Evidence for Senescent Cells to Cause Aortic Aneurysms

Cells enter a senescent state in response to molecular damage, a toxic environment, reaching the Hayflick limit on replication, or to aid in wound healing, among other reasons. A senescent cell halts replication and begins to secrete a mix of inflammatory signals, growth factors, and other molecules that influence surrounding cells. This is useful and beneficial when it occurs in potentially cancerous, damaged cells, or as a part of the wound healing process. Normally these cells quickly self-destruct or are destroyed by the immune system. It is when senescent cells evade destruction and linger for the long term that the problems begin. The signals that are beneficial in the short term become destructive to tissue function and structure, additionally producing chronic inflammation and all of its accompanying problems.

In recent years, the research community has finally adopted the SENS Research Foundation view of aging in the matter of senescent cells - fifteen years late to the party, but better late than never. Meaningful progress requires more scientists and sources of funding to be involved than was the case a decade ago, so it is good that this is happening. Researchers have now demonstrated that growing numbers of senescent cells contribute to a wide range of age-related conditions, and are likely the primary cause for some of them, such as arthritis. In animal studies, selectively destroying a sizable fraction of senescent cells can extend healthy life spans, and reverse the progression of age-related diseases. Senescent cells are in effect actively maintaining a disrupted, dysfunctional state of tissue function and metabolism. Removing them turns back these consequences, producing a narrow form of rejuvenation. Aging is itself an accumulation of damage, and these senescent cells are a form of damage.

The evidence for cellular senescence to be a significant contributing cause of specific age-related conditions continues to accumulate, and ever faster as more funding pours into this part of the field. The research results noted here are an example of the type, new discoveries in the relevance of senescence to age-related disease that are announced every few months. The more that is discovered, the better for all of our futures, given that work continues on ever better ways to remove senescent cells from old tissues. That the catastrophic thinning and structural failure of aorta walls involves senescent cells is one more potential benefit to be realized by senolytic therapies capable of clearing senescent cells.

Scientists find potential way to defuse 'time bomb' of cardiology

Ascending aortic aneurysms grow for decades without any warning signs and can be fatal once they rupture. It is known that these aneurysms are caused by the thinning of the aortic wall which weakens it and makes it silently grow like a balloon over time without any symptoms. If caught early enough, they can be surgically repaired at low risk, but if they go undetected, which many do, they will eventually rupture or cause a tear in the wall of the aorta, called an aortic dissection. While the phenomenon is well documented, the medical community previously had little evidence to understand the mechanisms causing it to occur or how to prevent it.

Now, researchers have shown that a process that is recognized in cancer biology is causing the cells to become destructive and eat away at the surrounding muscle tissue, weakening the aortic wall. "We discovered that within the wall of the aorta, a small proportion of the muscle cells have entered into a state called senescence. Rather than die, these senescent cells become destructive, secreting enzymes that chew the area around them. There are select research groups around the world that are coming up with compounds that have shown promise in clearing out senescent cells. They are thinking about it for certain aging-related diseases, but it could be positioned for this important problem as well."

Seno-destructive smooth muscle cells in the ascending aorta of patients with bicuspid aortic valve disease

We undertook in situ analysis of ascending aortas from 68 patients, seeking potentially damaging cellular senescence cascades. Aortas were assessed for senescence-associated-ß-galactosidase activity, p16Ink4a, and p21 expression, and double-strand DNA breaks. The senescence-associated secretory phenotype (SASP) of cultured-aged bicuspid aortic valve (BAV) aortic smooth muscle cells (SMCs) was evaluated by transcript profiling and consequences probed by combined immunofluorescence and circular polarization microscopy. The contribution of p38 MAPK signaling was assessed by immunostaining and blocking strategies.

Herein, we report that senescent SMCs accumulate in aneurysmal ascending aortas associated with bicuspid and tricuspid aortic valves. Moreover, we identified a particular predisposition to SMC senescence in BAV aortopathy, indicated by the presence of senescent SMCs in non-aneurysmal BAV aortas, enrichment of cellular senescence at the aortic convexity, and multivariable analysis of potential aneurysm risk factors. We further show that senescent aortic SMCs have a pronounced collagenolytic SASP, a destructive profile that is controlled by p38 MAPK. The findings identify a cellular aging cascade in human BAV disease and a "seno-destructive" SMC phenotype that may underlie the aortic wall degeneration.

Comments

this is what killed my grandmother

Posted by: scott emptage at June 26th, 2019 4:49 PM

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