Hypothesis: Senescent immune cells export oxidized mitochondrial DNA via exosomes to drive systemic aging through cGAS-STING activation

The immune system accelerates aging not only by secreting inflammatory cytokines but also by transferring damaged mitochondrial components to distant tissues. Recent work shows that senescent immune cells from aged mice induce widespread senescence when transplanted into young hosts[https://doi.org/10.1038/s41586-021-03547-7] and that hematopoietic DNA damage alone can prematurely age solid organs[https://doi.org/10.1038/s41586-021-03547-7]. Here we propose that the key vehicle is oxidized mitochondrial DNA (ox-mtDNA) packaged into exosomes released by senescent CD28⁻ T cells, S100A8⁺ neutrophils, and aged monocytes. Ox-mtDNA acts as a damage‑associated molecular pattern that activates the cytosolic cGAS‑STING pathway in parenchymal cells, leading to chronic type‑I interferon signaling, NAD⁺ depletion, and reinforcement of the senescence-associated secretory phenotype (SASP). This creates a feed‑forward loop: immune‑cell‑derived ox‑mtDNA amplifies tissue senescence, which in turn releases more DAMPs that further activate immune cells.

Testable predictions

1. Plasma levels of exosome‑associated ox‑mtDNA will correlate with biological age across mouse strains and human cohorts, and will be elevated in conditions of accelerated immunosenescence (e.g., Vav‑iCre Ercc1 mice).
2. Pharmacologic inhibition of exosome release (e.g., 'GW4869') or neutralization of extracellular mtDNA with anti‑DNA antibodies in aged mice will reduce tissue‑specific markers of senescence (p16^INK4a^, SASP factors) and improve organ function without altering overall leukocyte counts.
3. Parenchymal‑cell‑specific deletion of cGAS will protect mice from the systemic senescence induced by adoptive transfer of senescent immune cells, whereas STING deficiency will have a similar effect.
4. Isolated exosomes from senescent immune cells will induce senescence and cGAS‑STING activation in cultured fibroblasts or hepatocytes, an effect abrogated by pre‑treating the exosomes with 'DNase I' or by using mtDNA‑deficient (ρ⁰) immune cells.

Falsifiability

If blocking exosome secretion or scavenging extracellular mtDNA fails to diminish senescence markers in aged recipients of senescent immune cells, or if cGAS/STING loss does not attenuate the phenotype, the hypothesis that immune‑derived ox‑mtDNA drives aging would be refuted. Conversely, confirmation of any prediction would support the mechanistic link between immune senescence and organismal aging through mitochondrial DAMPs.

This perspective shifts the focus from soluble cytokines to organelle‑derived nucleic acids as a direct conduit by which the immune system burns the village, offering a complementary target for interventions aimed at breaking the immune‑driven aging cycle.