Facts

  • 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.

  • 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.

  • 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

  • Considering the characteristics of the heart as a blood-pum** organ, do more intracellular factors need to be considered when targeting NAD+ signals?

  • Do comorbidities of the aging heart affect the protective effect of NAD+ ?

  • 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. Inhibition in the rise in mitochondrial permeability may help to reduce the decline in cardiac function caused by heart failure [

Data availability

The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

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).

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Author notes

  1. These authors contributed equally: Bing Liang, **n-Lin Liu.

Authors and Affiliations

  1. Cancer Institute of The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, China

    Yang Yuan, Bing Liang, **n-Lin Liu, Wen-**g Liu, Bing-Huan Huang, Shan-Bo Yang, Yuan-Zhen Gao, **g-Sen Meng, Meng-Jiao Li, Ting Ye, Chuan-Zhi Wang & Dong-Ming **ng

  2. Interventional Medicine Center, Affiliated Hospital of Qingdao University, Qingdao, China

    **ao-Kun Hu

  3. School of Life Sciences, Tsinghua University, Bei**g, China

    Dong-Ming **ng

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Contributions

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.

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Correspondence to Dong-Ming **ng.

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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

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