Oxysterol Signatures Distinguish Age-Related Macular Degeneration from Physiologic Aging

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.
Highlights • Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. • Macrophage aging is pathogenic in numerous diseases of the elderly, including AMD. • Cholesterol dyshomeostasis is a central feature of aged macrophages. Although therapies directed against vascular endothelial growth factor (VEGF) have revolutionized the therapeutic landscape for age-related macular degeneration (AMD), these drugs do not work for all patients. In this work, we characterize how innate immune cells known as macrophages change during aging to better understand the mechanisms underlying AMD pathogenesis. Furthermore, we identify the subset of these changes that are a part of healthy aging versus those that contribute to age-associated disease. Our results suggest that plasma levels of 24-hydroxycholesterol may be a candidate biomarker for pathologic macrophage aging.