Cells become senescent on reaching the Hayflick limit to replication, or in response to stress and damage. A senescent cell ceases replication and generates pro-inflammatory signals. In the short term this is usually helpful, attracting the immune system to assist in issues such as regeneration following injury or cells with potentially cancerous DNA damage. When sustained for the long term, however, the signaling of senescent cells is harmful. Following the realization that senescent cells accumulate with age and that their inflammatory signaling contributes to degenerative aging, assessments of the burden of senescence used a few consensus markers, such as β-galactosidase and p16 expression.
As time went on, it became clear that senescence is more varied a state than first appreciated, differing by cell type, cause of senescent, time spent senescent, and no doubt other factors. While the initial consensus markers for senescence continue to be used, it is now generally accepted that these markers might not be capturing the picture originally thought to be the case. Today's open access paper is an example of the sort of research into the burden of senescence and its relationship to aging presently taking place in this new context. Researchers provide evidence for p16 expression in tissues to be a marker of resident or infiltrating immune cell senescence, not tissue cell senescence. Their interpretation is that this puts more of an emphasis on the aging of the immune system as a driver of systemic aging throughout the body.
Cellular senescence, as a major player among hallmarks of aging, has been reported as being able to accumulate senescent cells in various tissues during aging process. Cellular senescence can cause a halt in the proliferation of functional cells, ultimately resulting in organic dysfunction and induce sterile chronic inflammation through the secretion of senescence-associated secretory phenotypes (SASPs), which are known as 'inflammaging'. Previous studies applying senolytics or selective cytotoxicity in p16INK4A-overexpressed cells in aged mice have been supported the notion that removal of senescent cells can be alleviate not all but many aging-related phenotypes and lead to the prolongation of life span. Although the final phenotypes resulting from the removal of senescent cells have been confirmed in multiple previous studies, information about the specific cell types that accumulate as senescent cells and their removal remains scarce.
Organs are composed of two major components: the parenchyma and the stroma. Parenchymal cells, responsible for executing organ-specific functions, often exhibit rapid proliferation and turnover rates. Examples include gastrointestinal tract epithelial cells and skin keratinocytes. Conversely, the tissue stroma can be further categorized into cells providing structural support and immune cells. Cells providing structural support (hereinafter referred as structural stromal cells), such as fibroblasts and smooth muscle cells produce extracellular matrix (ECM) components and maintain tissue structures. The remaining stromal cells are immune cells, which may be resident, such as liver Kupffer cells and skin Langerhans cells, or infiltrating, such as bone marrow-derived cells and lymphocytes. These cells are involved in protecting organs from foreign invaders, chronic inflammation, and tissue regeneration related to the aging process.
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 / protease-activated receptor 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.
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