Intermittent JAK-STAT inhibition preserves stress‑responsive signaling hormesis and slows inflammaging

Hypothesis

Pulsed, low‑dose inhibition of the JAK‑STAT pathway maintains the capacity for acute interferon‑stimulated gene (ISG) induction while preventing chronic activation that drives senescence‑associated secretory phenotype (SASP) and tissue dysfunction. This approach yields a hormetic balance: enough pathway activity to trigger damage‑sensing repair programs, but insufficient sustained signaling to exhaust cellular responsiveness or promote maladaptive inflammation.

Mechanistic Rationale

Chronic JAK‑STAT signaling elevates basal pSTAT levels, blunting the response to new stimuli and converting a protective stress signal into exhausted, maladaptive signaling [3]. In contrast, transient suppression reduces ROS accumulation and limits SASP factor production without erasing the pathway’s ability to be re‑engaged by genuine danger signals [1,2]. NSAIDs such as ibuprofen extend lifespan in model organisms by lowering ROS and boosting SOD activity, independent of COX inhibition [4,5]. Opioids, however, accelerate aging hallmarks when used continuously [6,7]. We reason that the key variable is not mere pathway blockade but the temporal pattern of inhibition: intermittent dosing should restore signaling elasticity, preserve ISG inducibility after injury, and retain the longevity benefits seen with chronic NSAID use while avoiding the deleterious effects of unbroken JAK‑STAT activation.

Testable Predictions

1. Signal Responsiveness – Aged mice receiving intermittent JAK‑STAT inhibitor (e.g., low‑dose ruxolitinib 2 days on/5 days off) will show higher ISG fold‑induction after ex vivo IFN‑β stimulation than age‑matched controls receiving continuous inhibitor or vehicle.
2. SASP Burden – Serum IL‑6, IL‑1β, and MMP‑9 levels will be significantly lower in the intermittent group compared with both continuous treatment and untreated aged cohorts.
3. Functional Outcome – Grip strength, treadmill endurance, and tendon stem‑cell colony‑forming unit frequency will improve in the intermittent group to levels comparable with young adult mice, whereas continuous inhibition will produce only modest gains.
4. Longevity Readout – Median survival of intermittently treated mice will exceed that of vehicle and continuous‑treatment groups by at least 15 %.

Experimental Design

• Animals: 20‑month‑old C57BL/6J mice (n=15 per group). Groups: vehicle, continuous low‑dose ruxolitinib (5 mg/kg/day), intermittent ruxolitinib (5 mg/kg/day, 2 days on/5 days off), and young adult (4‑month) baseline.
• Duration: 6 months of treatment.
• Readouts: (a) ex vivo IFN‑β stimulated pSTAT1/ISG qPCR from splenocytes at 0, 3, and 6 months; (b) multiplex cytokine profiling of plasma; (c) functional assays (grip strength, treadmill, tendon stem‑cell CFU‑F); (d) survival monitoring.
• Statistical Analysis: Two‑way ANOVA with repeated measures for longitudinal data; log‑rank test for survival; post‑hoc Tukey correction.

Novel Insight

If intermittent JAK‑STAT inhibition sustains the pathway’s damage‑sensor capacity while curbing its chronic, SASP‑driven output, it would reframe pain‑ and inflammation‑modulating drugs not as blunt silencers but as tunable rheostats. This perspective directly addresses the mechanistic gap identified in the literature: whether we can retain immune competence and reparative signaling while still harvesting the longevity advantages of pathway modulation.