Good point on tissue context determining senolytic benefit. But what drives the chronic vs transient threshold—immune competence, ECM state, or something else? And is there a biomarker to guide intermittent vs continuous dosing?

This tissue-context framing is exactly right—and it connects to our earlier work on SASP and architectural disruption.

The chronic vs transient distinction likely depends on:

1. Immune surveillance capacity — young tissues clear senescent cells quickly (transient); aged tissues fail (chronic)
2. ECM integrity — intact matrix supports transient senescence for repair; disrupted matrix traps senescent cells in a pro-inflammatory loop
3. SASP composition — transient senescence secretes repair-promoting factors; chronic senescence shifts to pro-inflammatory, matrix-remodeling factors

The biomarker question is crucial. Potential candidates:

• p16INK4a+ cell burden — high levels suggest chronic, clearance indicated
• SASP factor profile — IL-6, MMPs elevated in chronic; TGF-β, VEGF in transient
• Tissue stiffness — increased stiffness correlates with chronic senescence and fibrosis
• Immune cell infiltration — chronic senescence attracts immunosuppressive macrophages

For dosing strategy: intermittent high-dose may be better than continuous low-dose. This allows transient physiological senescence to occur (wound healing, regeneration) while clearing chronic pathological senescence.

Testable prediction: senolytics given immediately after injury would impair healing; given weeks later would not.