Inflammation-resolution impairments in aging and atherosclerosis

SUMMARY Aging is a major risk factor for atherosclerotic cardiovascular disease (CVD) and yet mechanisms as to how aging impacts this disease remains vastly underexplored. Aging is associated with non-resolving inflammation (inflammaging). The resolution of inflammation requires the balance between pro- inflammatory leukotrienes (LTs, e.g. LTB4) or prostaglandins (PGs) and w3-derived specialized pro- resolving mediators (SPMs), like resolvins. While it is now known that atherosclerosis is associated with a reduced SPM:LT or PG mediator ratio, major gaps exist in our understanding of (a) the mechanisms regulating impaired resolution in age-related atherosclerosis and (b) how SPMs promote resolution. Our objective is to investigate mechanisms of defective resolution in aging so that we can develop novel strategies to treat atherosclerosis in the physiological context of aging. We found a new links in which aged atherosclerotic mice had impaired resolution of atherosclerosis, exhibited exuberant granulopoiesis and defective SPM signaling in the bone marrow. We propose three highly integrated, but independent, Aims to address mechanisms regulating myelopoiesis in aging and atherosclerosis and to determine the efficacy and mechanisms of resolvin therapies in aging and atherosclerosis. These Aims will address a fundamental gap in our understanding of the physiologically relevant context of aging in atherosclerosis. Completion of the proposed studies will provide mechanistic insight into dysregulated resolution processes in aging, define cells, mediators and mechanisms restraining plaque resolution/regression in aging, and establish rationales for new therapies. .