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The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina.
Aging Cell ( IF 8.0 ) Pub Date : 2020-01-14 , DOI: 10.1111/acel.13100 Daniel Chen 1 , Daniel L Chao 1 , Lorena Rocha 1 , Matthew Kolar 2 , Viet Anh Nguyen Huu 1 , Michal Krawczyk 1 , Manish Dasyani 1 , Tina Wang 3 , Maryam Jafari 1 , Mary Jabari 1 , Kevin D Ross 4 , Alan Saghatelian 2 , Bruce A Hamilton 4, 5 , Kang Zhang 1 , Dorota Skowronska-Krawczyk 1, 6
Aging Cell ( IF 8.0 ) Pub Date : 2020-01-14 , DOI: 10.1111/acel.13100 Daniel Chen 1 , Daniel L Chao 1 , Lorena Rocha 1 , Matthew Kolar 2 , Viet Anh Nguyen Huu 1 , Michal Krawczyk 1 , Manish Dasyani 1 , Tina Wang 3 , Maryam Jafari 1 , Mary Jabari 1 , Kevin D Ross 4 , Alan Saghatelian 2 , Bruce A Hamilton 4, 5 , Kang Zhang 1 , Dorota Skowronska-Krawczyk 1, 6
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Methylation of the regulatory region of the elongation of very‐long‐chain fatty acids‐like 2 (ELOVL2) gene, an enzyme involved in elongation of long‐chain polyunsaturated fatty acids, is one of the most robust biomarkers of human age, but the critical question of whether ELOVL2 plays a functional role in molecular aging has not been resolved. Here, we report that Elovl2 regulates age‐associated functional and anatomical aging in vivo, focusing on mouse retina, with direct relevance to age‐related eye diseases. We show that an age‐related decrease in Elovl2 expression is associated with increased DNA methylation of its promoter. Reversal of Elovl2 promoter hypermethylation in vivo through intravitreal injection of 5‐Aza‐2’‐deoxycytidine (5‐Aza‐dc) leads to increased Elovl2 expression and rescue of age‐related decline in visual function. Mice carrying a point mutation C234W that disrupts Elovl2‐specific enzymatic activity show electrophysiological characteristics of premature visual decline, as well as early appearance of autofluorescent deposits, well‐established markers of aging in the mouse retina. Finally, we find deposits underneath the retinal pigment epithelium in Elovl2 mutant mice, containing components found in human drusen, a pathologic hallmark of age related macular degeneration. These findings indicate that ELOVL2 activity regulates aging in mouse retina, provide a molecular link between polyunsaturated fatty acids elongation and visual function, and suggest novel therapeutic strategies for the treatment of age‐related eye diseases.
中文翻译：
脂质延长酶 ELOVL2 是视网膜老化的分子调节剂。
超长链脂肪酸样 2 ( ELOVL2 ) 基因延伸调控区的甲基化，一种参与长链多不饱和脂肪酸延伸的酶，是人类年龄最可靠的生物标志物之一，但ELOVL2是否在分子衰老中发挥功能作用的关键问题尚未解决。在这里，我们报告Elovl2在体内调节与年龄相关的功能和解剖衰老，重点是小鼠视网膜，与年龄相关的眼病直接相关。我们表明Elovl2表达的年龄相关降低与其启动子的 DNA 甲基化增加有关。Elovl2的逆转通过玻璃体内注射 5-Aza-2'-脱氧胞苷 (5-Aza-dc) 导致体内启动子高甲基化导致Elovl2表达增加并挽救与年龄相关的视觉功能下降。携带破坏Elovl2特异性酶活性的点突变 C234W 的小鼠表现出视力过早衰退的电生理特征，以及自发荧光沉积物的早期出现，这是小鼠视网膜中公认的衰老标志物。最后，我们在Elovl2的视网膜色素上皮下发现了沉积物突变小鼠，含有在人类玻璃疣中发现的成分，这是与年龄相关的黄斑变性的病理标志。这些发现表明，ELOVL2 活性调节小鼠视网膜的衰老，提供多不饱和脂肪酸伸长与视觉功能之间的分子联系，并为治疗与年龄相关的眼病提出了新的治疗策略。
更新日期：2020-01-14
中文翻译：
脂质延长酶 ELOVL2 是视网膜老化的分子调节剂。
超长链脂肪酸样 2 ( ELOVL2 ) 基因延伸调控区的甲基化，一种参与长链多不饱和脂肪酸延伸的酶，是人类年龄最可靠的生物标志物之一，但ELOVL2是否在分子衰老中发挥功能作用的关键问题尚未解决。在这里，我们报告Elovl2在体内调节与年龄相关的功能和解剖衰老，重点是小鼠视网膜，与年龄相关的眼病直接相关。我们表明Elovl2表达的年龄相关降低与其启动子的 DNA 甲基化增加有关。Elovl2的逆转通过玻璃体内注射 5-Aza-2'-脱氧胞苷 (5-Aza-dc) 导致体内启动子高甲基化导致Elovl2表达增加并挽救与年龄相关的视觉功能下降。携带破坏Elovl2特异性酶活性的点突变 C234W 的小鼠表现出视力过早衰退的电生理特征，以及自发荧光沉积物的早期出现，这是小鼠视网膜中公认的衰老标志物。最后，我们在Elovl2的视网膜色素上皮下发现了沉积物突变小鼠，含有在人类玻璃疣中发现的成分，这是与年龄相关的黄斑变性的病理标志。这些发现表明，ELOVL2 活性调节小鼠视网膜的衰老，提供多不饱和脂肪酸伸长与视觉功能之间的分子联系，并为治疗与年龄相关的眼病提出了新的治疗策略。
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