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Senescent skin cells, often termed zombie cells, present a curious paradox within the human body. While they contribute to inflammation and may promote various diseases, they also play a critical role in the immune system and wound healing.
Recent research sheds light on this complexity: not all senescent skin cells are the same.
In a significant advancement, researchers from Johns Hopkins University have classified senescent skin cells into three distinct subtypes, characterized by unique shapes, biomarkers, and functions. This discovery may enable scientists to selectively target and eliminate harmful cells while preserving those that are beneficial.
The study findings were published in the journal Science Advances.
“While we have always acknowledged that senescent cells in various tissues differ, we mainly viewed them uniformly within a specific cell type,” explained Jude Phillip, an assistant professor of biomedical engineering at Johns Hopkins University. “Our research indicates that when skin cells enter senescence, they can follow one of three different developmental pathways, each leading to a distinct subtype.”
Utilizing state-of-the-art machine learning and imaging technologies, the team analyzed skin cell samples from 50 healthy participants aged 20 to 90, sourced from the Baltimore Longitudinal Study—a NIH-funded initiative that stands as the longest ongoing study of aging in the United States.
Researchers isolated fibroblasts—cells crucial for maintaining tissue structure—and induced senescence by damaging their DNA, a natural process associated with aging. The resulting samples contained a combination of healthy and senescent fibroblasts due to the typical accumulation of senescent cells over time.
Using specialized staining techniques, the researchers captured images of the cells’ shapes and other defining characteristics of senescence. Custom algorithms analyzed these images, measuring 87 distinct attributes for every cell and classifying the fibroblasts into specific groups.
The investigation revealed that fibroblasts can appear in 11 distinct shapes and sizes. Notably, three were found to be specific to senescent skin cells, with one subtype, designated C10, being more prevalent among older participants.
In laboratory experiments, each fibroblast subtype exhibited different responses to existing drug therapies aimed at targeting senescent cells. For example, the drug combination Dasatinib and Quercetin, currently under investigation in clinical trials, effectively eliminated C7 senescent fibroblasts but showed limited efficacy against the age-related C10 subtype.
Although further exploration is necessary to delineate which fibroblast subtypes are detrimental or advantageous, this research highlights the potential for tailored drug therapies that can selectively target senescent cell subtypes.
“With our findings, we’re now poised to develop new drugs or therapies that can specifically attack the senescent subtype responsible for inflammation and disease as soon as it’s identified,” Phillip remarked.
This refined targeting may have particular significance in cancer treatment strategies, the researchers noted.
Some therapeutic approaches currently aim to induce senescence in cancer cells, transforming these uncontrolled replicators into non-viable zombie cells. While this can effectively halt tumor growth, the residual senescent cells may persist post-treatment. Conventional chemotherapy also inadvertently encourages neighboring cells, like fibroblasts, to enter senescence as an unintended side effect. This accumulation can exacerbate inflammation during a period when a patient’s immune system is especially vulnerable.
Consequently, patients may gain from post-chemotherapy treatments that eliminate detrimental senescent cells while preserving beneficial ones. Such therapies, referred to as senotherapies, are under exploration.
Looking ahead, the research team plans to investigate senescence subtypes within actual tissue samples to better understand their relationship with specific skin and age-related diseases.
“We aspire that with further development, our technology will enable predictions regarding the most effective drugs for targeting senescent cells tied to particular diseases,” Phillip stated. “Ultimately, we aim to enhance clinical practices by providing insightful information that will improve patient outcomes.”
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