Innate immune cell-intrinsic ketogenesis is dispensable for organismal metabolism and age-related inflammation

Aging is accompanied by chronic low-grade inflammation, but the mechanisms that allow this to persist are not well understood. Ketone bodies are alternative fuels produced when glucose is limited and improve indicators of healthspan in aging mouse models. Moreover, the most abundant ketone body, beta-hydroxybutyrate, inhibits the NLRP3 inflammasome in myeloid cells, a key potentiator of age-related inflammation. Given that myeloid cells express ketogenic machinery, we hypothesized this pathway may serve as a metabolic checkpoint of inflammation. To test this hypothesis, we conditionally ablated ketogenesis by disrupting expression of the terminal enzyme required for ketogenesis, 3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL). By deleting HMGCL in the liver, we validated the functional targeting and establish that the liver is the only organ that can produce the life-sustaining quantities of ketone bodies required for survival during fasting or ketogenic diet feeding. Conditional ablation of HMGCL in neutrophils and macrophages had modest effects on body weight and glucose tolerance in aging but worsened glucose homeostasis in myeloid cell-specific Hmgcl-deficient mice fed a high-fat diet. Our results suggest that during aging, liver-derived circulating ketone bodies might be more important for deactivating the NLRP3 inflammasome and controlling organismal metabolism.

Automated summary

Aging is accompanied by chronic low-grade inflammation, and ketone bodies have been found to have potential in improving healthspan in aging mouse models. The most abundant ketone body, beta-hydroxybutyrate, inhibits the NLRP3 inflammasome in myeloid cells, suggesting it may serve as a metabolic checkpoint for inflammation. By disrupting the expression of the enzyme required for ketogenesis, the researchers found that liver-derived circulating ketone bodies may play a crucial role in deactivating the NLRP3 inflammasome and controlling organismal metabolism during aging.