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Senescent cells (SCs) are cells that have stopped dividing and are no longer able to grow or divide, a phenomenon known as the "Hayflick limit". SCs have been hypothesized to be drivers of aging and are associated to aging and age-related diseaeses. Cellular senescence is considered to be one of the hallmarks of aging.
Senescent cells produce pro-inflammatory signalling molecules such as the senescence-associated secretory phenotype (SASP), releasing various factors that can trigger inflammation and dysfunction, while promoting apoptosis (cell death) in nearby tissues.
Typical components and central biomarkers of the SASP according to Aging Biomarker Consortium., Bao, H., Cao, J. et al. 2023
|Chemokines||IL-8, GROα, GROβ, GROγ, MCP1, MCP2, MCP4, CCL1, CCL3, CCL5, CCL11, CCL16, CCL20, CCL25, CCL26|
|Cytokines||IL-6, IL-7, IL-1α, IL-1b, IL-13, IL-15, IL23a, TNFα|
|Other inflammatory factors||TGF-β, GM-CSF, M-CSF, G-CSF, IFN-α1, IFN-γ, CCL13, MIF, LIF|
|Growth factors||AREG, EREG, heregulin, EGF, bFGF, HGF, FGF7, VEGF, ANG, SCF, CXCL12, GDF15, GDNF, IGFBP1, IGFBP2, IGFBP3, IGFBP4, IGFBP6, IGFBP7|
|Proteases and inhibitors||MMP1, MMP2, MMP3, MMP8, MMP10, MMP12, MMP14, TIMP1, TIMP2, PAI-1, PAI-2, tPA, uPA, cathepsin B, SPINK1, SERPINs|
|Receptors and ligands||ICAM1, ICAM3, OPG, sTNFRI, sTNFRII, TRAIL-R3, Fas, uPAR, SGP130, EGF-R, WNT16B|
|Insoluble molecules||Collagens, fibronectin, laminin|
Data are derived and processed from cellular senescence- and aging-related literatures (Acosta et al., 2008; Coppe et al., 2008a; Coppe et al., 2010; Coppe et al., 2008b; Gorgoulis et al., 2019; Kuilman et al., 2008; Rodier et al., 2011; Sun et al., 2012).
Circulating concentrations of senescence biomarkers of the SASP, could predict mortality in older adults. Elevated levels of a stress-induced cytokine growth factor GDF15 are most strongly associated with an increased risk of death in populations of all ages, even after adjustment for several risk factors.
Cellular senescence and aging
Due to the negative impact that SCs may have in neighbouring cells and tissues, some scientists believe that the clearance of senescent cells via senolytics may have therapeutic benefits, especially for treating age-related diseases such as cancer, cardiovascular disease or neurodegeneration. Cellular senescence has also been suggested as a driver of fibrotic pulmonary disease.
Cellular senescence can be viewed as a necessary, adaptive response of the body in response to injury, infection or other stresses. It also serves key purposes during tissue remodelling, wound repair or embryogenesis. However, chronic senescence can be maladaptive and lead to age-related diseases.
It is not clear whether removing senescent cells might have deleterious effects in vivo, and several studies are suggesting that they play a fundamental role in physiology and thus might be detrimental to remove them, even when accumulated chronically. For instance, eliminating senescent cells in mice promoted the development and progression of pulmonary hypertension.
See the full article on senolytics.
Senescent cells survive their own SASP, since they are protected by networks of senescent cell anti-apoptotic pathways (SCAPs). One mechanism of senolytics, therefore, is to interfere with these networks, so that the SASP also induce apoptosis in the senescent cells themselves. Senescent cells take time to re-build once they are ablated. Hence, an advantage of senolytic treatment is that it can be done in a "hit-and-run" fashion, thus avoiding off-target effects in comparison to other types of treatments.
A way to track if senolytics have any effect is to check out for senescent biomarkers. Some known markers of SCs are p16, p21 and senescence-associated β-galactosidase activity (SA-β-gal).
See the full article on negligible senescence.
The phenomenon of showing no signs of senescence, such as age-related dysfunctions.
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