Implications of NAD⁺ Metabolism in the Aging Retina and Retinal Degeneration

Abstract

Nicotinamide adenine dinucleotide (NAD+) plays an important role in various key biological processes including energy metabolism, DNA repair, and gene expression. Accumulating clinical and experimental evidence highlights an age-dependent decline in NAD+ levels and its association with the development and progression of several age-related diseases. This supports the establishment of NAD+ as a critical regulator of aging and longevity and, relatedly, a promising therapeutic target to counter adverse events associated with the normal process of aging and/or the development and progression of age-related disease. Relative to the above, the metabolism of NAD+ has been the subject of numerous investigations in various cells, tissues, and organ systems; however, interestingly, studies of NAD+ metabolism in the retina and its relevance to the regulation of visual health and function are comparatively few. This is surprising given the critical causative impact of mitochondrial oxidative damage and bioenergetic crises on the development and progression of degenerative disease of the retina. Hence, the role of NAD+ in this tissue, normally and aging and/or disease, should not be ignored. Herein, we discuss important findings in the field of NAD+ metabolism, with particular emphasis on the importance of the NAD+ biosynthesizing enzyme NAMPT, the related metabolism of NAD+ in the retina, and the consequences of NAMPT and NAD+ deficiency or depletion in this tissue in aging and disease. We discuss also the implications of potential therapeutic strategies that augment NAD+ levels on the preservation of retinal health and function in the above conditions. The overarching goal of this review is to emphasize the importance of NAD+ metabolism in normal, aging, and/or diseased retina and, by so doing, highlight the necessity of additional clinical studies dedicated to evaluating the therapeutic utility of strategies that enhance NAD+ levels in improving vision.

Systemic Treatment With Nicotinamide Riboside Is Protective in a Mouse Model of Light-Induced Retinal Degeneration

“…Photoreceptors and RPE have high metabolic demands 52 and metabolic dysregulation, including suppressed NAD + levels in either cell type, which are associated with retinal degeneration or disease. 10,53,54 It may be that the observed increase in NAD + after NR treatment, even after exposure to levels of light that would induce LIRD (Fig. 2), allowed increased or maintained retinal metabolic capac-ity that contributed to protection.…”

Possible A2E Mutagenic Effects on RPE Mitochondrial DNA from Innovative RNA-Seq Bioinformatics Pipeline

“…The detection of the nad1 gene sequence in both 3 h and 6 h treated samples could reflect the abundance of mutant forms of NAD + , following the oxidative stress condition of RPE cells. Even if the de novo pathway of NAD + biosynthesis seems to be unaffected in retinal aging and various conditions of retinal degenerations, the salvage pathway was found to be significantly altered, determining a significant decline in oxidative phosphorylation and an up-regulation of glycolytic respiration [ 90 , 91 ]. The final effect of these impairments is the mitochondrial ATP production decrease in the presence of A2E [ 92 ].…”

Targeting Diet and Exercise for Neuroprotection and Neurorecovery in Glaucoma

“…NAD acts as a cofactor in several REDOX reactions, and functions as a substrate for several protein classes, including NAD consumers: poly (adenosine diphosphate ribose) polymerases (PARP; involved in DNA damage repair [ 41 ]), sirtuins (SIRT; involved in transcription regulation, energy metabolism modulation, and DNA repair [ 42 ]), and sterile alpha and Toll/interleukin-1 receptor motif-containing protein 1 (SARM1; a regulator in neurodegenerative processes [ 43 ]). NAD levels decline during normal aging [ 44 ], and a disruption of NAD homeostasis is associated with several age-related neurodegenerative diseases, such as glaucoma, Alzheimer’s disease, and Parkinson’s disease [ 45 , 46 ].…”