Jadeja Ravirajsinh N, Powell Folami L, Jones Malita A, Fuller Jasmine, Joseph Ethan, Thounaojam Menaka C, Bartoli Manuela, Martin Pamela M
Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.
Education Innovation Institute, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.
Aging (Albany NY). 2018 Jun 12;10(6):1306-1323. doi: 10.18632/aging.101469.
Retinal pigment epithelium (RPE) performs numerous functions critical to retinal health and visual function. RPE senescence is a hallmark of aging and degenerative retinal disease development. Here, we evaluated the temporal expression of key nicotinamide adenine dinucleotide (NAD)-biosynthetic genes and associated levels of NAD, a principal regulator of energy metabolism and cellular fate, in mouse RPE. NAD levels declined with age and correlated directly with decreased nicotinamide phosphoribosyltransferase (NAMPT) expression, increased expression of senescence markers (p16, p21, ApoJ, CTGF and β-galactosidase) and significant reductions in SIRT1 expression and activity. We simulated the age-dependent decline in NAD and the related increase in RPE senescence in human (ARPE-19) and mouse primary RPE using the NAMPT inhibitor FK866 and demonstrated the positive impact of NAD-enhancing therapies on RPE cell viability. This, we confirmed in the RPE of mice injected sub-retinally with FK866 in the presence or absence of nicotinamide mononucleotide Our data confirm the importance of NAD to RPE cell biology normally and in aging and demonstrate the potential utility of therapies targeting NAMPT and NAD biosynthesis to prevent or alleviate consequences of RPE senescence in aging and/or degenerative retinal diseases in which RPE dysfunction is a crucial element.
视网膜色素上皮（RPE）执行着许多对视网膜健康和视觉功能至关重要的功能。RPE衰老 是衰老和视网膜退行性疾病发展的一个标志。在此，我们评估了小鼠RPE中关键烟酰胺腺嘌呤二核苷酸（NAD）生物合成基因的时间表达以及NAD的相关水平，NAD是能量代谢和细胞命运的主要调节因子。NAD水平随年龄下降，且与烟酰胺磷酸核糖转移酶（NAMPT）表达降低、衰老标志物（p16、p21、ApoJ、CTGF和β-半乳糖苷酶）表达增加以及SIRT1表达和活性的显著降低直接相关。我们使用NAMPT抑制剂FK866模拟了人（ARPE-19）和小鼠原代RPE中NAD随年龄的下降以及RPE衰老的相关增加，并证明了NAD增强疗法对RPE细胞活力的积极影响。在有或没有烟酰胺单核苷酸的情况下，我们在视网膜下注射FK866的小鼠的RPE中证实了这一点。我们的数据证实了NAD在正常情况下以及在衰老过程中对RPE细胞生物学的重要性，并证明了靶向NAMPT和NAD生物合成的疗法在预防或减轻RPE衰老在衰老和/或退行性视网膜疾病中的后果方面的潜在效用，在这些疾病中RPE功能障碍是一个关键因素。
