Abstract
Heart aging is the main susceptible factor to coronary heart disease and significantly increases the risk of heart failure, especially when the aging heart is suffering from ischemia-reperfusion injury. Numerous studies with NAD+ supplementations have suggested its use in anti-aging treatment. However, systematic reviews regarding the overall role of NAD+ in cardiac aging are scarce. The relationship between NAD+ signaling and heart aging has yet to be clarified. This review comprehensively summarizes the current studies on the role of NAD+ signaling in delaying heart aging from the following aspects: the influence of NAD+ supplementations on the aging heart; the relationship and cross-talks between NAD+ signaling and other cardiac aging-related signaling pathways; Importantly, the therapeutic potential of targeting NAD+ in delaying heart aging will be discussed. In brief, NAD+ plays a vital role in delaying heart aging. However, the abnormalities such as altered glucose and lipid metabolism, oxidative stress, and calcium overload could also interfere with NAD+ function in the heart. Therefore, the specific physiopathology of the aging heart should be considered before applying NAD+ supplementations. We believe that this article will help augment our understanding of heart aging mechanisms. In the meantime, it provides invaluable insights into possible therapeutic strategies for preventing age-related heart diseases in clinical settings.
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Facts
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NAD+ deficiency is the primary inducement to heart aging, resulting in decreased energy synthesis. The heart manifests as thinning of the ventricular wall and enlargement of the cardiac chamber diameter, which leads to heart failure with the continuation of the process.
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As an anti-aging target, NAD+ also plays an important regulatory role in the heart. NAD+ mediated deacetylation is widely involved in regulating transcriptional signals for cardiomyocytes protection and interacts with ROS and calcium signals.
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NAD+ mediated mitochondrial quality control is the core mechanism of preventing heart aging, involving mitochondrial dynamics, permeability, biological synthesis, and mitophagy. As a coenzyme, NAD+ also further stabilizes mitochondrial oxidative phosphorylation.
Open questions
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Considering the characteristics of the heart as a blood-pum** organ, do more intracellular factors need to be considered when targeting NAD+ signals?
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Do comorbidities of the aging heart affect the protective effect of NAD+ ?
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Do different forms of NAD+ precursor intervention affect the protective effect of NAD+ ?
Introduction
Aging is a gradual, continuous, naturally occurring process. It is closely related to the development of several common chronic diseases, such as type II diabetes, hypertension, neurodegenerative diseases, etc. [1, 2], which are manifested by the decline and failure of multiple organ functions [1]. Among them, heart failure caused by heart aging at the cellular level is a high-risk factor affecting the life span of an individual [3]. Cardiovascular drugs commonly used in the treatment cannot inhibit the development of the disease effectively; instead, they only play a partial role in reducing the symptoms. It is necessary to find novel approaches for preventing heart aging by targeting the endogenous signaling pathways in cardiomyocytes. However, the investigation of regulatory mechanisms in the heart is still insufficient. Many in vivo and in vitro studies showed the importance of NAD+-dependent Sirtuins (SIRTs) deacetylation activity in the anti-aging process [4, 5]. However, discussing a single mechanism may neglect other targets of auxiliary intervention since the function of NAD+ itself is also an important part of the mitochondrial respiratory chain, wherein it interacts with most of the intracellular molecules. Recently, it has been believed that the depletion of NAD+ with aging is associated with oxidative stress injury, which is a crucial factor of aging, and NAD+ deficiency has a certain degree of duality for myocardial protection. Whether NAD+ signaling is the key variable affecting other cellular signaling pathways needs to be further investigated. A recent FDA-approved anti-aging supplement, nicotinamide mononucleotide (NMN), regulates NAD+ signaling to achieve cell self-regulation and improves adaptation to the environment of the aging cell from the perspectives of regulating aging-related gene transcription and inhibiting aging-induced stress imbalance [6]. However, whether a large amount of NAD+ supplementations would definitely induce heart anti-aging effect is also controversial. Therefore, this article focuses on the mechanism of NAD+ signaling in cardiomyocytes and various intracellular senescence processes, trying to understand its impact on several cell endogenous processes such as inflammation, apoptosis, autophagy, mitochondrial damage, etc. We aim to identify more feasible research directions of NAD+, resolve the existing unknown areas, and provide novel strategies and inspiration for our related research.
Aging heart and associated mechanisms
Implications of NAD+ in pathophysiological processes driving heart aging
The aging heart is accompanied by decreased energy synthesis and functional levels, such as low ejection fraction, shortening fraction, and increased left ventricular diameter, causing dilated cardiomyopathy and insufficient blood supply, which are the main manifestations of heart failure [1, 7]. Myocardial aging is also a high-risk factor for malignant arrhythmia and atrial fibrillation [8]. DNA damage, inflammatory reaction, and abnormal lipid metabolism could be well-recognized pathological characteristics of the aging myocardium [9]. Notably, a lack of NAD+ in the cardiomyocytes may cause hypoxia, which is considered as one of the leading factors for aging [10]. At the organelle level, genetic evidence showed that the change in mitochondrial permeability caused by myocardial aging is the main reason for the increase in cardiac mechanical stress sensitivity. 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Poly (ADP-ribose) synthetase inhibitor has a heart protective effect in a rat model of experimental sepsis. Int J Clin Exp Pathol. 2015;8:9824–35. Seif AA. Nigella sativa attenuates myocardial ischemic reperfusion injury in rats. J Physiol Biochem. 2013;69:937–44. Airhart SE, Shireman LM, Risler LJ, Anderson GD, Nagana Gowda GA, Raftery D, et al. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE. 2017;12:e0186459. We would like to thank TopEdit (www.topeditsci.com) for the English language editing of this manuscript. This work is supported by author Yuan’s projects. National Natural Science Foundation of China (No. 3200830), China Postdoctoral Special Foundation (No. 2021T140356), and China Postdoctoral General Foundation (No. 2020M682120). YY, BL, XLL and DMX conceived this work. YY, BL, XLL, WJL, and BHH wrote the manuscript. WJL, BHH, SBY worked on summarizing data for the table. YY and YZG worked on optimizing visualized information delivery. WJL, SBY, and JSM analyzed data of the biological information. JSM, MJL, TY, CZW, and XKH assisted to investigate and collect references. XKH and DMX had critically read the manuscript. The authors declare no competing interests. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Yuan, Y., Liang, B., Liu, XL. et al. Targeting NAD+: is it a common strategy to delay heart aging?.
Cell Death Discov. 8, 230 (2022). https://doi.org/10.1038/s41420-022-01031-3 Received: Revised: Accepted: Published: DOI: https://doi.org/10.1038/s41420-022-01031-3Data availability
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