Aging is a progressive and irreversible physiological process driven by a complex network of interrelated molecular and cellular mechanisms. Among these, cellular senescence and chronic inflammation, as two core hallmarks of aging, are interlinked and jointly promote the development and progression of aging. However, the precise molecular crosstalk between these two processes remains unclarified. Mitochondrial DNA (mtDNA), as the only cytoplasmic DNA, has recently emerged as a pivotal "bridge" linking cellular senescence and chronic inflammation through various mechanisms. Anchored on the unique characteristics of mtDNA, this review systematically elucidates its central roles in mitochondrial dysfunction and oxidative stress, with a particular emphasis on the dynamic changes of mtDNA within the cytosol and extracellular space that construct and amplify the cellular "inflammation-senescence" coupling network. Furthermore, we propose a conceptual framework linking mtDNA mutation/damage to the cellular senescence and the propagation of chronic inflammation. Finally, we discuss the therapeutic potential of targeting mtDNA dynamics and highlight key challenges and future directions in this emerging field, offering novel insights for mitigating aging and age-related diseases.
Longevity & Aging