The Microbiome-Mitochondria Axis in aging: a self-reinforcing vicious cycle linking metabolic dysregulation, mitochondrial quality control failure, and inflammaging

Abstract

Aging is a progressive degenerative process of cellular and systemic homeostasis in organisms, with mitochondrial dysfunction and altered intercellular communication as core hallmarks of this process. During aging, the gut microbiome and mitochondria exhibit a highly synchronized degenerative trajectory: this is characterized by decreased microbial diversity, reduced abundance of beneficial short-chain fatty acid (SCFA)-producing bacteria, and expansion of pro-inflammatory pathobionts in the gut, alongside impaired oxidative phosphorylation efficiency, excessive reactive oxygen species (ROS) production, and compromised quality control in mitochondria. Built on the evolutionary cornerstone of endosymbiotic theory, this review establishes a theoretical framework for the Microbiome-Mitochondria Axis (MMA) and proposes that the ancient molecular homology between mitochondria and modern gut bacteria has preserved a sensitive cross-species signal crosstalk mechanism. This review systematically dissects the bidirectional communication mechanisms of the MMA. First, microbial metabolites—including SCFAs, tryptophan-derived indole metabolites, and secondary bile acids—regulate mitochondrial energy metabolism, oxidative stress responses, and dynamic homeostasis via key signaling pathways such as AMPK-PGC-1α, AhR-Nrf2, and FXR/TGR5. Conversely, dysfunctional mitochondria actively reshape the gut microenvironment and propagate sterile inflammation through multiple pathways: mitochondrial ROS (mtROS)-mediated intestinal barrier disruption, metabolic reprogramming of immune cells toward a pro-inflammatory phenotype, and activation of the cGAS-STING innate immune pathway triggered by mitochondrial DNA (mtDNA) release. Here, we propose a unified theoretical framework centered on the MMA as a self-reinforcing pathological loop. In this model, gut dysbiosis drives depletion of beneficial microbial metabolites, which triggers mitochondrial quality control failure, mtDNA leakage, and inflammaging; in turn, inflammaging exacerbates gut dysbiosis by remodeling the intestinal microenvironment, thus forming a closed, self-amplifying vicious cycle. The MMA links multiple hallmarks of aging, including epigenetic alterations, immunosenescence, and stem cell exhaustion, providing a unifying pathological basis for age-related disorders such as neurodegenerative diseases, cardiovascular diseases, sarcopenia, and osteoarthritis. It also offers a systematic entry point for anti-aging interventions targeting the bidirectional metabolic-immune crosstalk between the microbiome and mitochondria.