Mitochondrial G-quadruplex (mtG4) DNA structures accumulate in periosteal stem cells with age, blocking vital mitochondrial gene transcription and triggering cellular senescence that undermines bone repair capacity. The research team used transgenic tracking and organoid models to demonstrate that these mtG4 structures cause mitochondrial dysfunction, severe mitophagy, and stem cell deterioration in Pdgfra+ periosteal mesenchymal cells—the key players in bone healing. This discovery provides the first mechanistic explanation for why bone fractures and injuries heal progressively worse as we age, moving beyond correlative observations to identify a specific molecular culprit. The finding is paradigm-shifting because it pinpoints mitochondrial DNA topology, not just general mitochondrial decline, as the driver of age-related bone repair failure. This opens entirely new therapeutic avenues targeting mtG4 structures or their downstream effects, potentially through senolytic drugs that clear damaged stem cells or compounds that prevent mtG4 formation. Given that poor bone healing represents a major cause of disability and mortality in older adults, understanding this mechanism could lead to interventions that maintain skeletal repair capacity throughout aging, dramatically improving healthspan and reducing fracture-related complications.