Senescent Cells Both Help and Harm Skin Wound Healing Depending on Context

Skin wound healing is a tightly orchestrated process spanning hemostasis, inflammation, proliferation, and tissue remodelling. Cellular senescence—a state of stable proliferative arrest triggered by DNA damage, oxidative stress, or oncogenic signalling—has recently emerged as a pivotal, context-dependent modulator of this process. This review from researchers at Mexico's Instituto Nacional de Geriatría and Instituto Nacional de Rehabilitación synthesises current evidence on how CS shapes wound repair outcomes and how senotherapeutics might be leveraged clinically.

In acute wounds, CS is transiently induced in fibroblasts, endothelial cells, and other stromal populations at the wound site. Rather than being purely detrimental, this transient senescence is now understood to be functionally beneficial. The SASP—comprising cytokines, chemokines, growth factors, and matrix-remodelling enzymes—recruits innate immune cells to clear damaged tissue, stimulates myofibroblast differentiation critical for wound contraction, and promotes angiogenesis. Crucially, once the repair phase is complete, immune surveillance (primarily by NK cells and macrophages) efficiently clears these transient senescent cells, resolving the inflammatory signal and allowing tissue homeostasis to be restored.

Chronic wounds represent a pathological failure of this finely tuned process. Conditions such as type 2 diabetes, obesity, peripheral vascular disease, and advanced age all converge on a common outcome: accumulation of senescent cells that escape immune-mediated clearance. Sustained SASP secretion then creates a self-reinforcing cycle of chronic inflammation. The downstream consequences are multifactorial: keratinocyte migration across the wound bed is impaired, fibroblast proliferation and differentiation are dysregulated, and extracellular matrix remodelling becomes aberrant—with excess matrix metalloproteinase activity degrading scaffolding proteins rather than remodelling them productively. The net result is a wound locked in a non-healing state characterised by persistent inflammation and failed re-epithelialisation.

The therapeutic landscape reviewed includes two broad senotherapeutic categories. Senolytics—agents such as dasatinib, quercetin, navitoclax (ABT-263), and the combination of dasatinib plus quercetin—selectively induce apoptosis in senescent cells by targeting anti-apoptotic pathways (BCL-2 family, PI3K/AKT) that these cells rely on for survival. Preclinical data show these agents reduce senescent cell burden, lower SASP cytokine levels, and improve wound closure metrics. Senomorphics, including rapamycin (mTOR inhibitor), metformin, and JAK inhibitors, do not kill senescent cells but instead suppress SASP production, offering a potentially safer approach that preserves any residual beneficial functions of senescent cells. Both strategies are positioned as complementary rather than mutually exclusive.

The authors emphasise a critical translational challenge: therapeutic timing and selectivity. Interventions applied too early in acute wound healing risk ablating the beneficial transient senescence required for normal repair. Conversely, delayed or insufficient intervention in chronic wounds allows ongoing SASP-driven tissue damage. Future work must delineate precise temporal windows, senescent cell subtypes, and wound-specific SASP compositions to enable precision senotherapy.