Yale study finds aging of bone marrow accelerates atherosclerotic plaque formation

A study published Jan. 9 in the journal Nature Aging shows that aged bone marrow promotes the expansion of arterial smooth muscle cells, which exacerbates the buildup of fatty deposits in artery walls.

A research team, led by senior author Daniel Greif and first author Inamul Kabir of the Greif Lab at Yale University, investigated the effects of aging cells in the bone marrow on arterial smooth muscle cells (SMCs) and atherosclerosis. 

The team used clonal and single-cell analyses to determine that aged bone marrow in older people promotes the expansion of SMCs, exacerbating the buildup of fatty deposits, commonly known as plaques, in artery walls, a condition known as atherosclerosis, the leading cause of heart attacks and strokes.

“Our studies put forth deficient regulation of SMC clonal expansion by aged bone marrow-derived macrophages as a critical underlying factor in atherogenesis,” the authors wrote.

The researchers noted that age is a significant risk factor for atherosclerosis. With age, stem cells in the bone marrow accumulate mutations in a process called clonal hematopoiesis of indeterminate potential (CHIP), giving rise to dominant clones of white blood cells, such as macrophages, that cause inflammation. 

The study found that CHIP is implicated in conditions, such as strokes and heart attacks, and SMCs and macrophages are key components of atherosclerotic plaque.

The research team transplanted bone marrow from aged mice into younger, genetically altered atheroprone mice and discovered that aged bone marrow induced multiple SMCs to enter the plaques, worsening atherosclerosis. 

The study found that TET2, a major gene implicated in age-induced CHIP, regulates the recruitment to and expansion of SMCs in the plaque. As the test subjects aged, the authors learned that decreased levels of TET2 regulate the recruitment and expansion of SMCs in the plaque.

The study concluded bone marrow-derived from aged macrophages was deficient in regulating SMC clonal expansion, thus playing a critical role in atherogenesis. 

The study said the findings could lead to new therapies to reduce the burden of cardiovascular disease. Further investigation is needed to determine if the findings are applicable to other cell types and diseases, such as liver failure and neurodegenerative diseases, the study concluded.

Yale researchers Xinbo Zhang, Jui Dave, Raja Chakraborty, Rihao Qu, Rachana Chandran, Aglaia Ntokou, Eunate Gallardo-Vara, Binod Aryal, Noemi Rotllan, Rolando Garcia-Milian, John Hwa, Yuval Kluger, Kathleen Martin, and Carlos Fernández-Hernando also contributed to the study.