# A Multi‐Organ Atlas Links Gut Microbial Metabolites to Systemic Redox Changes in Aging Mice

## TL;DR

The study shows that gut microbial metabolites contribute to aging-related systemic redox changes and organ decline in mice.

## Contribution

A multi-organ, multi-omics atlas reveals a conserved aging signature driven by gut microbial metabolites and their systemic effects.

## Key findings

- Aging is marked by depletion of protective metabolites like LPCs and accumulation of pro-oxidative catabolites like TMAO and IAA.
- Microbial metabolic drift leads to organ-specific vulnerabilities such as hepatic lipid retention and pulmonary immune-redox activation.
- Restoring gut microbial balance via interventions improves intestinal barrier integrity and reduces oxidative stress.

## Abstract

Aging disrupts systemic metabolism, but the mechanisms by which gut microbial metabolites drive tissue‐specific decline remain unclear. We conducted a multi‐organ, multi‐omics atlas across the gut, serum, liver, lung, and cortex in young and early‐aged mice to address this. We identified a conserved aging signature marked by the microbiota‐associated depletion of protective circulating metabolites, such as lysophosphatidylcholines (LPCs), concurrently with the systemic accumulation of pro‐oxidative microbial catabolites, specifically trimethylamine N‐oxide (TMAO) and indole‐3‐acetic acid (IAA). This microbial‐metabolic drift disrupted systemic lipid transport and redox balance, leading to distinct organ‐level vulnerabilities: hepatic lipid retention and ferroptosis susceptibility, pulmonary immune‐redox activation, and cortical neurochemical dysregulation. To establish functional relevance, we conducted an integrated meta‐analysis of 40 independent studies encompassing natural aging models, fecal microbiota transplantation (FMT), and probiotic interventions. This quantitative synthesis provided convergent evidence that microbial remodeling is a functionally relevant correlate associated with systemic aging phenotypes by restoring intestinal barrier integrity (upregulating ZO‐1, MUC2), suppressing tissue inflammatory factors (IL‐6, IL‐1β, TNF‐α), and mitigating oxidative stress (reducing MDA and restoring SOD/GSH). Together, our findings highlight gut‐derived metabolic reprogramming as a modifiable, upstream driver of systemic aging, offering tractable targets for therapeutic intervention.

A gut‐derived metabolic signature drives systemic aging phenotypes. Integrated multi‐omics profiling of young versus aged mice identifies a conserved aging signature characterized by the depletion of protective lysophosphatidylcholines (LPC 22:0) and the concurrent accumulation of pro‐oxidative microbial catabolites (TMAO, IAA). This metabolic drift propagates across the serum‐liver‐lung‐cortex axis, driving systemic redox stress and organ‐specific decline. A comprehensive meta‐analysis of 50 independent studies provides translational validation, demonstrating that reversing this signature via microbiome interventions restores intestinal barrier integrity (ZO‐1), suppresses inflammation (IL‐6), and boosts antioxidant capacity (SOD/GPX), thereby establishing the gut‐metabolite axis as a modifiable redox hub for extending healthspan.