Gut Microbiota Fuel Aging Induced by Mitochondrial Dysfunction

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 PolgAmut 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.