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Senescent Cells Linked to Age-Related Blood Clot Formation

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Researchers at the Buck Institute, including Dr. Judy Campisi, have published a new study that shows, for the first time, that senescent cells are associated with age-related blood clots [1].

As we get older, increasing numbers of our cells enter into a state known as cellular senescence. Senescent cells do not divide or support the tissues of which they are part; instead, they emit a range of potentially harmful chemical signals known as the senescence-associated secretory phenotype (SASP), which encourages nearby healthy cells to enter the same senescent state.

The presence of high levels of SASP reduces tissue repair, increases chronic inflammation, and can even raise the risk of cancer and other age-related diseases.

Senescent cells normally destroy themselves via a programmed process called apoptosis, and they are also removed by the immune system; however, the immune system weakens with age, and increasing numbers of senescent cells escape this process and begin to accumulate in all the tissues of the body.

New study links SASP and blood clotting



With age, blood clots form more often and with greater ease, often in inappropriate situations or locations, such as within our arteries and veins. Chemotherapy is also known to increase the risk of blood clotting. These blood clots can lead to serious consequences by blocking blood vessels and causing ischemia, stroke, or heart attack, depending on the size and location of the clot.

In the new study, the researchers identified a total of 343 proteins present in the SASP produced by senescent human skin cells, with 44 of them associated with blood clotting. This effectively associates the increasing age-related burden of senescent cells, causing harmful changes to blood clotting dynamics.

The researchers validated the expression of these specific factors in mice exposed to the chemotherapy agent doxorubicin. This is a commonly used chemotherapy drug, and it not only destroys target cancer cells, it causes lots of nearby healthy cells to become senescent.

When treated with doxorubicin, the mice showed an increased incidence of blood clot formation, similar to when people undergo chemotherapy. However, when the researchers cleared senescent cells from the mice, this elevated occurrence of blood clotting was reversed as the SASP was reduced.

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.

Conclusion



This paper confirms that it is possible to map cellular senescence and the complex interplay of proteins produced during the process, which could be useful in analyzing disease progression and treatment. It also shows, for the first time, a direct link between cellular senescence and the increased risk of age-related blood clotting.

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Literature

[1] Wiley, C., Liu, S., Limbad, C., Zawadzka, A., Beck, J., Demaria, M., … & Desprez, P. Y. (2018). SILAC Analysis Reveals a Role for the Senescence-Associated Secretory Phenotype in Hemostasis.

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About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 500 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
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