Study summary · research use only
LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD(+) depletion
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This study (species not specified) investigated how cholesterol metabolism affects macrophage aging and neurodegeneration, focused on age-related macular degeneration (AMD). The authors report metabolic and genotoxic stress, acting through the liver X nuclear receptor, upregulated CD38 to promote lysosomal cholesterol efflux, leading to nicotinamide adenine dinucleotide (NAD+) depletion in macrophages. Cholesterol-mediated NAD+ depletion was associated with macrophage senescence and features of AMD, including subretinal lipid deposition and neurodegeneration. NAD+ augmentation reversed cellular senescence and macrophage dysfunction and prevented AMD-associated changes in the study, while genetic and pharmacological removal of senescent cells (senolysis) also reduced AMD and neurodegeneration findings. Subretinal administration of healthy macrophages promoted clearance of senescent macrophages and reduced AMD-related disease burden in the study.
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 protect against the development of AMD and neurodegeneration. Subretinal administration of healthy macrophages promotes the clearance of senescent macrophages, reversing the AMD disease burden. Thus, NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying age-related neurodegeneration.
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