Systemic Senolytic Treatment With Dasatinib + Quercetin Exhibits Age-dependent Effects On Acute Cutaneous Wound Healing

PURPOSE: Senescent cells (SnCs) are growth-arrested yet metabolically active cells that accumulate with age and after tissue injury. Although persistent SnCs impair regeneration, transient senescence(definition) contributes to normal wound repair. Senolytic therapies that selectively eliminate SnCs, such as the Dasatinib + Quercetin (D+Q) combination currently under evaluation in human clinical trials, may influence wound healing, but their in vivo effects remain poorly defined. We investigated whether systemic D+Q alters the kinetics or quality of cutaneous repair in young versus aged mice. METHODS: Full-thickness 10 mm dorsal excisional wounds were generated in young (2-month) and aged (24-month) male mice. Animals received daily oral D+Q or vehicle for 6 days. Wound area was quantified from standardized daily images and normalized to baseline. Healing kinetics, early wound expansion, and time to complete closure were compared between groups. Day 6 wound tissues were analyzed for senescence-associated gene expression (Cdkn2a/p16, Cdkn1a/p21, Il6) by qRT-PCR. RESULTS: Systemic D+Q did not impair wound closure in either young or aged mice. Instead, D+Q reduced the early post-injury wound expansion typically observed after excisional injury. In young mice, vehicle-treated wounds expanded by 10.5 percent on Day 1, whereas D+Q-treated wounds showed a 4.82 percent reduction in area. This effect was more pronounced in aged mice, where vehicle wounds expanded by 21.6 percent on Day 1 compared with only 4.77 percent in D+Q-treated wounds. Although young mice did not show statistically significant differences in overall healing time, D+Q did not delay closure and produced earlier progression toward healing relative to controls. In aged mice, D+Q provided a clear and consistent benefit across the healing course, with significant group differences at nearly all time points (p 0.05). D+Q also accelerated complete closure in aged animals: 42.9 percent of treated wounds fully healed by Day 16 and 85.7 percent by Day 22, compared with 0 percent and 57.1 percent in controls (t-test, p 0.05). qRT-PCR at Day 6 confirmed injury-induced senescence-associated transcriptional changes in both age groups and demonstrated distinct age-dependent responses to D+Q treatment. CONCLUSIONS: Systemic D+Q selectively improves wound repair in aged mice by limiting early injury-associated expansion and accelerating closure, without compromising healing in young skin. This age-specific benefit suggests that senolytic therapy may restore aspects of impaired reparative biology in aging tissue while sparing essential transient senescence programs in younger animals. These results provide a rationale for targeted senolytic approaches to enhance healing in older patients. *Source: https://ps-rc.org/meeting/Program/2026/154.cgi*