New insights into the role of cellular senescence and chronic wounds

Abstract

Chronic or non-healing wounds, such as diabetic foot ulcers (DFUs), venous leg ulcers (VLUs), pressure ulcers (PUs) and wounds in the elderly etc., impose significant biological, social, and financial burdens on patients and their families. Despite ongoing efforts, effective treatments for these wounds remain elusive, costing the United States over US$25 billion annually. The wound healing process is notably slower in the elderly, partly due to cellular senescence, which plays a complex role in wound repair. High glucose levels, reactive oxygen species, and persistent inflammation are key factors that induce cellular senescence, contributing to chronic wound failure. This suggests that cellular senescence may not only drive age-related phenotypes and pathology but also be a key mediator of the decreased capacity for trauma repair. This review analyzes four aspects: characteristics of cellular senescence; cytotoxic stressors and related signaling pathways; the relationship between cellular senescence and typical chronic non-healing wounds; and current and future treatment strategies. In theory, anti-aging therapy may influence the process of chronic wound healing. However, the underlying molecular mechanism is not well understood. This review summarizes the relationship between cellular senescence and chronic wound healing to contribute to a better understanding of the mechanisms of chronic wound healing.

Keywords: cellular senescence; chronic wounds; signal pathways; tissue repair; wound microenvironment.

Figure 1

Schematic diagram of the molecular mechanisms underlying cellular senescence and chronic wounds. Cellular senescence impairs chronic wound healing by disrupting tissue repair through inflammation, altered metabolism, and apoptosis resistance.

Figure 2

Characteristics of cellular senescence. The senescence response leads to significant alterations in cellular phenotype. These alterations encompass a largely irreversible cessation of cell proliferation, the acquisition of apoptosis resistance, and modifications in gene expression patterns. The presence or manifestation of senescence-associated markers, such as senescence-associated β-galactosidase, p16, senescence-associated DNA damage foci, and SAHFs, are neither consistently observed nor exclusive to the senescent state, and thus are not depicted.

Figure 3

IL-6/STAT3 signaling pathway and cellular senescence. IL-6 promotes cellular senescence and age-related diseases by activating STAT3. Upon activation, STAT3 becomes phosphorylated, translocates into the nucleus, and regulates the expression of genes involved in senescence and aging.

Figure 4

mTOR signaling pathway and cellular senescence. mTOR regulates cell growth and metabolism and is closely linked to cellular senescence. Its inhibition has been shown to extend lifespan, while promoting cellular senescence through the activation of both mTORC1 and mTORC2 pathways.

Figure 5

Insulin-like signaling pathway and cellular senescence. Insulin-like signaling, through Insulin-R and IGF-1R, influences aging by enhancing mTOR activity, inhibiting autophagy, and promoting low-grade inflammation linked to cellular senescence.

Figure 6

The relationship of cellular senescence and chronic wounds. Cellular senescence in chronic wound cases such as DFUs, chronic wounds of the elderly, PUs and Arterial wounds. Senescent cells accumulate induced by stressors at the wound site, promoting prolonged inflammation and impaired healing, thereby delaying recovery and increasing complications.