Metformin Rewrites Epigenetic Aging Rotifer Model Study Shows

Metformin – a Promising Anti-Aging Agent

Metformin, a frontline treatment for type 2 diabetes, is increasingly recognized as a promising anti-aging agent, acting through complex epigenetic modifications that extend beyond its traditional role as a diabetes medication.  Metformin has been shown to slow epigenetic aging in humans by up to 2.5 years, suggesting effects that reach far beyond glucose regulation. Its anti-aging potential is linked to its capacity to reshape the epigenetic landscape, including DNA methylation, histone modifications, and notably, RNA methylation.  Recent research from Nanjing Normal University and the Jiangsu Province Key Laboratory of Live Food for Fisheries highlights its ability to modulate RNA epigenetics, particularly m6A RNA methylation, thereby influencing cellular aging processes and longevity.

Rotifers Offer Unique Advantages for Aging Research

To investigate the molecular mechanisms behind metformin’s anti-aging effects, researchers have increasingly relied on the rotifer Brachionus asplanchnoidis,a uniquely suited yet underutilized model organism in aging research. This transparent, aquatic invertebrate boasts several advantages: a short 14-day lifespan, clonal reproduction, and approximately 70% genetic homology with humans. Critically, rotifers possess a conserved N6-methyladenosine (m6A) RNA modification system that closely resembles that of vertebrates, making them highly relevant for studying epitranscriptomic regulation.

Unlike more traditional invertebrate models such as C. elegans and Drosophila, rotifers lack complex and confounding life cycle stages like diapause, which can obscure aging studies. Their simple anatomy and optical transparency enable real-time, high-resolution observation of cellular and molecular changes associated with aging. Furthermore, their vertebrate-like m6A landscape allows researchers to explore RNA methylation dynamics and how interventions like metformin reshape these patterns to influence longevity. Altogether, these features establish rotifers as a powerful model system for dissecting the role of m6A modifications in aging and for evaluating potential geroprotective agents such as metformin.

Epitranscriptomic Remodeling by Metformin and Dietary Restriction (DR)

The studies revealed that administering 40 μM metformin extended rotifer lifespan by 9.5% and delayed reproductive aging, without impairing fecundity. The drug’s effects persisted even in the absence of metabolically active food, suggesting a direct mode of action on the host rather than through dietary modulation. Importantly, both metformin and DR significantly lowered global m6A RNA methylation levels and downregulated WTAP, a core component of the m6A writer complex. Using m6A-MeRIP-seq profiling, researchers showed that these interventions reshaped the epitranscriptomic landscape, altering hundreds of m6A peaks across key transcripts involved in transcriptional regulation and RNA processing. These data indicate that longevity benefits stem, at least in part, from the dynamic reprogramming of m6A marks—transforming mRNA lifespans and translation potential in favor of healthier cellular states.

The Central Role of MTR and Methionine Metabolism

A pivotal discovery in the study was the identification of MTR (methionine synthase) as a major downstream target of m6A regulation. Both metformin and DR reduced m6A methylation and mRNA stability of MTR, a key enzyme involved in converting homocysteine to methionine in the one-carbon cycle. This repression reduced the production of S-adenosylmethionine (SAM), a universal methyl donor whose levels are tightly linked to epigenetic regulation and aging.

The RNA-binding protein IGF2BP, known to stabilize m6A-modified transcripts, was shown to mediate this effect, further confirming that metformin and DR decrease MTR expression by destabilizing its mRNA via m6A-IGF2BP interactions. Experimental knockdown of IGF2BP or MTR produced similar physiological effects to metformin and DR, including extended reproductive period and delayed aging, although excessive MTR suppression resulted in developmental defects. These findings emphasize the importance of precisely tuning methionine metabolism rather than abolishing it altogether.

Validation of the m6A–MTR–SAM Axis in Longevity

To validate the role of methionine metabolism in mediating anti-aging effects, the researchers inhibited SAM synthesis pharmacologically using cycloleucine (cLEU), which extended lifespan and reproduced DR/metformin-like phenotypes. Conversely, supplementation with methionine or SAM negated the beneficial effects, suggesting that reduced SAM availability is a key contributor to longevity. This supports the concept that the m6A–MTR–SAM axis is a crucial post-transcriptional mechanism by which metformin and DR extend lifespan.

Conclusion

The study from Nanjing Normal University reveals a compelling mechanistic framework through which metformin and dietary restriction decelerate aging: by reprogramming m6A RNA methylation to suppress MTR, thereby limiting methionine metabolism and SAM synthesis. This post-transcriptional regulation fine-tunes cellular methylation capacity and gene expression, promoting longevity while avoiding developmental disruption. These insights not only deepen our understanding of how epigenetic interventions shape aging trajectories but also spotlight metformin as a prototype for epitranscriptomic drugs aimed at healthy lifespan extension. As the field moves forward, the rotifer model offers a promising platform to refine and validate next-generation gerotherapeutics.

Reference

Zhang Y, Liu X, Lian H, Chai Y, Zhou Y, Kan D, Ren J, Han C, Yang J. Metformin and Dietary Restriction Counteract Aging via Reducing m6A-Dependent Stabilization of Methionine Synthase mRNA in Brachionus asplanchnoidis (Rotifera). Aging Cell. 2025 May 27:e70113. doi: 10.1111/acel.70113. Epub ahead of print. PMID: 40424068.

 

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