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Research Paper|Volume 10, Issue 6|pp 1306—1323

Loss of NAMPT in aging retinal pigment epithelium reduces NAD+ availability and promotes cellular senescence

Ravirajsinh N. Jadeja1, Folami L. Powell1,2,3, Malita A. Jones1, Jasmine Fuller1, Ethan Joseph1, Menaka C. Thounaojam4, Manuela Bartoli3,4, Pamela M. Martin1,3,4,5
  • 1Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
  • 2Education Innovation Institute, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
  • 3James and Jean Culver Vision Discovery Institute, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
  • 4Department of Ophthalmology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
  • 5Georgia Cancer Center, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA
Received: April 16, 2018Accepted: June 4, 2018Published: June 12, 2018
https://doi.org/10.18632/aging.101469

Copyright: © 2018 Jadeja et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

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 (p16INK4a, p21Waf/Cip1, ApoJ, CTGF and β-galactosidase) and significant reductions in SIRT1 expression and activity. We simulated in vitro 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 vivo 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.