Senescent cells: A novel target for skin aging
Description: Advanced age is the main risk factor for most chronic diseases in humans, but the fundamental mechanisms that drive aging remain largely unknown. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumor cells. Senescent cells accumulate in various tissues and organs with aging and have been hypothesized to disrupt tissue structure and function because they can acquire a pro-inflammatory, tissue-destructive, pro-apoptotic senescence-associated secretory phenotype. Recently a biomarker for senescence, p16Ink4a, has been used to design a novel transgene for inducible elimination of p16Ink4a-positive senescent cells upon administration of a drug. The clearance of p16Ink4a-positive cells in mice delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan. Senescent cells might be therapeutically targeted using senolytic agents. Recent clinical trials in chronic human diseases showed that treatment with senolytics was associated with significant clinical improvement. In this project we aim to eliminate the p16Ink4a-positive senescent cells, which, according to our previous studies, accumulate in the epidermis of patients with dermatoporosis, an extreme skin aging condition, in the p16-3MR mouse skin by topical ganciclovir-mediated cell ablation. We will then compare the effect of this specific approach with topical senolytic agents in aged mouse skin and in the skin of dermatoporosis patients. The therapeutic removal of p16Ink4a-positive cells that accumulate during senescence may be an attractive approach to reverse skin aging. Our project is defined to address the following questions: -What is the effect of senolytic molecules on keratinocyte and fibroblast aging in vitro ? The effect of senolytic molecules on keratinocyte and fibroblast aging in cell cultures and full thickness human skin equivalents will be explored.-What is the effect of senolytic molecules on skin aging in mice? The effect of topical senolytics on the senescent cells of the skin of p16-3MR transgenic mice will be explored.-What is the effect of senolytic molecules on skin aging in dermatoporosis patients? The effect of topical senolytics on the skin of dermatoporosis patients will be explored.
Amount: CHF 388,000
Funding type: research
Funder scheme: Project funding
Start date: 2025-05-01
End date: 2028-04-30
Investigator: Kaya, Gürkan
Institution: University of Geneva – GE
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Funded outputs count: 0
Funder award ID: 10005297
OpenAlex ID: G5033717945