Targeting NAD+: is it a common strategy to delay heart aging?

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.

Fig. 1. Relationship between NAD+ deficiency and heart aging.

The lack of NAD+ in the aging heart could play a crucial role in causing various changes in different cellular pathways involved in cardiac damage. The outcomes of NAD+ deficiency include decreased heart function and increased ventricular dilation risks in inflammation and stress, all of which are well known to speed up the process of heart aging.

Fig. 2. Schematic diagram illustrating intracellular pathways of NAD+ synthesis, NAD+ metabolism, and NAD+ signaling pathway in mitochondria.

NAD+ can be synthesized from multiple precursors, including Trp, NA, NAM, NMN, NAR, and NR. NAD+ mainly exerts biological functions in mitochondria via regulating mitochondria membrane transporter SLC25A51 (MCART1 in the heart), affecting the transport of metabolic substrates, ATP, and ions. Sirtuins and PARP are the main NAD+ consumers.

Fig. 3. Schematic diagram showing the cross-talks between NAD+ and intracellular pathways in mitochondria and nucleus.

In cardiomyocytes, NAD+ regulates a variety of nuclear transcription regulatory proteins such as Sirts, FOXOs, and STATs through its induction of deacetylation. Its extensive regulatory capacity is not limited to the cytoplasm but also in mitochondria and inflammasomes. The initial factor may be related to AMPK and ROS signaling.

Fig. 4. Protein–protein interaction networks between NAD+ and associated regulatory proteins implicated in heart aging.

The presented network is drawn by the JAVA-based platform Cytoscape 3.8.2 (http://cytoscape.org): the protein-protein interaction (PPI) data were merged by multiple databases of Kyoto Encyclopedia of Genes and Genomes (KEGG), Wiki pathway, NDEx, PSICQUIC, and String. At first, the data covering the overlap part of cardiac hypertrophy and aging pathway were collected, which were then merged with the NAD+-related pathway. The disconnected nodes have been removed. The blue nodes and lines indicate direct upstream factors of NAD+. The red nodes and lines indicate the direct outcome of NAD+. NAD+, placed in the center of the network, is associated with several regulatory proteins, especially the Sirtuins, FOXOs, and STATs families, and the oxidative stress-related pathways implicated in heart aging.

Fig. 5. NAD+ associated mitochondrial protection in the aging heart.

The presented figure showed that NAD+ relates two aspects of protection. The inhibitory role of NAD+ is involved in mitochondrial permeability, oxidative stress, calcium homeostasis, mitochondrial dynamics of fission, pre-apoptosis of BH-3 only domain protein, NLRP3-induced inflammations, and autophagic exhaustion. They are suppressed by AKT, FOXOs, CD38, Sirt1, Bcl-2, respectively. The assisting role of NAD+ is involved in Nrf1-induced selective mitophagy, Hsp90-mediated selective autophagy, Sirt3/Nrf2-mediated mitochondrial biogenesis, PINK1-induced fusion process, PGC-1-1α-dependent mitochondrial DNA repair, and NAD+ itself- dependent OXPHOS.