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

Research output: Contribution to journalArticle

9 Scopus citations

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 ß-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.

Original languageEnglish (US)
Pages (from-to)1306-1323
Number of pages18
JournalAging
Volume10
Issue number6
DOIs
StatePublished - Jun 1 2018

Keywords

  • Age-related macular degeneration (AMD)
  • Aging
  • NAD+
  • NAMPT
  • Retinal pigment epithelium (RPE)
  • SIRT1
  • Senescence

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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