This study investigated how aging reduces CD8+ T cell antitumor and antiviral immunity, focusing on the role of β-hydroxybutyrate (3HB) bioavailability — specifically the hepatic BDH1 enzyme → SLC16A1 uptake → PRKAR1B β-hydroxybutyrylation → CREM transcription factor axis — in driving CD8+ T cell exhaustion.
Aging suppresses hepatic BDH1-dependent 3HB synthesis, leading to CD8+ T cell exhaustion via CREM-driven transcription of exhaustion-related genes; 3HB supplementation reversed these deficits and substantially restored CAR T cell antitumor activity in aged subjects.
The study relies heavily on mouse models and chemical probe tools (3Halk); direct clinical translation in aged humans is not yet established. Mechanistic findings center on a single effector (PRKAR1B), and off-target effects of 3HB supplementation on other immune or metabolic pathways are not fully characterized.
3HB (β-hydroxybutyrate) supplementation may be a viable strategy to reverse age-related CD8+ T cell exhaustion and improve CAR T cell immunotherapy outcomes in older patients. Clinicians designing immunotherapy trials for elderly patients should consider metabolic co-interventions targeting ketone body availability.
