Senescent Cells Linked To Atherosclerosis

Posted on 28 October 2016

New research suggests senescent cells may drive plaque formation in atherosclerosis

Atherosclerosis is one of the world’s biggest killers, and is caused by plaque formation in arteries across the body – typically resulting in stroke and heart attack events. We know that cellular senescence causes a range of negative effects throughout a range of tissues as we get older and it’s been labelled as one of the major hallmarks of human aging, but could it also be contributing to atherosclerotic plaque formation?

A recap on senescence

Cellular senescence is a unique cellular state in which a cell ceases to divide and adopts a distinctive appearance; spewing out an assortment of molecules called the SASP, which attract immune cells and contribute to rising inflammation with age. Research on animals has shown that eliminating senescent cells improves a number of health biomarkers and increases mouse lifespan by up to 35%. We know that senescence can occur in response to a number of different factors and may even come in an assortment of different types with different behaviours – each type of senescence being distinct. However, broadly speaking the phenomenon happens in response to either replicative exhaustion (the erosion of telomeres to such a short state that the genome becomes unstable), or increased stress and damage exposure. 

A cross section through an atherosclerotic plaque of an LDLR knockout mouse fed a high fat diet for 12 weeks. The plaque is stained for senescence-associated beta galactosidase to visualize senescent (often referred to as “zombie”) cells.  Credit: Jan van Deursen and Bennett Childs

A cross section through an atherosclerotic plaque of an LDLR knockout mouse fed a high fat diet for 12 weeks. The plaque is stained for senescence-associated beta galactosidase to visualize senescent (often referred to as “zombie”) cells.  Credit: Jan van Deursen and Bennett Childs

A new link

A new study has demonstrated that senescent cells contribute to all 3 stages of atherosclerosis progression. When mice with a mutation in the LDL receptor gene were fed with a high fat diet intended to accelerate atherosclerosis onset, they began forming lesions within a number of days. Under closer examination, to their surprise a large percentage of these streaks contained senescent cells. When they then selectively targeted these cells for destruction, the fatty streaks began to disappear. 

Preventing immune recruitment

In the 2nd stage of the disease, lesions and fatty streaks recruit circulating immune cells which then initiates the formation of more dangerous plaques. Two specific signalling molecules VCAM1 and MCP1 are known to attract these cells, and when the researchers analysed streak composition they found these signals were predominantly being produced by senescent cells. Eliminating the cells at this stage resulted in fewer and reduced plaques. 

Stopping fatal rupture

Senescent cells stained for beta galactosidase (blue)

Senescent cells stained for beta galactosidase (blue)

During the latter stages of atherosclerosis the plaques become vulnerable to fracture, which releases clots into the bloodstream and causes strokes and heart attacks. Senescent cells are known to release factors that break down and remodel surrounding tissue. The scientists discovered that these cells were promoting plaque maturation and rupture by dissolving the connective material holding the mass together. Furthermore, when the team again treated these with a senescent cell busting approach they inhibited further expansion and stabilised existing plaques.


“Our research shows that these cells are present throughout plaque development. We find that at the earliest stages of disease, senescent cells propel plaque enlargement through the secretion of factors that attract circulating monocytes to the plaque. At advanced disease stages, senescent cells produce enzymes that dissolve the fibrous cap that overlays the plaque to give it stability, thereby promoting plaque rupture, coagulation of platelets at the site of rupture, full arterial occlusion and myocardial infarction. We show that drugs that eliminate senescent cells (referred to senolytics) inhibit plaque expansion and preserve the cap, giving plaques long-term stability”

A bigger picture

While senescent cells do appear to have evolved as an anti-cancer response in part, they also play a role in wound healing. This study indicates their role is detrimental in the case of atherosclerosis and ties in well to the known hallmarks of aging which many scientists believe are the dominant factors driving age-related disease. While the research is again on mice alone, it is further evidence that tackling these hallmarks is likely to yield wide-ranging health benefits in multiple tissues. 

Read more at MedicalXpress

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