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

Jadeja, Ravirajsinh N.; Powell, Folami L.; Jones, Malita A; Fuller, Jasmine; Joseph, Ethan; Thounaojam, Menaka C.; Bartoli, Manuela; Martin, Pamela M.

doi:10.18632/aging.101469

Cited by 39 publications

(28 citation statements)

References 48 publications

(45 reference statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Zhang

Henneman

Girardot

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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Maintaining levels of nicotinamide adenine dinucleotide (NAD +), a coenzyme critical for cellular energetics and biosynthetic pathways, may be therapeutic in retinal disease because retinal NAD + levels decline during retinal damage and degeneration. The purpose of this study was to investigate whether systemic treatment with nicotinamide riboside (NR), a NAD + precursor that is orally deliverable and well-tolerated by humans, is protective in a mouse model of light-induced retinal degeneration. METHODS. Mice were injected intraperitoneally with vehicle or NR the day before and the morning of exposure to degeneration-inducing levels of light. Retinal function was assessed by electroretinography and in vivo retinal morphology and inflammation was assessed by optical coherence tomography. Post mortem retina sections were assessed for morphology, TUNEL, and inflammatory markers Iba1 and GFAP. Retinal NAD + levels were enzymatically assayed. RESULTS. Exposure to degeneration-inducing levels of light suppressed retinal NAD + levels. Mice undergoing light-induced retinal degeneration exhibited significantly suppressed retinal function, severely disrupted photoreceptor cell layers, and increased apoptosis and inflammation in the outer retina. Treatment with NR increased levels of NAD + in retina and prevented these deleterious outcomes. CONCLUSIONS. This study is the first to report the protective effects of NR treatment in a mouse model of retinal degeneration. The positive outcomes, coupled with human tolerance to NR dosing, suggest that maintaining retinal NAD + via systemic NR treatment should be further explored for clinical relevance.

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Section: Discussionmentioning

confidence: 99%

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

Zhang

Henneman

Girardot

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…Visfatin has been shown to delay cellular senescence via NAD(+)-Sirt1 signaling in mesenchymal stem cells, endothelial progenitor cells, aortic smooth muscle cells, and fibroblasts [29,45,46]. In addition, inhibition of visfatin with FK866 has been shown to promote cellular senescence in retinal pigment epithelium [28]. In contrast, visfatin has been proposed as a positive factor for the induction of senescence in human endothelial cells [30].…”

Section: Discussionmentioning

confidence: 99%

“…However, there are controversial results regarding the role of visfatin in cellular senescence. For example, it has been shown that visfatin reduces the senescence of endothelial progenitor cells, and its depletion promotes the senescence of retinal epithelial cells [28,29]. However, visfatin has also been shown to promote cellular senescence by inducing telomere damage in human vascular endothelial cells [30].…”

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confidence: 99%

Visfatin Induces Senescence of Human Dental Pulp Cells

Park

Jang

et al. 2020

Cells

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Dental pulp plays an important role in the health of teeth. The aging of teeth is strongly related to the senescence of dental pulp cells. A novel adipokine, visfatin, is closely associated with cellular senescence. However, little is known about the effect of visfatin on the senescence of human dental pulp cells (hDPCs). Here, it was found that in vivo visfatin levels in human dental pulp tissues increase with age and are upregulated in vitro in hDPCs during premature senescence activated by H2O2, suggesting a correlation between visfatin and senescence. In addition, visfatin knockdown by small interfering RNA led to the reduction in hDPC senescence; however, treatment with exogenous visfatin protein induced the senescence of hDPCs along with increased NADPH consumption, which was reversed by FK866, a chemical inhibitor of visfatin. Furthermore, visfatin-induced senescence was associated with both the induction of telomere damage and the upregulation of senescence-associated secretory phenotype (SASP) factors as well as NF-κB activation, which were all inhibited by FK866. Taken together, these results demonstrate, for the first time, that visfatin plays a pivotal role in hDPC senescence in association with telomere dysfunction and the induction of SASP factors.

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“…Dysfunctional mitochondria release multiple damage-associated molecular patterns (DAMPs), such as ATP, ROS, and mtDNA, activating the NLRP3 inflammasome, which in turn trigger the proteolytic maturation of proinflammatory cytokine precursors, such as IL-1β, and leads to the activation of the NF-κB pathway, supporting senescence biogenesis [155]. In contrast, interventions which reduce mitochondrial ROS such as nicotinamide mononucleotide (NAD) [156] and mitochondrial-targeted antioxidant MitoQ [157,158] have been shown to prevent telomere dysfunction and prevent senescence. NAD treatment via intravitreal administration in mice also preserves NAD+ and prevents RPE senescence [156].…”

Section: Role Of Mitochondrial Ros In the Induction Of Senescencementioning

confidence: 99%

“…In contrast, interventions which reduce mitochondrial ROS such as nicotinamide mononucleotide (NAD) [156] and mitochondrial-targeted antioxidant MitoQ [157,158] have been shown to prevent telomere dysfunction and prevent senescence. NAD treatment via intravitreal administration in mice also preserves NAD+ and prevents RPE senescence [156]. We have demonstrated that H 2 O 2 -induced senescence altered mitochondrial functions and treatment with a mitochondria-derived peptide, humanin, prevented mitochondrial ROS and delayed cellular senescence [39].…”

Section: Role Of Mitochondrial Ros In the Induction Of Senescencementioning

confidence: 99%

The Emerging Role of Senescence in Ocular Disease

Sreekumar¹,

Hinton

Kannan

2020

Oxidative Medicine and Cellular Longevity

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Cellular senescence is a state of irreversible cell cycle arrest in response to an array of cellular stresses. An important role for senescence has been shown for a number of pathophysiological conditions that include cardiovascular disease, pulmonary fibrosis, and diseases of the skin. However, whether senescence contributes to the progression of age-related macular degeneration (AMD) has not been studied in detail so far and the present review describes the recent research on this topic. We present an overview of the types of senescence, pathways of senescence, senescence-associated secretory phenotype (SASP), the role of mitochondria, and their functional implications along with antisenescent therapies. As a central mechanism, senescent cells can impact the surrounding tissue microenvironment via the secretion of a pool of bioactive molecules, termed the SASP. An updated summary of a number of new members of the ever-growing SASP family is presented. Further, we introduce the significance of mechanisms by which mitochondria may participate in the development of cellular senescence. Emerging evidence shows that extracellular vesicles (EVs) are important mediators of the effects of senescent cells on their microenvironment. Based on recent studies, there is reasonable evidence that senescence could be a modifiable factor, and hence, it may be possible to delay age-related diseases by modulating basic aging mechanisms using SASP inhibitors/senolytic drugs. Thus, antisenescent therapies in aging and age-related diseases appear to have a promising potential.

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

Cited by 39 publications

References 48 publications

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

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

Visfatin Induces Senescence of Human Dental Pulp Cells

The Emerging Role of Senescence in Ocular Disease

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