Senescent intimal foam cells are deleterious at all stages of atherosclerosis

By Bennett G. Childs, D. Baker, Tobias Wijshake, C. Conover, J. Campisi, J. V. van Deursen. Science, 2016

1,064 citations recorded by the source corpus.

Wreaking havoc while (growth-)arrested Cells enter a state of senescence in response to certain stresses. Studying mouse models, Childs et al. examined the role of senescent lipid-loaded macrophages (so-called “foam cells”) in the pathogenesis of atherosclerosis. At early stages of atherosclerosis, senescent foam cells promoted the expression of inflammatory cytokines. At later stages, they promoted the expression of matrix metalloproteases implicated in the rupture of atherosclerotic plaque, which can lead to blood clots. Experimental removal of the senescent cells had beneficial effects at both stages of the disease. Science, this issue p. 472 Senescent macrophages contribute to early and late stages of atherosclerosis and are potential targets for therapy. Advanced atherosclerotic lesions contain senescent cells, but the role of these cells in atherogenesis remains unclear. Using transgenic and pharmacological approaches to eliminate senescent cells in atherosclerosis-prone low-density lipoprotein receptor–deficient (Ldlr–/–) mice, we show that these cells are detrimental throughout disease pathogenesis. We find that foamy macrophages with senescence markers accumulate in the subendothelial space at the onset of atherosclerosis, where they drive pathology by increasing expression of key atherogenic and inflammatory cytokines and chemokines. In advanced lesions, senescent cells promote features of plaque instability, including elastic fiber degradation and fibrous cap thinning, by heightening metalloprotease production. Together, these results demonstrate that senescent cells are key drivers of atheroma formation and maturation and suggest that selective clearance of these cells by senolytic agents holds promise for the treatment of atherosclerosis.

Subfields: Immunology, Physiology

View Paper: https://www.semanticscholar.org/paper/d77de7872775bffbfe9acea2fc8c0316e9ec0b20

How researchers see this paper

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In Immunology

1. J. Kirkland
2. T. Tchkonia
3. A. Lichtman
4. Zhijian J. Chen
5. M. Demaria
6. Jesús Gil
7. Qi Chen
8. Yi Zhu

In Physiology

1. J. Kirkland
2. T. Tchkonia
3. Jesús Gil
4. M. Demaria
5. J. Campisi
6. Jodie Birch
7. T. Wyss‐Coray
8. Zhijian J. Chen

Citations in the corpus

• Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “These cells upregulate proteolytic SASP factors MMP12 and MMP13, which promote plaque instability (63) (FIGURE 3).”
• Senescence and the SASP: many therapeutic avenues (2020, background): “Finally, the physical build-up of senescent cells could contribute to disease, as is the case with the accumulation of senescent foamy macrophages in atherosclerotic plaques (Childs et al. 2016).”
• Senescence and aging: Causes, consequences, and therapeutic avenues (2018, background): “Subsequent studies showed that macrophages were the primary senescent cell present with higher levels of SA-β-Gal staining and SASP production, suggesting their key contribution to coronary heart disease (Childs et al., 2016).”
• Immunosenescence: molecular mechanisms and diseases (2023, background): “They upregulate the SASP factors MMP12 and MMP13 and recruit monocytes, stimulating more conversion to foamy macrophages and promoting plaque instability.(170) In patients infected with cytomegalovirus, CD8CD28 T-cell expansion is a risk factor for vascular dysfunction and is strongly associated wit”
• Measuring biological age using omics data (2022, background): “Aged cells may accelerate ageing of other cells through secretion of pro-ageing factors 191,192 , and certain cell types may be more susceptible to pro-ageing factors in their environment 186,189,190 . al.”
• A proteomic atlas of senescence-associated secretomes for aging biomarker development (2019, background): “Data from several laboratories, including our own, strongly support the idea that senescent cells and the SASP drive multiple age-related phenotypes and pathologies, including atherosclerosis [10], osteoarthritis [11], cancer metastasis, cardiac dysfunction [12,13], myeloid skewing [14,15], kidney d”
• Monocyte-Macrophages and T Cells in Atherosclerosis (2017, positive): “However, a more definitive causation study was recently conducted with Western-diet-fed Ldlr / mice in which lesional macrophages, VSMCs, and endothelial cells expressing p16Ink had been genetically eliminated (Childs et al., 2016).”
• Fisetin is a senotherapeutic that extends health and lifespan (2018, background): “Similarly, Navitoclax, which decreases abundance of some but not all human and mouse senescent cell types in vitro [33], reduces hematologic dysfunction caused by whole body radiation [31] and reduces senescent cell-like, intimal foam cell/macrophages in vascular plaques in high fat fed LdlR mice [3”