Year: 2026
Type: preprint
Abstract: ABSTRACT Aging is characterized by hallmarks whose mechanistic interdependencies remain poorly defined. Here, we investigate the bi-directional communication between gut microbiota and host mitochondria in the context of immune regulation, healthspan and lifespan. Using a mitochondrial dysfunction PolgA mut mouse model of accelerated aging, we tested the role of mitochondrial dysfunction in modulating microbial homeostasis and aging. We find that impairment of mitochondrial function hastens the decline of microbiota structure over time and induces immune dysregulation and inflammation through metabolic reprogramming of the myeloid immune subset. Further, we find that gut microbiota drives a paradoxical energy state by reducing mitochondrial function systemically while simultaneously driving energy-intensive programs including immune remodelling and protein synthesis, through mTOR signaling. Thus, aging emerges from the progressive imbalance between microbiota-driven energetic demand and declining mitochondrial energy supply. We postulate that microbiota promote host early-life fitness, at the cost of amplifying metabolic stress and inflammation later in life. HIGHLIGHTS Host-microbiota homeostasis imposes an energetic cost that accelerates aging Dysbiosis and immune myeloid reprogramming are hallmarks of both natural and accelerated aging Microbiota diminish OXPHOS subunit expression and activity systemically with age Microbiota amplify mTOR signaling and metabolic stress in peripheral tissues
Authors: Francesca Solagna, Daniel Martínez-Martínez, Norma Gabriela Zavala Torres, Annamaria Regina, Jonas Widder, Göksu Gökberk Kaya, Cosimo De Napoli, Schmidt Luisa, Ayesha Safoor, Jennifer van der Laan, Kaylee M. Morris, Susanne Brodesser, Aleksandra Trifunovic, Leonardo Nogara, Bert Blaauw, Marcus Krüger, Manolis Pasparakis, David E. Sanin, Mauro Corrado, Filipe Cabreiro
Institutions: University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Hammersmith Hospital, MRC London Institute of Medical Sciences, Imperial College London, Medical Research Council, Veneto Institute of Molecular Medicine, University of Padua, Johns Hopkins University, Johns Hopkins Medicine
Language: English
Topic: Gut microbiota and health
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: EXC 2030: CECAD Exzellent in Alternsforschung, G3469463779, G4353328979, G4536697403, G4591806611, G470880531, SFB 1218: Regulation der zellulären Funktion durch Mitochondrien, SFB 1403: Zelltod in Immunität, Entzündungen und Erkrankungen, Exploring the Gut Microbial Action of Metformin: Targeting the Gut Microbiota to Treat Metabolic Disease., G7600393579, G8948663249, G9000249672
OpenAlex ID: W7219152127