Distribution and impact of p16INK4A+ senescent cells in elderly tissues: a focus on senescent immune cell and epithelial dysfunction

Abstract

Cellular senescence, recognized as a key hallmark of aging, leads to the accumulation of senescent cells in various tissues over time. While the detrimental effects of these cells on age-related pathological conditions are well-documented, there is still limited information about how senescent cells are distributed in normal tissues of both young and aged organs. Our research indicates that fully senescent p16INK4A+ cells are rarely identified in the parenchyma of organic tissues and in the stromal cells crucial for structural maintenance, such as fibroblasts and smooth muscle cells. Instead, p16INK4A+ cells are more commonly found in immune cells, whether they reside in the organ or are infiltrating. Notably, p16INK4A+ senescent T cells have been observed to induce apoptosis and inflammation in colonic epithelial cells through Granzyme A-PARs signaling, compromising the integrity of the epithelial lining. This study showed that the senescence of immune cells could affect the phenotypical change of the parenchymal cells in the elderly and suggests that targeting immunosenescence might be a strategy to control functional decline in this population. Cellular senescence accumulates in tissues as we age, causing dysfunction and inflammation. However, the specific cell types that become senescent and their removal are not well understood. Researchers aimed to map senescent cells in young and elderly tissues, creating a “Senescence Atlas.” This study involved analyzing human tissues and mouse tissues using immunohistochemistry and single-cell RNA-sequencing. They focused on p16INK4A and found that senescent cells were rare in both young and elderly tissues. However, immune cells, especially T cells, showed increased senescence in elderly tissues. Results showed that senescent T cells release granzyme A, which activates protease-activated receptors in epithelial cells, leading to inflammation and cell death. This suggests that targeting senescent immune cells could improve organ function in the elderly. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.