视网膜多不饱和脂肪酸补充逆转衰老相关的小鼠视力下降

IF 14.6 1区 医学 Q1 CELL BIOLOGY
Fangyuan Gao, Emily Tom, Cezary Rydz, William Cho, Alexander V. Kolesnikov, Yutong Sha, Anastasios Papadam, Samantha Jafari, Andrew Joseph, Ava Ahanchi, Nika Balalaei Someh Saraei, David C. Lyon, Andrzej Foik, Qing Nie, Felix Grassmann, Vladimir J. Kefalov, Dorota Skowronska-Krawczyk
{"title":"视网膜多不饱和脂肪酸补充逆转衰老相关的小鼠视力下降","authors":"Fangyuan Gao,&nbsp;Emily Tom,&nbsp;Cezary Rydz,&nbsp;William Cho,&nbsp;Alexander V. Kolesnikov,&nbsp;Yutong Sha,&nbsp;Anastasios Papadam,&nbsp;Samantha Jafari,&nbsp;Andrew Joseph,&nbsp;Ava Ahanchi,&nbsp;Nika Balalaei Someh Saraei,&nbsp;David C. Lyon,&nbsp;Andrzej Foik,&nbsp;Qing Nie,&nbsp;Felix Grassmann,&nbsp;Vladimir J. Kefalov,&nbsp;Dorota Skowronska-Krawczyk","doi":"10.1126/scitranslmed.ads5769","DOIUrl":null,"url":null,"abstract":"<div >The retina is uniquely enriched in polyunsaturated fatty acids (PUFAs), primarily localized in cell membranes, where they govern membrane biophysical properties. During aging, alterations in lipid metabolism lead to reduced content of very long–chain PUFAs (VLC-PUFAs) in the retina, which is associated with normal age-related reductions in contrast sensitivity, diminished photoreceptor function and delayed rod-mediated dark adaptation recovery, and pathological age-related macular degeneration (AMD). <i>ELOVL2</i> (<i>elongation of very long chain fatty acids-like 2</i>) encodes a transmembrane protein that produces precursors to docosahexaenoic acid (DHA) and VLC-PUFAs. The methylation status of the <i>ELOVL2</i> promoter is currently one of the best predictors of chronological age. Here, we show that lower VLC-PUFA abundance in the aged mouse retina is accompanied by a reduction in visual function. Similarly, mice lacking ELOVL2-specific enzymatic activity (<i>Elovl2<sup>C234W</sup></i>) demonstrate reduced contrast sensitivity and slower rod-mediated dark adaptation. Intravitreal supplementation with the direct product of ELOVL2, 24:5n-3, in aged animals improved visual function for up to 4 weeks and reduced accumulation of APOE- and C3d-positive sub-RPE deposits. The gene expression pattern observed in supplemented retinas exhibited a partial rejuvenation profile, including decreased expression of aging-related genes and a transcriptomic signature resembling younger retinas. Last, human genetic data from the IAMDGC and UK Biobank linked two variants in the <i>ELOVL2</i> locus with the onset of intermediate AMD, underlining the translational importance of our findings. Our work highlights VLC-PUFA supplementation as a potential therapeutic opportunity and defines ELOVL2 as a promising target for interventions to prevent age-related vision loss.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 817","pages":""},"PeriodicalIF":14.6000,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Retinal polyunsaturated fatty acid supplementation reverses aging-related vision decline in mice\",\"authors\":\"Fangyuan Gao,&nbsp;Emily Tom,&nbsp;Cezary Rydz,&nbsp;William Cho,&nbsp;Alexander V. Kolesnikov,&nbsp;Yutong Sha,&nbsp;Anastasios Papadam,&nbsp;Samantha Jafari,&nbsp;Andrew Joseph,&nbsp;Ava Ahanchi,&nbsp;Nika Balalaei Someh Saraei,&nbsp;David C. Lyon,&nbsp;Andrzej Foik,&nbsp;Qing Nie,&nbsp;Felix Grassmann,&nbsp;Vladimir J. Kefalov,&nbsp;Dorota Skowronska-Krawczyk\",\"doi\":\"10.1126/scitranslmed.ads5769\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div >The retina is uniquely enriched in polyunsaturated fatty acids (PUFAs), primarily localized in cell membranes, where they govern membrane biophysical properties. During aging, alterations in lipid metabolism lead to reduced content of very long–chain PUFAs (VLC-PUFAs) in the retina, which is associated with normal age-related reductions in contrast sensitivity, diminished photoreceptor function and delayed rod-mediated dark adaptation recovery, and pathological age-related macular degeneration (AMD). <i>ELOVL2</i> (<i>elongation of very long chain fatty acids-like 2</i>) encodes a transmembrane protein that produces precursors to docosahexaenoic acid (DHA) and VLC-PUFAs. The methylation status of the <i>ELOVL2</i> promoter is currently one of the best predictors of chronological age. Here, we show that lower VLC-PUFA abundance in the aged mouse retina is accompanied by a reduction in visual function. Similarly, mice lacking ELOVL2-specific enzymatic activity (<i>Elovl2<sup>C234W</sup></i>) demonstrate reduced contrast sensitivity and slower rod-mediated dark adaptation. Intravitreal supplementation with the direct product of ELOVL2, 24:5n-3, in aged animals improved visual function for up to 4 weeks and reduced accumulation of APOE- and C3d-positive sub-RPE deposits. The gene expression pattern observed in supplemented retinas exhibited a partial rejuvenation profile, including decreased expression of aging-related genes and a transcriptomic signature resembling younger retinas. Last, human genetic data from the IAMDGC and UK Biobank linked two variants in the <i>ELOVL2</i> locus with the onset of intermediate AMD, underlining the translational importance of our findings. Our work highlights VLC-PUFA supplementation as a potential therapeutic opportunity and defines ELOVL2 as a promising target for interventions to prevent age-related vision loss.</div>\",\"PeriodicalId\":21580,\"journal\":{\"name\":\"Science Translational Medicine\",\"volume\":\"17 817\",\"pages\":\"\"},\"PeriodicalIF\":14.6000,\"publicationDate\":\"2025-09-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Science Translational Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.science.org/doi/10.1126/scitranslmed.ads5769\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Science Translational Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.science.org/doi/10.1126/scitranslmed.ads5769","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

视网膜富含多不饱和脂肪酸(PUFAs),主要存在于细胞膜中,在那里它们控制着膜的生物物理特性。在衰老过程中,脂质代谢的改变导致视网膜中超长链PUFAs (VLC-PUFAs)含量的减少,这与正常年龄相关的对比敏感度降低、光感受器功能减弱、杆状细胞介导的暗适应恢复延迟以及病理年龄相关性黄斑变性(AMD)有关。ELOVL2(超长链脂肪酸样2的延伸)编码一种跨膜蛋白,该蛋白产生二十二碳六烯酸(DHA)和VLC-PUFAs的前体。ELOVL2启动子的甲基化状态目前是实足年龄的最佳预测因子之一。在这里,我们发现老年小鼠视网膜中VLC-PUFA丰度的降低伴随着视觉功能的降低。同样,缺乏elovl2特异性酶活性(Elovl2C234W)的小鼠表现出对比度敏感性降低和杆状细胞介导的暗适应减慢。在老年动物的玻璃体内补充ELOVL2的直接产物24:5n-3,可改善视觉功能长达4周,并减少APOE-和c3d阳性亚rpe沉积物的积累。在补充视网膜中观察到的基因表达模式显示出部分返老还童的特征,包括衰老相关基因的表达减少和与年轻视网膜相似的转录组特征。最后,来自IAMDGC和UK Biobank的人类遗传数据将ELOVL2位点的两个变体与中期AMD的发病联系起来,强调了我们的发现的转化重要性。我们的工作强调了VLC-PUFA补充剂作为潜在的治疗机会,并将ELOVL2定义为预防年龄相关性视力丧失的有希望的干预目标。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Retinal polyunsaturated fatty acid supplementation reverses aging-related vision decline in mice
The retina is uniquely enriched in polyunsaturated fatty acids (PUFAs), primarily localized in cell membranes, where they govern membrane biophysical properties. During aging, alterations in lipid metabolism lead to reduced content of very long–chain PUFAs (VLC-PUFAs) in the retina, which is associated with normal age-related reductions in contrast sensitivity, diminished photoreceptor function and delayed rod-mediated dark adaptation recovery, and pathological age-related macular degeneration (AMD). ELOVL2 (elongation of very long chain fatty acids-like 2) encodes a transmembrane protein that produces precursors to docosahexaenoic acid (DHA) and VLC-PUFAs. The methylation status of the ELOVL2 promoter is currently one of the best predictors of chronological age. Here, we show that lower VLC-PUFA abundance in the aged mouse retina is accompanied by a reduction in visual function. Similarly, mice lacking ELOVL2-specific enzymatic activity (Elovl2C234W) demonstrate reduced contrast sensitivity and slower rod-mediated dark adaptation. Intravitreal supplementation with the direct product of ELOVL2, 24:5n-3, in aged animals improved visual function for up to 4 weeks and reduced accumulation of APOE- and C3d-positive sub-RPE deposits. The gene expression pattern observed in supplemented retinas exhibited a partial rejuvenation profile, including decreased expression of aging-related genes and a transcriptomic signature resembling younger retinas. Last, human genetic data from the IAMDGC and UK Biobank linked two variants in the ELOVL2 locus with the onset of intermediate AMD, underlining the translational importance of our findings. Our work highlights VLC-PUFA supplementation as a potential therapeutic opportunity and defines ELOVL2 as a promising target for interventions to prevent age-related vision loss.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信