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Each cell in an organism has an average life span. For example, cells lining the surface of the human gut or skin typically live 3-5 days before they die.1 In contrast, stem cells and neurons can survive for many years.2 The process by which a cell arrests their growth after completing its life span is called cell senescence.
What Is Cell Senescence?
Cell senescence occurs when a cell stops dividing and arrests in the G1 phase of the cell cycle.3 During this phase, the cell undergoes numerous phenotypic and metabolic changes. Some of these phenotypic changes include chromatin remodeling with global demethylation and heterochromatin foci formation, which alters the cell’s gene expression landscape.4 Additionally, senescent cells are larger in size and more granular.5 Senescent cells are eradicated from the body either through apoptosis or by immune cells such as macrophages.4
Although cell senescence is often associated with aging, it is an important process during embryogenesis, wound healing, and maintaining homeostasis.6 For instance, during central nervous system development, parts of the neural tube undergo senescence for proper formation of the brain and spinal cord.7
Cell senescence was first identified by Leonard Hayflick and Paul Moorhead in 1961, when they serially passaged human fibroblast cells in culture.8 They noticed that the cells stopped dividing after 40-60 passages. The number of cell divisions before cell cycle arrest is now known as the Hayflick limit.8
To detect senescent cells in the laboratory, researchers use markers such as senescence-associated ß-galactosidase (SAßG), which exists in the lysosome of these cells.9
Credit:The Scientist
What Triggers Cell Senescence?
Cell senescence is triggered by a variety of internal or external cellular insults. Examples of internal stresses leading to senescence include shortening of the telomeres, DNA damage, mitochondrial dysfunction, nutrient deprivation, oncogenic pathway activation.3 Some examples of external stresses are radiation and chemotherapeutic agents.3
Senescence-Associated Secretory Phenotype
A major characteristic of senescent cells is the senescence-associated secretory phenotype or SASP.10 SASP encompasses a senescent cell’s secreted components, or secretome, and includes pro-inflammatory cytokines, chemokines, proteases, growth factors, reactive oxygen species (ROS), and extracellular matrix proteins.10 Senescent cells use these metabolically active components to communicate with surrounding cells and change the environment in either a positive or negative manner. For instance, SASP can recruit immune cells to remove senescent cells, remodel tissue by secreting angiogenic factors, or promote senescence in other cells through paracrine signalling.10
Senescence and Aging
Senescence is an important contributor to aging as it depletes various cell pools, including progenitor and stem cells that can replace damaged tissue over time.11 The SASP of senescent cells enhances inflammation, which increases susceptibility to many age-related diseases, such as heart disease, diabetes, and cancer.11 SASP-mediated paracrine signaling can also encourage neighboring cells to undergo senescence.11
Senescence and Cancer
A major hallmark of cancer progression is cell proliferation. As such, researchers previously thought that the senescence pathway suppressed tumors as it eliminated proliferative cells.12 However, there is increasing evidence that the SASP may contribute to cancer progression by creating an immunosuppressive environment.12
Anti-senescent Treatments
Researchers have developed drugs called senolytics to selectively target senescent cells that are resistant to apoptosis. These drugs work by upregulating antiapoptotic pathways.5 Eliminating these cells is important in diseases such as fibrosis (e.g., pulmonary fibrosis), where tissue is scarred and thickened.13 Additionally, patients with obesity or diabetes have high levels of senescent cells in adipose tissue, which contributes to fat cell size.14 For pulmonary fibrosis and diabetic kidney disease, researchers have conducted clinical trials testing senolytics and observed promising results.5
Another class of drugs called senomorphics inhibits SASP.5 Reducing SASP is critical for preventing the spread of senescence to neighboring cells or tissues. For example, ruxolitinib reduces inflammation by inhibiting Janus kinases (JAKs), proteins involved in cytokine production.9 This drug was shown to be an effective treatment in a chronic obstructive pulmonary disease mouse model.15
References
- J. Park et al., “Promotion of intestinal epithelial cell turnover by commensal bacteria: role of short-chain fatty acids,” PLoS ONE, 11(5):e0156334, 2016.
2. L. Ottoboni et al., “Therapeutic plasticity of neural stem cells,” Front Neurol, 11, 2020.
3. Kumari R, Jat P. “Mechanisms of cellular senescence: cell cycle arrest and senescence associated secretory phenotype,” Front Cell Dev Biol, 2021.
4. V. Gorgoulis et al., “Cellular senescence: defining a path forward,” Cell, 179(4):813-27, 2019.
5. N.S. Gasek et al., “Strategies for targeting senescent cells in human disease,” Nat Aging, 1(10):870-79, 2021.
6. S. Da Silva-Álvarez et al., “The development of cell senescence,” Exp Gerontol, 128:110742, 2019.
7. M. Storer et al., “Senescence Is a developmental mechanism that contributes to embryonic growth and patterning,” Cell, 155(5):1119-30, 2013.
8. L. Hayflick, P.S. Moorhead, “The serial cultivation of human diploid cell strains,” Exp Cell Res, 25(3):585-621, 1961.
9. W. Huang et al., “Cellular senescence: the good, the bad and the unknown,” Nat Rev Nephrol, 18(10):611-27, 2022.
10. D. McHugh, J. Gil, “Senescence and aging: causes, consequences, and therapeutic avenues,” J Cell Biol, 217(1):65-77, 2018.
11. R. Di Micco et al., “Cellular senescence in ageing: from mechanisms to therapeutic opportunities,” Nat Rev Mol Cell Biol, 22(2):75-95, 2021.
12. J. Yang et al., “The paradoxical role of cellular senescence in cancer,” Front Cell Devl Biol, 9, 2021.
13. F. Hernandez-Gonzalez et al., “Cellular senescence in lung fibrosis,” Int J Mol Sci, 22(13):7012, 2021.
14. A.K. Palmer et al., “Senolytics: potential for alleviating diabetes and its complications,” Endocrinology, 162(8):bqab058, 2021.
15. D. Beaulieu et al., “Phospholipase A2 receptor 1 promotes lung cell senescence and emphysema in obstructive lung disease. Euro Respir J, 2021.
