LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD⁺ depletion.

ABSTRACT: Although dysregulated cholesterol metabolism predisposes aging tissues to inflammation and a plethora of diseases, the underlying molecular mechanism remains poorly defined. Here, we show that metabolic and genotoxic stresses, convergently acting through liver X nuclear receptor, upregulate CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD⁺) depletion in macrophages. Cholesterol-mediated NAD⁺ depletion induces macrophage senescence, promoting key features of age-related macular degeneration (AMD), including subretinal lipid deposition and neurodegeneration. NAD⁺ augmentation reverses cellular senescence and macrophage dysfunction, preventing the development of AMD phenotype. Genetic and pharmacological senolysis

SUBMITTER: Terao R 

PROVIDER: S-EPMC11223747 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature