@article{7ed0d6130b96422e8db82ce6d58f6ef7,
title = "Oxysterol Signatures Distinguish Age-Related Macular Degeneration from Physiologic Aging",
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.",
keywords = "Age-related macular degeneration, Aging, Cholesterol, Lipids",
author = "Lin, {Jonathan B.} and Abdoulaye Sene and Andrea Santeford and Hideji Fujiwara and Rohini Sidhu and Ligon, {Marianne M.} and Shankar, {Vikram A.} and Norimitsu Ban and Mysorekar, {Indira U.} and Ory, {Daniel S.} and Apte, {Rajendra S.}",
note = "Funding Information: This work was supported by NIH Grants R01 EY019287 (R.S.A.), R01 NS081985 (D.S.O), R01 AG052494 (I.U.M.), P30 EY02687 (Vision Core Grant), and P30 DK020579 (Diabetes Research Center Metabolomics Core); the Starr Foundation (R.S.A.); the Carl Marshall Reeves and Mildred Almen Reeves Foundation (R.S.A.); the Bill and Emily Kuzma Family Gift for retinal research (R.S.A.); a Physician-Scientist Award and a Nelson Trust Award from Research to Prevent Blindness (R.S.A.); the Jeffrey Fort Innovation Fund (R.S.A.); and the Thome Foundation (R.S.A.). Additional funding comes from an unrestricted grant to the Department of Ophthalmology and Visual Sciences of Washington University School of Medicine from Research to Prevent Blindness. J.B.L. was supported by the Washington University in St. Louis Medical Scientist Training Program (NIH Grant T32 GM007200), the Washington University in St. Louis Institute of Clinical and Translational Sciences (NIH Grants UL1 TR002345, TL1 TR002344), and the VitreoRetinal Surgery Foundation. M.M.L. was supported by NIH Grants T32 GM007200 and T32 AI007172. The funders had no involvement in any aspect of this study or manuscript preparation. R.S.A. had full access to all of the data in the study and had final responsibility for the decision to submit for publication. Funding Information: The authors thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis (NIH Grants P30 CA91842 and UL1 TR000448). We also thank David Scherrer for technical assistance and Stephanie Schultz for helpful discussions. Publisher Copyright: {\textcopyright} 2018 The Authors",
year = "2018",
month = jun,
doi = "10.1016/j.ebiom.2018.05.035",
language = "English",
volume = "32",
pages = "9--20",
journal = "EBioMedicine",
issn = "2352-3964",
}