The mitochondrial logic of inflammaging: how energy imbalance drives fibroblast SASP and tissue-specific aging

The conversion of metabolic disequilibrium into chronic inflammatory signaling represents a central and actively investigated question in ageing biology. Among stromal cells, fibroblasts are key effectors of tissue remodeling and inflammation, acquiring a senescence(definition)-associated secretory phenotype (SASP) that sustains age-related pathology. Here, we delineate a mechanistic framework in which disruption of energy homeostasis drives mitochondrial dysfunction(definition), innate immune activation, and SASP secretion. Mitochondria act as metabolic sentinels that sense energetic stress through altered AMP/ATP and NAD + /NADH ratios, leading to the generation of mitochondrial danger signals—reactive oxygen species (mtROS) and mitochondrial DNA (mtDNA). These signals converge on canonical immune pathways, including the cGAS–STING axis, NLRP3 inflammasome, and NF-κB signaling, thereby converting metabolic distress into persistent pro-inflammatory output. Using periodontal ligament fibroblasts as a disease-relevant model, we highlight how microbial biofilm exposure induces mitochondrial metabolic reprogramming that amplifies fibroblast SASP, promotes osteoclastogenesis, extracellular-matrix degradation, and alveolar bone resorption. At the transcriptional level, regulatory networks involving NF-κB, C/EBPβ, STATs, and the mTOR(definition)–AMPK hub integrate mitochondrial signals to sustain inflammatory senescence. We propose that restoring mitochondrial metabolic homeostasis serves as a highly promising strategy to break the self-perpetuating cycle in which energy imbalance triggers SASP activation, which in turn contributes to chronic inflammation. Researchers must first characterize the tissue-specific mitochondrial signatures of SASP. Subsequently, developing precise, lesion-targeted metabolic interventions will open new avenues for mitigating inflammaging(definition) and rejuvenating stromal function across ageing tissues.