Single‐Cell Profiling Across Immune Tissues and Organs Reveals Immunosenescence Signatures in Male Rhesus Monkeys

ABSTRACT Aging gradually impairs immune system function, yet its systemic features across immune organs remain poorly characterized in primates. Here, we perform single‐cell transcriptomic profiling of bone marrow, spleen, mesenteric lymph nodes, and peripheral blood mononuclear cells from young and naturally aged male rhesus monkeys. Our study revealed extensive transcriptional remodeling across tissues, particularly the marked upregulation of GZMB expression across multiple cell types in aged monkeys, highlighting it as a candidate biomarker of immunosenescence. Gene regulatory network analysis identifies BHLHE40 as a key transcription factor enriched in multiple CD8 + T cell subtypes during aging, regulating pro‐inflammatory and exhaustion‐related genes. We also observe an age‐associated expansion of CD8 + central memory T cells with increased CCL5 and reduced IL7R expression, consistent with a shift toward a dysfunctional state. In the bone marrow, we discover a distinct naïve B cell population with low PDCD4 expression that declines with age, potentially compromising humoral immunity. These findings offer a comprehensive single‐cell atlas of immune aging in a non‐human primate model, providing novel insights into cell‐type‐specific and tissue‐dependent features of immunosenescence. Our work establishes a valuable resource for future translational studies and biomarker discovery in human aging.