Cellular Senescence and Aging | Ajou Translational Medicine (ATM) Lab

The human body follows a chronological progression from youth to old age and, ultimately, to death. Similarly, cells, the smallest functional units of the body, also undergo a lifecycle from youth to aging. A cell differentiates from a stem cell, replicates repeatedly to perform its specific functions, and eventually enters a state of senescence, characterized by cell cycle arrest. Does this mean that the tissues of elderly individuals are predominantly composed of senescent cells? In fact, this is not the case. The body maintains its functions through an efficient turnover system, generating new cells from stem cells. Additionally, when the immune system functions properly, immune cells effectively eliminate senescent cells from normal tissues. This turnover is particularly rapid in epithelial cells, such as skin keratinocytes or the lining cells of the gastrointestinal tract, which are exposed to significant mechanical stress and external stressors. Their high turnover rate ensures the maintenance of tissue integrity and function despite constant wear and tear. In other words, epithelium might not be the place for senescent cell accumulation. Rather, tissue stroma, which composed of slow replicating mesenchymal cells, might be the place for senescent cells accumulation.

Indeed, our previous studies have shown that the proportion of senescent cells in normal tissues of elderly individuals does not significantly increase compared to those in younger individuals even in the stromal area (Park et al., 2024) (Kim et al., 2023). Given that the elderly often experience both clinical and subclinical dysfunction of their organs, the main question arises: what drives the functional decline observed in the tissues of elderly individuals?

Here, we hypothesize that another cell population, distinct from both young and senescent cells, may contribute to the functional decline of tissues in the elderly. We have termed this population “mid-old cells.” Mid-old cells are characterized by their ability to continue proliferating, albeit with functional limitations. Notably, these cells are frequently observed in fibroblast populations, where they exhibit reduced extracellular matrix synthesis and impaired tissue regeneration.

Our future research aims to uncover the precise relationship between cellular senescence and aging, specifically identifying which systems’ senescence primarily drives the functional decline associated with aging (Park et al., 2024). Investigating the mechanisms by which mid-old cells contribute to functional decline will be another key focus of our future work.

References

2024

Exp. Mol. Med.

(1st author) Distribution and impact of p16^INK4A+ senescent cells in elderly tissues: a focus on senescent immune cell and epithelial dysfunction

Soon Sang Park, Young-Kyoung Lee, Young Hwa Kim, and 8 more authors

Experimental & Molecular Medicine, 2024

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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.

2023

Nat. Commun.

(1st author) Mid-old cells are a potential target for anti-aging interventions in the elderly

Young Hwa Kim, Young-Kyoung Lee, Soon Sang Park, and 11 more authors

Nature Communications, 2023

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This article is selected for the TOP 25 frequently read Nature Communications article in 2023

The biological process of aging is thought to result in part from accumulation of senescent cells in organs. However, the present study identified a subset of fibroblasts and smooth muscle cells which are the major constituents of organ stroma neither proliferative nor senescent in tissues of the elderly, which we termed “mid-old status” cells. Upregulation of pro-inflammatory genes (IL1B and SAA1) and downregulation of anti-inflammatory genes (SLIT2 and CXCL12) were detected in mid-old cells. In the stroma, SAA1 promotes development of the inflammatory microenvironment via upregulation of MMP9, which decreases the stability of epithelial cells present on the basement membrane, decreasing epithelial cell function. Remarkably, the microenvironmental change and the functional decline of mid-old cells could be reversed by a young cell-originated protein, SLIT2. Our data identify functional reversion of mid-old cells as a potential method to prevent or ameliorate aspects of aging-related tissue dysfunction.