NAD+ Repletion as a Promising Senotherapeutic Agent
Introduction
Age-related macular degeneration (AMD) has become one of the leading cause of low vision and even blindness in the elderly, especially in those above 50. In 2020, approximately 1.8 million people aged over 50 are blinded by AMD and approximately 6.2 million people have moderate and severe visual impairment worldwide. By 2040, it is estimated that there will be about 288 million individuals with AMD worldwide. Strikingly, replenishing NAD+ may be a promising therapeutic option against early AMD.About AMD
AMD is an aging phenotypes in the eyes, which mainly affects the central fixation point of eyes (macula). There are two types of AMD: dry AMD (non-exudative or atrophic) and wet AMD (neovascular or exudative). Almost all of the AMD cases starts with dry AMD. In AMD, loss of central vision can be severe and permanent. Remarkably, dietary supplements containing antioxidant vitamins, minerals (zinc and copper), lutein and zeaxanthin, to some extent, can alleviate the progress of early AMD. Nicotinamide mononucleotide (NMN), a derivative of vitamin B3 (niacin), has been unveiled to a promising senotherapeutic agent for AMD.Cholesterol overload as one of the triggers for AMD
An imbalance between cholesterol influx (entry into cells) and efflux (exit from cells) can lead to intracellular cholesterol overload, which is the initiating event in diverse triggers of senescence including AMD. This surplus can initiate cytopathic and pathological processes that are detrimental to cell health. One specific consequence of a cholesterol efflux defect is the senescence of macrophages, which are immune cells that help to clean up cellular debris. Additionally, such a defect can lead to the accumulation of lipofuscin within the eyes.
LXR/CD38/NAD+ axis underlying the development of AMD
LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion. Specifically, cholesterol accumulation in bone-marrow-derived macrophages deficient in cholesterol efflux upregulates the transcription of CD38 through LXR activation, which thereby promotes the degradation of NAD+ and induces the cellular senescence, eventually promoting AMD phenotype.Suppressive impacts of NAD+ augmentation upon macrophage senescence states in AMD model mice
Cholesterol-mediated NAD+ depletion induces macrophage senescence and dysfunction, promoting subretinal lipid deposition and neurodegeneration, two key features of AMD. Replenishing NMN to augment NAD+ level reverses macrophage senescence and dysfunction, preventing the development of AMD phenotype, as indicated by the facilitated clearance of subretinal drusenoid deposits (SDDs) and the reduced accumulation of lipofuscin+ macrophages.
Conclusion
NAD+ deficit induced by excess intracellular cholesterol is the converging mechanism of macrophage senescence and a causal process underlying AMD. Supplementing NMN to boost NAD+ level serves as a promising senotherapeutic agent for age-related neurodegeneration.Reference
[1 Chinese Vitreo-Retina Society of Chinese Medical Association, Fundus Disease Group of Chinese Ophthalmologist Association. Evidence-based guidelines for diagnosis and treatment of age-related macular degeneration in China (2023) [J]. Chin J Ophthalmo. 2023,59(05):347-366. DOI:10.3760/cma.j.cn112142-20221222-00649[2] Terao R, Lee TJ, Colasanti J, et al. LXR/CD38 activation drives cholesterol-induced macrophage senescence and neurodegeneration via NAD+ depletion. Cell Rep. Published online April 15, 2024. DOI:10.1016/j.celrep.2024.114102
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