Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies

Poljšak, Borut; Kovač, Viljem; Milisav, Irina

doi:10.3390/antiox11091637

Cited by 12 publications

(14 citation statements)

References 192 publications

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“…A potential way to prevent NAD + decline with time would be frequent NR re-application. However, one needs to be careful, as the biological effects of prolonged NAD + boosting are unclear and might possibly cause adverse effects on cellular homeostasis [52]. For example, NR has been shown to decrease endogenous antioxidant activity and impair redox homeostasis in young rats [53].…”

Section: Discussionmentioning

confidence: 99%

NAD+ Acts as a Protective Factor in Cellular Stress Response to DNA Alkylating Agents

Ruszkiewicz,

Papatheodorou,

Jäck

et al. 2023

Cells

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Sulfur mustard (SM) and its derivatives are potent genotoxic agents, which have been shown to trigger the activation of poly (ADP-ribose) polymerases (PARPs) and the depletion of their substrate, nicotinamide adenine dinucleotide (NAD+). NAD+ is an essential molecule involved in numerous cellular pathways, including genome integrity and DNA repair, and thus, NAD+ supplementation might be beneficial for mitigating mustard-induced (geno)toxicity. In this study, the role of NAD+ depletion and elevation in the genotoxic stress response to SM derivatives, i.e., the monofunctional agent 2-chloroethyl-ethyl sulfide (CEES) and the crosslinking agent mechlorethamine (HN2), was investigated with the use of NAD+ booster nicotinamide riboside (NR) and NAD+ synthesis inhibitor FK866. The effects were analyzed in immortalized human keratinocytes (HaCaT) or monocyte-like cell line THP-1. In HaCaT cells, NR supplementation, increased NAD+ levels, and elevated PAR response, however, did not affect ATP levels or DNA damage repair, nor did it attenuate long- and short-term cytotoxicities. On the other hand, the depletion of cellular NAD+ via FK866 sensitized HaCaT cells to genotoxic stress, particularly CEES exposure, whereas NR supplementation, by increasing cellular NAD+ levels, rescued the sensitizing FK866 effect. Intriguingly, in THP-1 cells, the NR-induced elevation of cellular NAD+ levels did attenuate toxicity of the mustard compounds, especially upon CEES exposure. Together, our results reveal that NAD+ is an important molecule in the pathomechanism of SM derivatives, exhibiting compound-specificity. Moreover, the cell line-dependent protective effects of NR are indicative of system-specificity of the application of this NAD+ booster.

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Section: Discussionmentioning

confidence: 99%

NAD+ Acts as a Protective Factor in Cellular Stress Response to DNA Alkylating Agents

Ruszkiewicz,

Papatheodorou,

Jäck

et al. 2023

Cells

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“…NAD + is crucial in multiple metabolic processes, such as glycolysis, oxidative phosphorylation, pyruvate dehydrogenase complex, and the tricarboxylic acid cycle [56]. NAD + is required for over 500 enzymatic reactions [57,58] and plays a crucial role in cell signaling, survival pathways, and various cellular functions such as metabolic pathways, DNA repair, chromatin remodeling, endocrine signaling, cellular senescence, inflammation, apoptosis, proliferation, mitochondrial function, lipid and glucose homeostasis, and immune cell function [57]. The involvement of NAD + in the physiological process of aging has gained attention in recent years.…”

Section: Nad + and Its Metabolism 41 Overview Of Nad + And Its Import...mentioning

confidence: 99%

A Molecular Perspective and Role of NAD+ in Ovarian Aging

Ahmed,

Riaz,

et al. 2024

IJMS

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The decline in female fecundity is linked to advancing chronological age. The ovarian reserve diminishes in quantity and quality as women age, impacting reproductive efficiency and the aging process in the rest of the body. NAD+ is an essential coenzyme in cellular energy production, metabolism, cell signaling, and survival. It is involved in aging and is linked to various age-related conditions. Hallmarks associated with aging, diseases, and metabolic dysfunctions can significantly affect fertility by disturbing the delicate relationship between energy metabolism and female reproduction. Enzymes such as sirtuins, PARPs, and CD38 play essential roles in NAD+ biology, which actively consume NAD+ in their enzymatic activities. In recent years, NAD+ has gained much attention for its role in aging and age-related diseases like cancer, Alzheimer’s, cardiovascular diseases, and neurodegenerative disorders, highlighting its involvement in various pathophysiological processes. However, its impact on female reproduction is not well understood. This review aims to bridge this knowledge gap by comprehensively exploring the complex interplay between NAD+ biology and female reproductive aging and providing valuable information that could help develop plans to improve women’s reproductive health and prevent fertility issues.

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“…The elevation of inflammatory factors can also stimulate the CD38 enzyme. The heightened activity of these NAD + ‐consuming enzymes, and other factors such as alcohol metabolism, may result in the excessive consumption of NAD + , leading to a specific decline in NAD + levels 2,3,52,199‐201 . SIRTs and PARPs also have potential therapeutic and protective roles during the maturation of oocytes, which may be one of the mechanisms through which precursors like NA, NR, and NMN exert beneficial effects.…”

Section: Exploring Precursors and Synthesis Pathways In Ovarian Funct...mentioning

confidence: 99%

Exploring nicotinamide adenine dinucleotide precursors across biosynthesis pathways: Unraveling their role in the ovary

Ren,

Zhang,

Chen

et al. 2024

The FASEB Journal

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Natural Nicotinamide Adenine Dinucleotide (NAD+) precursors have attracted much attention due to their positive effects in promoting ovarian health. However, their target tissue, synthesis efficiency, advantages, and disadvantages are still unclear. This review summarizes the distribution of NAD+ at the tissue, cellular and subcellular levels, discusses its biosynthetic pathways and the latest findings in ovary, include: (1) NAD+ plays distinct roles both intracellularly and extracellularly, adapting its distribution in response to requirements. (2) Different precursors differs in target tissues, synthetic efficiency, biological utilization, and adverse effects. Importantly: tryptophan is primarily utilized in the liver and kidneys, posing metabolic risks in excess; nicotinamide (NAM) is indispensable for maintaining NAD+ levels; nicotinic acid (NA) constructs a crucial bridge between intestinal microbiota and the host with diverse functions; nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) increase NAD+ systemically and can be influenced by delivery route, tissue specificity, and transport efficiency. (3) The biosynthetic pathways of NAD+ are intricately intertwined. They provide multiple sources and techniques for NAD+ synthesis, thereby reducing the dependence on a single molecule to maintain cellular NAD+ levels. However, an excess of a specific precursor potentially influencing other pathways. In addition, Protein expression analysis suggest that ovarian tissues may preferentially utilize NAM and NMN. These findings summarize the specific roles and potential of NAD+ precursors in enhancing ovarian health. Future research should delve into the molecular mechanisms and intervention strategies of different precursors, aiming to achieve personalized prevention or treatment of ovarian diseases, and reveal their clinical application value.

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Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies

Cited by 12 publications

References 192 publications

NAD+ Acts as a Protective Factor in Cellular Stress Response to DNA Alkylating Agents

NAD+ Acts as a Protective Factor in Cellular Stress Response to DNA Alkylating Agents

A Molecular Perspective and Role of NAD+ in Ovarian Aging

Exploring nicotinamide adenine dinucleotide precursors across biosynthesis pathways: Unraveling their role in the ovary

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