Hypothesis: Pharmacological senolysis in aged tissues does not merely remove damaged cells; it dismantles a senescent cell-maintained, constitutive interferon signaling network that functions as a critical tumor-suppressive barrier. This leads to a transient reduction in inflammatory markers but a subsequent increase in vulnerability to oncogenic transformation due to loss of chronic interferon-stimulated gene (ISG) expression.

Mechanistic Rationale: Chronic ISG expression in aged tissues, particularly in the liver, is driven by senescent cells and is protective against tumorigenesis under oncogenic stress [GSE313646]. This represents an adaptive immune priming mechanism, not signal exhaustion, potentially maintained via unphosphorylated STAT protein accumulation [PMC4443896]. Senescent cells are the primary source of the SASP factors that sustain this local interferon-rich microenvironment.

Senolytics (e.g., Dasatinib+Quercetin) clear these p16-positive cells [PMC10148948], directly removing the cellular source of the protective SASP. The immediate consequence is a reduction in tissue-level inflammation. However, the downstream effect is the collapse of the constitutive ISG network that provided chronic, low-level tumor surveillance. This creates a window of opportunity for initiated cells to progress. The system trades a controlled, senescence-associated "inflammaging" for a loss of immune vigilance, a classic case of solving one problem (chronic inflammation) by creating a more dangerous one (oncogenic escape).

Testable Predictions:

1. Aged mice treated with senolytics prior to a low-dose carcinogen (e.g., DEN for liver cancer) will exhibit higher tumor incidence and multiplicity compared to vehicle controls. The protective ISG signature (e.g., Ifit1, Isg15, Stat1) in liver tissue should be significantly diminished 2-4 weeks post-senolytic treatment, prior to tumor detection.
2. The tumor-suppressive effect of chronic interferon will be context-dependent and lost upon senescent cell clearance. Aged Stat1-liver-specific knockout mice should show high tumor burden, but senolytic treatment in aged wild-type mice should phenocopy this susceptibility, demonstrating that senescent cells act through the IFN/STAT1 pathway.
3. Senolytic-induced tumor vulnerability will be rescued by exogenous, low-dose IFN-α administration, which would artificially restore the protective ISG milieu without requiring senescent cells. This would prove the functional link is the interferon signal, not the senescent cell per se.

Implication: This hypothesis reframes the role of senescent cells in aging. They are not just sources of dysfunction but architects of a tissue-specific, interferon-dependent defense system. Senolytic therapies may need precise timing or combination with interferon-mimetics to avoid inadvertently increasing cancer risk in the elderly, the population most likely to receive such treatments.