obese mouse model, with metformin administered before and during pregnancy. Key findings include:

• No significant differences observed in placental telomere length, fibrosis, or calcification between metformin and placebo groups.
• DNA methylation analysis using placental “epigenetic clocks” showed no difference in predicted gestational age between groups.
• Transcriptomic analysis (RNAseq and microarray) revealed no enrichment of ageing-related gene pathways or senescence markers with metformin treatment.
• in vitro, metformin altered expression of two genes (PPARGC1A and ERBB4), but these changes were not consistent with a broader anti-ageing effect.
• Mouse placentas showed minimal transcriptomic changes with metformin, and no enrichment of senescence or preterm birth-associated gene sets. 

The authors conclude that metformin does not appear to accelerate or decelerate placental ageing in obese pregnancies. These findings support the continued use of metformin for gestational diabetes management but do not support its use for preventing placental ageing-related complications in non-diabetic pregnancies.