Aging-US: Loss of NAMPT in aging retinal pigment epithelium09-08-2021
Aging-US published a Special Collection on Eye Disease which included "Loss of NAMPT in aging retinal pigment epithelium reduces NAD+ availability and promotes cellular senescence" which reported that retinal pigment epithelium performs numerous functions critical to retinal health and visual function.
Here, the authors evaluated the temporal expression of key nicotinamide adenine dinucleotide -biosynthetic genes and associated levels of NAD+, a principal regulator of energy metabolism and cellular fate, in mouse RPE.
They simulated in vitro the age-dependent decline in NAD+ and the related increase in RPE senescence in human and mouse primary RPE using the NAMPT inhibitor FK866 and demonstrated the positive impact of NAD+-enhancing therapies on RPE cell viability. This was confirmed in vivo in the RPE of mice injected sub-retinally with FK866 in the presence or absence of nicotinamide mononucleotide.
Dr. Pamela M. Martin and Dr. Ravirajsinh N. Jadeja said, "The retinal pigment epithelium (RPE) performs numerous functions essential to normal retinal health and function."
RPE serves as a physiologic barrier between the photoreceptor cells and the choroidal blood supply and in doing so, plays an essential role in protecting the retina from systemic insults by regulating immune responses and thereby limiting the entry of infectious or otherwise detrimental agents into retina.
Figure 10. In vivo administration of nicotinamide mononucleotide (NMN) prevents FK866-induced NAD+ depletion and RPE senescence. Male C57BL/6J mice were injected sub-retinally with 10 μM FK866 (right eye) at day 0 and day 7 and sacrificed on day 15 (7 days after the last dose). RPE/eye cup was then collected for further analysis. Simultaneously, a group of mice were treated with 150 mg/kg NMN (i.p.) for 14 days. Left eye was injected with PBS to use as controls. (A) NAD+ content and (B) SIRT-1 expression was evaluated by NAD assay and western blotting respectively. A representative western blot image from three replicates is shown. Data are presented as mean ± S.E.M for n=5. *p<0.05 compared to CON (Vehicle treated) and @p<0.05 compared to FK866.
This is the premise of a number of recent studies including the present investigation in which we focused on nicotinamide adenine dinucleotide and factors governing its bioavailability in relation to the overall impact on RPE viability. NAD+, a central metabolic cofactor, plays a critical role in regulating cellular metabolism and energy homeostasis. The ratio of NAD+ to NADH regulates the activity of various enzymes essential to metabolic pathways including glycolysis, the Kreb’s cycle, and fatty acid oxidation.
There is a wealth of clinical and experimental data stemming from studies of other primary diseases of aging demonstrating clearly a generalized decline in the availability of NAD+ in association with increased age and the related reduction in the activity of a number of downstream metabolic pathways that contribute to the development and progression of degenerative processes.
Members of the sirtuin family, poly ADP-ribose polymerases and the efficacy of therapies capable of impacting them have been evaluated in the context of aging retina and RPE. However, little attention has been given to upstream factors that regulate NAD+ biosynthesis, particularly in RPE. Given the importance of RPE to retinal health and function, in the present investigation we focused on evaluating the impact of NAD+ and factors that regulate its availability on RPE viability both in vivo and in vitro.
This finding is highly relevant to the clinical management of AMD but perhaps also broadly to the management of other degenerative retinal diseases in which RPE is prominently affected.
The Martin/Jadeja Research Team concluded in their Aging-US Research Output that these present data demonstrating an age-dependent decline in NAMPT expression and in turn, NAD+ generation in RPE which ultimately promotes RPE senescence supports strongly the rationale for enhancing NAMPT expression and associated NAD+ generation therapeutically.
Based upon the present experimental observations, future preclinical studies evaluating NMN or other therapies that have a direct impact on NAMPT expression and NAD+ metabolism in the context of aging and age-related retinal disease development and progression are highly warranted.
Full Text - https://www.aging-us.com/article/101469/text
Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research as well as topics beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, cancer, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR among others), and approaches to modulating these signaling pathways.