Senescent Cells Implicated in Age-Related Changes in Blood Clotting

Senescent cells are created constantly in the body as the result of a number of processes: the Hayflick limit, wound healing, a toxic local environment, DNA damage, and so forth. Near all are destroyed quite quickly, either via programmed cell death or by the immune system. Some few linger, however, and secrete a potent mix of molecules known as the senescence-associated secretory phenotype (SASP). The SASP produces wide-ranging damage and dysfunction in tissues, causing issues such as chronic inflammation, fibrosis, and harmful behavior or increased senescence in nearby cells. Thus senescent cell burden is one of the important causes of aging, and efforts to produce senolytic therapies capable of selectively destroying these cells are a very important new branch of medicine.

As noted in today's scientific materials, researchers have recently provided data to associate the burden of senescent cells in older individuals with detrimental changes in blood clotting. This adds one more item to a very long list of harmful effects resulting the SASP. With age, blood clots form more readily, and in inappropriate circumstances, such as inside major blood vessels. This can cause serious issues such as thrombosis, the blocking of blood vessels and consequent ischemia, or worse, such as a stroke or heart attack should a sizable clot fragment and the fragments block a more vital blood vessel elsewhere.

The data here associating components of the SASP with increased susceptibility to blood clotting is interesting to compare with a recent review paper on changes in platelet function with age. The biochemistry of the age-related hyperactivity of platelets, leading to increased clotting, has been examined in a proximate sense, but reaching backwards to root causes is something that the research community has never been all that good at following through on. The work here is a good example of starting with a known cause of aging and working forwards, a much more efficient approach, and one that must become more widespread in the research community if we are to see meaningful progress in treatments for age-related conditions in the years ahead.

Cellular senescence is associated with age-related blood clots

Cells that become senescent irrevocably stop dividing under stress, spewing out a mix of inflammatory proteins that lead to chronic inflammation as more and more of the cells accumulate over time. Researchers have identified 44 specific senescence-associated proteins that are involved in blood clotting, marking the first time that cellular senescence has been associated with age-related blood clots. "The incidence of venous thrombosis, which includes deep vein thrombosis and pulmonary embolism is extremely low until the age of 45, when it begins to rise rapidly. Over time it becomes a major risk factor for death. By 80, the condition affects five to six people per thousand individuals. Blood clots are also a serious side effect of chemotherapy, which sets off a cascade of senescence in those undergoing treatment. That's why blood thinners, which carry their own risks, are often included in treatment protocols."

In this study, researchers validated the expression of some of the specific factors in cultured cells and in mice, which were treated with doxorubicin, a widely-used chemotherapy drug which induces widespread senescence. Those mice showed increased blood clotting, similar to what happens in humans who undergo chemotherapy. "Conversely, when we selectively removed senescent cells in specially bred transgenic mice, the increased clotting caused by doxorubicin went away."

SILAC Analysis Reveals Increased Secretion of Hemostasis-Related Factors by Senescent Cells

Cellular senescence irreversibly arrests cell proliferation, accompanied by a multi-component senescence-associated secretory phenotype (SASP) that participates in several age-related diseases. Using stable isotope labeling with amino acids (SILACs) and cultured cells, we identify 343 SASP proteins that senescent human fibroblasts secrete at 2-fold or higher levels compared with quiescent cell counterparts. Bioinformatic analysis reveals that 44 of these proteins participate in hemostasis, a process not previously linked with cellular senescence.

We validated the expression of some of these SASP factors in cultured cells and in vivo. Mice treated with the chemotherapeutic agent doxorubicin, which induces widespread cellular senescence in vivo, show increased blood clotting. Conversely, selective removal of senescent cells using transgenic p16-3MR mice showed that clearing senescent cells attenuates the increased clotting caused by doxorubicin. Our study provides an in-depth, unbiased analysis of the SASP and unveils a function for cellular senescence in hemostasis.

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