Current senolytic strategies indiscriminately clear senescent cells, potentially eliminating crucial wound-healing and tissue-patterning functions [PMC4349629]. The core pathological driver is not the senescent cell itself, but the age-related failure to clear it after its protective work is done PMC4349629. While immune surveillance impairment is observed, the precise mechanism remains elusive.

Hypothesis: Chronic, tonic Type I interferon (IFN-I) signaling, driven by age-related cGAS-STING activation, directly induces a phagocytic arrest in tissue-resident and recruited macrophages. This IFN-I-mediated "clearance paralysis" converts an acute, beneficial senescence response into a chronic, pathological state by preventing macrophage-mediated removal of senescent cells, regardless of their SASP profile.

Novel Mechanistic Reasoning: The established rewiring of immune cells from STAT1 to STAT3 under chronic IFN-I exposure [PMC12432374] is more than a signaling shift—it may reprogram fundamental macrophage effector functions. Specifically:

1. STAT3 Dominance: High STAT3 activity is known to suppress pro-inflammatory and phagocytic gene programs while promoting an anti-inflammatory, fibrotic phenotype. Chronic IFN-I could bias macrophages toward a STAT3-high state that is intrinsically poor at recognizing and engulfing senescent cells.
2. Receptor Interference: IFN-I upregulates inhibitory receptors (e.g., SIRPα) or downregulates "eat-me" signal receptors (e.g., receptors for calreticulin, a potential senescent cell surface marker) on macrophages, creating a local "do-not-touch" signal.
3. Metabolic Dysregulation: IFN-I is a potent modulator of macrophage metabolism, potentially pushing cells toward an oxidative phosphorylation state unfavorable for the energetic demands of sustained phagocytosis.

This creates a vicious cycle: failed clearance increases senescent cell burden, which further stimulates cGAS-STING via cytosolic DNA [PMC11106474], elevating IFN-I and deepening the phagocytic arrest. The acute, beneficial SASP (e.g., PDGF-AA [PMC4349629]) thus becomes chronically secreted because its producers aren't removed, driving fibrosis and inflammation. The same cell, secreting the same factors, transitions from healer to pathogen solely due to the immune system's failure to close the loop.

Testable Predictions:

1. In Vivo: In young wound models, adoptive transfer of macrophages preconditioned with chronic IFN-I (or from aged donors) will fail to clear senescent fibroblasts and impair wound resolution, despite the senescent cells' initially beneficial SASP.
2. In Vitro: Human monocyte-derived macrophages exposed to low-dose, prolonged IFN-α/β will show dramatically reduced phagocytosis of autologous senescent fibroblasts (induced by ionizing radiation or oncogene activation) compared to acutely activated controls. This defect will correlate with STAT3 activation and SIRPα upregulation.
3. Therapeutic Test: Combining transient STING inhibition (to break the IFN-I cycle) with a low-dose, pulse senolytic (to clear the accumulated backlog) will improve tissue regeneration in aged mice more effectively than either intervention alone, by restoring the natural clearance wave. This predicts that restoring immune surveillance is more effective than universal killing.

Falsification would occur if macrophage phagocytic capacity for senescent cells is unaffected by chronic IFN-I exposure, or if aged tissues show no correlation between IFN-I levels, macrophage phagocytic arrest, and senescent cell accumulation.