Excess Intracellular Cholesterol Provokes Macrophage Senescence

One the important themes of the research and development at Repair Biotechnologies is that localized excesses of cholesterol arise with age, leading to excess intracellular cholesterol, which is a pathological mechanism that disrupts cell behavior and kills cells. Getting rid of these localized excesses of cholesterol is challenging, however, unless resorting to some form of engineered protein machinery or gene therapy. Cells cannot break down cholesterol and there is no good way to bind enough of the excess cholesterol to some form of small molecule for sequestration and disposal without also targeting vital cholesterol in cell membranes and elsewhere. As this paper notes, excess cholesterol is clearly a meaningful problem in aging. 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 an...
Source: Fight Aging! - Category: Research Authors: Tags: Daily News Source Type: blogs