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Yet, 33%\u201350% of individuals on lipid\u2010lowering therapy continue to exhibit elevated inflammation. Middle age (MA) represents a critical window for disease acceleration, underscoring a need to better understand nonresolving inflammation in this time frame. Here, we rendered young (2\u2009months) and MA mice (10\u2009months) hypercholesterolemic with an AAV8\u2010PCSK9 virus and western diet (WD). Following 20\u2009weeks on WD, mice were switched to a chow diet for 6\u2009weeks to induce lipid lowering. This design models dietary cholesterol reduction to dissect lipid\u2010driven versus inflammation\u2010driven pathways in atherosclerosis. At baseline atherosclerosis, we found that MA mice had increased plaque necrosis as well as increased circulating and bone marrow PMN compared to young mice. After chow switch, unlike in young mice, MA mice had increased plaque necrosis and reduced remodeling, as well as increased circulating white blood cells and bone marrow hematopoietic stem cell progenitors (HSPCs). In MA chow\u2010switched mice, circulating neutrophils correlated with necrosis whereas young mice exhibited no correlation. Furthermore, MA atherosclerotic mice had bone marrow HSPCs and neutrophils that exhibited a more activated phenotype relative to young after chow switch. In addition, we observed elevated neutrophil\u2013endothelial contacts in the hippocampal vasculature of MA mice after chow switch. While dietary intervention and lowered plasma cholesterol restrained atheroprogression in young, it was inadequate in MA mice, failing to reduce systemic inflammation and indicating the need for complementary therapies during this time frame.<\/jats:p>","DOI":"10.1096\/fj.202503638rr","type":"journal-article","created":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T10:15:48Z","timestamp":1770459348000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cholesterol Lowering Alone Fails to Reverse Atherosclerotic Plaque Necrosis, Granulopoiesis, and Neurovascular Neutrophils in Middle\u2010Aged Mice"],"prefix":"10.1096","volume":"40","author":[{"given":"Olivia","family":"Gannon","sequence":"first","affiliation":[{"name":"Department of Immunology and Microbial Disease Albany Medical College  Albany New York 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