The oocyte-enriched metabolite serotonin alleviates cellular senescence and aging phenotypes in the mouse

Whether metabolites enriched at early developmental stages affect cellular and organismal aging remains unclear. In this study, we comprehensively profiled the metabolic landscape of mouse oocytes in comparison to cleavage-stage embryos. Our analysis revealed that oocytes display accumulation of reductive metabolites that diminish following fertilization. Notably, we identified serotonin (5-hydroxytryptamine, 5-HT) as an oocyte-enriched metabolite with protective roles in aging. The underlying mechanisms operate through dual pathways: (i) in a canonical pathway serotonin acts via its receptor 5HTR1B to modulate mitochondrial function, and (ii) in a non-canonical pathway serotonin promotes serotonylation of HSP90β, which effectively reduces endoplasmic reticulum stress. Overall, our study demonstrates that oocyte-enriched metabolites including serotonin can alleviate aging-related cellular and systemic phenotypes, suggesting new avenues for anti-aging strategies.