Immunosenescence and Inflammaging: From Pathological Hallmarks to Rejuvenation Strategies.

Abstract

Immunosenescence-the age-related decline of immune function-drives a state of chronic, sterile inflammation termed inflammaging. Far from passive deterioration, this process is actively orchestrated by distinct but interconnected hallmarks: erosion of lymphoid organs, myeloid-biased hematopoiesis, accumulation of immune-evasive senescent cells, and metabolic-epigenetic reprogramming that locks cells into dysfunctional states. These core nodes form a self-perpetuating cycle that propagates pathology across multiple organ systems, fueling neurodegeneration, cancer, musculoskeletal decline, and gut dysbiosis. Critically, the field has transitioned from descriptive phenomenology to mechanism-based intervention. This review synthesizes emerging therapeutic strategies targeting specific nodes of the immunosenescence network. We examine senotherapeutics that sensitize senescent cells for immune clearance, HSC and thymic rejuvenation to restore lymphocyte production, and metabolic-epigenetic interventions to correct intracellular deficits. By integrating these insights, we propose a precision medicine framework that moves beyond broad immunosuppression toward rational combinatorial regimens. This roadmap aims to decouple protective immunity from pathological drivers, extending healthspan and redefining the paradigm of geriatric care.