Study reveals how ageing cells may trigger heart attacks and strokes

Ageing cells may help trigger unstable plaques in blood vessels linked to heart attacks and strokes, preclinical research suggests.

The findings could help explain how disturbed blood flow contributes to plaques becoming dangerous and forming clots.

They may also shed light on cardiovascular side effects linked to some cancer treatments, which can accelerate cellular ageing.

Researchers at The University of Texas MD Anderson Cancer Center identified a molecular pathway that drives inflammation inside blood vessel plaques.

The study focused on senescent cells, which are ageing or stressed cells that have stopped dividing but do not die.

The researchers found that the loss of two protective proteins, known as LATS1/2, activated an enzyme called CD38 in cells lining blood vessels.

These cells, known as endothelial cells, help keep blood vessels stable.

When CD38 was activated, the cells changed how they used energy and became more unstable.

This led to inflammation, leaky blood vessels, abnormal vessel growth and plaques that were more likely to form clots.

Atherosclerotic plaques are fatty deposits that build up inside arteries. If they rupture or become unstable, they can cause blood clots that block blood flow and trigger a heart attack or stroke.

Thrombosis means a blood clot forming inside a blood vessel.

The study was co-led by Sivareddy Kotla, associate professor of cardiology, and Jun-ichi Abe, professor of cardiology.

“Our findings provide a previously unknown mechanistic link between senescence and thrombosis, which helps explain why some plaques can suddenly become dangerous,” Kotla said.

“Understanding how aging cells rewire their surroundings and trigger plaque instability is essential for the development of therapeutic strategies that can reduce the risk of serious cardiovascular events.”

The researchers used advanced molecular profiling in preclinical models to study how endothelial cells change when LATS1/2 proteins are lost.

Removing these proteins made the cells senescent but also abnormally active.

This led to instability, leaky vessels, inflammation, abnormal vessel growth and plaques that could form clots.

Further analysis showed a dramatic increase in CD38 levels in these cells.

In preclinical models, increasing CD38 rewired the cells’ metabolism and energy use, driving inflammation.

This destabilised plaques and led to blood clot formation.

Blocking CD38 reversed these effects in laboratory and animal models.

Although the findings are still preclinical, the team also analysed human plaque samples and found similar metabolic signatures and molecular pathways.

The researchers said the findings could be relevant to people receiving cancer treatments.

Many cancer treatments can cause senescence in both tumour cells and healthy tissues, which may contribute to side effects including heart attacks, strokes and vascular inflammation.

Understanding the mechanisms involved could help researchers explore ways to prevent or reduce these complications.

“These findings reveal an entirely new connection between blood flow patterns, cellular metabolism and vascular disease,” Abe said.

“We hope this work will open new avenues for preventing plaque progression and thrombotic complications.”

The researchers said more studies are needed to explore potential biomarkers and targets.

However, they said the work provides a rationale for investigating CD38-targeted therapies as a possible way to stabilise plaques and reduce the risk of thrombosis.

Some CD38 inhibitors are already approved by the US Food and Drug Administration for other cancer types, suggesting they may be repurposed if further studies support their use.

The study was supported by the National Institutes of Health, the Cancer Prevention and Research Institute of Texas and institutional funding.