# The Gut–Extracellular Vesicle–Mitochondria Axis in Reproductive Aging: Antioxidant and Anti-Senescence Mechanisms

## TL;DR

This paper explores how gut microbiome, extracellular vesicles, and mitochondria interact to influence reproductive aging and potential treatments.

## Contribution

The paper introduces a new gut–EV–mitochondria axis framework linking systemic signals to reproductive aging.

## Key findings

- Gut microbiome metabolites like urolithin A and short-chain fatty acids improve mitochondrial function and reduce senescence.
- Extracellular vesicles transport antioxidant enzymes and microRNAs that regulate redox balance and inflammation.
- A unified gut–EV–mitochondria axis is proposed to explain systemic effects on gamete quality and fertility longevity.

## Abstract

Cellular senescence, mitochondrial dysfunction, and cumulative oxidative stress (OS) are the main causes of the progressive decreases in oocyte and sperm quality that define reproductive age. There is growing evidence that these processes are controlled by systemic variables, such as metabolites produced from the gut microbiome and extracellular vesicle (EV)-mediated intercellular communication, rather than being exclusively regulated at the tissue level. Antioxidant enzymes, regulatory microRNAs, and bioactive lipids that regulate mitochondrial redox balance, mitophagy, and inflammatory signaling are transported by EVs derived from reproductive organs, stem cells, immune cells, and the gut microbiota. Concurrently, microbiome-derived metabolites such as urolithin A, short-chain fatty acids, and polyphenol derivatives enhance mitochondrial quality control, activate antioxidant pathways, and suppress senescence-associated secretory phenotypes. This narrative review integrates the most recent research on the relationship between redox homeostasis, mitochondrial function, gut microbiota activity, and EV signaling in the context of male and female reproductive aging. We propose an emerging gut–EV–mitochondria axis as a unified framework through which systemic metabolic and antioxidant signals affect gamete competence, reproductive tissue function, and fertility longevity. Finally, we discuss therapeutic implications, including microbiome modulation, EV-based interventions, and senotherapeutic strategies, highlighting key knowledge gaps and future research directions necessary for clinical translation.