Pharmacological intervention targeting neuroimmune axis in the aging hypothalamus prevents age-associated physiological decline

Abstract Systemic physiological aging is largely driven by disrupted metabolic homeostasis, yet the central mechanisms of this metabolic dysfunction remain poorly defined. Here, we identify the hypothalamus as a critical hub driving systemic aging through neuroimmune-mediated mechanisms. Single-cell transcriptomic and immunohistochemical analyses revealed that aged hypothalami exhibit significant infiltration of CD8⁺ T lymphocytes, beginning in middle age, with signatures of activation and tissue residency. These T cells intimately interact with tanycytes and microglia, promoting neuroinflammation and progressive tanycyte loss, a defining hallmark of hypothalamic aging. T cell receptor profiling revealed a substantial presence of invariant natural killer T (iNKT) and mucosal-associated invariant T (MAIT) cells, likely activated through cytokine-driven, antigen-independent mechanisms. In aged hypothalamus, microglia secrete chemokines CCL3 and CCL4, whose ectopic expression in young mice was sufficient to trigger persistent hypothalamic T cell infiltration and accelerated systemic aging. Circulating oxidized LDLs (OxLDLs) were identified as upstream inducers of this chemokine response. Notably, pharmacological blockade of the CCL3/4-CCR5 axis with Maraviroc and Cenicriviroc prevented T cell recruitment and ameliorated metabolic and physiological impairments. Given the clinical safety of CCR5 antagonists and individuals lacking functional CCR5 remain generally healthy throughout life, our findings highlight midlife CCL3/4-CCR5 inhibition as a translatable therapeutic target for delaying age-related decline and promoting healthspan.