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.
Similar content being viewed by others
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-pumping 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 [11]. It is suggested that the decrease in ATP synthesis is also an important cause and an inducer of heart failure in the aging organisms [12]. A comparative study of the effects of glucose uptake on aging-induced myocardial mitochondria damage showed that the difference in energy intake could not alter the fact that aging causes damage to myocardial mitochondria [13, 14]. NAD+ and its downstream signals may be the key regulatory factors of energy utilization, which are associated with age and gender difference. However, an exploration of goNAD+al hormone regulation in cardiac aging is still lacking. In general, the metabolic abnormality is the first step to be considered in NAD+-deficiency-induced aging [15]. Low aerobic energy supply and high levels of glycolysis are the main reasons for the aging of most tissues or organs. Studies have shown that after mitochondrial irreversible and complete aging, a higher NAD+/NADH ratio helps reduce glycolysis, avoiding the abnormal metabolism of tryptophan due to lysosome-associated membrane protein 2 (LAMP-2) deficiency [16]. Furthermore, some studies suggested that the decrease in NAD+ with aging is closely related to mitochondrial permeability transition pore (mPTP) opening in cardiovascular stress. These results indicate that the reduction in mitochondrial NAD+ preservation may be a substantial cardiomyocyte senescence-inducing factor, manifested by the decrease in adaptability to adverse homeostasis changes, such as high glucose, hypoxia, drug stress, or ischemia–reperfusion (I/R) injury [7]. The mitochondrial repair mechanism is further declined by reducing mitochondrial oxygen consumption efficiency, thus forming a vicious circle [17]. Figure 1 is a schematic diagram showing the relationship between NAD+ deficiency and heart aging (Fig. 1).
Implicated mechanisms of the anti-aging effect of NAD+
Due to mitochondrial damage, excessive accumulation of reactive oxygen species (ROS), mainly stress-induced H2O2, can cause membrane lipid peroxidation and further damage to cellular structures, including cytomembrane, mitochondrial membrane endoplasmic reticulum, etc. The aging heart is also accompanied by an overall decrease in antioxidant activities of enzymes, such as manganese-dependent superoxide dismutase (MnSOD), or a direct injury to DNA and mtDNA, which lead to high expression of apoptosis factors [12]. Oxidative stress injury is a common feature in the process of aging in most tissues and organs, including the heart [9]. The accompanying DNA damage is also an essential factor of myocardial aging and is commonly associated with aging-induced inflammatory response (senescence-associated secretory phenotype, SASP) [18]. For example, the cluster of differentiation 38 (CD38) and tumor necrosis factor (TNF-α) downregulated NAD+ through competitive binding of NAD+ precursor, which interfered with the synthesis of NAD+ by enzymes [19]. Knockdown of NAD+ hydrolase, a CD38 ectoenzyme, effectively inhibited D-gal-induced cardiomyocyte senescence and significantly reduced the senescence markers p16 and p26, leading to a prolonged life span of cardiomyocytes [20]. In particular, a similar phenomenon was also manifested in chemotherapeutic drug-induced cardiomyocyte toxicity, which has a certain association with senescence properties. For instance, chronic doxorubicin (DOX) intervention can also lead to cardiomyocyte aging, suggesting that the aging mechanism shares many irreversible stress factors with the cardiac injury pathway, such as decreased Sirtuins expression, increased p38 mitogen-activated protein kinases (p38MAPK) signaling, and decreased antioxidant enzyme levels represented by MnSOD [21, 22].
From the perspective of molecular mechanism in aging cardiomyocytes, the reduction in self-regulation and adaptability or direct damage to DNA and mtDNA, promotes an increase in oxidative stress and apoptosis and induces high expression of pro-inflammatory cytokines, such as nuclear factor kappa-light-chain-enhancer of activated B (NF-κB). In this way, more exogenous stress factors will accelerate the aging process, forming a vicious circle. On the other hand, NF-κB is also directly and positively regulated by Clock Circadian Regulator (CLOCK) genes. In the perspective of protective mechanisms of aging cardiomyocytes, inhibition of BMAL1/Clock by NAD+ reduced NF-κB binding to DNA, which further decreased the formation of pro-inflammatory mediators and improved mitochondrial function [23]. In addition, the biological rhythm of the cardiovascular system also involves the regulation of PPARγ. The downstream target gene REV-ERB of PPARγ is one of the core CLOCK components [24]. Moreover, PPAR is closely related to the expression and activity of antioxidant enzymes [25]. Therefore, the aging process could be driven by various cellular mechanisms within the organism [26].
NAD+ synthesis and metabolism in the aging heart
NAD+ synthesis
NAD+ is a crucial coenzyme in mitochondrial oxidative phosphorylation (OXPHOS), and it is the oxidized form of NADH of complex I. NAD+ acts as a major hydrogen carrier and plays a vital role in the electron transport chain. In other words, NAD+ can also be considered to be consumed by the TCA cycle but to regenerate from NADH by electron transport chain [27]. Recent studies have shown that similar to ROS, NAD+ acts as an intracellular second messenger and may establish mitochondrial protection through the NAD+/Sirt pathway [28]. NAD+ is mainly synthesized from NAM by the rate-limiting enzyme Nam phosphoribosyltransferase (NAMPT) and degraded to Nam by NAD+-degrading enzymes in mammals [29]. NAD+ can also be re-synthesized from nicotinic acid (NA) and nicotinic acid riboside (NAR) using nicotinate phosphoribosyltransferase and NAM riboside kinase ½ (NRK1/2), respectively. However, most tissues rely on amidated synthetic forms. NRKs and NAMPT can recover nicotinamide riboside (NR) and NAM into NMN, further converted into NAD+ by NMNAT eventually [30, 31]. Studies have shown that the aging-related WRN gene regulates the transcription of the critical NAD+ biosynthetase NMN adenyltransferase 1 (NMNAT1) [32]. Loss of the NAMPT gene also affects the survival in adult mammals [33]. NAD+ improves the mitochondrial quality by restoring the metabolic environment of intracellular NAD+ by DAF-16/FOXO controlled, germline tumor affecting-1 (DCT-1-) and Unc-51 like autophagy activating kinase 1(ULK-1)-dependent mitophagy. With aging, NAMPT has specific compensatory properties related to the upregulation of CD38 in decomposed NAD+ [34]. However, NAD+ supplementation also induces the synthesis of NAMPT, promotes a virtuous cycle of NAD+ synthesis, and contributes to anti-aging [34]. Some studies believe that the expression levels of NAMPT and NRK2 have little effect on the cellular NAD+ content but may cause the maladaptation of aging myocardium during endurance exercise or work overload [29, 35]. In humans, short-term 3-day NAD+ supplementations, such as NMN, NAM, NAR, and other NAD+ precursors, can produce mitochondrial conservation effects and play a key role in regulating redox status and energy metabolism, thereby inhibiting heart failure [36]. NAD+ depletion is one of the significant pathogeneses of heart and kidney diseases, and NAD+ supplementation shows therapeutic potential as an approach to restore metabolic levels and physiological functions. In particular, NAD+ plays an auxiliary substrate function in the deacylation reaction of the SIRTs family. Therefore, enhancing SIRT activity by NAD+ supplementation may be viable for treating heart disease [28].
NAD+ and energy synthesis
NAD+ supplementation showed a specific anti-apoptosis ability in cardiomyocytes. The preserved NAD+ in the mitochondrial matrix could inhibit mitochondrial damage and induce the release of cytochrome C (Cyt C) [23, 37]. mPTP is a voltage-gated ion channel across mitochondrial inner and outer membranes and is closely linked to mitochondrial damage. It is directed by voltage-gated ion channel (VDAC), adenine nucleotide translocase (ANT), F1F0ATP synthase, cyclophilin D (CypD), cyclosporin A (CsA), and transmembrane protein complexes composed of other subunits. Supplementation of NAD+ through the SIRT3 signal acts on the binding of CypD to intimal ANT, which helps to delay the opening of mPTP, thus protecting the mitochondria [36]. CypD knockout (KO) in elderly mice showed better anti-aging effects, such as inhibition of mitochondrial swelling and a higher NAD+/NADH ratio, but further exploration is needed to explain the exact mechanism in heart tissue [38]. Moreover, the aerobic oxidation of acetyl-CoA in mitochondria is affected by NADH and succinic acid [39]. In the mitochondrial inner membrane, the free penetration of phosphopyruvate (PEP), an intermediate product of glucose metabolism, can inhibit the oxidation of NADH, improving the dehydrogenation efficiency of succinic acid, and promote the oxidative phosphorylation reaction, suggesting that the supplement of energy synthesis substrate is beneficial for the preservation of NADH in cells. Additionally, improving glucose utilization efficiency helps reduce the myocardial inflammatory response and inhibit injury-induced myocardial fibrosis [40]. However, some studies on cardiac I/R injury suggest that excessive NADH supplementation may induce more superoxide production and aggravate oxidative stress injury [41]. Excessive NADH may promote anaerobic glycolysis that potentially accelerates the aging process [27, 42]. Therefore, the abnormalities such as altered glucose and lipid metabolism, oxidative stress, and calcium overload could interfere with NAD+ function in the heart. And specific physiopathology of the aging heart should be considered before applying NAD+ supplementations [43]. Moreover, NAD+ supplementation can also be considered to use as a substrate to promote PARP-mediated DNA repair for promoting myocardial anti-aging effect [40]. A conclusive diagram illustrating the intracellular pathways of NAD+ synthesis and metabolism and the NAD+ signaling pathways in mitochondria of the aging heart is in Fig. 2.
Molecular mechanisms underlying the anti-aging effect of NAD+
Cross-talk with pathways inside the nucleus
As mentioned earlier, the low level of energy synthesis and unbalanced oxidative stress are important initial links, which lead to the increased expression of pre-apoptotic signals and inflammatory factors. Therefore, the downstream regulatory factors, such as 5 ′ AMP-activated protein kinase (AMPK), which are sensitive to ATP energy levels, play a vital role in the inductive mechanism. Studies have shown that AMPKα2 was highly related to the biological rhythm of cardiomyocytes, in which AMPKα2 had a more apparent inductive effect [44]. The regulation of senescence by AMPK mainly links to the SIRTs family, and the intracellular signals generated by AMPK are important core substances that inhibit the senescence of cardiomyocytes. In Sirt1-deficient mice, the aging heart showed reduced tolerance to ischemic stress, associated with decreased ATP synthesis and increased mitochondrial ROS production [45]. In the absence of NAD+, reduced deacetylation of NF-κB by Sirt1 initiated the transcription of pre-apoptotic factor NLPR3, which ultimately led to the increase in inflammasome and the induction of age-related inflammatory factors expression [23]. Sirt1 gene KO decreased ejection fraction, increased oxidative stress, and increased endoplasmic reticulum stress in the aging mice [46]. The binding of ATP to the C-terminal of Sirt1 might limit its activity and inhibit its anti-stress damaging effect [47]. Moreover, it has been shown that AMPKα2 deficiency inhibited NAD+ synthesis, the expression of the Sirt1/PGC-1α pathway, and affected the repairability of cardiomyocytes [44]. Recent reports suggested that Sirt1-mediated NK-κB inhibitory regulation was also depend on the effect of Sirt6 gene silencing on DNA repair targeting H3K56Ac, but information on myocardial tissues is still lacking [48]. In NAD+-dependent deacetylase Sirtuin-3 (Sirt3-/-) mice, the absence of Sirt3 caused increased sensitivity to Ca2+ in cardiomyocytes, resulting in swelling of mitochondria, which ultimately affected the life span of the mice and accelerated the senescence of cardiomyocytes [11].
It is well known that regulation of cardiomyocyte protein deacetylation is involved in a wide range of interactions between DNA transcription and histone modification, including those of the Sirtuins gene itself, and is affected by NAD+ levels and its related salvage pathway [17]. Sirt2 expressed in the cytosol has recently been considered to be involved in the anti-aging mechanism of the heart. Using a serum deprivation test, the increase in Sirt2 gene transcription level was regulated by the upstream RhoA/SRF signal through its SRF binding site, inducing feedback on energy metabolism, stress, toxic metabolism, etc [49]. RhoA/SRF signaling inhibitor CCG-1432 canceled the Sirt2 induction [49]. Recently, Sirt7 has also been reported to have tissue-specific anti-aging effects in the myocardium, which may be associated with deacetylated activations of Sirt1 and Sirt2 [49,50,51]. The FOXOs family is a class of nuclear transcription factors regulated by upstream Akt/PI3K cardiac protective signals. FOXO1, FOXO3, and FOXO4 have been shown to exert anti-aging effects in the organism, and FOXOs-assisted protective expression was unaffected in the transverse aortic constriction (TAC) model with MnSOD deficiency [22]. Upregulation of Sirt induced deacetylation of downstream FOXO genes and inhibition of NAD+ synthesis caused downregulation of the Sirt3/FOXO4 pathway, which was consistent with inhibited TCA cycle and ATP synthesis, thus affecting the survival of mice [32]. Inhibition of NAD+ also resulted in increased acetylation of SOD2, PGC-1α, GCN5, and p65; decreased activity of protective enzymes; and increased aging-related heart damage [34]. Another critical factor, the STAT protein family, the signal transducer and activator of transcription, consists of seven species (STAT-1, STAT-2, STAT-3, STAT-4, STAT-5a, STAT-5b, and STAT-6), all of which are expressed in the heart. STAT are tyrosine kinases that can be activated by Janus kinase (JAK), causing their translocation into the nucleus to form dimers or heterodimers, resulting in the regulation of gene transcription. The JAK/STAT pathway activation plays a vital role in expressing stress response genes. Moreover, the activation of STAT1 is related to cell apoptosis. However, it can be inhibited by Sirt1 [43]. On the contrary, the activation of mitochondrial STAT-3 inhibited mPTP and thus contributed to cardiac protection [52, 53]. The localization of STAT proteins in the heart is not limited to cytosol and nucleus. Recent studies have shown that STAT was expressed in the mitochondria of cardiomyocytes [54]. Most studies of STAT proteins in cardiac function have focused their roles in cell apoptosis, heart failure, hypertrophy, and I/R damage [55]. To better understand the mechanisms underlying heart aging, the role of STATs in aging hearts should be further investigated.
Cross-talk with ROS signaling
IGF-1/insulin signaling is necessary for prolonging the life of cardiomyocytes [56]. Activation of downstream signals, Akt/PI3K, and mechanistic target of rapamycin (mTOR) can further induce autophagy and other cytoprotective mechanisms, which helps to provide a stable metabolic environment and balance the oxidative stress. These signals interact with NAD+ signaling, which affects the regulation of survival-related nuclear transcription signals [57]. Recently reported, deacetylation based on NAD+ signaling was able to enhance the expression of key proteins implicated in PI3KIII-dependent autophagy or promoted Parkin-independent mitophagy through the liver kinase B1 (LKB1)/AMPK/tuberous sclerosis complex 2 (TSC2) or the SIRT3/FUNDC1 pathways [9]. The imbalance in oxidative stress regulation is the significant consequence of ROS production, which further affects the life span of an organism. Recent studies have shown that ROS can also induce cell apoptosis through multiple intracellular signal mediation, thus accelerating cell aging [40]. Conversely, a moderately high level of ROS is necessary for myocardial protection, which is achieved by inducing protective signals [58, 59]. Therefore, the NAD+ signal may be an essential rebalancing factor of ROS signal [33].
NADH dehydrogenase, a complex I protein, transfers electrons from NADH to Flavine MonoNucleotide (FMN), FES centers, and ubiquinone. Under abnormal mitochondrial membrane potentials, these pathways easily generate ROS [39]. ROS regulates cardiac contractility at multiple levels. Due to the direct modification of ion channels and transporters and the changes in intracellular contraction signals. Overactive NAD(P)H oxidase (Nox), xanthine oxidase, or excessive ROS generated by mitochondria are considered to play a leading role in cardiomyopathy [60]. Furthermore, in MnSOD ± mice, the expression of Nox1 did not change, suggesting that the factors that cause an increase in ROS are not the determinants of Nox1 expression. The key enzyme causing the ROS-induced ROS generation (RIRG) phenomenon may be Nox4, responsible for accelerated aging in MnSOD-deficient mice [22]. The abnormal cardiac activity begins with rapid activation of voltage-gated sodium channels (such as Nav1.5 and voltage-dependent L-type calcium channel (LTCC)) to propagate action potentials. ROS-dominated oxidative stress is thought to affect the life span of organisms [61]. Simultaneously, ROS activates intracellular REDOX signals, such as proto-oncogene tyrosine-protein kinase Src (c-Src), Protein tyrosine kinase 2 (Pyk2), extracellular signal-regulated kinases (ERKs) 1/2 (ERK1/2), and big mitogen-activated protein kinase 1 (BmK1) [61]. These factors affect the expression of proteins in NAD+ signaling by varying degrees.
Nrf2 is a vital gene transcription factor that regulates antioxidation and redox reactions. However, it is expressed at low levels during the aging process [22]. Nrf2 deficiency can lead to dysregulation of cardiomyocytes under oxidative stress and increased sympathetic excitability [62, 63]. Therefore, applying dietary restrictions or implementing some drug interventions can induce the regulation of Nrf2/ARE and increase the expression of antioxidant enzymes, such as GSH. This process is influenced by Kelch-like ECH-associated protein 1 (KEAP-1), a cytoplasmic inhibitory protein. KEAP-1 restricts GSH gene expression by forming a complex through Nrf2 [64]. In addition, the activation of ARE induces the activation of NAD(P)H quinone oxidoreductase-1 (NQO1) and heme oxygenase-1 (HMOX1), which further enhances the antioxidant capacity [65]. Furthermore, the high expression of γ-glutamylcysteine synthetase catalytic (GCLC) through the Nrf2 signal helps inhibit the aging and apoptosis induced by high glucose intake in myocardial cells [48]. PGC-1α, an inducer of Nrf2, is another crucial substance that promotes the synthesis of antioxidant enzymes. The lack of PGC-1α in the kidney causes a decrease in NAD+ synthesis and affects TFEB-dependent lysosome function [66]. PGC-1 is regulated by the upstream NAD+/AMPK signal, which provides cardiac protection by phosphorylating TSC2 to inhibit mTOR [9]. Therefore, NAD+ is the crucial bridge between energy metabolism and oxidative stress regulation [45].
Cross-stalk with calcium signaling
Poor calcium storage capacity of the myocardium, which is the main reason for the decline in myocardial function during aging, is related to poor calcium transport [67]. NAD+ signal interacts with Ca2+ signal in myocardium [40]. Repeated apnea and intermittent hypoxia cause NAD(P)H oxidase (Nox)-dependent ROS production, wherein most of the ROS are superoxide anion that further activates phospholipase C, resulting in the activation of calmodulin kinase C (CaMK) and protein kinase C [8, 68]. It has been shown that NR as an exogenous supplement could promote CaMKII-mediated RyR2 phosphorylation in the diastolic phase by increasing NAMPT/NAD+ and promoting calcium release from the Sarcoplasmic Reticulum (SR) [8]. Due to the decrease in stress resistance caused by the aging of the myocardium, the sodium-calcium exchanger (NCX) was reversed under the action of stress factors, resulting in intracellular calcium overload [69]. The sensitivity of mitochondrial NADH reductase and ERK pathway to ROS stress decreased Na+/H+ antiporter (NHX) expression [70]. The downregulation of NHX possessed practical significance in inhibiting the increase in pH and calcium overload caused by Na+ influx and H+ outflow during the recovery process, which helps avoid the vicious circle of oxidative stress caused by the high concentration of intracellular Na+. Some studies have also shown that inhibition of CD38 contributed to saving NAD+ and reduced calcium overload through inhibition of Ca2+ mobilization [71]. These hypotheses may serve as a series of intervention methods, aiming to enhance the regulation of NAD+-related protective signals. In addition, more protective signals might be beneficial for delaying myocardial aging and improving tolerance. For example, NMN as a precursor supplement contributes to the formation of Sirt7-dependent cardioprotection, which involves the deacetylation of GATA4 and the interaction with TGF-β1 signal [72]. Increased NAD+ deacetylation could inhibit the protein kinase R-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2 pathway and reduce endoplasmic reticulum stress [73]. Moreover, it could also promote an adaptation of the aging myocardium to hypoxia by activating the HIF-1 signal and NO signal [10, 74]. This evidence strengthens the associations among NAD+, ROS, and calcium. Figure 3 shows the cross-talks between NAD+ signaling and other intracellular pathways such as ROS and Ca2+ signaling in mitochondria and different transcription factors in the nucleus. Besides, a protein-protein interaction network (Fig. 4) illustrates the interactions between NAD+ and main regulatory proteins in pathways implicated in aging hearts.
NAD+ regulates mitochondrial homeostasis in the aging heart
Mitochondrial dysfunction and mitochondrial quality control
Mitochondrial quality control coordinates various processes (proteostasis, biogenesis, dynamics, and mitophagy) to maintain cell homeostasis. Mitochondrial dysfunction, amplified by failing quality control processes, is believed to be a major mechanism underlying cardiac aging and cardiovascular disease. There is a reduction in the ability of mitochondria to produce NAD+ in aging cardiomyocytes, which is accompanied by mitochondrial DNA damage [11]. Increased expression of uncoupling proteins (UCP) promotes aging-associated mitochondrial dysfunction in the heart [45, 75]. UCP also acts on the abnormal calcium transport between the endoplasmic reticulum and mitochondria, causing mitochondrial calcium overload through RyR2 and VDAC, which leads to weakened stress tolerance [67]. Inhibition of mPTP opening contributes to preserving NADH and ATP, induces a virtuous cycle of NAD+ synthesis, and delays mitochondrial depolarization [34]. In aging rats, NMN supplementation reduced the increase in mitochondrial membrane potential (ΔΨm) when undergoing subsequent I/R stress [76]. Mitochondrial depolarization induces various endogenous mitochondrial protective mechanisms, such as the regulation of mitophagy and mPTP pores. A recent study showed that Parkin-induced mitophagy might be an essential mechanism for inhibiting myocardial aging [77]. In the heart, PINK1 is upstream of parkin. PINK1/Parkin-dependent mitophagy pathway depends on the macroautophagy protein level and the mitochondrial outer membrane protein guidance. The transcriptions of both PINK1 and Parkin are associated with NAD+-mediated nucleus signaling, for example, Nrf1/2 [78]. Parkin, as an E3 ubiquitin ligase, mediates the ubiquitination of VDAC1, where parkin can be recruited by PINK1 from the cytoplasm to the outer membrane of mitochondria with decreased ΔΨm, and p62 can be further recruited to the mitochondria to induce the autophagosomal membrane to enclose the mitochondria and initiates mitophagy [79]. Hence, damaged mitochondria can be selectively scavenged by mitophagy. Parkin also ubiquitinates the mitochondrial fusion protein Mitofusin 1 and 2 (mfn1/2), thereby promoting the repair of damaged mitochondria by regulating mitochondrial dynamics [80]. Phosphorylation of serine/threonine kinase PINK1 activates parkin and induces its translocation from cytoplasm to mitochondria, which contributes to the anti-aging effect in the heart [81]. Tom70 protein is a component of the translocase of mitochondrial outer membrane (TOM) complex. It may be the initial protein recognized by precursor proteins of parkin and p62. TOM was found to guide parkin and p62 to locate on mitochondrial membrane and promote mitophagy and was reported to inhibit pathological cardiac hypertrophy [82].
An exogenous injection of uncoupling agent carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP) resulted in proton gradient reduction, blockage oxidative phosphorylation F1F0 ATPase coupling, mitochondrial membrane depolarization, all of which are associated with cardiomyocytes aging [83]. However, FCCP restores NAD+ because of inhibited OXPHOS [27]. It was found that exogenous FCCP enhanced the transport of parkin to mitochondrial membrane [79], suggesting that mitochondrial membrane depolarization is the chief factor in inducing mitophagy. In addition, a BH-3-specific domain protein also mediated parkin [84]. These proteins may also be affected by senescence-related apoptotic signals [85]. For instance, Bcl-2 and Bcl-xl acted as anti-apoptotic proteins by binding to BH-3 protein, and NAD+ enhanced their expression through phosphorylation of Akt and STAT1 signal [86, 87]. At the mitochondrial outer membrane, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (Bnip3) and NIX interact with microtubule-associated proteins 1A/1B light chain 3 (LC3) of the autophagosome, which not only mediated outer membrane permeability but also acted as a mitophagy initiation signal [88]. However, it has been reported that the upregulation of mitophagy mediated by parkin might be related to mitochondrial damage in cardiac stem cells (human cardiac progenitor cells/hCPCs). In contrast, the mitophagy mediated by Bnip3 and NIX would be more closely related to the aging mechanism [74]. Bnip3 promotes mitochondrial membrane depolarization by directly opening mPTP. mPTP opening, Ca2+, and ROS also reversely induce Bnip3, thereby upregulating the level of mitophagy [89]. However, it has been reported that a low Sirt1 level during aging could induce increased expression of Bnip3 in the heart, which might be related to the reduced induction of reparative mitophagy, which further caused the opening of the outer membrane pore and aggravated mitochondrial damage [45]. Moreover, Bnip3 induced mitochondrial Bax, which further affected the TOM complex through mitochondrial transmembrane Bim [90]. Therefore, Bnip3 might mediate parkin translocation to mitochondria through the Tom protein complex. In addition, NIX is bound to LC3 through GABA type A receptor-associated protein (GABARAP) for initiation in NIX-dependent mitophagy. However, the mitophagy mediated by NIX might not be related to depolarization but cardiac hypoxia [74]. Furthermore, it is suggested that overexpressed BH-3-mediated mitophagy and autophagy might give rise to autophagic exhaustion, leading to speeding up of heart aging process [91].
Mitochondria-related apoptosis and its possible regulation
The regulation of autophagy by intracellular ROS level involves tumor suppressor protein p53 and TP53-induced glycolysis and apoptosis regulator (TIGAR) [92]. TIGAR is a class of fructose-2,6-diphosphate, which reorients the metabolic intermediate of glucose decomposition to the oxidative branch of the pentose phosphate pathway. P53 regulates TIGAR, which is associated with decreased NAD+/NADH redox couple [93, 94]. Recently, TIGAR was found to aggravate LV dysfunction, fibrosis, and oxidative stress in a pressure-overload heart failure model [95]. Normal TIGAR upregulated the production of NADPH, thereby reducing the level of ROS in cells and the sensitivity of cells to apoptosis-related oxidative stress [96]. Studies have shown that p53/TIGAR mediates the inhibition of mitophagy. In p53 and TIGAR KO mice hearts, an increase in ROS involves the activation of Bnip3 and mitophagy [93]. Exogenous antioxidant N-acetylcysteine can upregulate p53/TIGAR-mediated inhibition of Bnip3-dependent mitophagy, indicating that ROS signaling is essential for the p53/TIGAR/Bnip3-dependent mitophagy inhibition pathway [97]. In addition, p53 also induced damage-regulated autophagy regulator (DRAM) and Bax [93]. Studies have shown that p53/DRAM might promote autophagic apoptosis by upregulating mitophagy. Therefore, p53 is a regulator that balances the properties of mitophagy and could be an inhibitor that explicitly delays heart failure during the aging process and the TIGAR-represented glycolysis mechanism.
Studies have shown that overexpression of P49/strap in the aging heart led to reduced NAD+/NADH ratio, protein deacetylation induction, inhibition of PGC-1-induced mitochondrial fusion proteins mfn1/2 and Opa, and mitochondrial impairment [17]. Moreover, NAD+ also directly deacetylated Opa-1 to regulate its gene transcription, which further increased the ratio of Opa-1/VDAC1 and promoted the regulation of mitochondrial dynamics, leading to strengthened mitochondrial fusion and inhibition of mitochondrial senescence [98]. High expression of p49 also inhibited the Sirtuin signal-related mitochondrial repair mechanism, closely related to Sirt3, Sirt4, and Sirt5 expressions in mitochondria [49]. For example, in HUEVCs cells, Sirt4 regulates ATP homeostasis via AMPK and mitochondrial inner membrane ADP/ATP-translocase 2, which inhibited malonyl-CoA decarboxylase, and led to an increase in malonyl-CoA levels [99]. In addition, inhibited Sirt4 affects the transport of long-chain fatty acids to the mitochondrial matrix, blocking carnitine palmitoyltransferase 1 and inducing senescent lipid metabolism abnormalities [99]. This change further inhibited mitochondrial OXPHOS and induced glycolysis, causing storage of mitochondrial fatty acids with irreversible changes in morphology in the end [16]. With the increase in age, the quality and function of mitochondria decrease, resulting in the development of insulin resistance and metabolic diseases in the elderly. Moreover, Wnt signaling plays a vital role in the progression of heart disease, including decreased insulin sensitivity, cardiovascular remodeling, and structural changes, such as fibrosis, sclerosis, atherosclerosis, smooth muscle cell proliferation, and hypertrophy [100]. It is known that Wnt/β-catenin signaling has a developmental stage-specific biphasic effect on the cardiomyogenesis of mouse embryonic stem cells. Wnt signaling promotes cardiomyocyte differentiation at an early stage and inhibits it at a late stage [101]. Although the Wnt signal can affect myocardial mitochondrial damage through GSK-3β, it is also an intermediate bridge among insulin signal, angiotensin II (AngII) signal, and calcium signal, causing a reduction in the functional performance of the heart during the treatment of heart failure and arrhythmia [102]. However, there is no direct evidence of interaction between NAD+ and the Wnt/β-catenin pathway in the cardiovascular field of aging. Considering the typical role of Wnt signaling in anti-aging of multiorgan, NAD+-dependent deacetylase Sirt1 may also directly or indirectly regulate the epigenetic changes around the promoter region of the LGR 5 gene which can be a novel concept for future research [103]. Figure 5 is a schematic diagram showing mechanisms of NAD+ associated mitochondrial protection.
In conclusion, NAD+ is a fundamental regulator of mitochondrial homeostasis, genomic stability, neuroprotection, healthy aging, and longevity. Studies have shown that WRN regulates the transcription of NMNAT1, a critical NAD+ biosynthetic enzyme [33]. At the organism level, NAD+ supplementation significantly prolongs the life span of Caenorhabditis elegans and Drosophila melanogaster affected by Werner Syndrome (WS) and delays animal aging and stem cell dysfunction. The accelerated senescence of WS is mediated by a metabolic disorder, impaired mitochondrial function, and mitochondrial phagocytosis. By maintaining an optimum level of NAD+, cells can respond to the WS phenotype, which provides a basis for NAD+ to simultaneously act in the maintenance of multiple organ functions, thereby benefiting the working environment of the heart.
Therapeutic potential of targeting NAD+ in delaying heart aging
Endogenous regulation
Clinical experiments have shown a high correlation between the reduction in blood NAD+ levels and heart failure in the elderly [104]. There are still some limitations in the existing interventions for heart aging. Some new interventional strategies used to prevent cardiovascular stresses via synthesis of more NAD+ have been established, such as ischemic preconditioning (IP), continuous low-to-medium intensity exercise, and other more exogenous drug strategies. For example, AngII mediated an increase in NADPH through JNK and p38MAPK pathways. However, this also caused an increase in the mitochondrial ROS production [105]. A moderate increase in ROS could promote adaptability to IP-cardiac oxidative stress and mediate mitochondrial protective signaling [106]. Moreover, sevoflurane post-treatment could preserve NAD+ levels and inhibit mPTP opening in the aging myocardium under stress by increasing the expressions of PI3K and ERK1/2 pathways [107]. Exogenous mPTP inhibitor CsA, when interacting with CypD, prevented Ca2+-induced CypD from combining with ANT and inhibited Ca2+ mitochondrial output, which gave rise to decreased ΔΨm, and blocked ROS production. Moreover, CsA was used as a clinical drug to resist organ rejection. Its significant inhibitory effect on immune function makes it unsuitable for treating long-term chronic diseases, including cardiac hypertrophy and heart failure [11]. Additionally, IGF-1 could also activate Sirt1 regulation by phosphorylation of JNK1. Whether this pathway is dependent on the NAD+ signal remains to be further explored. Sirt1 KO caused oxidative stress damage, leading to an increase in the MDA production [40]. Furthermore, a precursor of NAD+, supplementation with NMN helps inhibit the aging-induced myocardial remodeling and heart failure and provides a new treatment strategy [72]. In a human study, NMN supplementation improved cardiac glycogen synthesis and gluconeogenesis in various subjects. With the increased level of mitochondrial function, PCr/ATP ratio and cardiac work capacity also increased [60]. In cardiomyocytes, the high NAD+ level may co-exist with the ATP/O2 coupling [19]. However, a high NADH level is also an important factor in triggering oxidative stress, enhancing SDH enzyme activity, and preserving PEP help to inhibit this process and improve the duration of NMN efficacy [39]. To optimize the intervention plan that can stimulate the downstream protective mechanism of NAD+ signaling, it is suggested that the properties of NMN utilization for anti-heart aging should be evaluated for the state of metabolism.
NAD+ is an important regulatory target of oxidative stress, whether in the form of oxygen or nitrogen radicals. The NAD+-related Sirt1 pathway acts on the deacetylation of eNOS and induces its activation, which helps reduce the harmful effects of ROS. It should be pointed out that in the absence of NAD+ signal induction, a higher eNOS level may damage cardiomyocytes [22]. Nonetheless, NO is thought to help inhibit hypertrophic cardiomyopathy by inducting cGMP pathways [71]. Recent studies have shown that NO-mediated cysteine oxidation may inhibit the glutathione by mitochondrial Sirt3 and Sirt5, thereby accelerating cardiomyocyte senescence and tissue inflammatory expression [108]. Other studies have shown that the upregulation of Sirt1 expression accompanied cell senescence induced by high glucose and high fat intake. Simultaneously, the aging of cardiomyocytes was inhibited through the AMPK pathway [61]. The main factor of cardiomyocytes senescence by high glucose and fat intake may be related to inhibiting mitochondrial adenosine transport [99]. Resveratrol administration revealed high Nrf2 induction ability in the concentration range of 1–20 μM, which led to the inhibition of high-glucose-induced apoptosis, increased amount of DNA fragments, and prolonged life span [109]. When combined with long-term low-intensity exercise, Resveratrol supplementation effectively increased NAD+ level and enhanced the activities of cardiac antioxidant enzymes, such as GSH, SOD, and CAT [110]. Similar biological effects were also demonstrated by natural active substances rich in polyphenols and oleic acid esters, etc [111, 112]. It should also be noted that some factors that regulate NAD+ levels may have different expressions based on specific cellular states. For example, Over-activated Sirt1 and Sirt4 could aggravate cardiac hypertrophy [113]. Zhu et al. [69] reported that isoflurane-induced drug preconditioning used to treat acute myocardial stress could not generate NAD+ benefits in elderly rats and was directly related to the mitochondrial damage caused by a decrease in GSK-3β phosphorylation. It is suggested that moderate precursor supplementation and normal mitochondrial function are important prerequisites for maintaining the effective action of NAD+ protection signaling on aging cardiomyocytes. Furthermore, the loss of NAD+ leads to the interruption of oxidative phosphorylation, which is also an important cause of age-related oxidative stress injury [69, 114].
Strategy for choosing inhibitors
It is feasible to activate NAD+ expression by other endogenous stimuli to induce adaptive improvement and inhibit heart failure. For example, the energy restriction assists the NAD+-induced deacetylation of downstream p53 and NF-κB via Sirt2, leads to prolonged life span and improved anti-aging effect cardiomyocytes [49, 115]. Recent studies have shown that exercise can significantly increase the expression level of myocardial NAD+. Although the specific mechanism is still unclear, it may be related to ATP consumption leading to a higher AMPK level [116]. Conversely, the deletion of the NAD+ encoding gene can cause the loss of anti-heart failure effects, such as initially suppressed arrhythmia, systolic dysfunction, fibrosis, and compensatory heart rate [117]. An adequate supply of NAD+ in cardiomyocytes inhibits the transcription level of pro-inflammatory factors by reducing oxidative stress, decreasing the inflammatory response such as CD38, one of the NADases. Reduction in DNA oxidative stress damage, inactivation of PARP1, inhibition of NAD+ clearance pathway, and NAD+ synthesis can be achieved by reducing ROS [118]. Similarly, CD38 inhibitors, such as 78C, protect against cardiomyocyte senescence by preserving NAD+ [19]. In a previous study, continuous two weeks treatment with PARP1 blocker PJ-34 showed inhibition of endothelial cell aging, improvement in eNOS-mediated peripheral vascular protection, enhanced NAD+-dependent endothelial function, improved mitochondrial functional homeostasis and ROS inhibition [119]. Therefore, it is speculated that the various exogenous NAD+ precursor preservatives have similar protective effects on cardiac aging. However, further research is needed to verify this speculation [119]. In contrast, the NAMPT blocker FK866, an emerging tumor growth inhibitor, reduced cardiomyocyte stress tolerance [120]. Specifically, if we want to use NAD+ precursor supplement to prevent cardiotoxicity-related heart failure caused by drugs (e.g., Doxorubicin), more complex factors such as inflammation, tumors, metabolic abnormalities, neurodegeneration, and other diseases should be considered in advance. In other words, we cannot simply use, for instance, NMN to treat patients undergoing chemotherapy or similar treatments. For example, during tumor treatment with certain chemotherapeutics, where the NMN pathway needs to be blocked, it may be more feasible to use NAR instead of NMN [31].
Targeting the inflammatory response
Since inflammation is one of the main features of heart aging, when exogenous stress is stimulated to induce adaptability, it is imperative to use the exogenous supplement to suppress the adverse effects of stress and reduce inflammation-induced senescence (SASP) [56]. The senescence of cardiomyocytes significantly increased the expression of TNF-α and NF-κB. TNF-α caused mitochondrial mPTP opening, apoptosis, and downregulation of phosphatase and tensin homolog signal, resulting in excessive Bnip3-dependent mitophagy and mitochondrial dysfunction [79, 80]. Further, TNF-α decreased the level of NAD+ and produced ROS by inducing an increase in NAD(P)H oxidase expression [65]. TNF-α also caused an increase in CD38 expression and the conversion of NAD+ to NAADP and CADPR. By acting as a regulator, TNF-α increases calcium release from the cardiac endoplasmic reticulum and causes intracellular calcium overload. Higher adrenaline sensitivity exacerbates the cardiac burden and the risk of mitochondrial injury [121]. As for the downstream mechanism, due to the inhibition of NAD+/Sirt pathway, downregulation of Sirt1 causes decreased expression of FOXO, p53, PPARα, and Akt in the nucleus; reduced transcription levels of antioxidant enzymes, such as Bcl-xL; increased levels of intracellular oxidative stress; decreased autophagy; decreased fatty acid oxidation capacity; and increased level of apoptosis. On the other hand, the expression of NLRP3 inflammasome in myocardial tissue is necessary for the NAD+/Sirt1-mediated anti-aging mechanism [57]. However, some studies have suggested using small molecule drugs to inhibit the formation of NLRP3 complex that helps inhibit myocardial fibrosis, dilated cardiomyopathy, and atherosclerosis [56]. Therefore, NAD+ might be a transformer that affects the endogenous effects of NLPR3, and appropriate NAD+ supplementation could reduce myocardial inflammation using activated SIRTs and NRF2 signaling (Table 1).
Conclusions
NAD+ depletion is one of the primary pathogenesis of heart disease, and NAD+ supplementation has shown therapeutic potential for restoring healthy metabolism and physiological functions. The pluripotency of this abundant coenzyme NAD+ facilitates its availability for exerting a therapeutic effect. In particular, NAD+ acts as an auxiliary substrate in the deacylation reaction carried out by multiple interactions between nucleus transcription signaling in the heart. These NAD+-dependent signals are associated with or directly control several aspects of metabolism, especially in the mitochondria. A large amount of data indicated that supplementing NAD+ to enhance multiple intercellular cross-talks may be a feasible treatment option for inhibiting overall body aging. Simultaneously, it should be considered that the heart, as a blood-pumping organ, is highly dependent on the metabolic environment and ion homeostasis. Notably, both suitable doses and the form of NAD+ precursor supplements are crucial for gaining their optimum benefits. NAD+ supplementation should be used with caution in certain circumstances, such as myocardial hypoxia and hypertrophy. Further studies are needed to elucidate a closer connection between multiple cardioprotective signals and NAD+, which will help to improve the accuracy and effectiveness of interventions on heart aging.
Data availability
The datasets generated during and analyzed during the current study are available from the corresponding author on reasonable request.
References
Ruiz-Meana M, Bou-Teen D, Ferdinandy P, Gyongyosi M, Pesce M, Perrino C, et al. Cardiomyocyte ageing and cardioprotection: consensus document from the ESC working groups cell biology of the heart and myocardial function. Cardiovasc Res. 2020;116:1835–49.
Partridge L, Fuentealba M, Kennedy BK. The quest to slow ageing through drug discovery. Nat Rev Drug Discov. 2020;19:513–32.
Eisenberg T, Abdellatif M, Schroeder S, Primessnig U, Stekovic S, Pendl T, et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med. 2016;22:1428–38.
Annesley SJ, Fisher PR. Mitochondria in health and disease. Cells. 2019;8:680.
Grabowska W, Sikora E, Bielak-Zmijewska A. Sirtuins, a promising target in slowing down the ageing process. Biogerontology. 2017;18:447–76.
Das A, Huang GX, Bonkowski MS, Longchamp A, Li C, Schultz MB, et al. Impairment of an endothelial NAD(+)-H(2)S signaling network is a reversible cause of vascular aging. Cell. 2018;173:74–89. e20
Sarikhani M, Maity S, Mishra S, Jain A, Tamta AK, Ravi V, et al. SIRT2 deacetylase represses NFAT transcription factor to maintain cardiac homeostasis. J Biol Chem. 2018;293:5281–94.
Feng D, Xu D, Murakoshi N, Tajiri K, Qin R, Yonebayashi S, et al. Nicotinamide phosphoribosyltransferase (Nampt)/nicotinamide adenine dinucleotide (NAD) axis suppresses atrial fibrillation by modulating the calcium handling pathway. Int J Mol Sci. 2020;13:4655.
Aman Y, Frank J, Lautrup SH, Matysek A, Niu Z, Yang G, et al. The NAD(+)-mitophagy axis in healthy longevity and in artificial intelligence-based clinical applications. Mech Ageing Dev. 2020;185:111194.
Lee CF, Caudal A, Abell L, Nagana Gowda GA, Tian R. Targeting NAD(+) metabolism as interventions for mitochondrial disease. Sci Rep. 2019;9:3073.
Hafner AV, Dai J, Gomes AP, Xiao CY, Palmeira CM, Rosenzweig A, et al. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine 166 suppresses age-related cardiac hypertrophy. Aging. 2010;2:914–23.
Sabbah HN. Targeting mitochondrial dysfunction in the treatment of heart failure. Expert Rev Cardiovasc Ther. 2019;14:1305–13.
Schneider J, Han WH, Matthew R, Sauvé Y, Lemieux H. Age and sex as confounding factors in the relationship between cardiac mitochondrial function and type 2 diabetes in the Nile Grass rat. PLoS ONE. 2020;15:e0228710.
Barcena de Arellano ML, Pozdniakova S, Kühl AA, Baczko I, Ladilov Y, Regitz-Zagrosek V. Sex differences in the aging human heart: decreased sirtuins, pro-inflammatory shift and reduced anti-oxidative defense. Aging. 2019;11:1918–33.
Migaud M, Kraus WL, Chen D, Ziegler M, Guarente LP, Bohr VA, et al. NAD metabolism and signaling. Cambridge, MA, USA: Cell Press; 2019.
Del Favero G, Bonifacio A, Rowland TJ, Gao S, Song K, Sergo V, et al. Danon disease-associated LAMP-2 deficiency drives metabolic signature indicative of mitochondrial aging and fibrosis in cardiac tissue and hiPSC-derived cardiomyocytes. J Clin Med. 2020;9:2457.
Zhang X, Williams ED, Azhar G, Rogers SC, Wei JY. Does p49/STRAP, a SRF-binding protein (SRFBP1), modulate cardiac mitochondrial function in aging? Exp Gerontol. 2016;82:150–9.
Yeo D, Kang C, Ji LL. Aging alters acetylation status in skeletal and cardiac muscles. GeroScience. 2020;42:963–76.
Tarragó MG, Chini CCS, Kanamori KS, Warner GM, Caride A, de Oliveira GC, et al. A potent and specific CD38 inhibitor ameliorates age-related metabolic dysfunction by reversing tissue NAD(+) decline. Cell Metab. 2018;27:1081–95. e1010.
Wang LF, Cao Q, Wen K, Xiao YF, Chen TT, Guan XH, et al. CD38 deficiency alleviates D-galactose-induced myocardial cell senescence through NAD(+)/Sirt1 signaling pathway. Front Physiol 2019;10:1125.
Ruan Y, Dong C, Patel J, Duan C, Wang X, Wu X, et al. SIRT1 suppresses doxorubicin-induced cardiotoxicity by regulating the oxidative stress and p38MAPK pathways. Cell Physiol Biochem. 2015;35:1116–24.
Roos CM, Hagler M, Zhang B, Oehler EA, Arghami A, Miller JD. Transcriptional and phenotypic changes in aorta and aortic valve with aging and MnSOD deficiency in mice. Am J Physiol Heart Circ Physiol. 2013;305:H1428–1439.
Volt H, GarcÃa JA, Doerrier C, DÃaz-Casado ME, Guerra-Librero A, López LC, et al. Same molecule but different expression: aging and sepsis trigger NLRP3 inflammasome activation, a target of melatonin. J Pineal Res. 2016;60:193–205.
Chen L, Yang G. PPARs integrate the mammalian clock and energy metabolism. PPAR Res. 2014;2014:653017.
Antonopoulos AS, Margaritis M, Verheule S, Recalde A, Sanna F, Herdman L, et al. Mutual regulation of epicardial adipose tissue and myocardial redox state by PPAR-γ/adiponectin signalling. Circ Res. 2016;118:842–55.
Anderson R, Richardson GD, Passos JF. Mechanisms driving the ageing heart. Exp Gerontol. 2018;109:5–15.
Luengo A, Li Z, Gui DY, Sullivan LB, Zagorulya M, Do BT, et al. Increased demand for NAD(+) relative to ATP drives aerobic glycolysis. Mol Cell. 2021;81:691–707. e696
Hershberger KA, Martin AS, Hirschey MD. Role of NAD(+) and mitochondrial sirtuins in cardiac and renal diseases. Nat Rev Nephrol. 2017;13:213–25.
Hara N, Osago H, Hiyoshi M, Kobayashi-Miura M, Tsuchiya M. Quantitative analysis of the effects of nicotinamide phosphoribosyltransferase induction on the rates of NAD+ synthesis and breakdown in mammalian cells using stable isotope-labeling combined with mass spectrometry. PLoS ONE. 2019;14:e0214000.
Fletcher RS, Lavery GG. The emergence of the nicotinamide riboside kinases in the regulation of NAD+ metabolism. J Mol Endocrinol. 2018;61:R107–r121.
Liu HW, Smith CB, Schmidt MS, Cambronne XA, Cohen MS, Migaud ME, et al. Pharmacological bypass of NAD(+) salvage pathway protects neurons from chemotherapy-induced degeneration. Proc Natl Acad Sci USA. 2018;115:10654–9.
Zhang LQ, Van Haandel L, Xiong M, Huang P, Heruth DP, Bi C, et al. Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase. Cell Death Dis. 2017;8:e2705.
Fang EF, Hou Y, Lautrup S, Jensen MB, Yang B, SenGupta T, et al. NAD(+) augmentation restores mitophagy and limits accelerated aging in Werner syndrome. Nat Commun. 2019;10:5284.
Yarbro JR, Emmons RS, Pence BD. Macrophage immunometabolism and inflammaging: roles of mitochondrial dysfunction, cellular senescence, CD38, and NAD. Immunometabolism. 2020;2:e200026.
Deloux R, Tannous C, Ferry A, Li Z, Mericskay M. Aged nicotinamide riboside kinase 2 deficient mice present an altered response to endurance exercise training. Front Physiol. 2018;9:1290.
Zhang R, Shen Y, Zhou L, Sangwung P, Fujioka H, Zhang L, et al. Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure. J Mol Cell Cardiol 2017;112:64–73.
Zhai X, Han W, Wang M, Guan S, Qu X. Exogenous supplemental NAD+ protect myocardium against myocardial ischemic/reperfusion injury in swine model. Am J Transl Res. 2019;11:6066–74.
Shum LC, White NS, Nadtochiy SM, Bentley KL, Brookes PS, Jonason JH, et al. Cyclophilin D knock-out mice show enhanced resistance to osteoporosis and to metabolic changes observed in aging bone. PLoS ONE. 2016;11:e0155709.
Baily CN, Cason RW, Vadvalkar SS, Matsuzaki S, Humphries KM. Inhibition of mitochondrial respiration by phosphoenolpyruvate. Arch Biochem Biophys. 2011;514:68–74.
Vinciguerra M, Santini MP, Martinez C, Pazienza V, Claycomb WC, Giuliani A, et al. mIGF-1/JNK1/SirT1 signaling confers protection against oxidative stress in the heart. Aging Cell. 2012;11:139–49.
Granger DN, Kvietys PR. Reperfusion injury and reactive oxygen species: the evolution of a concept. Redox Biol. 2015;6:524–51.
Diguet N, Trammell SAJ, Tannous C, Deloux R, Piquereau J, Mougenot N, et al. Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy. Circulation. 2018;137:2256–73.
Braidy N, Guillemin GJ, Mansour H, Chan-Ling T, Poljak A, Grant R. Age related changes in NAD+ metabolism oxidative stress and Sirt1 activity in wistar rats. PLoS ONE. 2011;6:e19194.
Um JH, Pendergast JS, Springer DA, Foretz M, Viollet B, Brown A, et al. AMPK regulates circadian rhythms in a tissue- and isoform-specific manner. PLoS ONE. 2011;6:e18450.
Wang L, Quan N, Sun W, Chen X, Cates C, Rousselle T, et al. Cardiomyocyte-specific deletion of Sirt1 gene sensitizes myocardium to ischaemia and reperfusion injury. Cardiovasc Res. 2018;114:805–21.
Hsu YJ, Hsu SC, Hsu CP, Chen YH, Chang YL, Sadoshima J, et al. Sirtuin 1 protects the aging heart from contractile dysfunction mediated through the inhibition of endoplasmic reticulum stress-mediated apoptosis in cardiac-specific Sirtuin 1 knockout mouse model. Int J Cardiol. 2017;228:543–52.
Kang H, Oka S, Lee DY, Park J, Aponte AM, Jung YS, et al. Sirt1 carboxyl-domain is an ATP-repressible domain that is transferrable to other proteins. Nat Commun. 2017;8:15560.
Santos-Barriopedro I, Bosch-Presegué L, Marazuela-Duque A, de la Torre C, Colomer C, Vazquez BN, et al. SIRT6-dependent cysteine monoubiquitination in the PRE-SET domain of Suv39h1 regulates the NF-κB pathway. Nat Commun. 2018;9:101.
Zhang X, Azhar G, Wei JY. SIRT2 gene has a classic SRE element, is a downstream target of serum response factor and is likely activated during serum stimulation. PLoS ONE. 2017;12:e0190011.
Ianni A, Yuan X, Bober E, Braun T. Sirtuins in the cardiovascular system: potential targets in pediatric cardiology. Pediatr Cardiol. 2018;39:983–92.
Fang J, Ianni A, Smolka C, Vakhrusheva O, Nolte H, Krüger M, et al. Sirt7 promotes adipogenesis in the mouse by inhibiting autocatalytic activation of Sirt1. Proc Natl Acad Sci USA. 2017;114:E8352–e8361.
Porter GA, Urciuoli WR, Brookes PS, Nadtochiy SM. SIRT3 deficiency exacerbates ischemia-reperfusion injury: implication for aged hearts. Am J Physiol Heart Circ Physiol. 2014;306:H1602–1609.
Huang CH, Tsai MS, Chiang CY, Su YJ, Wang TD, Chang WT, et al. Activation of mitochondrial STAT-3 and reduced mitochondria damage during hypothermia treatment for post-cardiac arrest myocardial dysfunction. Basic Res Cardiol. 2015;110:59.
Meier JA, Larner AC. Toward a new STATe: the role of STATs in mitochondrial function. Semin Immunol. 2014;26:20–28.
Knight RA, Scarabelli TM, Stephanou A. STAT transcription in the ischemic heart. JAKSTAT. 2012;1:111–7.
Liu D, Richardson G, Benli FM, Park C, de Souza JV, Bronowska AK, et al. Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies. Clin Sci. 2020;134:2243–62.
MarÃn-Aguilar F, Lechuga-Vieco AV, Alcocer-Gómez E, Castejón-Vega B, Lucas J, Garrido C, et al. NLRP3 inflammasome suppression improves longevity and prevents cardiac aging in male mice. Aging Cell. 2020;19:e13050.
Palikaras K, Lionaki E, Tavernarakis N. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature. 2015;521:525–8.
Bazopoulou D, Knoefler D, Zheng Y, Ulrich K, Oleson BJ, Xie L, et al. Developmental ROS individualizes organismal stress resistance and lifespan. Nature. 2019;576:301–5.
Whitson JA, Bitto A, Zhang H, Sweetwyne MT, Coig R, Bhayana S, et al. SS-31 and NMN: two paths to improve metabolism and function in aged hearts. Aging Cell. 2020;19:e13213.
Kao CL, Chen LK, Chang YL, Yung MC, Hsu CC, Chen YC, et al. Resveratrol protects human endothelium from H(2)O(2)-induced oxidative stress and senescence via SirT1 activation. J Atherosclerosis Thrombosis. 2010;17:970–9.
Arsiwala T, Pahla J, van Tits LJ, Bisceglie L, Gaul DS, Costantino S, et al. Sirt6 deletion in bone marrow-derived cells increases atherosclerosis - Central role of macrophage scavenger receptor 1. J Mol Cell Cardiol. 2020;139:24–32.
Balasubramanian P, Asirvatham-Jeyaraj N, Monteiro R, Sivasubramanian MK, Hall D, Subramanian M. Obesity-induced sympathoexcitation is associated with Nrf2 dysfunction in the rostral ventrolateral medulla. Am J Physiol Regul Integr Comp Physiol. 2020;318:R435–r444.
Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, Losonczy G, et al. Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am J Physiol Heart Circ Physiol. 2011;301:H363–372.
Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, Pearson K, et al. Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol. 2010;299:H18–24.
Lynch MR, Tran MT, Ralto KM, Zsengeller ZK, Raman V, Bhasin, SS, et al. TFEB-driven lysosomal biogenesis is pivotal for PGC1α-dependent renal stress resistance. JCI insight. 2019;5:e126749.
Fernandez-Sanz C, Ruiz-Meana M, Miro-Casas E, Nuñez E, Castellano J, Loureiro M, et al. Defective sarcoplasmic reticulum-mitochondria calcium exchange in aged mouse myocardium. Cell Death Dis. 2014;5:e1573.
Zhang YS, Liu B, Luo XJ, Li TB, Zhang JJ, Peng JJ, et al. Nuclear cardiac myosin light chain 2 modulates NADPH oxidase 2 expression in myocardium: a novel function beyond muscle contraction. Basic Res Cardiol. 2015;110:38.
Zhu J, Rebecchi MJ, Tan M, Glass PS, Brink PR, Liu L. Age-associated differences in activation of Akt/GSK-3beta signaling pathways and inhibition of mitochondrial permeability transition pore opening in the rat heart. J Gerontol A Biol Sci Med Sci. 2010;65:611–9.
Feger BJ, Starnes JW. Myocardial Na+/H+ exchanger-1 (NHE1) content is decreased by exercise training. J Physiol Biochem. 2013;69:305–12.
Boslett J, Helal M, Chini E, Zweier JL. Genetic deletion of CD38 confers post-ischemic myocardial protection through preserved pyridine nucleotides. J Mol Cell Cardiol. 2018;118:81–94.
Yamamura S, Izumiya Y, Araki S, Nakamura T, Kimura Y, Hanatani S, et al. Cardiomyocyte Sirt (Sirtuin) 7 ameliorates stress-induced cardiac hypertrophy by interacting with and deacetylating GATA4. Hypertension. 2020;75:98–108.
Prola A, Pires Da Silva J, Guilbert A, Lecru L, Piquereau J, Ribeiro M, et al. SIRT1 protects the heart from ER stress-induced cell death through eIF2α deacetylation. Cell Death Differ. 2017;24:343–56.
Korski KI, Kubli DA, Wang BJ, Khalafalla FG, Monsanto MM, Firouzi F, et al. Hypoxia prevents mitochondrial dysfunction and senescence in human c-Kit(+) cardiac progenitor cells. Stem Cells. 2019;37:555–67.
Ren J, Yang L, Zhu L, Xu X, Ceylan AF, Guo W, et al. Akt2 ablation prolongs life span and improves myocardial contractile function with adaptive cardiac remodeling: role of Sirt1-mediated autophagy regulation. Aging Cell. 2017;16:976–87.
Hosseini L, Vafaee MS, Badalzadeh R. Melatonin and nicotinamide mononucleotide attenuate myocardial ischemia/reperfusion injury via modulation of mitochondrial function and hemodynamic parameters in aged rats. J Cardiovasc Pharmacol Ther 2020;25:240–50.
Gao B, Yu W, Lv P, Liang X, Sun S, Zhang Y. Parkin overexpression alleviates cardiac aging through facilitating K63-polyubiquitination of TBK1 to facilitate mitophagy. Biochim Biophys Acta Mol Basis Dis. 2020;1867:165997.
Suliman HB, Keenan JE, Piantadosi CA. Mitochondrial quality-control dysregulation in conditional HO-1(-/-) mice. JCI Insight. 2017;2:e89676.
Huang C, Andres AM, Ratliff EP, Hernandez G, Lee P, Gottlieb RA. Preconditioning involves selective mitophagy mediated by Parkin and p62/SQSTM1. PLoS ONE. 2011;6:e20975.
Gong G, Song M, Csordas G, Kelly DP, Matkovich SJ, Dorn GW 2nd. Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice. Science. 2015;350:aad2459.
Das S, Mitrovsky G, Vasanthi HR, Das DK. Antiaging properties of a grape-derived antioxidant are regulated by mitochondrial balance of fusion and fission leading to mitophagy triggered by a signaling network of Sirt1-Sirt3-Foxo3-PINK1-PARKIN. Oxid Med Cell Longev. 2014;2014:345105.
Li J, Qi M, Li C, Shi D, Zhang D, Xie D, et al. Tom70 serves as a molecular switch to determine pathological cardiac hypertrophy. Cell Res. 2014;24:977–93.
Mizukami H, Saitoh S, Machii H, Yamada S, Hoshino Y, Misaka T, et al. Senescence marker protein-30 (SMP30) deficiency impairs myocardium-induced dilation of coronary arterioles associated with reactive oxygen species. Int J Mol Sci. 2013;14:9408–23.
Lee Y, Lee HY, Hanna RA, Gustafsson AB. Mitochondrial autophagy by Bnip3 involves Drp1-mediated mitochondrial fission and recruitment of Parkin in cardiac myocytes. Am J Physiol Heart Circ Physiol. 2011;301:H1924–1931.
Moyzis AG, Sadoshima J, Gustafsson AB. Mending a broken heart: the role of mitophagy in cardioprotection. Am J Physiol Heart Circ Physiol. 2015;308:H183–192.
Abeyrathna P, Su Y. The critical role of Akt in cardiovascular function. Vasc Pharmacol. 2015;74:38–48.
Zhang WY, Zhang QL, Xu MJ. Effects of propofol on myocardial ischemia reperfusion injury through inhibiting the JAK/STAT pathway. Eur Rev Med Pharmacol Sci. 2019;23:6339–45.
Rikka S, Quinsay MN, Thomas RL, Kubli DA, Zhang X, Murphy AN, et al. Bnip3 impairs mitochondrial bioenergetics and stimulates mitochondrial turnover. Cell Death Differ. 2011;18:721–31.
Yuan Y, Pan SS. Parkin mediates mitophagy to participate in cardioprotection induced by late exercise preconditioning but Bnip3 does not. J Cardiovasc Pharmacol. 2018;71:303–16.
Frank DO, Dengjel J, Wilfling F, Kozjak-Pavlovic V, Hacker G, Weber A. The pro-apoptotic BH3-only protein Bim interacts with components of the translocase of the outer mitochondrial membrane (TOM). PLoS ONE. 2015;10:e0123341.
Matsumoto C, Jiang Y, Emathinger J, Quijada P, Nguyen N, De La Torre A, et al. Short telomeres induce p53 and autophagy and modulate age-associated changes in cardiac progenitor cell fate. Stem Cells. 2018;36:868–80.
Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, et al. TIGAR, a p53-inducible regulator of glycolysis and apoptosis. Cell. 2006;126:107–20.
Hoshino A, Matoba S, Iwai-Kanai E, Nakamura H, Kimata M, Nakaoka M, et al. p53-TIGAR axis attenuates mitophagy to exacerbate cardiac damage after ischemia. J Mol Cell Cardiol. 2012;52:175–84.
Dodson M, Darley-Usmar V, Zhang J. Cellular metabolic and autophagic pathways: traffic control by redox signaling. Free Radic Biol Med 2013;63:207–21.
Okawa Y, Hoshino A, Ariyoshi M, Kaimoto S, Tateishi S, Ono K, et al. Ablation of cardiac TIGAR preserves myocardial energetics and cardiac function in the pressure overload heart failure model. Am J Physiol Heart Circ Physiol. 2019;316:H1366–h1377.
Bensaad K, Cheung EC, Vousden KH. Modulation of intracellular ROS levels by TIGAR controls autophagy. EMBO J. 2009;28:3015–26.
Yamanaka R, Hoshino A, Fukai K, Urata R, Minami Y, Honda S, et al. TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension. Am J Physiol Heart Circ Physiol. 2020;319:H1087–h1096.
Benigni A, Cassis P, Conti S, Perico L, Corna D, Cerullo D, et al. Sirt3 deficiency shortens life span and impairs cardiac mitochondrial function rescued by Opa1 gene transfer. Antioxid Redox Signal. 2019;31:1255–71.
Pecher SJ, Potthast AB, von Versen-Höynck F, Das AM. Impact of short-term hypoxia on sirtuins as regulatory elements in HUVECs. J Clin Med. 2020;9:2604.
Gay A, Towler DA. Wnt signaling in cardiovascular disease: opportunities and challenges. Curr Opin Lipidol. 2017;28:387–96.
Morita H, Komuro I. Heart failure as an aging-related phenotype. Int Heart J. 2018;59:6–13.
Azim N, Ahmad J, Iqbal N, Siddiqa A, Majid A, Ashraf J, et al. Petri Net modelling approach for analysing the behaviour of Wnt/[inline-formula removed]-catenin and Wnt/Ca(2+) signalling pathways in arrhythmogenic right ventricular cardiomyopathy. IET Syst Biol. 2020;14:350–67.
Uchida R, Saito Y, Nogami K, Kajiyama Y, Suzuki Y, Kawase Y, et al. Erratum: Publisher Correction: Epigenetic silencing of Lgr5 induces senescence of intestinal epithelial organoids during the process of aging. NPJ Aging Mech Dis. 2019;5:5.
Breton M, Costemale-Lacoste JF, Li Z, Lafuente-Lafuente C, Belmin J, Mericskay M. Blood NAD levels are reduced in very old patients hospitalized for heart failure. Exp Gerontol. 2020;139:111051.
Kimura S, Zhang GX, Nishiyama A, Shokoji T, Yao L, Fan YY, et al. Role of NAD(P)H oxidase- and mitochondria-derived reactive oxygen species in cardioprotection of ischemic reperfusion injury by angiotensin II. Hypertension. 2005;45:860–6.
Saotome M, Katoh H, Yaguchi Y, Tanaka T, Urushida T, Satoh H, et al. Transient opening of mitochondrial permeability transition pore by reactive oxygen species protects myocardium from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2009;296:H1125–1132.
Li H, Zhou C, Chen D, Fang N, Yao Y, Li L. Failure to protect against myocardial ischemia-reperfusion injury with sevoflurane postconditioning in old rats in vivo. Acta Anaesthesiol Scand. 2013;57:1024–31.
Kalous KS, Wynia-Smith SL, Summers SB, Smith BC. Human sirtuins are differentially sensitive to inhibition by nitrosating agents and other cysteine oxidants. J Biol Chem. 2020;295:8524–36.
Ungvari Z, Bailey-Downs L, Gautam T, Jimenez R, Losonczy G, Zhang C, et al. Adaptive induction of NF-E2-related factor-2-driven antioxidant genes in endothelial cells in response to hyperglycemia. Am J Physiol Heart Circ Physiol. 2011;300:H1133–1140.
Tung BT, Rodriguez-Bies E, Thanh HN, Le-Thi-Thu H, Navas P, Sanchez VM, et al. Organ and tissue-dependent effect of resveratrol and exercise on antioxidant defenses of old mice. Aging Clin Exp Res. 2015;27:775–83.
Liu B, Ma R, Zhang J, Sun P, Yi R, Zhao X. Preventive effect of small-leaved kuding tea (Ligustrum robustum (Roxb.) Bl.) polyphenols on D-galactose-induced oxidative stress and aging in mice. Evid Based Complement Altern Med. 2019;2019:3152324.
Enot DP, Niso-Santano M, Durand S, Chery A, Pietrocola F, Vacchelli E, et al. Metabolomic analyses reveal that anti-aging metabolites are depleted by palmitate but increased by oleate in vivo. Cell Cycle. 2015;14:2399–407.
Matasic DS, Brenner C, London B. Emerging potential benefits of modulating NAD(+) metabolism in cardiovascular disease. Am J Physiol Heart Circ Physiol. 2018;314:H839–h852.
Zhu J, Rebecchi MJ, Glass PS, Brink PR, Liu L. Cardioprotection of the aged rat heart by GSK-3beta inhibitor is attenuated: age-related changes in mitochondrial permeability transition pore modulation. Am J Physiol Heart Circ Physiol. 2011;300:H922–930.
Katare PB, Nizami HL, Paramesha B, Dinda AK, Banerjee SK. Activation of toll like receptor 4 (TLR4) promotes cardiomyocyte apoptosis through SIRT2 dependent p53 deacetylation. Sci Rep. 2020;10:19232.
Wen DT, Zheng L, Li JX, Cheng D, Liu Y, Lu K, et al. Endurance exercise resistance to lipotoxic cardiomyopathy is associated with cardiac NAD(+)/dSIR2/PGC-1alpha pathway activation in old Drosophila. Biol Open. 2019;8.
Wen DT, Zheng L, Ni L, Wang H, Feng Y, Zhang M. The expression of CG9940 affects the adaptation of cardiac function, mobility, and lifespan to exercise in aging Drosophila. Exp Gerontol. 2016;83:6–14.
Guan XH, Hong X, Zhao N, Liu XH, Xiao YF, Chen TT, et al. CD38 promotes angiotensin II-induced cardiac hypertrophy. J Cell Mol Med. 2017;21:1492–502.
Tarantini S, Yabluchanskiy A, Csipo T, Fulop G, Kiss T, Balasubramanian P, et al. Treatment with the poly(ADP-ribose) polymerase inhibitor PJ-34 improves cerebromicrovascular endothelial function, neurovascular coupling responses and cognitive performance in aged mice, supporting the NAD+ depletion hypothesis of neurovascular aging. GeroScience. 2019;41:533–42.
Oyarzún AP, Westermeier F, Pennanen C, López-Crisosto C, Parra V, Sotomayor-Flores C, et al. FK866 compromises mitochondrial metabolism and adaptive stress responses in cultured cardiomyocytes. Biochem Pharmacol. 2015;98:92–101.
Lin WK, Bolton EL, Cortopassi WA, Wang Y, O’Brien F, Maciejewska M, et al. Synthesis of the Ca(2+)-mobilizing messengers NAADP and cADPR by intracellular CD38 enzyme in the mouse heart: Role in beta-adrenoceptor signaling. J Biol Chem. 2017;292:13243–57.
Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016;24:795–806.
Jia P, Liu C, Wu N, Jia D, Sun Y. Agomelatine protects against myocardial ischemia reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Transl Res. 2018;10:1310–23.
Charles S, Raj V, Ramasamy M, Ilango K, Arockiaraj J, Murugesan S, et al. Pharmacological inhibition of guanosine triphosphate cyclohydrolase1 elevates tyrosine phosphorylation of caveolin1 and cellular senescence. Eur J Pharmacol. 2019;848:1–10.
Tian L, Cao W, Yue R, Yuan Y, Guo X, Qin D, et al. Pretreatment with Tilianin improves mitochondrial energy metabolism and oxidative stress in rats with myocardial ischemia/reperfusion injury via AMPK/SIRT1/PGC-1 alpha signaling pathway. J Pharmacol Sci. 2019;139:352–60.
Zhang L, Yao J, Wang X, Li H, Liu T, Zhao W. 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.
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).
Author information
Authors and Affiliations
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.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
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/.
About this article
Cite this article
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/s41420-022-01031-3