Alterations in the Immune‐Fibrotic Axis Are Spatially Localized in the Aging Heart

The immune-fibrotic axis functions as a vicious feedback loop where age-related chronic, low-grade systemic inflammation (inflammaging) drives maladaptive tissue repair and fibrosis, while senescent fibrotic cells in turn amplify systemic inflammation. In the aging heart, immune dysregulation and fibroblast activation drive tissue scarring and stiffening and a higher risk of heart failure and vascular disease. To identify cardiac regions and cell types affected with age, we monitored transcriptional changes across whole hearts of 6- and 24-month-old male and female mice. Spatially resolved signatures of macrophages and fibroblasts, non-cardiomyocyte populations highly involved in inflammaging, were enriched predominantly in the valves and aorta. With age, two cell types simultaneously adopted maladaptive programs: Macrophages displayed reduced immune homeostasis together with increased chemotactic and stromal programs, while more widely distributed fibroblast-lineage cells displayed alterations in extracellular matrix organization and intercellular signals, as well as upregulation of senescence-associated Cdkn1a (encoding p21) and other activated features shared with human cardiac fibroblasts. The major biological significance of these findings is that cardiac immune-fibrotic remodeling is not a uniform, heart-wide process. Instead, it varies with cell type, with valves and aorta emerging as major sites where age-associated programs converge to progressively compromise cardiac structure and function.