Targeting the inflamed paraventricular hypothalamic-bone marrow axis rejuvenates lymphopoiesis in aged mice

Older individuals are prone to infectious disease, cancer and exhibit reduced vaccine efficacy due to age-associated immune dysfunction. The immune and nervous systems are anatomically and functionally connected, and brain aging contributes to the development of neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases. However, how the aging brain contributes to age-associated immune dysfunction, and which organ systems are involved, remains poorly understood. Here, we show that bone marrow from elderly humans and mice displays a reduced frequency and aberrant transcriptomes of common lymphoid progenitors (CLPs), accompanied by impaired lymphopoiesis. Neural denervation preserved lymphopoiesis and CLP abundance, indicating neural regulation of the bone marrow. Retrograde tracing from the bone marrow identified corticotropin-releasing hormone-expressing neurons in the paraventricular nucleus (PVN-CRH neurons) as a major participant in controlling lymphoid output. Mechanistically, aging triggers Toll-like receptor 4 (TLR4)–interferon signaling in PVN-CRH neurons, eliciting inflammatory hyperactivation. This hyperactivity destabilized DNA nucleotidylexotransferase (TdT/DNTT) expression in hematopoietic stem and progenitor cells (HSPCs) and disrupted lymphoid developmental trajectories in bone marrow via sympathetic output-β adrenergic receptors signal. Chemogenetic inhibition of aged PVN-CRH neurons or CRH neuron-specific TLR4 ablation restored CLPs and B-cell production in bone marrow and improved the H1N1 vaccine response in aged mice. In conclusion, our findings reveal a brain–bone marrow axis that becomes dysregulated with aging and propose neuromodulation as a potential strategy to rejuvenate immune function in older individuals.