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

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.