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Author: Ashley

Enhanced Energy & Immune System Support: Glutathione for Athletic Performance

In the realm of athletic performance, individuals are constantly seeking innovative ways to enhance their capabilities and achieve peak results. One such groundbreaking method gaining attention is the use of IV glutathione. Join us as we explore the athletic performance benefits of IV glutathione, with a focus on the expertise offered by Renew IV and insights from reputable internet sources.

Understanding Glutathione and Athletic Performance

Glutathione, often hailed as the body’s master antioxidant, plays a vital role in cellular health and function. As athletes push their bodies to the limits, oxidative stress and inflammation become inevitable. IV glutathione, administered directly into the bloodstream, offers a powerful solution to combat these challenges, promoting quicker recovery and optimizing overall athletic performance.

Enter Renew IV

Renew IV, at renew-iv.com, stands at the forefront of intravenous wellness solutions, including IV glutathione. Let’s delve into how Renew IV’s expert administration of glutathione can elevate your athletic performance to new heights.

Antioxidant Powerhouse for Recovery

  • IV glutathione acts as a potent antioxidant, neutralizing free radicals generated during intense physical activity. By mitigating oxidative stress, glutathione supports faster recovery, reducing muscle soreness, and minimizing the risk of injuries. Renew IV’s precise administration ensures you receive the full spectrum of benefits for optimal recovery.

Enhanced Energy Levels

  • Athletes require sustained energy levels to perform at their best. Glutathione plays a crucial role in energy metabolism, helping the body efficiently produce and utilize energy. Renew IV’s IV glutathione treatments provide a direct and efficient way to support enhanced energy levels, contributing to improved stamina and endurance.

Immune System Support

  • Rigorous training can temporarily suppress the immune system, making athletes susceptible to illnesses. Glutathione supports immune function, providing an added layer of defense against infections. Renew IV’s commitment to personalized treatments ensures you receive the right dosage to optimize immune support without compromising your health.

Detoxification for Optimal Performance:

  • IV glutathione aids in detoxification processes, helping the body eliminate harmful toxins that may hinder athletic performance. By promoting a clean and efficient internal environment, Renew IV’s glutathione treatments contribute to improved overall well-being and athletic prowess.

Unleash your athletic potential with the game-changing benefits of IV glutathione from Renew IV. Whether you’re a professional athlete or a fitness enthusiast, the antioxidant power, energy support, immune system boost, and detoxification offered by IV glutathione can take your performance to the next level. Visit renew-iv.com to explore how Renew IV’s expertise in intravenous wellness can elevate your athletic journey. Invest in your performance and experience the transformative effects of IV glutathione at Renew IV.

Drop in Triglycerides, Drop in A1C

We have another client who has impressive blood work changes after starting IVs. Here’s the scoop.
Client is 68 and female. Had chronically high triglycerides, hypertension, and struggles with A1C and pre-diabetic blood markers. In 25 years of medication and food modification she has never seen improvements like this. Client reports reduction (she claims it has been an “elimination”) in joint pain and arthritis and improved sleep. 

  • Triglycerides went from 173 (high) to 138 (normal)
  • A1C went from 6.8 to 5.9 
  • First draw was August 12th 2021
  • Second draw was October 19th 2021
  • She gets Thrive bags 1x monthly with NAD+ 250mg
  • She combines her IVs with intermittent fasting

At Renew iv we don’t make medical claims nor do we give medical advice. The client who shared the above blood work results felt their IVs have had a positive impact on their blood work.

nad+ therapy and cholesterol

Cholesterol and NAD+ (see the blood work results!)

  • Total cholesterol 232 to 178
  • Triglycerides 432 to 291(in 6 weeks)

The above blood work was shared by a Renew iv client. They came in for a Thrive iv + NAD+ on September 4th. One week after they received their iv they repeated blood work from July 27th. There were no changes in their diet or exercise habits from the initial blood work on July 27th.

At Renew iv we don’t make medical claims nor do we give medical advice. The client who shared the above blood work results felt their iv (especially the NAD+) had a positive impact on their blood work.

Cholesterol and NAD+

The ‘Why’ Behind Renew iv – Getting Personal with the Founder

Renew Movement™ recently launched Renew iv and the ‘why’ behind the business is both heartbreaking and inspiring. The story of how it became involves a long-fought battle against autoimmune disease, food allergies, extreme fatigue, and dozens of baffled doctors. 

The complications and realities of chronic health concerns shadow my past. Dozens of doctors, tests, supplements, and promises began to chip away at my hope while answers remained elusive. However, we’re going to look at what appears to be working, like a small unbelievable miracle. The story requires a tinge of history. History being extreme fatigue (I mean extreme), excessive sleep (10+ hours a night with supplemental 02 due to low oxygenation). I was constantly tired and rarely felt well. 

renew-iv nad therapy

(Ashley O’Connell, Owner/Founder)

Fast forward… I’ve been trying something new and (drumroll) I’m sleeping 6-7 hours a night (not always with oxygen!) AND I have energy during the day. Like, real, get things done, feel okay, kind of energy. I’m pretty sure this is how non-autoimmune people feel, possibly? Dare I say, I feel normal… even a bit spontaneous. I simultaneously feel calmer because the constant reminder of illness is no longer the lens I see the day through. 

What is it? I’m confident it’s the NAD+ (which is an iv) and injections I’ve been taking (along with iv vitamins, especially Vitamin B). I source fresh, high-quality compounded ingredients and source Vitamin C from tapioca instead of corn. I’m extra careful about ingredients and freshness, something I will never compromise on. We have a wonderful Medical Director who oversees the injections and infusions and amazing nurses who provide the services. If this resonates, Google NAD+ or reach out to our team anytime. 

Our COVID Story

My husband, Corin, and I contracted covid. We’re both vaccinated (him Pfizer, me J&J). Neither of us had the vaccine booster when we got sick. Here’s our story.

10/31: Corin felt like he had a cold. He did an at home rapid test. The result was negative.

11/2: Corin thought he might have pneumonia. His lungs were hurting. His second rapid test was negative.

11/3: We went to the doctor’s office to check for pneumonia. His lungs were clear. We ask the doctor to do another covid test. That afternoon we get the call, it’s covid. We immediately shut everything down and got the kids from school. We called everyone we’d been in contact with. Corin was now sleeping 18+ hours a day and feeling terrible. I took myself and our sons for PCR tests. **Corin was so disoriented that he hit a curb and damaged his car coming home from the doctor (first sign of brain fog issues).

11/4: Corin went down hard and was getting sicker by the day. He was waking up for food and home IVs but appeared disoriented and unable to perform small tasks (dropping things and losing his balance). He was becoming dehydrated with a worsening cough. I was checking his pulse ox while he slept – it was holding steady. My results came in- I was positive too.

11/5-7: I presented with a head cold and a minor sore throat – no other symptoms. My husband was much worse and I was very concerned about his “brain fog” symptoms. His pulse ox was in the 90s indicating the brain fog was likely coming from inflammation in his brain. He was getting worse and our doctor was concerned so he was admitted into the ER for a CT scan to rule out a stroke. While he was in the ER they gave him antibodies. The CT showed that he did not have signs of a stroke but he was still experiencing concerning symptoms.

The following weeks were a blur. Our nine year old eventually tested positive but he was asymptomatic. Quarantine felt like forever and I was secretly terrified for my Corin’s health but I was determined to do everything I could to keep him healthy.

“My husband regained all cognitive functioning before we were out of quarantine…”

You might be asking why this story is appearing in a Renew newsletter… I want to talk about NAD+. As you know, I’m a big fan of NAD+ and I get IVs and shots often. NAD+ reduces systemic inflammation and covid can cause inflammatory issues that lead to cytokine storms, loss of taste and smell, brain fog and much more. I went into my covid journey with plenty of NAD+ in my system. My husband didn’t.

I maintained my NAD+ regimen throughout having covid. When Corin was diagnosed he started NAD+ IVs and shots at home. He got an IV every other day with NAD+ and a Myers Cocktail. Corin regained all cognitive functioning before he was out of quarantine.

Covid is complicated and every person’s system is different. I believe that IV hydration with immune boosting vitamins and inflammation fighting NAD+ played a role in minimizing my symptoms and my husband’s quick recovery from brain fog issues. I’m beyond grateful we had access to hydration, nutrients and NAD+ through our covid journey.

Wishing you the best of health.

~ Ashley

Please note that we don’t offer medical advice at Renew and the above is my personal experience, not a medical claim.

Concierge IVs coming soon!

Our journey would have been much different without access to IVs. We have decided to offer concierge home services for IVs. We will be introducing the details in early January.

Therapeutic potential of boosting NAD+ in aging and age-related diseases

Abstract

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor in all living cells that is involved in fundamental biological processes. NAD+ depletion has been associated with hallmarks of aging and may underlie a wide-range of age-related diseases, such as metabolic disorders, cancer and neurodegenerative diseases. Emerging evidence implicates that elevation of NAD+ levels may slow or even reverse the aspects of aging and also delay the progression of age-related diseases. Here we discuss the roles of NAD+-synthesizing and -consuming enzymes in relationships to aging and major age-related diseases. Specifically, we highlight the contribution of NAD+ depletion to aging and evaluate how boosting NAD+ levels may emerge as a promising therapeutic strategy to counter aging-associated pathologies and/or accelerated aging.

1. Introduction

Nicotinamide adenine dinucleotide (NAD+) is an important cofactor in all living cells that is involved in fundamental biological processes, namely metabolism, cell signalling, gene expression, DNA repair, among others [1][2][3][4]. Originally, Harden and Young described NAD+ in 1906 as a molecular fraction (“cozymase”) that accelerated fermentation in yeast extracts. Over subsequent years, NAD+ was identified as a nucleoside sugar phosphate, which plays a role in redox reactions [5]. However, evidence stemming from recent studies have unveiled numerous roles of NAD+ metabolism on aging and longevity. In particular, an age-dependent decline in NAD+ levels have consistently been reported, possibly due to an imbalance in the synthesis and consumption of NAD+. Decreased levels of NAD+ are associated with the hallmarks of aging as well as several age-related diseases, including metabolic disorders, cancer and neurodegenerative diseases. Replenishment of NAD+ levels via administration of its precursors have been demonstrated to display beneficial effects against aging and age-related diseases. Importantly, boosting NAD+ levels have been shown to extend lifespan of various laboratory animal models including worms, flies, and rodents [3][5][6][7][8].

As a cofactor, NAD+ is found in abundance in the mitochondria, cytoplasm, and nucleus. It is essential for many cellular metabolism pathways that include: glycolysisfatty acid β-oxidation, and the tricarboxylic acid cycle. Whilst the reduced form of NAD+ (NADH) is a primary hydride donor in the production of ATP via anaerobic glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) [6][9]. On the other hand, NAD+ is consumed by the NAD+-dependent sirtuins and the DNA damage sensors poly (ADP-ribose) polymerases (PARPs) in the processes of protein deacetylation and poly-ADP-ribosylation (PARylation), respectively. In addition, NAD+ glycohydrolases (i.e. CD38 and CD157) also consume NAD+ via conversion of NAD+ into ADP-ribose (ADPR) or cyclic-ADPR [1][2][3]. Thus, the importance of NAD+ has expanded from a key element in intermediate metabolism to a critical regulator of multiple cell signalling pathways; and is now a major player contributing to aging and age-related diseases [6].

In mammals, NAD+ is synthetized from a variety of dietary sources, including NAD+ itself (it is metabolized in the gut, then synthesized again in cells) as well as from one or more of its major precursors that include: tryptophan (Trp), nicotinic acid (NA), nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and nicotinamide (NAM). Based upon the bioavailability of its precursors, there are three pathways for the synthesis of NAD+ in cells: (i) from Trp by the de novo biosynthesis pathway or kynurenine pathway; (ii) from NA in the Preiss–Handler pathway; and (iii) from NAM, NR, and NMN in the salvage pathway [5][6].

Accumulating evidence demonstrates an age-dependent decline in NAD+ levels and associate its depletion to several hallmarks of aging and age-related diseases (Fig. 1[6]. Here, we summarize the roles of NAD+-synthesizing and -consuming enzymes in aging and age-related diseases. Specifically, we highlight the contribution of NAD+ depletion to mammalian aging and evaluate how boosting endogenous NAD+ levels might emerge as a promising therapeutic strategy to counter aging-associated pathologies and/or accelerated aging.

Fig. 1. NAD+ decline at the core of hallmarks of aging. A schematic representation of age-dependent decline in NAD+ levels which contribute to ten hallmarks of aging, namely DNA damage, epigenetic alteration, deregulated nutrient-sensing, loss of proteostasis, altered cellular communication, cellular senescence, stem cell exhaustion, mitochondrial dysfunction, compromised autophagy, and possibly telomere attrition. Figure modified from Fang et al. 2017 [10].

2. Recent progress on the roles of NAD+ in aging

Mounting evidence has indicated that NAD+ levels decline with age in multiple types of tissues, which include the liver, skeletal muscle, adipose tissue, heart, brain, kidney, pancreas, lungs, spleen, skin, as well as extracellular fluids [3][10]. In addition, an age-dependent decline in NAD+ levels in Caenorhabditis elegans (C. elegans), mice, and human post-mortem tissues are reported. Thus, highlighting a universal age-dependent decrease of NAD+ across species. However, it remains elusive whether this is due to increased NAD+ consumption and/or decreased synthesis [6]. In this section, we provide an overview of methods that could potentially boost endogenous levels of NAD+.

2.1. NMN and aging

NMN is a physically stable natural compound that serves as an efficient NAD+ precursor. In mammals, NMN is synthesized from nicotinamide, a form of water-soluble vitamin B3 and 5′-phosphoribosyl-1-pyrophosphate (PRPP), by the rate-limiting enzyme, nicotinamide phosphoribosyl transferase (NAMPT). In addition, it can also be synthesized from NR via NR kinases (NRKs)-mediated phosphorylation reactions. NMN is subsequently converted into NAD+ by NMN adenylyl transferases (NMNATs) [5]. Over the years, it has become increasingly evident that systemic administration of NMN in rodents enhances the biosynthesis of NAD+ in various peripheral tissues including liver, pancreas, adipose tissue, heart, skeletal muscle, kidney, eyes, and blood vessels [5][6][11][12][13][14][15][16][17][18][19]. Furthermore, NMN has also been shown to elevate levels of NAD+ in hypothalamus and hippocampus following an intraperitoneal injection, thereby indicating its ability to penetrate the blood-brain barrier (BBB) [20][21]. More importantly, long-term (1-year) oral administration of NMN (up to 300 mg/kg) has recently been shown to be well tolerated without any obvious deleterious or toxic effects in normal wild type C57BL/6 mice [22].

NMN has been shown to have remarkable beneficial effects that counter normal aging. In models of aging, long-term administration of NMN protects against age-associated functional decline as demonstrated by increases in energy metabolism, insulin sensitivitylipid metabolism, mitochondrial oxidative metabolism, eye function, bone density and immune function [10][22]. On the other hand, it suppressed age-related changes in gene expression and adipose tissue inflammation [22]. Moreover, it has been shown to maintain neural stem/progenitor cell population and restore skeletal muscle mitochondrial function as well as arterial function in aged mice [15][19][20]. In addition, loss of enzymes involved in NAD+ synthesis, namely NAMPT during the process of aging, led to decrease in NAD+ content and reduced SIRT1 activity; consequently, promoted cellular senescence in retinal pigment epithelium, which performs numerous functions critical to retinal health and visual function [23].

NMN administration may counteract age-predisposed metabolic diseases and neurodegeneration. In age-related pathophysiological conditions, NMN ameliorated impairments in glucose tolerance and promoted insulin secretion/sensitivity in age- or diet-induced diabetic mice, Nampt+/− mice, as well in aged wild-type and β cell-specific Sirt1-overexpressing (BESTO) mice [5][6][11][24][25][26]. Likewise, promotion and overexpression of the mitochondrial Nmnat3 in mice, also involved in NAD+ biosynthesis, resulted in improved glucose tolerance during the process of aging as well as in models of high-fat induced obesity [27]. The beneficial effect was suggested to be a result of improved mitochondrial function and by an independent mechanism of NAD+–SIRT1–PGC1α axis, which despite previously being reported to contribute to improved mitochondrial function, was not activated in these transgenic mice despite elevated levels of NAD+ [27]. Furthermore, NMN protects the heart and brain from ischaemia-induced damage [28][29]. In rodent models of Alzheimer’s disease (AD), administration of NMN decreased AD-associated β-amyloid (Aβ) pathology and improved cognitive function. In addition, it restored mitochondrial function and ameliorated inflammation, synaptic loss as well as protected against neuronal cell death [30][31][32]. The beneficial effect of NMN was also evident in premature aging conditions as demonstrated by extended lifespan and improved healthspan in the C. elegans model of xeroderma pigmentosum group A (XPA, a nucleotide excision DNA repair (NER) disorder with severe neurodegeneration) [33], and Ataxia telangiectasia (A-T, due to mutation of ATM which encodes a master regulator of DNA damage response) [34][35]. Moreover, in mice with hypomorphic BubR1 (a mitotic check-point kinase) exhibited characteristics of premature aging as evidenced by shorter lifespan, which was restored by NMN supplementation [17]. Altogether, these findings highlight NMN induced restoration of NAD+ levels serve as beneficial therapeutic strategy in countering aging as well as age-related pathological conditions in animal models.

2.2. NR and aging

NR is a natural NAD+ precursor. It can directly be converted into NMN via the activity of NRKs, thereby bypassing the requirement of the NAMPT in the salvage pathway, and therefore offers to provide an additional pathway for elevation of NAD+ levels. Similar to NMN, NR also exhibited beneficial effects in protection against aging and age-related diseases. It has been shown to promote longevity as well improve healthspan in multiple laboratory animal models [36][37][38][39][40][41]. In age-related disease, in particular obesity, diabetes and cardiovascular conditions NR was able to decrease weight gain, improve glucose tolerance and increase survival rates, respectively in rodents [42][43][44]. In addition, in models of diabetes and high-fat diet, NR was able to improve metabolic function and reduce lipid accumulation as well as increasing lifespan [40][44][45][46]. Furthermore, supplementation of NR reversed the progressive wasting syndrome and restored endurance in Nampt skeletal muscle knockout micemdx model of Duchenne’s muscular dystrophy [47][48].

NR ameliorates neurodegeneration in animal models. In animal models of age-related neurodegenerative diseases such as AD and Parkinson’s disease (PD), NR has been shown to improve memory, learning, motor function and mitochondrial function as well as protected against neuronal cell death [49][50][51][52]. In particular, chronic NR administration in the amyloidogenic models of AD delayed the development and progression of Aβ pathology in AD mice, SH-SY5Y cells, and AD C. elegans [50][52]. In addition, it was able to promote longevity and inhibit/delay cognitive decline in AD C. elegans and mice, with the enhanced process of mitochondrial proteostasis and modulation of β-secretase 1 (BACE-1) activity via peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC)-1alpha highlighted as possible underlying mechanisms [50][52]. Further evidence reinforcing the beneficial effects of NR as a therapeutic strategy in AD was provided by a recent study using triple transgenic model of AD (3 × Tg), which exhibited not only reduced phosphorylated tau pathology and inhibited cognitive decline; but also, normalised AD-associated neuroinflammation and synaptic dysfunction. Moreover, DNA damage was reduced, in addition, following chronic administration of NR in a DNA repair-deficient 3 × Tg/Polβ +/− mouse model [6][51]. The underlying mechanism proposed was the reduction in DNA damage results in reduced activity of NAD+ consuming enzyme PARPs that is involved in DNA repair; thereby increase in the levels of NAD+, which in turn contributes to neurogenesis and inhibits AD-associated pathology, neuroinflammation and mitochondrial dysfunction [51]. Likewise, NR treated induced pluripotent stem cells (iPSCs) derived from PD patients harbouring mutations in the lysosomal enzyme β-Glucocerebrosidase (GBA) gene (GBA-PD), the most common genetic risk for PD, resulted in elevated levels of NAD+ and NAM which coincided with improved mitochondrial morphology and function [49][53]Mitophagy was suggested to be a possible mechanism promoted by NR, which may underlie improved mitochondrial quality control [49]. In addition, flies model of GBA-PD expressing human N370S GBA raised on food containing NR displayed improved motor function and significantly decline in loss of dopamine-containing neuronal population [49]. Additionally, NR has shown significant neuroprotection in a series of DNA repair-deficient premature aging diseases, including XPA, A-T, and Cockayne syndrome (CS, due to impairment of NER) [33][34][54].

2.3. NAM and aging

NAM is also a precursor for NAD+ and a key molecule involved in energy metabolism. Low doses of NAM have been shown to increase lifespan in yeast and C. elegans, however, higher doses have been associated with reduced lifespan via inhibition of Sir2 activity [39][55][56][57][58]. In models of aging and high fat diet-induced obesity, NAM improved healthspan although it failed to extend lifespan as illustrated by comparable mean and maximum lifespan [59]. In the model of obesity, it has able to restore glucagon storage to similar levels as age-matched standard-diet mice as well as ameliorate diet-induced hepatosteatosisoxidative stress and inflammation [59]. It was suggested that the beneficial impact of NAM may be attributes to improved mitochondrial function and countering age and high fat diet induced DNA damage [59]. Further evidence reinforcing the beneficial impact of NAM stemmed from a mouse model of glaucoma, which inhibited the development glaucoma in the eyes [60]. Moreover, these findings were replicated by Nmnat1 gene therapy whereby an intravitreal administration of adeno-associated virus AAV2.2 carrying a plasmid to overexpress murine Nmnat1 under a CMV promoter was performed in D2 eyes [60]. The improvement of mitochondrial health and metabolism was suggested to be the underlying mechanism for countering glaucoma mediated by NAM supplementation and Nmnat1 gene therapy [60].

3. Other approaches to regulate NAD+

3.1. PARP inhibition

The NAD+ consuming enzymes, PARPs, cleave NAD+ into NAM and ADP-ribose (ADPR), as a result generating a chain of ADPR. PARP1 is the most abundant PARPs, which is ubiquitously expressed and is a major consumer of NAD+ in response to DNA damage whereby it contributes to facilitation of the DNA repair process [61]. Both PARPs and sirtuins share NAD+ as a common substrate thus compete for its consumption. It has been reported that PARP1 activity increased with the inevitable process of aging possibly due accumulation of DNA damage [33]. Consequently, the NAD+ pool is depleted which results in reduced activity of sirtuins [62]. Evidence stemming from genetic deletion of PARP1 in mice as well as pharmacological inhibition of PARPs revealed increase in NAD+ content and enhanced activities of sirtuins, in particular SIRT1 and SIRT6 [33][34][39]. Elevated SIRT1 activity was associated with increased mitochondrial content and oxidative metabolism as well as protection against metabolic dysfunction, DNA damage, and neurodegeneration [4][10][62].

In addition, increased PARP1 activity has been reported in animal models of age-related neurodegenerative diseases, namely AD and PD [63][64][65]. Deletion of PARP1 in AD mice protected against cognitive decline as well as attenuated neuroinflammation and Aβ-induced neurotoxicity [66]. In PD rodents, PARP1 pharmacological inhibitors or deletion resulted in resistance to the toxic effects and loss of dopamine-containing neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA), respectively [67][68][69]. Thus, implicating the contribution of PARP1 hyperactivity in processes leading to neurodegeneration. Moreover, hyperactivity of PARP1 is reported in models of premature aging that resulted decrease in SIRT1 activity, a feature that was reversed by replenishment of NAD+ using its precursors [33][34]. Therefore, a potential therapeutic counter for depleted NAD+ pool in aging and age-related diseases could be inhibition of its consumer, PARPs, which will enable activity of sirtuins that plays a pivotal role in regulating cellular processes.

3.2. CD38 inhibition

CD38 is one of the primary NADases in mammals. It can modulate the levels of NAD+ via hydrolysis of NAD+ itself as well degradation of its precursors, NMN and NR. Primarily, CD38 hydrolyses NAD+ to produce of ADPR and NAM [70][71][72]. It is a key player in several physiological processes, including nuclear Ca2+ homoeostasis, immunity, inflammation, glucose and lipid homoeostasis, transferring of mitochondria from astrocytes to neurons, as well as social behaviour [6][73][74][75][76][77]. An age-dependent increase in levels of CD38 protein has been reported in multiple tissues and organs, which as a result contributes to NAD+ decline [78]. Therefore, CD38-dependent modulation of NAD+ can alter the activity of NAD+-consuming enzymes and affect cellular signalling and metabolism [71][72]. Inhibition of CD38 can also promote NAD+ levels and improve glucose and lipid metabolism, which protects against age- and diet-induced diabetes and obesity [72][75]. In APP/PS1 model of AD, CD38 depletion resulted in elevation of NAD+ levels that were associated with decrease in Aβ pathology and associated neuroinflammation accompanied by improvement spatial learning behaviour [79]. However, due to the reported important neuroprotective activities of CD38, further stringent and comprehensive evaluation of the procedures of CD38 inhibition as a safe anti-aging strategy [76][77].

3.3. NNMT knockdown

Nicotinamide N-methyltransferase (NNMT) catalyses the methylation of NAM N1-methyl-2- pyridone-5-carboxamide (2py) and N1-methyl-4-pyridone-3-carboxamide (4py) using the universal methyl donor S-adenosyl methionine (Met) (SAM). Both products of NAM methylation are eventually excreted in the urine; thus, NNMT removes NAM from the NAD+ biosynthesis pathway and thereby contributes to decrease in levels of NAD+ [80]. It is predominantly expressed in the liver and adipose tissue but is also found in other tissues including kidney, lung, muscle, heart, brain, and tumour cells. NNMT has been shown to be involved in various disease conditions such as metabolic disorders, neurodegenerative diseases and cancer [80]. In conditions such as obesity and diabetes, NNMT levels have been reported to be upregulated significantly, which in turn are associated with the disease phenotype [81][82]. In fact, genetic knockdown as well as pharmacological inhibition of NNMT was shown to be beneficial in protection against obesity in rodent models of obesity [83][84].

3.4. Genetic promotion of NAD+ biosynthesis

In addition to abovementioned techniques that have shown to enhance NAD+ biosynthesis, genetic tools in the form of Lactobacillus brevis (LbNOX), a water-forming NADH oxidase, has been demonstrated to also induce an increase in compartment-specific levels of NAD+/NADH ratio in HeLa cells [85]. It catalyses a four-electron reduction of oxygen to water (2 NADH + 2H+ + O2 → 2 NAD+ + 2 H2O) [85][86]. The NAD+/NADH ratio plays a role in cellular metabolism by affecting the activity of NAD+-dependent enzymes such as sirtuins. LbNOX was shown to ameliorate proliferative and metabolic defects induced by a dysfunctional electron transport chain (ETC) by recycling the pool of NAD+ [85]. This, therefore offers to be a novel approach whereby NAD+ levels could potentially be boosted via genetic manipulation in order to understand the fundamental molecular mechanisms in models of aging and age-related diseases.

4. Methods to detect subcellular NAD+

In view of the importance of NAD+ in life, aging, and diseases, it is necessary to accurately detect subcellular NAD+ levels to further unveil its intracellular functions as well as to develop sub-cellular organelle-targeted therapeutic approaches. Traditionally, several assays, such as high-performance liquid chromatography (HPLC)-based methods (e.g., HPLC/MALDI/MS) and fluorometric-based commercial kits have been utilised to detect whole NAD+ [26][48] at both cellular levels and/or sub-cellular levels (by isolating sub-cellular fractions ahead). There have some challenges of using these methods to accurately detect sub-cellular NAD+ levels because of the highly instability of NAD+ as well as impossibility of NAD+ detection in live cells/tissues. The recent development of genetically encoded fluorescent biosensors such as SoNar and a biosensor with a bipartite NAD+-binding domain have enabled imaging of relative levels of free NAD+ in the subcellular compartments [87][88]. Quantification of NAD+ using fluorescent biosensor targeted to different compartments of mammalian cells showed that mitochondria contain more than twice as much free NAD+ as other compartments [87]. Specifically, the concentration of NAD+ was reported to be approximately 110 μM in the cytoplasm and the nucleus relative to 230 μM in the mitochondrion [87]. These levels are consistent with other reports demonstrating that, in highly metabolically active, post mitotic cells, such as neurons, mitochondria have higher NAD+ levels compared with other sub-cellular compartments [1]. It was further demonstrated genetic and pharmacologic inhibition of NAMPT result in a reduction in NAD+ concentration in all compartments, but depletion of mitochondrial NAD+ occurred at a slower rate. Furthermore, the nuclear and cytoplasmic pools were shown to be readily exchangeable, whilst the mitochondrial pool may maintain mitochondrial NAD+ levels via NAD+ biogenesis by mitochondrial isoform NMNAT3 and import from the cytoplasm [87]. Another recent development has been offered in the form of NAD+ flux quantification that is isotope-tagged and used for analysis of NAD+ metabolism. It demonstrated that approximately 50% decrease in NAD+ consumption following treatment with SIRT1/2 and PARP1/2 inhibitors; thereby implicating both are major consumers of NAD+ [89]. The use of such approaches in models of aging and age-related diseases in combination with NAD+ promoting methods would allow the identification of subcellular localisation as well as consumption, which in turn would allow to identify the underlying molecular mechanisms and pathways attributed to NAD+ benefits.

5. Clinical translation

Encouraged by significant and replicable benefits of NAD+ precursors, NR and NMN, in aging and disease animal models, a series of clinical trials of NR and NMN in normal aged population and individuals with diseases have been performed [10]. NAD+ precursors, in particular NR has been demonstrated to elevate blood concentration of NAD+ in healthy individuals in a dose-dependent manner and without any toxic effects [90]. In particular, single oral self-administration of NR (1000 mg) over a period of seven days in a 52 years old male increased blood concentration of NAD+ by 2.7-folds and 45.5-fold increase in nicotinic acid adenine dinucleotide (NAAD), an NAD+ biosynthesis intermediate [90]. In addition, a randomized double-blind pharmacokinetic study of single oral administration NR (doses: 100 mg, 300 mg, and 1000 mg) with seven-days gap conducted in 12 healthy patients (aged 30–55 years old) revealed a dose-dependent increase in NAD+ and NAAD levels, with no reported adverse effects [90]. The encouraging results in animal models of aging and age-related diseases of chronic administration of NAD+ precursors have led to studies in humans [91][92]. An eight-week randomized, double-blinded, placebo-controlled study in 120 healthy adults (60–80 years old) demonstrated NR (250 mg and 500 mg) induced dose-dependent increase of blood NAD+ level that becomes apparent after 4-weeks and is sustained till the end of the study [91]. Importantly, no serious adverse effects were reported, thereby implicating the chronic administration of NR is a safe and effective way to increase NAD+ levels [91]. These findings are reinforced by a 2 × 6-week randomized, double-blind, placebo-controlled crossover clinical trial conducted in 55–79 years old individuals that showed NR (oral 500 mg, twice a day) to be well tolerated and able to effectively elevates NAD+ levels in healthy adults [92]. Moreover, it was able to reduce systolic blood pressure and aortic stiffness, which are considered measures of cardiovascular disease [92]. Thus, not only the NAD+ precursors are safely administrated but they may also recapitulate the beneficial effects that were evident in animal models, which is an exciting prospect for future clinical trials. However, in conditions such as pancreatic cancer, cell growth has been shown to be dependent of the NAD+ salvage pathway [93]. Hence, inhibition of NAD+ synthesis (via Nampt inhibition) and/or promotion of its consumption (via CD38 NADase) prevented cancer cell growth [93][94]. Therefore, implicating that there should be a thorough evaluation for the use of approaches that promote NAD+ biosynthesis as it may be contributor rather than a counter-mechanism in certain conditions. Clinical trials of NAD+ precursors on age-related diseases, such as diabetes, premature aging diseases, and neurodegenerative diseases are in progress [10].

6. Outstanding questions and future perspectives

Age is the primary cause of the majorly of human diseases and interventional strategies/therapeutics targeting on human aging is arguably the most efficient approach to achieve healthy aging and the improvement of the quality of life worldwide. Although, maintaining a healthy diet, fasting, and exercise may improve the quality of life, it may not be feasible option for all individuals. Therefore, the beneficial effects of NAD+ discussed in the present review, highlight possible ways for improving the quality of life via hindering numerous pathological hallmarks of aging and thereby improving the quality of life and delay age-related diseases (summarized in Fig. 2). Preclinical evidence of NAD+ replenishment that could potentially delay and/or prevent metabolic conditions, hearing loss, muscle atrophy, and cognitive decline are really encouraging for future perspectives. Moreover, NAD+ precursors, in particular NR has been shown to be safely administrated and also able to demonstrate improvement of cardiovascular functions in human. Thus, implicating a possible translational aspect of preclinical benefits of NAD+ supplementation, which is an exciting prospect and opens avenues for future studies to test the impact of elevated NAD+ biosynthesis in aging and age-associated diseases in human.

Fig. 2. Physiological and pharmacological strategies for boosting NAD+ levels. Inhibiting the age-related decline in NAD+ levels is critical for preventing age- or disease-related frailties. Physiological strategies that could potentially boost NAD+ levels include exercise, fasting, and maintaining a healthy diet. Pharmacologically, boosting NAD+ can be achieved via either supplementation of its precursors, NR and NMN, or inhibition of its consumers by use of CD38 and PARPs inhibitors. Figure modified from Fang et al. 2017 and Fivenson et al. 2017 [10][95].

Despite extensive research on NAD+ biosynthesis and its implications in health and disease, there are major questions that are yet to be explored. Firstly, what levels of NAD+ are to be associated with healthy aging and age-related diseases? In particular, it is of great relevance to elucidate organ and sub-cellular localisation as well levels of NAD+ in health and disease. Such observations would allow to map health- and disease-specific alterations of NAD+, which could be utilised to develop therapeutic interventions that promote NAD+ in a region-specific manner as a counter-mechanism. Decline in NAD+ has been implicated during the process of aging and age-associated diseases, thereby may be affect various processes that are likely to key contributors and drivers of associated dysfunction. Thus, preclinical studies driven towards unveiling the pathways and mechanisms underlying the beneficial effects of NAD+ replenishment in healthy aging and models of disease are required in order to understand how NAD+ contributes to delay and/or prevent hallmarks associated with aging. In particular, it is important to elucidate whether individual or multiple hallmark(s) mechanisms associated with aging are countered by NAD+ replenishment. This would allow understanding of the mode of NAD+ action and the interconnection and contribution of the various hallmarks of aging. NAD+ precursors have thus far shown to be safely and effectively administrated in healthy old humans, elevating NAD+ levels in blood, but its safety and tolerance is yet to be determined in individuals with age-related diseases. Therefore, future clinical trials are required to assess the safety of NAD+ precursors in patients with age-associated diseases such as diabetes and AD. Though, as abovementioned, careful evaluation of the role of NAD+, whether friend or foe in disease, must be taken into account for each disease-condition. Altogether, NAD+ replenishment may serve as a potential therapeutic strategy for aging and multiple conditions to improve the quality of life of the increasing aged population.

Conflicts of interest

The authors declare there is no conflict of interest.

Acknowledgements

This research was supported by the HELSE SøR-ØST (E.F.F., #2017056), The Research Council of Norway (E.F.F., #262175 and #277813), and two NIA Intra-laboratory grants (2016, 2017 to E.F.F. and V.A.B.). The E.F.F. laboratory has CRADA arrangements with ChromaDex. We thank Øystein Horgmo (Senior Photographer, Medical Photography and Illustration Service, UiO) for making some elements in Fig. 1Fig. 2.

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Originally published here: https://www.sciencedirect.com/science/article/pii/S2468501118300063