Metformin and Dietary Restriction Counteract Aging via Reducing m6A–Dependent Stabilization of Methionine Synthase mRNA in Brachionus asplanchnoidis (Rotifera)

Abstract

ABSTRACTMetformin, a medication primarily used to treat diabetes, has gained attentions for its potential antiaging properties. Although the metabolic and cellular pathways behind its longevity effects have been widely studied, few studies have explored the epigenetic regulatory effects of metformin, which are a crucial factor in aging processes. In this study, we examined the antiaging effects of metformin using the Brachionus rotifer as a model, focusing on the regulation of mRNA N6–methyladenosine (m6A), a key RNA modification involved in mRNA stability, translation, and splicing. We found metformin significantly extended the rotifers' lifespan, mimicking the effects of dietary restriction (DR), a well–established antiaging intervention. Both metformin and DR modulate m6A dynamics, with a notable reduction in the m6A modification of MTR (5–methyltetrahydrofolate–homocysteine methyltransferase). This reduction led to decreased MTR expression and lowered levels of S–adenosylmethionine (SAM), a critical metabolite in the one–carbon cycle. We propose that the downregulation of MTR through m6A modification limits methionine synthesis and imposes methionine restriction, a key factor in promoting longevity. Our findings reveal a novel epitranscriptional regulatory model by which metformin and DR modulate m6A to extend lifespan, highlighting MTR as a central regulator of aging and suggesting potential therapeutic strategies for healthy aging through m6A and methionine metabolism.