Aging microenvironment induces CD8(+) T cell exhaustion by suppressing hepatic β-hydroxybutyrylate synthesis.

Aging reduces hepatic β-hydroxybutyrate synthesis, causing CD8+ T cell exhaustion and impairing antitumor and antiviral immunity in aged hosts.

• Why it matters: Understanding how aging suppresses immune function is crucial for developing strategies to enhance immunotherapy effectiveness in older populations, who are more vulnerable to infections and cancer.
• What they did: The study used metabolic analysis, genetic ablation, and chemical probes to show that decreased hepatic BDH1-dependent 3HB production limits T cell function, and that supplementing 3HB restores immunity by modulating protein β-hydroxybutyrylation and gene expression.
• The result: Restoring 3HB levels improves CD8+ T cell activity and CAR T cell efficacy in aged models, revealing a hepatic metabolism-driven pathway that can be targeted to counteract immunosenescence.