Epigenetic loss of a canonical STING‑enhancer RNA drives JAK‑STAT tachyphylaxis and converts cytosolic DNA sensing into a unified aging program

Hypothesis: Age‑dependent silencing of a specific enhancer RNA (eRNA‑STING1) that sustains full‑length STING expression depletes canonical cGAS‑STING signaling, forcing cells into a tachyphasic JAK‑STAT state that misinterprets pathway exhaustion as adaptive downregulation. This single epigenetic lesion redirects cytosolic DNA sensing toward noncanonical STING‑NF‑κB signaling, perpetuating SASP, senescence, mitochondrial ROS, and stem‑cell dysfunction—thereby producing the observed hallmarks of aging as downstream branches of one upstream failure.

Mechanistic reasoning: In young cells, eRNA‑STING1, transcribed from a SIRT1‑dependent enhancer, binds STING pre‑mRNA and promotes inclusion of exon 6, preserving the isoform capable of robust TBK1 phosphorylation and IRF3 activation [1]. Aging reduces nuclear SIRT1 activity, diminishing eRNA‑STING1 levels [2]. Loss of this eRNA shifts STING splicing toward a truncated isoform that retains the transmembrane domain but lacks the C‑terminal tail required for TBK1 recruitment, thereby favoring TRAF6‑dependent NF‑κB activation while impairing cGAMP‑driven IRF3 signaling [3]. Consequently, despite rising cytosolic mtDNA and nuclear DNA fragments, canonical ISG induction wanes, while chronic low‑level NF‑κB drives JAK‑STAT activation, ROS production, and further mtDNA release—a feedforward loop of signal exhaustion [4][5]. The resulting JAK‑STAT tachyphylaxis mirrors the observed loss of p‑STAT1/STAT2 in aged tissues [6] and explains why blocking JAK‑STAT further worsens phenotypes, whereas restoring canonical STING signaling rescues responsiveness.

Testable predictions: (1) CRISPRa‑mediated reactivation of eRNA‑STING1 in aged mouse fibroblasts will restore STING exon 6 inclusion, increase p‑TBK1 and ISG expression, and reduce SASP cytokines despite persistent cytosolic DNA. (2) Satellite cells from eRNA‑STING1‑activated aged mice will show improved proliferation and reduced p‑16^INK4a^ compared with controls. (3) Pharmacological SIRT1 activation (e.g., with NAD⁺ boosters) in aged mice should elevate eRNA‑STING1 levels, canonical STING signaling, and ameliorate multiple hallmarks (greying fur, grip strength, hippocampal neurogenesis). Falsification: If eRNA‑STING1 restoration fails to rescue canonical ISG responses or does not improve functional readouts across tissues, the hypothesis that a single epigenetic regulator coordinates aging decline is refuted.

This framework re‑positions the hallmarks not as independent processes but as convergent outcomes of lost signaling fidelity, directing therapeutic strategies toward enhancing canonical STING‑eRNA activity rather than broad pathway inhibition.