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Cellular senescence is a state of exiting the cell cycle, resisting apoptosis, and changing phenotype. Senescent cells (SCs) can be identified by large, distorted morphology and irreversible inability to replicate. In early development, senescence has beneficial roles like tissue patterning and wound healing, where SCs are cleared by the immune system. However, there is a steep rise in SC number as organisms age. The issue with SC accumulation stems from the loss of cellular function, alterations of the microenvironment, and secretions of pro‐inflammatory molecules, consisting of cytokines, chemokines, matrix metalloproteinases (MMPs), interleukins, and extracellular matrix (ECM)‐associated molecules. This secreted cocktail is referred to as the senescence‐associated secretory phenotype (SASP), a hallmark of cellular senescence. The SASP promotes inflammation and displays a bystander effect where paracrine signaling turns proliferating cells into senescent states. To alleviate age‐associated diseases, researchers have developed novel methods and techniques to selectively eliminate SCs in aged individuals. Although studies demonstrated that selectively killing SCs improves age‐related disorders, there are drawbacks to SC removal. Considering favorable aspects of senescence in the body, this paper reviews recent advancements in elimination strategies and potential rejuvenation targets of senescence to bring researchers in the field up to date.
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Multiplexed single-cell imaging reveals diverging subpopulations with distinct senescence phenotypes during long-term senescence induction
Abstract Cellular senescence is a phenotypic state that contributes to the progression of age-related disease through secretion of pro-inflammatory factors known as the senescence-associated secretory phenotype (SASP). Understanding the process by which healthy cells become senescent and develop SASP factors is critical for improving the identification of senescent cells and, ultimately, understanding tissue dysfunction. Here, we reveal how the duration of cellular stress modulates the SASP in distinct subpopulations of senescent cells. We used multiplex, single-cell imaging to build a proteomic map of senescence induction in human epithelial cells induced to senescence over the course of 31 days. We map how the expression of SASP proteins increases alongside other known senescence markers such as p53, p21, and p16INK4a. The aggregated population of cells responded to etoposide with an accumulation of stress response factors over the first 11 days, followed by a plateau in most proteins. At the single-cell level, however, we identified two distinct senescence cell populations, one defined primarily by larger nuclear area and the second by higher protein concentrations. Trajectory inference suggested that cells took one of two discrete molecular paths from unperturbed healthy cells, through a common transitional subpopulation, and ending at the discrete terminal senescence phenotypes. Our results underscore the importance of using single-cell proteomics to identify the mechanistic pathways governing the transition from senescence induction to a mature state of senescence characterized by the SASP.
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- Award ID(s):
- 2242980
- PAR ID:
- 10567754
- Publisher / Repository:
- Springer Science + Business Media
- Date Published:
- Journal Name:
- GeroScience
- Volume:
- 47
- Issue:
- 3
- ISSN:
- 2509-2723
- Format(s):
- Medium: X Size: p. 3891-3905
- Size(s):
- p. 3891-3905
- Sponsoring Org:
- National Science Foundation
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