Cellular senescence has emerged as a central mechanism driving cutaneous aging, impaired regeneration, and various dermatologic pathologies. Initially evolved as a protective mechanism to prevent malignant transformation and facilitate wound repair, senescence becomes maladaptive when senescent cells persist.
Senescent keratinocytes, fibroblasts, and melanocytes can secrete pro-inflammatory mediators and other factors, collectively termed the senescence-associated secretory phenotype (SASP). This may degrade extracellular matrix components, disrupt pigmentary balance, and impair barrier function. Senescent cells are resistant to conditions that cause death of non-senescent cells and are generally removed by the immune system. However, persisting senescent cells can become increasingly pro-inflammatory and fibrotic, possibly due to accumulating DNA damage within these cells.
Two primary geroscience-based therapeutic paradigms have been proposed: senolytics, which selectively eliminate senescent cells, and senomorphics, which modulate or suppress SASP activity without inducing senescent cell death. In dermatology, these approaches are particularly relevant given skin’s accessibility, visible aging markers, and ability to serve as a translational platform for systemic gerotherapeutic interventions.
Interfering with the development of senescent cells—such as by targeting regulators of senescent cell formation like p16, retinoblastoma protein (pRB), p53, or p21—can be detrimental due to the protective roles of transient senescence in wound healing and cancer suppression. However, senolytics, which do not prevent senescent cells from developing but rather act by clearing already formed persisting and tissue-damaging senescent cells, offer the potential to delay, prevent, alleviate, or treat aged or fibrotic skin.
Because of the days to weeks required for senescent cells to fully form and their inability to divide, senolytics can be administered intermittently, for example, every two weeks or once a month. Conversely, senomorphics generally need to be administered continuously or more frequently than senolytics. Some agents possess both senolytic and senomorphic properties.
This review considers the mechanistic underpinnings of senescence in skin, the evidence for both therapeutic approaches, and future directions for integrating senotherapeutics into regenerative and aesthetic dermatology. Advances in cutaneous biomarkers, topical delivery systems, and AI-assisted patient stratification are expected to accelerate translation into clinical practice.
What this study does not show
This review does not provide direct evidence from clinical trials or studies demonstrating the efficacy of senolytic or senomorphic therapies in human subjects.
Evidence scorecard
- Analytic validity: Not established
- Clinical validity: Not established
- Clinical utility: Not established