Oxysterol Signatures Distinguish Age-Related Macular Degeneration from Physiologic Aging
Jonathan B. Lin,
Abdoulaye Sene,
Andrea Santeford,
Hideji Fujiwara,
Rohini Sidhu,
Marianne M. Ligon,
Vikram A. Shankar,
Norimitsu Ban,
Indira U. Mysorekar,
Daniel S. Ory,
Rajendra S. Apte
Affiliations
Jonathan B. Lin
Department 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
Abdoulaye Sene
Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
Andrea Santeford
Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
Hideji Fujiwara
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Rohini Sidhu
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Marianne M. Ligon
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
Vikram A. Shankar
Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
Norimitsu Ban
Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA
Indira U. Mysorekar
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA; Center for Reproductive Health Sciences, Department of Obstetrics and Gynecology, Washington University School of Medicine, St. Louis, MO, USA
Daniel S. Ory
Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
Rajendra S. Apte
Department of Ophthalmology & Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA; Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, MO, USA; Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, USA; Corresponding author at: 660 South Euclid Avenue, Box 8096, St. Louis, MO 63110, USA.
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. Keywords: Age-related macular degeneration, Aging, Lipids, Cholesterol
