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Oxysterol Signatures Distinguish Age-Related Macular Degeneration from Physiologic Aging
Jonathan B Lin1, Abdoulaye Sene2, Andrea Santeford2
1Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; Neuroscience Graduate Program, Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
Macrophage aging is pathogenic in numerous diseases, including age-related macular degeneration (AMD), a leading cause of blindness in older adults. Although prior studies have explored the functional consequences of macrophage aging, less is known about its cellular basis or what defines the transition from physiologic aging to disease. Here, we show that despite their frequent self-renewal, macrophages from old mice exhibited numerous signs of aging, such as impaired oxidative respiration. Transcriptomic profiling of aged murine macrophages revealed dysregulation of diverse cellular pathways, especially in cholesterol homeostasis, that manifested in altered oxysterol signatures. Although the levels of numerous oxysterols in human peripheral blood mononuclear cells and plasma exhibited age-associated changes, plasma 24-hydroxycholesterol levels were specifically associated with AMD. These novel findings demonstrate that oxysterol levels can discriminate disease from physiologic aging. Furthermore, modulation of cholesterol homeostasis may be a novel strategy for treating age-associated diseases in which macrophage aging is pathogenic.
Insights
Macrophage aging contributes to diseases like age-related macular degeneration (AMD). This study reveals altered cholesterol metabolism and oxysterol signatures in aged macrophages, with specific markers linked to AMD, suggesting new therapeutic targets.
Area of Science:
- Immunology
- Gerontology
- Ophthalmology
Background:
- Macrophage aging is implicated in various diseases, including age-related macular degeneration (AMD), a major cause of vision loss.
- The cellular basis of macrophage aging and its transition to disease states remain incompletely understood.
Purpose of the Study:
- To investigate the cellular and molecular changes associated with macrophage aging.
- To identify biomarkers that distinguish physiologic aging from disease-related aging, specifically in the context of AMD.
Main Methods:
- Transcriptomic profiling of aged murine macrophages.
- Analysis of oxysterol levels in murine macrophages and human blood samples.
- Correlation analysis between oxysterol levels and AMD diagnosis.
Main Results:
- Aged macrophages, despite self-renewal, display signs of aging, including impaired oxidative respiration.
- Transcriptomic analysis revealed dysregulated cholesterol homeostasis and altered oxysterol profiles in aged macrophages.
- Plasma 24-hydroxycholesterol levels were specifically associated with AMD in humans, distinguishing it from normal aging.
Conclusions:
- Oxysterol levels serve as discriminators between physiologic aging and AMD.
- Targeting cholesterol homeostasis pathways presents a potential therapeutic strategy for age-related diseases involving macrophage aging.
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