NMN – ALIVE BY NATURE – All about NAD+

Highlights

 NMN improved behavioral measures of cognitive impairments in AD-Tg mice.
 NMN decreased β-amyloid production, amyloid plaque burden, synaptic loss, and inflammatory responses in AD-Tg mice.
 NMN reduced JNK activation in AD-Tg mice.
 NMN regulated the expression of APP cleavage secretase in AD-Tg mice.

Abstract

Amyloid-β (Aβ) oligomers have been accepted as major neurotoxic agents in the therapy of Alzheimer’s disease (AD). It has been shown that the activity of nicotinamide adenine dinucleotide (NAD+) is related with the decline of Aβ toxicity in AD. Nicotinamide mononucleotide (NMN), the important precursor of NAD+, is produced during the reaction of nicotinamide phosphoribosyl transferase (Nampt). This study aimed to figure out the potential therapeutic effects of NMN and its underlying mechanisms in APPswe/PS1dE9 (AD-Tg) mice. We found that NMN gave rise to a substantial improvement in behavioral measures of cognitive impairments compared to control AD-Tg mice. In addition, NMN treatment significantly decreased β-amyloid production, amyloid plaque burden, synaptic loss, and inflammatory responses in transgenic animals. Mechanistically, NMN effectively controlled JNK activation. Furthermore, NMN potently progressed nonamyloidogenic amyloid precursor protein (APP) and suppressed amyloidogenic APP by mediating the expression of APP cleavage secretase in AD- Tg mice. Based on our findings, it was suggested that NMN substantially decreases multiple AD- associated pathological characteristically at least partially by the inhibition of JNK activation.

Introduction

As a chronic neurodegenerative disorder, Alzheimer’s disease (AD) is clinically featured by progressive pattern of cognitive deficits and memory impairment. Disturbed energy metabolism in the brain and oxidative stress are two potential factors leading to neural degeneration and cognitive impairments [1]. Aβ oligomers are found to be associated with the pathology of AD [2]. Recent studies indicates that Aβ oligomers inhibit synaptic transmission prior to neuronal cell death [3] and LTP (long-term potentiation), an experimental model for synaptic plasticity and memory [4]. In addition, Aβ oligomers are also found to be relevant to the producing of the free oxygen radical. So far, there is no curative treatment for AD [5]. Considering the varied and well-defined pathologies of AD, new therapies with the functions of reducing pathologies are needed to prevent or slow disease progression.

Nicotinamide adenine dinucleotide (NAD), oxidized (NAD+) or reduced (NADH), plays a key role in many metabolic reactions, for both forms of NAD regulate transfer of hydrogens metabolic reactions, oxidative or reductive [6], as well as mitochondrial morphological dynamics in brain [7]. Among these two forms, oxidized NAD is particularly important to mitochondrial enzyme reactions and cellular energy metabolism [8, 9]. In normal conditions, as people ages, the level of NAD+ drops [6], inhibiting cellular respiration and further causing decreased mitochondrial ATP and possibly cellular death. NAD+ serves a substrate for enzymes that depend on NAD+, such as ADP-ribosyl cyclase (CD38), poly(ADP-ribose) polymerase 1 (PARP1), and Sirtuin 1 (SIRT1) [10].

To treat neurodegenerative diseases, NAD+ depletion and cellular energy deficits need to be prevented for protecting nerves [10]. There are four pathways synthesizing NAD+ in mammals. The salvage pathway (primary route) way is to use nicotinamide, nicotinic acid, nicotinamide riboside, or the de novo pathway with tryptophan [11]. As an essential precursor of NAD+, Nicotinamide mononucleotide (NMN) is produced during the reaction of nicotinamide phosphoribosyltransferase (Nampt). Nampt is essential to regulating NAD+ synthesis [12], for it stimulates phosphoribosyl components to separate from phosphoribosyl pyrophosphates and to combine with nicotinamides. In this way, NMN is generated and with NMN adenylyltransferase, NMN is converted to NAD+. However, the potential therapeutic effects of NMN on AD remain unclear.

c-Jun N-terminal kinases (JNKs) are a family of protein kinases that play a central role in stress signaling pathways implicated in gene expression, neuronal plasticity, regeneration, cell death, and regulation of cellular senescence [13]. Activation of JNK has been identified as a key element responsible for the regulation of apoptosis signals and therefore, it is critical for pathological cell death associated with neurodegenerative diseases and, among them, with Alzheimer’s disease (AD) [14].

As suggested, NAD+ may be essential to brain metabolism and might influence memory and learning. According to recent studies, the stimulation of NAD level is relevant to the reduced amyloid toxicity in AD animal models [15]. Therefore, in this study, the potential therapeutic effects of NMN and the mechanisms of its action regulated in JNK in APPswe/PS1dE9 mice with AD were investigated.

Materials and Methods

Animals

The Institutional Animal Experiment Committee of Tongji University, China, approved all procedures conforming to the Animals’ Use and Care Policies. APPswe/PS1dE9 transgenic mice (6 months old) were purchased from Beijing Bio-technology, China. All animals were maintained in an environment that was pathogen-free. During the experimental period, water and food were accessible to all mice, and the body weight of mice and the intake of food and water were identified at the beginning of the study and then on a weekly basis. In addition, all mice that receive the treatment were observed for their general health. APPswe/PS1dE9 transgenic mice (AD-Tg) and their nontransgenic wild-type mice (NTG) were randomly assigned into four groups with six mice in each group, and each type was treated by NMN and vehicle, respectively Subcutaneous adiministration of NMN (100 mg/kg, Sigma N3501) in sterile (Phosphate Buffered Saline) PBS (200 μl) was applied to each mouse of NMN-treated groups every other day for 28 days. Each mouse with vehicle treatment subcutaneously received sterile PBS (200 μl) every other day for 28 days.

Behavioral Tests

Behavioral tests were carried out by 2 experimenters who were blinded to the treatments twelve weeks after the treatments.

Memory and spatial learning test

To evaluate the memory and spatial learning of all animals, a Morris water navigation task was performed as described previously [16]. Generally, a tracking system (Water 2020; HVS Image, Hampton, UK) was utilized to monitor the trajectory of all mice. During the training trials, a platform with the diameter of 5cm was hidden 1.5 cm below the surface of water and maintained at the same quadrant. In every trial, all mice had at most 1 minute to find the hidden platform and climb onto it. If one mouse cannot find the platform within 1 minute, the experimenters would manually guide the mouse to the platform and kept it there for 10 seconds. The trial was carried out 4 times daily for 6 days. The escape latency referring to the time that a mouse spent in finding the platform is considered as spatial learning score. Following the last training trial, the probe trial was carried out for spatial memories by allowing animals to take a free swim in the pool with the platform removed for 1 minute (swim speeds are equal). The time that each animal took to reach the previously platform-contained quadrant was measured for spatial memories.

Measurement of Passive Avoidance

To assess contextual memories, passive avoidance test was carried out, which was described in the previous studies [17]. Briefly speaking, a two-compartment apparatus with one brightly lit and one dimly lit was used. During the training trial, the animal was put into the light lit compartment. After 60 seconds, the door between the two compartments was opened. The acquisition latency refers to the first latency time of mice to ran into the dimly lit compartment. After coming into the lit compartment, mice were exposed to a mild foot shock (0.3mA) for 3 seconds with the door closed. After 5 seconds, the animals were taken out of the compartment. One day later after the acquisition trial, the mice underwent a retention test. Like in the acquisition test, the latency to go into the dark compartment without foot shock was regarded as retention latency to test retention memory. Longer latency indicates better retention.

Tissue Preparation

Following the two behavioral tests, 24 mice were first anesthetized and then infused with icy normal saline in a transcardial way. The brains were taken out and cut into 2 hemibrains along the midsagittal plane. One of the hemispheres was kept in PBS with 4% paraformaldehyde. Following the xylene treatment, the other fixed hemisphere was maintained in the paraffin for immunohistochemical tests. Then the cerebral cortex and the hippocampus were separated quickly from the hemisphere on the ice. For biochemical tests, they were maintained at −80°C following the separation. The hippocampus, brain cortex, and as well as the whole brain were weighed, respectively.

Immunohistochemistry

Immunohistochemical staining was carried out as described [16]. Briefly speaking, 10 μm brain slices were deparaffinized and rehydrated. To retrieve antigens, proteinase K (200μg/ml) was treated for the staining of Aβ, and sodium citrate (0.01M, pH 6.0) was for the staining of microglia and astrocyte. Sections were blocked through incubation with fetal bovine serum (2%) and Triton X-100 (0.1%) for nonspecific binding. For immunohistochemical analysis, the section was incubated at 4°C for a night with anti-Aβ1-16 monoclonal antibody (1:600; Cell Signaling Technology, Massachusetts, USA) and monoclonal antibody anti-Iba1 (1:1,000; Osaka Wako Pure Chemical Industries, Japan) for rabbits and also monoclonal anti-Aβ antibody (1:200; Billerica, MA) for mouse.

Olympus (Tokyo, Japan) microscope with a connection to a digital microscope camera was applied to capture the images for quantitative analyses. The plaques in μm2s and the proportion of area kept by plaques positive to Aβ1–16 respectively, microglia positive to Iba1 were obtained with imaging software (Bethesda Media Cybernetics, MD). The mean value of every parameter was obtained from 6 sections with an equidistant interval of 150μm through the hippocampal region of each mouse in all groups. All measurements were blindedly conducted.

Enzyme-Linked Immunosorbent Assay (ELISA)

As described before, soluble Aβ fractions and insoluble ones were obtained from both the cortex and hippocampi of brain homogenates of mouse using RIPA (Radioimmunoprecipitation assay buffer) buffer and formic acid, respectively [18]. The levels of both the insoluble and soluble Aβ were identified using the ELISA kits (Camarillo Invitrogen, CA). Besides, concentrations of oligomeric Aβ of brain homogenates treated with RIPA were obtained employing an ELISA kit for amyloid β oligomer (Gunma Immuno-Biochemical Laboratories, Japan).

Proinflammatory Cytokines Measurement

As described, mouse brain proinflammatory cytokine was evaluated [19]. The expressions of TNFα, IL-6, and IL-1β were identified with immunoassay kits (Minneapolis R&D Systems, Minnesota, USA) which is for measuring these factors in mouse.

Western blotting (WB) analysis

The cortex and hippocampus tissue was homogenized with icy PBS and the lysate was for Western blot. At first SDS-PAGE (Sodium Dodecyl Sulfate Polyacrylamide Gel Electrophoresis) was applied to divide the proteins on NuPage Bis-Tris gel (12%, Invitrogen). The separated protein was subsequently transferred to nitrocellulose membrane which was blocked with 5% nonfat milk and probed overnight at 4°C with anti-p-JNK, anti-JNK, anti-APP, anti-sAPPα, anti- sAPPβ, anti-phosphorylated APP (p-APP, Thr668), anti-ADAM10, anti-BACE1 (CA Santa

Cruz Biotechnology, USA), anti-CDK5, anti–p-CDK5, anti–p-GSK3β, anti-GSK3β, anti-SYP, anti–postsynaptic density-95, anti–β-actin Abcam (Cambridge, MA, USA). The membrane was cleaned with TBS/0.05% Tween-20 and incubated at room temperature with secondary antibodies conjugated with horseradish peroxidase for 60 minutes, following incubation with primary antibodies. Enhanced chemiluminescence reagents (Pierce, Rockford, IL, USA) were used for detecting signals.

Statistical Analysis

The data were expressed as mean ± SD. The comparisons in the speed of swimming and escape latency between the groups during the test of memory and spatial learning were made employing two-way ANOVA with repeated measures. Next, post hoc least significant difference (LSD) test was used for multiple comparison. Before post hoc LSD test or Student t test, 1-way ANOVA was employed for the rest data. Statistical analyses were carried out with Prism version 5. A P < 0.05 was considered statistically significant.

Results

NMN Treatment Rescues Cognitive impairments in AD-Tg Mice

The test of memory and spatial learning has shown that 1-year-old AD-Tg mice have experienced impairment in memory and spatial learning [16]. In our study, comparied to the vehicle-/NMN-treated wild-type (WT) mice, the vehicle-treated AD-Tg mice had a longer escape latency, which showed severe impairment of spatial learning in the test (Fig. 1A). However, with shorter escape latency, NMN treatment greatly improved the impairment of spatial learning in vehicle-treated AD-Tg animals (Fig. 1A). Besides, it was also identified that compared with two wild-type groups, vehicle-treated AD-Tg animals spent less time in the target quadrant during the probe trial (p < 0.01), suggesting severe spatial memory impairment. AD-Tg mice treated with NMN spent longer time in the target quadrant, which indicates marked alleviation of the spatial learning impairments present in AD-Tg mice treated with vehicle (p<0.01) (Fig. 1B).

To further identify the alleviation of memory deficits by NMN treatment in AD-Tg mouse, contextual memories were evaluated employing the measurement of passive avoidance [17]. As illustrated in Fig. 1C, retention latency was decreased compared with two wild-type mice groups (p < 0.01), suggesting impaired contextual memories in the AD-Tg animals treated by vehicle. In contrast, NMN-treated mice exhibited longer retention latency compared with those treated with vehicles (p < 0.01), demonstrating outstanding reversal of NMN in contextual memories. All these data indicate that NMN treatment markedly improves cognitive impairments in AD-Tg animals.

NMN Suppresses JNK Phosphorylation in AD-Tg Mice

JNK, also called a protein kinase activated by stress, is said to play a role in a couple of pathophysiological processes in AD [13]. Therefore, in this study, we tested the inhibitory effects of NMN on the activation of JNK through Western blotting. It was revealed by quantitative analysis that p-JNK level was significantly grown in hippocampus and cerebral cortex in the vehicle-treated AD-Tg mice when contrasting to two wild-type groups (Fig. 2A; p < 0.01), whereas NMN gave rise to a sharp decline in p-JNK in hippocampus and cerebral cortex with a comparison to the vehicle-treated AD-Tg mice (Fig. 2B; P< 0.01). Both reductions symbolized a reverse to the wild-type level. But the whole expression of JNK kept unchanged in all the 4 groups. Conclusively, all data indicate that NMN treatment has an inhibitory effects on JNK activation in AD-Tg mice.

NMN Treatment Decreases the Level of Aβ and Deposition in AD-Tg Mice

The role of reduced activation of JNK in the changes of the Aβ level and deposition was studied in AD-Tg mice through employing histological and biochemical analyses. As presented in Figs. 3A-D, it was found that NMN-treated AD-Tg mice had a sharp reduction in the levels of Aβ when comparing to the vehicle treatment group (p < 0.01). Comparing to the vehicle treatment group, NMN treatment gave rise to a marked decrease in Aβ oligomers (p < 0.01) (Fig. 3E). Immunohistochemical staining identified this observation, indicating the lessened diffuse plaques and also the shrinked area taken by diffuse plaques in AD-Tg mice treated by NMN compared to the vehicle treatment group (Figs. 4A-D). Thus, on the basis of the findings, it was demonstrated that the generation of Aβ in the brain of AD-Tg mice is effectively decreased by the inhibited activation of JNK with NMN treatment.

NMN Treatment Changes the Processing of APP in AD-Tg Mice

To study the mechanism of inhibition on the production of Aβ and deposition, the effects of NMN on the processing of APP were examined by Western blotting. As presented in Figs. 5A-C, the level of full-length APP expression was greatly increased in the brain of AD-Tg mouse treated with vehicle compared with wild-type ones (p < 0.01). However, they kept unaltered between the group treated with vehicle and that with NMN. Importantly, it was found that NMN treatment remarkably lowered the increased levels of p-APP in the AD-Tg mice treated by vehicle (p < 0.01). Besides, α-secretase cleaved sAPPα and β-secretase cleaved sAPPβ in the brain tissues of Tg mice were tested via Western blotting. It was shown by quantitative analyses that NMN treatment led to a remarkable elevation of sAPPα (p < 0.01) and a marked decline in sAPPβ (p < 0.01) compared with the transgenic mice treated by vehicle (Figs. 5D-F). Based on these data, it was indicated that NMN treatment is strongly effective in suppressing the phosphorylation of APP, improving cleaving of APP by α-secretase, and decreasing the cleaving of APP by β-secretase in AD-Tg mice brains.

NMN Treatment Improves Inflammatory Responses in AD-Tg Mice

Since JNK activation is indicated to play a role in the inflammatory response induced by Aβ in previous studies [20], whether reduced activation of JNK influences neural inflammation in AD- Tg animals was investigated. The role of NMN on the neural inflammation was identified by measuring proinflammatory cytokines that were in the lysates of cortical tissues. It was found that the level of IL-6, IL-1β, and TNFα were sharply declined in the AD-Tg mice treated by NMN relative to those by vehicle (Figs. 6A-C). According to these findings, NMN treatment is indicated to be potently effective in the amelioration of neural inflammation in AD-Tg mice brains.

NMN Treatment Ameliorates Synaptic Loss in AD-Tg Mice

The loss of synapse is an important pathological characteristic of AD and said to be relevant to the cognitive impairments of AD [21]. The changes in SYP (presynaptic marker) level and PSD- 95 level (postsynaptic marker) were investigated via Western blotting. It was showed by quantitative analysis that SYP levels and the levels of PSD-95 expression substantially reduced in hippocampus and brain cortex of AD-Tg mice treated with vehicle relative to WT ones

(p < 0.01), whereas NMN treatment significantly elevated SYP levels and the levels of PSD-95 expression in hippocampus and brain cortex relative to AD-Tg mice treated with vehicle (p < 0.01) (Fig. 6D-F). This finding suggest that NMN treatment sharply ameliorates the loss of synapse in AD-Tg mice brains.

Discussion

In the present study, it is mainly found that NMN treatment substantially improves primary pathological characteristics of the AD-modeled AD-Tg mice, including cognitive impairments, neuroinflammation, Aβ pathology, and synaptic loss, which consistent with a recent study [22]. It was also found that NMN treatment inhibited JNK activation and amyloidogenic processing of APP by mediating the expression of APP-cleavage secretase, and also facilitated APP processing in AD-Tg mice. The data prove that NMN treatment greatly reduces multiple AD-associated pathological characteristics, at least partially by the inhibition of JNK activation.

Numerous studies have reported the increase of abnormal activation of JNK in both the transgenic AD mice models and the AD patients [23-25]. Conforming to the above previous studies, we also found that the level of phosphorylated JNK in AD-Tg mice treated by vehicle was higher than that in the wild-type group, but NMN treatment in AD-Tg mice potently suppressed the phosphorylation of JNK to the basic level of WT groups. The controlled activation of JNK through NMN gave rise to a substantial decrease of Aβ pathology in AD-Tg animals. According to the studies before, active JNK is proved to engage in BACE1 expressions and PS1 expressions [26, 27]. In addition, the increased BACE1 and PS1 in AD-Tg mice treated by vehicle were found to be greatly suppressed by NMN to the basic level of WT groups (data not shown). More interestingly, it was also observed that NMN treatment led to substantially elevated sAPPα and reduced sAPPβ. It was notable that according to the previous studies, APP phosphorylation at the site of Thr668 is proved to promote the β-secretase cleavage of APP to grow Aβ generation in vitro [28]. In present study, we also found that the administration of NMN in AD-Tg mice significantly declined the elevated phosphorylation of APP to the primary level of WT controls, indicating an in vivo inhibition mechanism of Aβ pathology through NMN treatment. Collectively, all these findings indicate that the potent effects of NMN on the marked decrease in Aβ pathology in the brains of AD-Tg mice may be responsible for its enhancement of nonamyloidogenic APP processing. What we found is consistent to a recent study demonstrating that genetic depletion of JNK3 in 5XFAD mice is attributed to a significant decrease in the levels of Aβ and the total plaque loads [29]. Recently numerous studies suggested energy failure and accumulative intracellular waste also play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer’s disease (AD) in particular regulated by potential role of several metabolic pathways Wnt signaling, 5′ adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co- activator 1-α (PGC-1α) [30, 31]. It will be warrant to study if NMN also participate in regulation of these signaling pathways.

Some recent studies indicate that enhanced neuroinflammation is essential to the development of AD [32-34]. In our study, a marked decline in the proinflammatory cytokines levels (IL-6, IL-1β, and TNFα) proved that NMN treatment effectively controlled the neuroinflammatory responses of the brain of AD-Tg mouse. Considering the key role of oligomeric and fibrillar Aβ for activation of microglia cells and astrocytes with the subsequent generation of proinflammatory cytokines [34], the reduction in neuroinflammatory responses may be less important to the substantial reduction in Aβ pathologies presented in the AD-Tg mice treated by NMN. Several previous studies had proved that JNK represents an important mediator for activation of glial cell and proinflammatory cytokines [35, 36]. Thus, the favorable effects of NMN on lowered inflammatory responses in AD-Tg groups can be largely responsible for its direct control of inflammation by inhibiting JNK activation. Based on the previous reports, it was proved that some proinflammatory cytokines (ie, IL-1β, interferon gamma, and TNFα) may elevate the expression of β-secretase and γ-secretase to ameliorate amyloidogenic APP processing and Amyloid-β production by an in vitro JNK-mediated pathway [33]. Hence, we have reasons to believe that the reduced proinflammatory cytokines through NMN treatment may be effective in reducing the production of Aβ in vivo. Moreover, in our study, it was demonstrated that NMN treatment ameliorates cognitive impairments in AD-Tg mouse models. An increasing evidence has proved that grown Aβ levels, neuroinflammation, synaptic dysfunction and loss are closely related to the cognitive dysfunction in AD [37]. In addition, our data confirms the finding of a recent research, which revealed that genetic down-regulation of JNK3 gives rise to a remarkable amelioration of cognitive impairments in 5XFAD mice [29]. Collectively, our findings, along with all the previous research, demonstrate that the inhibited JNK activaty by NMN is potently effective in ameliorating AD-associated cognitive deficits.

Synaptic loss is a major pathological change of AD and is tightly associated with AD-related cognitive impairments [37]. It was presented that PSD-95, a biomarker of postsynaptic density, is essential to synapse maturation and synaptic plasticity [38], and that SYP, a presynaptic protein, also acts as an integral membrane protein in the synapse and it plays a key role in plasticity of synapses [39]. Therefore, it can be soundly supposed that the greatly lowered expression of PSD- 95 and SYN presented in the study may suggest the impairment of synaptic integrity and plasticity in AD-Tg mice treated by vehicle. Intriguingly, the treatment of NMN in AD-Tg animals substantially elevated the lowered PSD-95 and SYN expression level back to the primary level of WT controls. Since it was demonstrated by several studies that Amyloid-β- induced synaptic loss and dysfunction are regulated through the JNK activation [40, 41], the possible mechanisms behind NMN treatment leading to the elevated expression of PSD-95 and SYN in AD-Tg animals may be responsible for its inhibitory effects on JNK activation. Thus, it is possible that the treatment of NMN may ameliorate the impaired synaptic plasticity which is caused by toxic Aβ species in AD-Tg mice.

In summary, this study provides essential preclinical evidences that NMN takes effects in reversing cognitive deficits and substantially lowering the burden of amyloid plaque, neuroinflammation, cerebral amyloid-β concentrations, and loss of synapse in middle-aged AD- Tg mice, at least partially by the inhibition of JNK activation. According to our findings, NMN could be a new target for disease-modifying treatments of AD.

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22 Best Anti-Aging Supplements

Geroprotectors are substances that support healthy aging, slow aging, or extend healthy life. Sometimes people refer to them as “aging suppressants,” “anti-aging drugs,” “gerosuppressants,” “longevity therapeutics,” “senolytics,” or “senotherapeutics.” They include various foods, nutraceuticals (supplements), and pharmaceuticals (drugs). Unfortunately none comes close to realizing the age-old aspiration of ending aging altogether (yet), but some may make a practical difference for many people.

I’ve used several geroprotectors for years. And I’m exploring ways to incorporate others into my diet, if they’re applicable to my personal situation and meet a few general criteria:

First, I look for geroprotectors supported by multiple studies on humans – not just anecdotal evidence, one study, or studies on non-human animals. Although I’ve nothing against the health benefits of placebo, I prefer knowing that something more than only placebo is at work.

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Based on those criteria, I’ve compiled a list of top tier natural geroprotectors. These are, to the best of my knowledge, the most well-researched and effective geroprotectors available in the United States without a prescription. I’ve excluded from this list any geroprotectors that are primarily nootropic geroprotectors (such as ginkgo and melatonin), which you can find in my list of top tier nootropics. This information is for educational purposes only. It is not medical advice. Please consult a physician before and during use of these and other geroprotectors.

1) Berberine

Barberry

Berberine is a compound of extracts from herbs such as barberry. Supplementation may provide a strong decrease to blood glucose, and a notable decrease to total cholesterol, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Berberine may also provide a subtle increase to HDL-C; and a subtle decrease to insulin, LDL-C, and triglycerides. Evidence for these effects may not be as reliable. See the Berberine article for more studies and details.

2) Blueberry

Blueberry

Blueberry is the fruit of a perennial flowering plant native to North America. Supplementation may provide a notable decrease to DNA damage, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

See the Blueberry article at Examine.com for more studies and details.

3) Boswellia Serrata (Frankincense)

Frankincense

Boswellia Serrata is a plant native to India and Pakistan. Supplementation may provide notable support for long-term joint function, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

See the Boswellia Serrata article at Examine.com for more studies and details.

4) Cocoa

Cocoa

Cocoa comes from the seeds of evergreen trees native to tropical regions of Central and South America. Supplementation may provide a notable increase to blood flow, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Cocoa may also provide a subtle increase to insulin sensitivity, and photoprotection; and a subtle decrease to general oxidation, platelet aggregation, and LDL-C. Evidence for these effects may not be as reliable.

5) Coenzyme Q10

Coenzyme Q10

Coenzyme Q10 is a molecule found in the mitochondria of humans and other organisms. Supplementation may provide a notable decrease to lipid peroxidation, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Coenzyme Q10 may also provide a subtle increase to blood flow, endothelial function, and exercise capacity; and a subtle decrease to blood pressure, exercise-induced oxidation, and general oxidation. Evidence for these effects may not be as reliable. See the Coenzyme Q10 article at Examine.com for more studies and details.

6) Creatine

Creatine

Creatine is a nitrogenous organic acid that occurs naturally in vertebrates. Supplementation may provide a strong increase to power output and a notable increase to hydration, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Creatine may also provide a subtle increase to anaerobic running capacity, lean mass, bone mineral density, muscular endurance, testosterone, VO2 max, and glycogen resynthesis; and a subtle decrease to blood glucose, lipid peroxidation, and muscle damage. Evidence for these effects may not be as reliable. See the Creatine article at Examine.com for more studies and details.

7) Curcumin

Turmeric

Curcumin is the bioactive in Turmeric, which is a perennial plant native to Southern Asia. Supplementation may provide a notable increase to antioxidant enzyme profile and a notable decrease to inflammation and pain, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Curcumin may also provide a subtle increase to HDL-C, and functionality in the elderly or injured; a subtle decrease to blood pressure, general oxidation, lipid peroxidation, and triglycerides; and subtle support for long-term joint function. Evidence for these effects may not be as reliable. See the Curcumin article for more studies and details.

8) DHEA (Dehydroepiandrosterone)

DHEA

DHEA is a natural hormone in humans and other animals. Supplementation may provide a notable increase to estrogen or testosterone (depending on the need of the body), according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

See the Dehydroepiandrosterone article at Examine.com for more studies and details.

9) Fish Oil

Fish

Fish Oil, as the name suggests, is an oil that accumulates in the tissues of some fish species. Supplementation may provide a strong decrease to triglycerides, thereby supporting a healthy cardiovascular system, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Fish Oil may also provide a subtle increase HDL-C, endothelial function, and photoprotection; and a subtle decrease to blood pressure, inflammation, natural killer cell activity, platelet aggregation, and LDL-C. Evidence for these effects may not be as reliable. See the Fish Oil article at Examine.com for more studies and details.

10) Garlic

Garlic

Garlic is a bulbous plant native to Central Asia. Supplementation may provide a notable increase to HDL-C and a notable decrease to LDL-C, total cholesterol, and blood pressure, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Garlic may also provide a subtle decrease to triglycerides and a strong decrease to rate of sickness. Evidence for these effects may not be as reliable. See the Garlic article at Examine.com for more studies and details.

11) Horse Chestnut (Aesculus Hippocastanum)

Horse Chestnut

Horse Chestnut is a deciduous flowering tree native to South East Europe. Supplementation may provide notable support to long-term circulatory function, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Horse Chestnut may also provide a subtle decrease to pain. Evidence for this effect may not be as reliable. See the Horse Chestnut article at Examine.com for more studies and details.

12) Magnesium

Magnesium

Magnesium is an essential dietary mineral found in food like nuts, cereals, and vegetables. Supplementation may provide a notable decrease to blood pressure (only in cases of high blood pressure), according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Effect of magnesium supplementation on blood pressure: a meta-analysis. In 2012, this meta-analysis found that Magnesium “appears to achieve a small but clinically significant reduction in [blood pressure]”.
Oral Magnesium Supplementation Reduces Insulin Resistance In Non-diabetic Subjects – A Double-blind, Placebo-controlled, Randomized Trial. In 2011, this study found that Magnesium “improves insulin sensitivity even in normomagnesemic, overweight, non-diabetic subjects “, but “blood pressure and lipid profile did not show significant changes”.
Oral Magnesium Supplementation Reduces Ambulatory Blood Pressure In Patients With Mild Hypertension. In 2009, this study found that Magnesium “is associated with small but consistent ambulatory [blood pressure] reduction in patients with mild hypertension”.
Effects Of Oral Magnesium Supplementation On Insulin Sensitivity And Blood Pressure In Normo-magnesemic Nondiabetic Overweight Korean Adults. In 2009, this study found that Magnesium “does not reduce [blood pressure] and enhance insulin sensitivity in normo-magnesemic nondiabetic overweight people … however, it appears that magnesium supplementation may lower [blood pressure] in healthy adults with higher [blood pressure]”.
The Effect Of Lowering Blood Pressure By Magnesium Supplementation In Diabetic Hypertensive Adults With Low Serum Magnesium Levels: A Randomized, Double-blind, Placebo-controlled Clinical Trial. In 2009, this study found that Magnesium “significantly reduces [systolic blood pressure] and [diastolic blood pressure] in diabetic hypertensive adults with hypomagnesaemia”.

Supplementation with Magnesium may also provide a subtle increase to insulin sensitivity, aerobic exercise, and muscle oxygenation; and a subtle decrease to blood glucose, and insulin. Evidence for these effects may not be as reliable. See the Magnesium article at Examine.com for more studies and details. also check out my article on Magnesium Glycinate supplementation. Magnesium is an ingredient in Thrivous Serenity.

13) Nitrate

Beetroot

Nitrate is a molecule produced in the body in small amounts and available in vegetables like beetroot. Supplementation may provide a notable decrease to blood pressure, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Nitrate may also provide a notable increase to anaerobic running capacity; and a notable decrease to oxygenation cost of exercise. Evidence for these effects may not be as reliable.

14) Olive Leaf

Olive Leaf

Olive Leaf comes from an evergreen tree native to the Mediterranean, Africa, and Asia. Supplementation may provide a notable decrease to blood pressure and oxidation of LDL, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Olive Leaf may also provide a subtle increase to HDL-C; and a subtle decrease to LDL-C, total cholesterol, cell adhesion factors, and DNA damage. Evidence for these effects may not be as reliable. See the Olive Leaf Extract article at Examine.com for more studies and details.

15) Pycnogenol (Pine Bark)

Maritime Pine

Pycnogenol is an extract from bark of the maritime pine, native to the Mediterranean. Supplementation may provide a notable increase to blood flow, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Pycnogenol may also provide a subtle decrease to leg swelling; and subtle support for long-term joint function. Evidence for these effects may not be as reliable. See the Pycnogenol article at Examine.com for more studies and details.

16) Salacia Reticulata

Salacia Reticulata

[“Kothala Himbutu” by Satheesan.vn under CC BY-SA 3.0 / cropped]

Salacia Reticulata is a plant native to the forests of Sri Lanka. Supplementation may provide a notable decrease to blood glucose and insulin, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

See the Salacia Reticulata article at Examine.com for more studies and details.

17) SAMe (S-Adenosyl Methionine)

SAMe

SAMe is a naturally-occurring compound found in most tissues and fluids of the human body. Supplementation may provide notable support for long-term joint function, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with SAMe may also provide a subtle increase to functionality in elderly or injured; and a notable decrease to pain. Evidence for these effects may not be as reliable. See the S-Adenosyl Methionine article at Examine.com for more studies and details.

18) Spirulina

Spirulina

[“Spirulina” by Lara Torvi under CC BY 2.0 / cropped]

Spirulina is a blue-green algae. Supplementation may provide a notable decrease to lipid peroxidation and triglycerides, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Spirulina may also provide a strong decrease to allergies, nasal congestion, and liver fat; a notable increase to power output; a notable decrease to blood pressure and general oxidation; a subtle increase to HDL-C and muscular endurance; and a subtle decrease to LDL-C and total cholesterol. Evidence for these effects may not be as reliable. See the Spirulina article at Examine.com for more studies and details.

19) TUDCA (Tauroursodeoxycholic Acid)

TUDCA

TUDCA is a bile acid found naturally in trace amounts in humans and in large amounts in other animals like bears. Supplementation may provide a notable decrease to liver enzymes, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with TUDCA may also provide a notable increase to insulin sensitivity. Evidence for this effect may not be as reliable. See the Tauroursodeoxycholic Acid article at Examine.com for more studies and details.

20) Vitamin B3 (Niacin)

Niacin

Vitamin B3, also known as Niacin, is an essential dietary vitamin found in foods like liver, chicken, beef, fish, peanuts, cereals, and legumes. Supplementation may provide a strong increase to HDL-C and a notable decrease to LDL-C and triglycerides, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Vitamin B3 may also provide a subtle increase to blood glucose and insulin; and a subtle decrease to insulin sensitivity and vLDL-C. Evidence for some of these effects may not be as reliable. See the Vitamin B3 article at Examine.com for more studies and details.

21) Vitamin D

Vitamin D3

Vitamin D is an essential dietary vitamin naturally synthesized in the skin from sun exposure. Supplementation may provide a notable decrease to risk of falls, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Vitamin D may also provide a notable increase to functionality in elderly or injured; and a subtle decrease to blood pressure, bone fracture risk, and fat mass. Evidence for some of these effects may not be as reliable. See the Vitamin D article at Examine.com for more studies and details.

22) Vitamin K

Vitamin K1

Vitamin K is an essential dietary vitamin found in foods like leafy green vegetables and some fruits. Supplementation may provide a notable increase to bone mineral density, according to multiple peer-reviewed, double-blind, placebo-controlled studies in humans:

Supplementation with Vitamin K may also provide a notable decrease to bone fracture risk. Evidence for this effect may not be as reliable. See the Vitamin K article at Examine.com for more studies and details.

The post Best Anti-aging supplements other than NR and NMN appeared first on Alivebynature - Evidence Based Reviews.

DO NOT TAKE MORE THAN ONE CAPSULE ON YOUR FIRST EXPERIENCE WITH NMN PLUS!

We include a very small dose of Niacin in the formula for NMN PLUS.

NIACIN is well known to cause an uncomfortable “Niacin Flush“ in some people.

We used a dosage that is about 1/2 of what research shows affects less than 1% of users. Read more about this, and what you can do to minimize niacin flush.

In addition to dosage, avoid taking NMN PLUS on an empty stomach to further minimize the chance you might experience a flush.

After the first trial or 2, you can increase to 2 capsules at a time if you desire.

Tolerance to Niacin Flush builds up rapidly. The few people that do experience it find it diminishes and no longer occurs after 4-7 days of continued use with a particular dosage, and can be increased further.

For those that want ONLY NMN, we offer NMN PURE, which contains 125 mg of NMN per capsule and nothing else, but that product will not be available to ship until Dec 8, 2017.

Time of Day

Humans have a natural Circadian rhythm with a peak NAD+ levels around Noon, and a second, smaller peak in the middle of the night.

It is not yet known if supplementing with 2 doses to emulate the 2 natural peaks is beneficial, or, just one peak in the middle of the day. Experts such as Dr Brenner, Dr Sinclair, and others are on both sides of this issue.

If you chose to take NMN Plus twice a day, we recommend:

1 Capsule between 8-10am
1 Capsule before bedtime

If you chose to take NMN Plus once per day, we recommend

1 Capsule between 8-10 am, until you are sure you don’t experience Niacin Flush

after acclimated for a few days

2 Capsules between 8-10 am

INGREDIENTS in NMN PLUS

In addition to NMN, which is the IMMEDIATE PRECURSOR used by our bodies to produce NAD+, we include the other 3 major precursors:

NAM (Nicotinamide)
Tryptophan
NA (Niacin)

Obviously, it would be easier to produce only the single ingredient NMN PURE, but we are so convinced the proven NAD+ boosting ability of the secondary precursors make this product more effective, we have gone many months of research, development, and testing, in addition to the expense, to offer this Complete NAD+ Booster.

to read more about NMN and other NAD+ precursors Click here

to read more about NAD+ Click here

NMN PLUS – THE COMPLETE NAD+ BOOSTER

$46.95

Unlike NR, NMN makes it’s way INTACT through the liver quickly and remains available in the bloodstream for many hours (18,97,98,99)

NMN is the Immediate Precursor to NAD+.

NMN is quickly metabolized into tissues throughout the body, where it bypasses the NAMPT bottleneck and restores NAD+ levels in tissues more effectively than other NAD+ precursors.

Read about the science behind NMN.

OTHER PRECURSORS – MAKING NMN EVEN MORE EFFECTIVE

Boosting NAD+ in the liver is great, but is a small part of the health benefits you get from restoring NAD+ thoughout the body.

All the precursors are effective at boosting NAD+ in the liver, so why waste NMN on that simple task?

Niacin (NA) is the fastest, elevating NAD+ to peak levels in liver in 15 minutes (R)
Tryptophan is the preferable substrate for NAD+ production in the liver(R)
Administration of tryptophan, NA, or NAM to rats showed that tryptophan resulted in the highest hepatic NAD+ concentrations(R)

Including Niacin and Tryptophan help elevate NAD+ levels in the liver to their maximum quickly, sparing NMN to be released into the bloodstream and make its way into tissues throughout the body much more effectively.

Like NR, NAM is also very slow acting, taking 8 hours to reach peak NAD+ levels in the liver when used by itself (16).

We include NAM in NMN Plus to act as a slow release NAD+ booster to ensure levels stay high, and potentially sparing NMN from being utilized for NAD+ metabolism in the liver throughout the day.

According to Dr. Charles Brenner:

“Not every cell is capable of converting each NAD+ precursor to NAD+ at all times…the precursors are differentially utilized in the gut, brain, blood, and organs” (R).

NMN – NICOTINAMIDE MONONUCLEOTIDE

THE IMMEDIATE PRECURSOR to NAD+
“NMN makes its way through the liver, into muscle, and is metabolized to NAD+ in 30 minutes” (R)
Treatment for 1 week with NMN was able to restore NAD+ levels in old mice (22 months) to that of 6 month old mice (R)

NAM – NICOTINAMIDE

Converts to NAD+ thru a 2 step salvage pathway(R)
Is much slower, taking 8 hours to reach peak NAD+ in humans (R)
Has been shown to increase NAD+ level in liver (47%), but was weaker in kidney (2%), heart (20%), blood (43%) or lungs (17%) (R)

NA – NICOTINIC ACID (NIACIN)

Elevates NAD+ to peak levels in liver in 15 minutes (R)
raised NAD+ in liver (47%), and impressively raised kidney (88%), heart (62%), blood (43%) and lungs (11%) (R)
“has been used for primary and secondary coronary heart disease prevention for over 40 years”(R)
“NA is one of the most effective means to improve cardiovascular risk factors”(R)
Long term human studies show 6.2% and 7.8% reduced All Cause Mortality rate (R)
Can cause uncomfortable “flushing” in higher dosages, which limits its usage(R)

TRYPTOPHAN

In the liver tryptophan is the preferable substrate for NAD+ production (R)
Administration of tryptophan, NA, or NAM to rats showed that tryptophan resulted in the highest hepatic NAD+ concentrations(R)
Shown to be beneficial in several neurological conditions, including insomnia, Parkinson disease, schizophrenia, depression, anxiety, and autism. (R, R)

Click here for pricing and more product info

The post NMN Plus – Dosage Recommendations appeared first on Alivebynature - Evidence Based Reviews.

As we age, our levels of the Co-enzyme Nicotinamide Adenine Dinucleotide NAD+ drop significantly in multiple organs in mice and humans (5,8,10).

NAD+ decrease is described as a trigger in age-associated decline(23), and perhaps even the key factor in why we age (5).

In 2013, research published by Dr David Sinclair demonstranted that short term supplementation with Nicotinamide MonoNucleotide (NMN) reversed many aspects of aging, making the cells of old mice resemble those of much younger mice, and greatly improving their health (8).

The quotes below are directly from that research:

NMN was able to mitigate most age-associated physiological declines in mice”

“treatment of old mice with NMN reversed all of these biochemical aspects of aging”

Since that landmark 2013 study, dozens of others have been published investigating the efficacy of supplementation with NMN in treatment and prevention of a wide range of disease including cancer, cardiovascular disease, diabetes, Alzheimers, Parkinsons, and more (5,6,7,9,10,11,13,14,15,16).

According to Dr Sinclair:

enhancing NAD+ biosynthesis by using NAD+ intermediates, such as NMN and NR, is expected to ameliorate age-associated physiological decline

WHAT IS NAD+

NR benefits chart NAD+ is a key co-enzyme that the mitochondria in every cell of our bodies depend on to fuel all basic functions. (3,4)

NAD+ play a key role in communicating between our cells nucleus and the Mitochondria that power all activity in our cells (5,6,7)

NAD+ LEVELS DECREASE WITH AGE

NAD+ levels decrease As we age, our bodies produce less NAD+ and the communication between the Mitochondria and cell nucleus is impaired. (5,8,10).

Over time, decreasing NAD+ impairs the cell’s ability to make energy, which leads to aging and disease (8, 5) and perhaps even the key factor in why we age (5).

NAD+ METABOLISM IN HUMANS

NAD+ can be synthesized in humans from several different molecules (precursors), thru 2 distinct pathways:
De Novo Pathway

Tryptophan
Nicotinic Acid (NA)

Salvage Pathway

NAM – Nicotinamide
NR – Nicotinamide Riboside
NMN – Nicotinamide MonoNucleotide

The NAD+ supply is constantly being consumed and replenished through the Salvage Pathway, with approximately 3g of NAM metabolized to NMN and then to NAD 2-4 times per day (14).

The salvage pathway sustains 85% or more of our NAD+ (14)
Nampt is the rate-limiting step in the salvage process (97).
As we age, Nampt enzyme activity is lower, resulting in less NAM recycling, less NAD+, more disease and aging (97,101).

ALL PRECURSORS BOOST NAD+ SIGNIFICANTLY IN LIVER

NAM, NA, NMN, NR, and Tryptophan ALL elevate levels of NAD+ significantly in the liver, which has many benefits for metabolic health.

This chart from the Trammell thesis shows the impact on liver NAD+ for mice given NR, NAM, and NA by oral gavage 0.25, 1, 2, 4, 6, 8 and 12 hours before testing.

Charts showing NMN impact on NAD+ levels in the liver are below.

* Note: These charts are somewhat deceptive. It shows NAM (green bar) elevated NAD+ nearly as much as NR (black bar)

However if they used equal mg of each supplement, which is how people actually purchase and use them, it would show NA about equal with NR and NAM far effective than NR at elevating NAD+ in the liver.

Mice in these experiments didn’t receive equal WEIGHTS of each precursor. Instead researchers chose to use quantity of molecules, which makes NR look “better” by comparison.

In this case, “185 mg kg⁻¹ of NR or the mole equivalent doses of Nam and NA”(16).

Molecular weight for NR is 255 grams, NAM is 122 grams, and NA 123 grams. So this chart used a ratio of 255 grams of NR to 122 and 123 grams of NAM and NA.

NMN

“NMN makes its way through the liver, into muscle, and is metabolized to NAD+ in 30 minutes” (R)

Is much slower, taking 8 hours to reach peak NAD+ in humans (R)

NAM

Has very similar NAD+ profile to NR, taking 8 hours to reach peak NAD+ in humans (R)
Has been shown to increase NAD+ level in liver (47%), but was weaker in kidney (2%), heart (20%), blood (43%) or lungs (17%) (R)

NA (Niacin)

Elevates NAD+ to peak levels in liver in 15 minutes (R)
raised NAD+ in liver (47%), and impressively raised kidney (88%), heart (62%), blood (43%) and lungs (11%) (R)

TRYPTOPHAN

In the liver tryptophan is the preferable substrate for NAD+ production (R)
Administration of tryptophan, NA, or NAM to rats showed that tryptophan resulted in the highest hepatic NAD+ concentrations(R)

ONLY NMN BYPASSES THE NAMPT BOTTLENECK IN TISSUES THROUGHOUT THE BODY

Restoring NAD+ to youthful levels in ALL CELLS throughout the body is the goal.

However, many tissues cannot utilize NAD+ directly from the blood as NAD+ cannot readily pass through the cellular membrane.

Muscle tissue, for example, depends on cells internal recycling of NAD+ through the salvage pathway which is controlled by Nampt.

To restore depleted NAD+ levels in such cells, a precursor must:

Be available in the bloodstream
Once inside a cell, be able to bypass the Nampt bottleneck

NA and Tryptophan
NA and Tryptophan act through the De Novo pathway, which supplies a small percentage of our NAD+, primarily in the liver

NAM
NAM is abundant in the blood and easily carried into such cells throughout the body, but depends on Nampt, which is the rate limiting enzyme in the salvage pathway.

NR
When taken orally as a supplement, most NR does not make it through the digestive system intact, but is broken down to NAM (97,98,99).

For more info on how NR is converted to NAM in the body.

NR can bypass the Nampt bottleneck, but is not normally available in the bloodstream

After oral NMN supplementation, levels of NMN in the bloodstream are quickly elevated and remain high longer than NAM, NA, or NR (18,22,97,98,99)

Oral NMN supplements:

Make their way intact thru the digestive system (22)
Quickly elevates levels of NMN in the bloodstream for use throughout the body (22)
Quickly elevates levels of NMN in tissues throughout the body (22)
Quickly raises levels of NAD+ in blood, liver and tissues through the body (22,23)
Remain elevated longer than NAM, NA, or NR (18)

Only NMN is readily available in the bloodstream to all tissues, and bypasses the Nampt bottleneck in the Salvage pathway

ORAL NMN IS READILY AVAILABLE THROUGHOUT THE BODY

The chart at right shows levels of a double labeled NAD+ (C13-d-nad+) in liver and soleus muscle at 10 and 30 minutes after oral administration of double labeled NMN.

This clearly shows that NMN makes it way through the liver intact, through the bloodstream, into muscle, and is metabolized to NAD+ in 30 minutes (22) .

This quote below is directly from that study.

Orally administered NMN is quickly absorbed, efﬁciently transported into blood circulation, and immediately converted to NAD+in major metabolic tissues (22).

NMN QUICKLY RAISES NAD+ IN LIVER AND BLOOD

mouse-single-dose
In this 2016 study, mice were given a single dose of NMN in water.

NMN levels in blood showed it is quickly absorbed from the gut into blood circulation within 2–3 min and then cleared from blood circulation into tissues within 15 min

NMN INCREASES NAD+ and SIRT1 DRAMATICALLY IN ORGANS

In this 2017 study, NMN supplementation for 4 days significantly elevated NAD+ and SIRT1, which protected the mice from Kidney damage.

NAD+ and SIRT1 levels were HIGHER in OLD Mice than in YOUNG Mice that did not receive NMN.

LONG TERM SUPPLEMENTATION WITH NMN

mouse-long-term-research

In a long-term experiment documented in the 2016 study (22) , mice were given 2 different doses of NMN over 12 months.

Testing revealed that NMN prevents some aspects of physiological decline in mice, noting these changes:

Decreased body weight and fat
Increased lean muscle mass
Increased energy and mobility
Improved visual acuity
Improved bone density
Is well-tolerated with no obvious bad side effects
Increased oxygen consumption and respiratory capacity
Improved insulin sensitivity and blood plasma lipid profile

Here are some quotes from the study:

NMN suppressed age-associated body weight gain, enhanced energy metabolism, promoted physical activity, improved insulin sensitivity and plasma lipid profile, and ameliorated eye function and other pathophysiologies

NMN-administered mice switched their main energy source from glucose to fatty acids

These results strongly suggest that NMN has signiﬁcant preventive effects against age-associated impairment in energy metabolism

NMN effectively mitigates age-associated physiological decline in mice

LOWER FAT AND INCREASED LEAN MUSCLE MASS

Researchers found that NMN administration suppressed body weight gain by 4% and 9% in the 100 and 300 mg/kg/day groups.

Analyses of blood chemistry panels and urine did not detect any sign of toxicity from NMN.

Although health span was clearly improved, there was no difference in maximum lifespan observed.

These results suggest that NMN administration can significantly suppress body weight gain without side effects

INCREASED OXYGEN CONSUMPTION AND RESPIRATORY CAPACITY
screen-shot-2016-11-04-at-2-22-48-pm

Oxygen consumption significantly increased in both 100 and 300 mg/kg/day groups during both light and dark periods (Figure 3A).

Energy expenditure also showed significant increases (Figure 3B).

Respiratory quotient significantly decreased in both groups during both light and dark periods (Figure 3C),

This suggests that NMN-administered mice switched their main energy source from glucose to fatty acids.

The mice that had been receiving NMN for 12 months exhibited energy levels, food and water consumption equivalent to the mice in the control group that were 6 months younger.

NMN administration has significant preventive effects against age associated physical impairment

HUMAN STUDIES – LONG TERM SUPPLEMENTATION WITH NMN

The first clinical trial of NMN in humans is currently underway by an international collaborative team between Keio University School of Medicine in Tokyo and Washington University School of Medicine (33).

Participants are 50 healthy women between 55 and 70 years of age with slightly high blood glucose,BMI and triglyceride levels.

Using a dose of 2 capsules of 125mg NMN per day over a period of 8 weeks, researchers are testing for:

change in insulin sensitivity
change in beta-cell function
works to control blood sugar
blood vessels dilate
effects of NMN on blood lipids
effects of NMN on body fat
markers of cardiovascular and metabolic health

According to the study:

“Data from studies conducted in rodents have shown that NMN supplementation has beneficial effects on cardiovascular and metabolic health, but this has not yet been studied in people”

Testing of metabolic parameter will continue for 2 years after supplementation has ended, so final results will not be published for some time yet, but preliminary results are expected to be announced in early 2018.

FOODS THAT CONTAIN NMN

NMN is found in many food sources such as edamame, broccoli, cucumber,cabbage, avocado, tomato, beef and shrimp.

As such, it is likely free from serious side effects in humans, and has been available for purchase commercially for over 2 years.

DOSAGE

In the long term (12 month) 2016 mouse study (22), both 100 and 300mg/kg per day improved oxygen consumption, energy expenditure, and physical activity more.

According to the FDA guidelines, an equivalent would be about 560 mg for a 150lb human.

It should be noted that NMN administration did not generate any obvious toxicity, serious side effects, or increased mortality rate throughout the 12-month-long intervention period, suggesting the long-term safety of NMN.

The current Human study uses a dosage of 2 capsules of 125 mg, which seems to be the most commonly used dosage.

SUMMMARY

NAD+ levels decrease throughout the body as we age, contributing to disease and aging.

Restoring NAD+ levels can ameliorate many age released health issues.

All the NAD+ precursors are effective at raising NAD+ levels in the liver.

Raising NAD+ in the liver has many benefits, but is not effective in tissues and organs that cannot access NAD+ directly from the bloodstream and so depend on internal cellular NAD+ recycling.

For these tissues, utilizing each cells internal Salvage Pathway is necessary to restore NAD+ levels.

NR is not stable in the body and not normally found in the bloodstream, so is not readily available as NR to many tissues. Once metabolized to NAD+ it cannot enter cells. If metabolized to NAM it cannot bypass the Nampt bottleneck.

NMN is the only precursor that is stable and available to cells through the bloodstream, and can bypass the Nampt bottleneck to quickly restore NAD+ throughout the body.

NMN IS THE WHOLE BODY NAD+ BOOSTER

NMN PLUS – THE COMPLETE NAD+ BOOSTER

$46.95

Unlike NR, NMN makes it’s way INTACT through the liver quickly and remains available in the bloodstream for many hours (18,97,98,99)

NMN is the Immediate Precursor to NAD+.

NMN is quickly metabolized into tissues throughout the body, where it bypasses the NAMPT bottleneck and restores NAD+ levels in tissues more effectively than other NAD+ precursors.

Read about the science behind NMN.

OTHER PRECURSORS – MAKING NMN EVEN MORE EFFECTIVE

Boosting NAD+ in the liver is great, but is a small part of the health benefits you get from restoring NAD+ thoughout the body.

All the precursors are effective at boosting NAD+ in the liver, so why waste NMN on that simple task?

Niacin (NA) is the fastest, elevating NAD+ to peak levels in liver in 15 minutes (R)
Tryptophan is the preferable substrate for NAD+ production in the liver(R)
Administration of tryptophan, NA, or NAM to rats showed that tryptophan resulted in the highest hepatic NAD+ concentrations(R)

Like NR, NAM is also very slow acting, taking 8 hours to reach peak NAD+ levels in the liver when used by itself (16).

We include NAM in NMN Plus to act as a slow release NAD+ booster to ensure levels stay high, and potentially sparing NMN from being utilized for NAD+ metabolism in the liver throughout the day.

According to Dr. Charles Brenner:

“Not every cell is capable of converting each NAD+ precursor to NAD+ at all times…the precursors are differentially utilized in the gut, brain, blood, and organs” (R).

NMN – NICOTINAMIDE MONONUCLEOTIDE

THE IMMEDIATE PRECURSOR to NAD+
“NMN makes its way through the liver, into muscle, and is metabolized to NAD+ in 30 minutes” (R)
Treatment for 1 week with NMN was able to restore NAD+ levels in old mice (22 months) to that of 6 month old mice (R)

NAM – NICOTINAMIDE

Converts to NAD+ thru a 2 step salvage pathway(R)
Is much slower, taking 8 hours to reach peak NAD+ in humans (R)
Has been shown to increase NAD+ level in liver (47%), but was weaker in kidney (2%), heart (20%), blood (43%) or lungs (17%) (R)

NA – NICOTINIC ACID (NIACIN)

Elevates NAD+ to peak levels in liver in 15 minutes (R)
raised NAD+ in liver (47%), and impressively raised kidney (88%), heart (62%), blood (43%) and lungs (11%) (R)
“has been used for primary and secondary coronary heart disease prevention for over 40 years”(R)
“NA is one of the most effective means to improve cardiovascular risk factors”(R)
Long term human studies show 6.2% and 7.8% reduced All Cause Mortality rate (R)
Can cause uncomfortable “flushing” in higher dosages, which limits its usage(R)

TRYPTOPHAN

In the liver tryptophan is the preferable substrate for NAD+ production (R)
Administration of tryptophan, NA, or NAM to rats showed that tryptophan resulted in the highest hepatic NAD+ concentrations(R)
Shown to be beneficial in several neurological conditions, including insomnia, Parkinson disease, schizophrenia, depression, anxiety, and autism. (R, R)

Click here for pricing and more product info

OTHER RESEARCH WITH NMN

Aging

Head to Head Comparison of Short-Term Treatment with the NAD(+) Precursor Nicotinamide Mononucleotide (NMN) and 6 Weeks of Exercise in Obese Female Mice (Uddin, 2016)

NAD(+) levels were increased significantly both in muscle and liver by NMN
NMN-supplementation can induce similar reversal of the glucose intolerance
NMN intervention is likely to be increased catabolism of fats
NMN-supplementation does mimic exercise

DNA Damage

A conserved NAD+ binding pocket that regulates protein-protein interactions during aging (Sinclair, 2017)

This study showed supplementation with NMN was able to repair the DNA in cells damaged by radiation.

the cells of old mice were indistinguishable from young mice after just one week of treatment.”

Diabetes & Metabolic disease

Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice (Yoshino, 2011)

NMN was immediately utilized and converted to NAD+ within 15 min, resulting in significant increases in NAD+ levels over 60 min

administering NMN, a key NAD+ intermediate, can be an effective intervention to treat the pathophysiology of diet- and age-induced T2D

Surprisingly, just one dose of NMN normalized impaired glucose tolerance

Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (Gomes, Sinclair,2013)

raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse

treatment of old mice with NMN reversed all of these biochemical aspects of aging

restore the mitochondrial homeostasis and key biochemical markers of muscle health in a 22-month-old mouse to levels similar to a 6-month-old mouse

CardioVascular Disease

Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and repercussion (Yamamoto, 2014)

NMN significantly increased the level of NAD+ in the heart

NMN protected the heart from I/R injury

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice (de Picciotto, 2016)

NMN reduces vascular oxidative stress
NMN treatment normalizes aortic stiffness in old mice
NMN represents a novel strategy for combating arterial aging

Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure (Zhang, 2017)

NMN can reduce myocardial inflammation

NMN thus can cut off the initial inflammatory signal, leading to reduced myocardial inflammation

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels.

restoration of cardiac function and energy metabolism upon NMN supplementation
remarkable decrease in whole-body EE and cardiac energy wasting

Neurological Injury

Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway (Wei, 2017)

NMN treats brain injury in ICH by suppressing neuroinflammation/oxidative stress

NMN treatment protects against cICH-induced acute brain injury
NMN treatment reduces brain cell death and oxidative stress
These results further support the neuroprotection of NMN/NAD+

Alzheimers

Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model (Long, 2015)

We now demonstrate that mitochondrial respiratory function was restored

Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death (Wang, 2016)

NMN could restore cognition in AD model rats.
The beneficial effect of NMN is produced by ameliorating neuron survival, improving energy metabolism and reducing ROS accumulation.
These results suggest that NMN may become a promising therapeutic drug for AD

Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease(Yao, 2017)

NMN Treatment Rescues Cognitive impairments
NMN Treatment Improves Inflammatory Responses

Kidney Disease
Nicotinamide Mononucleotide, an NAD+ Precursor, Rescues Age-Associated Susceptibility to AKI in a Sirtuin 1-Dependent Manner (Guan, 2017)

Supplementation with NMN restored kidney SIRT1 and NAD+ content in 20-month-old mice and protected both young and old mice from acute kidney injury.

References:

The post Can NMN really reverse Aging? (backup) appeared first on Alivebynature - Evidence Based Reviews.

This POST has been redirected to a PAGE – is only here to show in recent posts and such widgets.

WHAT IS NAD+

NAD+ is a key co-enzyme that the mitochondria in every cell of our bodies depend on to fuel all basic functions. (3,4)

NAD+ play a key role in communicating between our cells nucleus and the Mitochondria that power all activity in our cells (5,6,7)

Scientists have now confirmed a direct link between falling NAD+ levels and aging in both animal and in human subjects.

Read more about NAD+

NAD+ DECLINES WITH AGE

As we age, our bodies produce less NAD+ and the communication between the Mitochondria and cell nucleus is impaired. (5,8,10).

Over time, decreasing NAD+ impairs the cell’s ability to make energy, which leads to aging and disease (8, 5) and perhaps even the key factor in why we age (5).

Read more about NAD+

NAD+ METABOLISM IN HUMANS

NAD+ can be synthesized in humans from several different molecules (precursors), thru the De Novo and Salvage Pathways.

The salvage pathway sustains 85% or more of our NAD+ (14), with approximately 3g of NAM metabolized to NMN and then to NAD 2-4 times per day (14).

Nampt is the rate-limiting step in the salvage process (97).

NMN BYPASSES THE NAMPT BOTTLENECK

As we age, Nampt enzyme activity is lower, resulting in less NAM recycling, less NAD+, more disease and aging (97,101).

Restoring NAD+ in the Liver does not solve NAD+ deficiency throughout the body as NAD+ cannot readily pass through the cellular membrane.

Muscle tissue, for example, depends on cells internal recycling of NAD+ through the salvage pathway which is controlled by intercellular Nampt.

NMN IS QUICKLY METABOLIZED IN TISSUES THROUGHOUT THE BODY

Oral NMN supplements:

Make their way intact thru the digestive system (22)
Quickly elevates levels of NMN in the bloodstream for use throughout the body (22)
Quickly elevates levels of NMN in tissues throughout the body (22)
Quickly raises levels of NAD+ in blood, liver and tissues through the body (22,23)

mouse-single-dose
This 2016 study found NMN is rapidly metabolized to NAD+ in tissues throughout the body.

The red line in chart to right shows NMN quickly absorbed into blood circulation within 2–3 min, and then into tissues within 15 minutes.

The blue line shows NAD+ levels begin to increase significantly in tissue within 15 minutes.

This chart at left from the same study shows levels of a double labeled NAD+ in liver and soleus muscle at 10 and 30 minutes after oral administration of double labeled NMN.

This clearly shows the NMN makes its way through the liver and into muscle in 30 minutes.

NMN INCREASES NAD+ and SIRT1 DRAMATICALLY IN ORGANS

In this 2017 study, NMN supplementation for 4 days significantly elevated NAD+ and SIRT1, which protected the mice from Kidney damage.

NAD+ and SIRT1 levels were HIGHER in OLD Mice than in YOUNG Mice that did not receive NMN.

LONG TERM STUDY ON NMN

This 12 month long study designed to evaluate the long-term effects of oral supplementation of NMN in mice published in Oct 2016.

Mice were feed 100 or 300Mg/Kg of NMN per day by oral garage. The 100 Mg dosage showed more improvement in some metabolic parameters, which 300 Mg per kg a day was more effective at others.

Using the FDA guidelines on conversion, the 100 Mg dosage equates to 560 mg per day in a 70 kg human.

better glucose control
increased energy
less weight gain
better mobility
better overall health
immune function

Below are some quotes from that study.

“NMN was able to mitigate most age-associated physiological declines in mice”

“treatment of old mice with NMN reversed all of these biochemical aspects of aging”

HUMAN STUDIES – LONG TERM SUPPLEMENTATION WITH NMN

There are at least 2 clinical trials of NMN in humans currently underway.

The first was started in late 2016 by Keio University School of Medicine in Tokyo (R).

The second was begun in the summer of 2017,by Washington University School of Medicine (R).

The Washington University study appears to be much larger and investigates more health parameters.In that study, participants are 50 healthy women between 55 and 70 years of age with slightly high blood glucose,BMI and triglyceride levels.

Using a dose of 2 capsules of 125mg NMN per day over a period of 8 weeks, researchers are testing for:

change in insulin sensitivity
change in beta-cell function
works to control blood sugar
blood vessels dilate
effects of NMN on blood lipids
effects of NMN on body fat
markers of cardiovascular and metabolic health

According to the study:

“Data from studies conducted in rodents have shown that NMN supplementation has beneficial effects on cardiovascular and metabolic health, but this has not yet been studied in people”

Testing of metabolic parameters will continue for 2 years after supplementation has ended, so final results will not be published for some time yet, but preliminary results are expected to be announced in early 2018.

Aging

Head to Head Comparison of Short-Term Treatment with the NAD(+) Precursor Nicotinamide Mononucleotide (NMN) and 6 Weeks of Exercise in Obese Female Mice (Uddin, 2016)

NAD(+) levels were increased significantly both in muscle and liver by NMN
NMN-supplementation can induce similar reversal of the glucose intolerance
NMN intervention is likely to be increased catabolism of fats
NMN-supplementation does mimic exercise

DNA Damage

A conserved NAD+ binding pocket that regulates protein-protein interactions during aging (Sinclair, 2017)

This study showed supplementation with NMN was able to repair the DNA in cells damaged by radiation.

the cells of old mice were indistinguishable from young mice after just one week of treatment.”

Diabetes & Metabolic disease

Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice (Yoshino, 2011)

NMN was immediately utilized and converted to NAD+ within 15 min, resulting in significant increases in NAD+ levels over 60 min

administering NMN, a key NAD+ intermediate, can be an effective intervention to treat the pathophysiology of diet- and age-induced T2D

Surprisingly, just one dose of NMN normalized impaired glucose tolerance

Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (Gomes, Sinclair,2013)

raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse

treatment of old mice with NMN reversed all of these biochemical aspects of aging

restore the mitochondrial homeostasis and key biochemical markers of muscle health in a 22-month-old mouse to levels similar to a 6-month-old mouse

CardioVascular Disease

Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and repercussion (Yamamoto, 2014)

NMN significantly increased the level of NAD+ in the heart

NMN protected the heart from I/R injury

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice (de Picciotto, 2016)

NMN reduces vascular oxidative stress
NMN treatment normalizes aortic stiffness in old mice
NMN represents a novel strategy for combating arterial aging

Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure (Zhang, 2017)

NMN can reduce myocardial inflammation

NMN thus can cut off the initial inflammatory signal, leading to reduced myocardial inflammation

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels.

restoration of cardiac function and energy metabolism upon NMN supplementation
remarkable decrease in whole-body EE and cardiac energy wasting

Neurological Injury

Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway (Wei, 2017)

NMN treats brain injury in ICH by suppressing neuroinflammation/oxidative stress

NMN treatment protects against cICH-induced acute brain injury
NMN treatment reduces brain cell death and oxidative stress
These results further support the neuroprotection of NMN/NAD+

Alzheimers

Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model (Long, 2015)

We now demonstrate that mitochondrial respiratory function was restored

Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death (Wang, 2016)

NMN could restore cognition in AD model rats.
The beneficial effect of NMN is produced by ameliorating neuron survival, improving energy metabolism and reducing ROS accumulation.
These results suggest that NMN may become a promising therapeutic drug for AD

Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease(Yao, 2017)

NMN Treatment Rescues Cognitive impairments
NMN Treatment Improves Inflammatory Responses

Kidney Disease
Nicotinamide Mononucleotide, an NAD+ Precursor, Rescues Age-Associated Susceptibility to AKI in a Sirtuin 1-Dependent Manner (Guan, 2017)

Supplementation with NMN restored kidney SIRT1 and NAD+ content in 20-month-old mice and protected both young and old mice from acute kidney injury.

** These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.

References:

The post Can Nicotinamide Mononucleotide (NMN) really reverse aging? appeared first on Alivebynature - Evidence Based Reviews.

Scientists are discovering new ways that NAD⁺ facilitates healthy longevity.^1-3

NAD⁺ levels markedly decline with age, creating an energy deficit that decreases the body’s ability to retain youthful function.⁴

To give you an idea how impactful NAD⁺ can be, by age 50 a typical person may have only half the NAD⁺ they did in youth. By age 80, NAD⁺ levels drop to only 1% to 10% expressed in youth.

Deficiency of NAD⁺ predisposes us to accelerated aging and impedes our ability to fully benefit from resveratrol.

Fortunately, it is easy to restore your cellular NAD⁺ to higher ranges.

As a co-factor in cell energy transfer, NAD⁺ plays a critical role in regulating aging processes.

NAD⁺ is the acronym for nicotinamide adenine dinucleotide.

Found in virtually all living cells, NAD⁺ is essential to sustaining life.⁴

A fascinating aspect of NAD⁺ is its dual role in protecting against factors that age us. This includes mitigating chemical stress, inflammation, DNA damage, and failing mitochondria.

At the same time, NAD⁺ promotes longevity by facilitating DNA repair and providing cellular benefits associated with caloric restriction and exercise.⁵

In other words, while a decline in NAD⁺ levels may negatively influence lifespan, restoring NAD⁺ is increasingly being viewed as a cutting-edge tool to promote longevity.

There is growing evidence that supplementing with a vitamin-like precursor of NAD⁺ called nicotinamide mononucleotidecan promote longevity in life forms ranging from simple worms to mammals like mice.^5-11

One study showed an average 5% increase in the lifespan of old mice—even though supplementation did not begin until the mice were nearing the end of their natural lifespan (24 months).¹¹

That would be the equivalent of gaining nearly an additional four years of life based on today’s average human expectancy of 78.8 years.¹²

A rigorous scientific review of NAD⁺ reveals that its longevity benefits arise from eight different, but interrelated, functions.

This article briefly summarizes each anti-aging mechanism played by NAD⁺ in your body.

Anti-Aging Mechanism #1:

NAD⁺ May Contribute to Longer Telomeres

NAD⁺ is required for functioning of the sirtuin proteins that contribute to longevity—and specifically to maintaining the length of critical telomeres.

Telomeres are stretches of repetitive DNA strands that cap the ends of chromosomes. Like the burning of a fuse, telomeres at the ends of our chromosomes steadily shorten every time a cell replicates itself. Once telomeres reach a critically short length, cell renewal virtually stops, leading to accelerated aging or death of the cell.¹³

Telomere shortening is both a marker of cellular aging and a predictor of shortened lifespan.¹⁴

Researchers have been searching for drugs and other interventions that might lengthen telomeres, in order to extend lifespan and/or health span. To date, exercise and weight loss have been reliably shown to be effective at telomere lengthening.^15-17

Certain other nutrients, such as resveratrol, may activate sirtuins and contribute to extending lifespan, but emerging evidence suggests sirtuins function best with an ample supply of NAD⁺.

Conclusion: The possibility of extending telomere length with NAD⁺ holds out hope for slowing the aging process and improving longevity.

WHAT YOU NEED TO KNOW

Restore Cellular Energy with NAD⁺

NAD⁺ is required for proper cellular energy utilization, but its levels decline with age.
It is also required for eight fundamental processes, each of which contributes to accelerated aging when NAD⁺ levels drop.
NAD⁺ is unstable and cannot be used as a supplement, but nicotinamide mononucleotide is a useful precursor to NAD⁺ that is capable of restoring cellular NAD⁺ levels.
Studies show that nicotinamide mononucleotide supplementation can slow cellular aging and improve many of the metabolic defects common to the aging process, including obesity, diabetes, cardiovascular disease, and neurodegenerative conditions.
Supplementation with nicotinamide mononucleotide offers a way of supporting essential body systems.

Anti-Aging Mechanism #2:

NAD⁺ Promotes DNA Repair

Even though DNA is protected by its chromosomal shelter, it is highly vulnerable to damage.

This can lead to broken DNA strands and mutations in crucial genes. Accumulated DNA damage contributes to the aging process and can result in specific lifespan-shortening diseases like cancer and poor immune function.¹⁸

When DNA is damaged, it activates an enzyme known as PARP-1 that carries out DNA repair within cells.¹⁹ To carry out its function, PARP-1 consumes enormous amounts of NAD⁺. As NAD⁺ is depleted, the ability of PARP-1 to repair DNA is significantly hindered.^19-28

The good news is that replenishing NAD⁺ to cells can restore DNA repair and prevent cell death under stress.^26,29In two different animal models of neurodegenerative disease, increasing cellular NAD⁺ reduced the severity of the disorder, normalized neuromuscular function, delayed memory loss, and extended lifespan.³⁰

Conclusion: Improving DNA repair with NAD⁺ may slow cellular aging, reduce the persistence of cancer-causing mutations, and play an important role in preventing inflammatory conditions such as atherosclerosis.^31,32

With advanced age, cell NAD+ levels plummet to near zero.
Normal aging may one day be classified as “NAD+ deficiency syndrome.”
Fortunately, there are proven ways to boost NAD+ levels.

Anti-Aging Mechanism #3:

NAD⁺ Modulates Immune-Cell Signaling

As we age, our immune cells begin to lose their focus. Some become overactive, contributing to autoimmune disease, while others slow down, which increases the risk of infection. This process, called immunosenescence, is intimately related to mitochondrial function and energy balance,³³ both of which depend on NAD⁺ activity.

Intracellular levels of NAD⁺ regulate immune and inflammatory pathways, including the cytokine TNF-alpha, a critical signaling molecule.^34,35

Conclusion: Adequate intracellular NAD⁺ is vital for youthful cellular energy, a critically important factor in fending off immunosenescence and maintaining defenses against infections and autoimmune disease.

Anti-Aging Mechanism #4:

NAD⁺ Induces Energy-Intensive Enzymes

A universal feature of aging is the loss of cellular energy, which results in diminished ATP levels and inadequate cellular fuel necessary to power your body.^23,36,37

One cause of this energy loss is a breakdown in the efficiency of the electron transport chain, the main pathway through which we extract energy from food (and of which NAD⁺ is an essential component).^23,38 Disorders ranging from obesity and diabetes to bone loss have been associated with loss of this vital pathway.^38,39

Studies now show that restoring electron transport chain function by raising levels of NAD⁺ is a rapid and efficient means of promoting the essential enzymes involved in energy extraction and sustaining youthful cell function. This helps to reduce physiological decline and provides protection from age-related disease.^22,40

Conclusion: Improving the energy-extraction process in all cells with NAD⁺ increases their capacity to do the work they are specialized for. It also protects mitochondria from early death, a benefit that is associated with reduced cellular aging and lowered risks for cardiovascular and brain disease.^41-45

Anti-Aging Mechanism #5:

NAD⁺ Promotes Chromosome Stability

Our chromosomes are complex structures housing our DNA. Access to DNA strands for “reading out” genetic instructions requires biochemical control of those proteins to make sure each gene functions properly.⁴⁶

But like any complex molecular structure, chromosomes can become unstable. Eventually, this triggers errors in the ways our genes are interpreted—which ultimately contributes to deleterious changes in cell function and structure. Aging is accelerated in the presence of increased chromosome instability.^47-49

The enzymes involved in sustaining stable chromosomal structures require NAD⁺ in order to function properly.

In animal models showing that NAD⁺ contributes to longevity, a major factor has been shown to be sufficient availability of the nutrient.^46,50,51 And studies show that when enzymes that require NAD⁺ are inactive, chromosome structure suffers and cells replicate abnormally.⁵⁰

Conclusion: NAD⁺ supplementation is a promising cutting edge strategy to improve chromosome stability, a treatment that may slow down cellular aging (senescence) and lower the risk of cancer.

Anti-Aging Mechanism #6:

NAD⁺ Is a Neurotransmitter

Neurotransmitters are brain chemicals that relay signals between nerve cells. In doing so, they help regulate body-wide functions such as mood, appetite, and stress.

NAD⁺ has been found to meet all criteria for a neurotransmitter.^52,53

Evidence for NAD⁺’s neurotransmitter function has now been found in intestinal and blood vessel smooth muscles, as well as in the brain itself.⁵²

Conclusion: Ample NAD⁺ nutrition appears essential for sustaining brain health.

Anti-Aging Mechanism #7:

NAD⁺ Activates Sirtuins

Proteins called sirtuins are major regulators of cellular aging because they influence fundamental functions such as DNA repair and inflammatory responses. They also influence whether cells enter a replicative cycle or instead die a programmed death (apoptosis).⁵³

Compounds that activate sirtuins are eagerly sought as chemical “fountains of youth.” Familiar supplements like resveratrol and quercetin have been evaluated as promising sirtuin activators.^2,54-56

NAD⁺ is required for sirtuins to function.^57-59

Conclusion: Sirtuin activation has shown great promise in fighting cardiovascular disease and preserving aging brain function, but these longevity-promoters cannot function without sufficient NAD⁺.^4,54

Anti-Aging Mechanism #8:

NAD⁺ Supports Energy Production

NAD⁺ was first discovered as an important part of the process that channels chemical energy from foods to the ATP fuel our cells require. Recent studies have revealed that NAD⁺ is itself a form of “energy currency” similar to ATP.⁶⁰

NAD⁺ is also a functional signaling molecule in processes related to energy production, including PARP-1 and sirtuins. When DNA damage occurs, PARP-1 consumes large quantities of NAD⁺, leading to reduced energy production. In addition, high levels of NAD⁺ can activate sirtuins, permitting them to carry out their metabolic and stress-protective responses and contributing to longevity.²³

Conclusion: Supporting efficient energy production and adequate ATP levels requires consistent and abundant NAD⁺. This is critical because waning energy supplies contribute to the aging process.

How to Boost NAD⁺

NAD⁺ is biologically unstable, which makes it unsuitable for oral supplementation. Fortunately, there’s a solution.

About a decade ago, researchers discovered that the compound nicotinamide mononucleotide is rapidly converted by natural cellular enzymes into active NAD⁺.

Studies show that supplementing with nicotinamide mononucleotide is an effective means of raising cellular NAD⁺levels.^6,22,61

nicotinamide mononucleotide is readily available for oral supplementation, and it is highly bioavailable.⁶² These benefits make nicotinamide mononucleotide the leading oral candidate to boost cellular NAD⁺, and research is revealing just how effective it is.⁶³

The Metabolic Benefits of Boosting NAD⁺

nicotinamide mononucleotide boosts NAD⁺ and appears useful in preventing diseases associated with abnormal energy utilization. These include obesity, diabetes, and atherosclerosis, which are components of metabolic syndrome.

A mouse study revealed that prediabetic mice given nicotinamide mononucleotide have better glucose tolerance, less weight gain and liver damage, and slower development of fatty livers. Similarly, in diabetic mice, nicotinamide mononucleotide markedly reduced blood sugar, weight gain, and liver fat, while also preventing diabetic nerve damage.⁶⁴

nicotinamide mononucleotide is especially beneficial in combatting nonalcoholic fatty liver disease (NAFLD), which is considered the liver manifestation of metabolic syndrome. Interventions that reduce NAFLD generally improve all-around metabolic health.

Studies in animal models of NAFLD have shown that nicotinamide mononucleotide supplementation corrects biochemical and microscopic liver changes in mice fed a high-fat diet.^65,66

In another study of obesity induced by a high-fat diet, supplementation with nicotinamide mononucleotide increased NAD⁺ levels, activated sirtuins, and protected against the oxidative stresses and other damage induced by the diet (many of NAD⁺’s longevity mechanisms mentioned above).²²

Additional NAD⁺ Benefits

Brain tissue is highly sensitive to alterations in NAD⁺ levels.⁶⁷ A mouse study showed that supplementation with nicotinamide mononucleotide increased NAD⁺ levels in the brain, slowed cognitive decline in mice with Alzheimer’s, and enhanced the plasticity in neurons that underlies learning and memory.⁶⁷

Regular exercise is a panacea for most of the age-accelerating processes in our bodies. Recent studies are showing that nicotinamide mononucleotide helps improve exercise performance by improving mitochondrial dynamics and muscle function.⁶⁸

And in animals that had undergone removal of part of their livers, researchers showed that nicotinamide mononucleotide supplementation promoted new DNA synthesis, cell replication, and increased liver mass—a vivid demonstration of its healing powers.⁶⁹

Summary

NAD⁺ beneficially enhances eight core cellular anti-aging mechanisms.

When these cell functions are impaired, the consequence is accelerated aging that contributes to disorders as diverse as Alzheimer’s and osteoporosis.

Restoring cell NAD⁺ levels has been shown to preserve youthful function—and even reverse some age-induced deterioration.

nicotinamide mononucleotide has been shown not only to restore NAD⁺ levels in tissues, but also to provide more NAD⁺ activity than can be obtained from diet alone.

Supplementation with nicotinamide mononucleotide can slow cellular aging and improve many metabolic defects common to degenerative processes, including diabetes, declining heart function and neurodegenerative conditions.

The post Anti-aging effect of NAD+ boosters appeared first on Alivebynature - Evidence Based Reviews.

The results achieved by Professor David Andrew Sinclair in his quest for reversing aging have moved from the exceptional to the phenomenal. This brief essay lists the evidence and suggests what may be the best value for money route to implementing an effective lowest-cost protocol for delivering similar or the same results.

This brief Answer/Essay suggests a probable best available delivery method of implementing a protocol for achieving the highest NMN dosage (perhaps well beyond Sinclair’s 500mg/day for 90 days) at the least cost.

The background to Professor David Andrew Sinclair’s recent results

Some of these are listed at the quite readable 2 April 2017 article of the “Daily Mail online” at Is this pink pill the elixir of youth?

You should note that:

“In the body, NMN is converted into a related chemical called nicotinamide adenine dinucleotide (NAD), which is found in every cell of living organisms and is essential for life. NAD is crucial in fuelling the seven different genes in our body that govern ageing.

However, our NAD levels decline by about 50 per cent as we age, turning off the body’s defences against ageing and age-related diseases such as cancer, diabetes, heart disease and Alzheimer’s.”

And

“Professor Sinclair is so convinced of his pill’s safety that not only has he been taking it himself, so has his 77-year-old father.

The results certainly sound encouraging. Before he started taking a 500mg NMN pill every morning, 47-year-old Professor Sinclair had his blood tested and was told his body had a biological age of 58.

After consuming NMN for three months, he was tested again and his biological age was 32.

As for his father, he’s recently been out-pacing the professor’s younger brother on mountaineering expeditions in their native Australia.

‘He’s as vigorous as he was in his 20s and 30s, and he seems to be getting more energetic,’ says Professor Sinclair.

The manufacturing process of the NMN pill is complicated and expensive, and it currently costs Professor Sinclair more than $1,000 (£797) a month to buy it just for himself.”

I think I may know know how to get the same dose result (of over 500mg of NMN a day) at a much lower cost as outlined below.

“For a start, what his NMN pill cannot do is rejuvenate our exterior appearance — especially if we’re already old.

The fact that Professor Sinclair, a father of three young children, still has no grey hairs and very few wrinkles seems a miracle in itself, but he suggests it isn’t because of his pills.

Hair loss, grey hair and wrinkled skin are not yet reversible, he says, although if you start taking NMN young, it may delay visible ageing, as it’s much easier to prevent hair loss and grey hair than reverse it.”

Key points:

NMN restores the numbers of mitichondria in the nigrostratial “black brain” to youthful levels (ie to age-25 similars) within three months.

Summary of what Sinclair has done with NMN

The results so far are

When Sinclair’s mother had her left lung removed, he was told by her doctors that her remaining life expectancy was about a year. Sinclair was not accepting that and he prescribed his mother NMN and she lived for 20 years.
Sinclair has taken 500mg of NMN a day for 90 days, with the result his blood-assessed biological age of 58 fell to 32 when his actual age was 47
Sinclair’s 77 year old father has taken NMN which has reduced his apparent age by about two or three decades and he has successfully taken up mountaineering
Sinclair’s younger brother was so affected by being outpaced by his 77 year old father that he too is now taking NMN.

The Most Effective Delivery System For NMN

Buccal (in the cheeks) and sublingual (under the tongue) delivery is probably the best available method for getting NMN into the bloodstream and onward into the cells of the 200 tissues which need it. See the quoted-below entry about pharmacokinetics on the Wikipedia site about the absorption of Resveratrol, which notes that buccal or sublingual delivery may be up to 250 times more effective than oral delivery for resveratrol.

The molecular weight of NMN is 324 — very low compared to insulin which is about 6,500. Nicotinamide riboside (NIAGEN) for comparison has a molecular weight of 255. Resveratrol has a similar molar mass of 228. NMN also partially dissolves in water. That makes NMN a potentially good candidate for sublingual delivery. See

Sublingual administration — Wikipedia

If you take these tablets sublingually, the absorption could be up to 250 times greater than swallowed tablets.

Many assessments of the solubility and persistence of resveratrol and other AMPK stimulaters or Sirts activators may be mistaken, because these small molecules mainly use the blood as a transport system to get to the brain, muscle and other cells which are their target area of activity. The general measure of the blood content of (say) resveratrol immediately after dosage or after four hours does not necessarily indicate that these molecules have been cleared from the body by the actions of the kidneys or the liver, because these substances may have migrated into their target cells.

Alcohol seems to improve the effectiveness of some sublingual delivery as the Pharmacokinetic extract above implies. Perhaps the best and quickest method of sublingual delivery is to add about a gram of Xylitol under the tongue, which makes the NMN disappear quickly. Xylitol is not only a sugar but also an alcohol — see the Wikipedia entry at Xylitol — Wikipedia

This makes Xylitol perhaps an ideal catalyst for the sublingual delivery of NMN.

Incidentally, one of the best discussions of the bioavailability of NAD can be read at https://www.nature.com/articles/…

That article summarises the current state of knowledge about where Sirtuins 1–7 reside and what they do. Just to provide a brief taste, the overview states

Another excellent article about Mitochondrial Metabolism, Sirtuins, and Agingby Michael N. Sack and Toren Finkel is at

http://cshperspectives.cshlp.org…

The vital importance of NMN in activating all of the seven Sirtuins is a key explanation of the wide-ranging activity of this supplement. The Sirtuins do not simply increase the numbers of mitochondria within the cell, they stimulate the death and destruction of damaged mitochondria and improve intercellular communication, and they almost seem to act as a kind of team of proteins, restoring cellular functions to a much higher level of youthful effectiveness.

The post Sublingual NMN The Best NAD+ booster? appeared first on Alivebynature - Evidence Based Reviews.

Life-extension biohacks are on the rise. There have been many stories recently about radical techniques to stop aging such as blood transfusions from young to old animals, genetic tinkering, severe dietary restriction and other extreme methods that show some promise. But most are a long way from being useful for most people.

The exception is this new research, published March 22 in Cell, which identifies the key cellular mechanisms behind vascular aging and the key role it plays on muscle health.

Scientists at Harvard Medical School, Massachusetts Institute of Technology (MIT) and the University of New South Wales used Nicotinamide Mononucleotide (NMN), a substance found in foods and naturally occurs in the body.

These researchers fed 400 mg/kg of NMN per day to 20-month-old mice, an age comparable to 70 years in people. After two months, the mice had increased muscular blood flow, enhanced physical performance and endurance and the old mice became as fit and strong as young mice.

AGING ARTERIES

We are as old as our arteries, the adage goes, so could reversing the aging of blood vessels hold the key to restoring youthful vitality?

In this study, the answer appears to be yes, at least in mice.

“We’ve discovered a way to reverse vascular aging by boosting the presence of naturally occurring molecules in the body that augment the physiological response to exercise,” said study senior investigator David Sinclair, Professor in the Department of Genetics and co-Director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School.

As we grow old, we become weak and frail. A constellation of physiological changes—some subtle, some dramatic — precipitate this inevitable decline.

As we age, our tiniest blood vessels wither and die, causing reduced blood flow and compromises oxygenation of organs and tissues. Vascular aging is responsible for a myriad of disorders, such as cardiac and neurological conditions, muscle loss, impaired wound healing and overall frailty.

Scientists have known that loss of blood flow to organs and tissues leads to the build-up of toxins and low oxygen levels. Endothelial cells — which line blood vessels — are essential for the growth of new blood vessels that supply oxygen-rich and nutrient-loaded blood to organs and tissues.

But as these endothelial cells age, blood vessels atrophy, new blood vessels fail to form and blood flow to most parts of the body gradually diminishes. This dynamic is particularly striking in skeletal muscle, which is highly vascularized and depends on a robust blood supply to function.

REDUCED BLOOD FLOW TO MUSCLES

Muscles begin to shrivel and grow weaker with age, a condition known as sarcopenia. The process can be slowed down with regular exercise, but even exercise becomes ineffective.

Sinclair and team wondered: What precisely curtails blood flow and precipitates this unavoidable decline? Why does even exercise lose its protective power to sustain muscle vitality? Is this process reversible?

In a series of experiments, the team found that reduced blood flow develops as endothelial cells start to lose a critical protein known as sirtuin1, or SIRT1. Supplementation with NMN boosts NAD+, stimulates SIRT1 and restores growth of endothelial cells.

RESULTS

After two months of receiving NMN, new blood vessels sprouted within the skeletal muscles of old mice. Capillary density increased and matched the capillary growth of young mice.

Remarkably, blood flow increased and the animals’ endurance (measured by how long they could run on a treadmill before before exhausting) was 56%-80% greater than that of untreated old mice: 1,400 feet compared to 780 feet.

Treated mice received the benefits of exercise just as mice half their age. In young animals, exercise spurs the creation of new blood vessels (neovascularization) and boosts muscle mass, which declines with age in both people and mice.

NMN restored the vascular system of old mice to that of young mice
Mice treated with NMN had a 1.6-fold increase in time and distance runs compared to untreated mice
In young, sedentary animals, NMN did not alter the capillarity or exercise capacity
In young animals, NMN + exercise resulted in 70% more capillaries than untreated, sedentary mice

NMN restored the blood-vessel- and muscle-boosting effects of a good treadmill run, basically “reversing vascular aging in the mice,” said study co-leader, David Sinclair of Harvard Medical School.

With exercise, the effect is even more dramatic: 32-month-old mice (equivalent to a 90-year-old human) were able to run on average TWICE as far as untreated mice.

The benefits of exercise diminish with time as decreased blood flow and muscle deterioration prevents adequate recovery. It is truly amazing that elderly animals were able to make such dramatic physiological improvements.

NMN BOOSTS NAD+

NMN is found in certain foods and effectively stimulates NAD+ metabolism, a coenzyme the mitochondria depend on to fuel all basic functions within cells. (3,4)

One function of NAD+ is to facilitate communication between the cell nucleus and the mitochondria that power all activity in our cells. (5,6,7)

In previous studies, scientists confirmed a direct link between falling NAD+ levels and aging in both animal and in human subjects and are learning that NAD+ precursors — NMN and NR — can restore NAD+ levels to prevent and even reverse aspects of aging.

NOT THE FIRST BIG NEWS FOR NMN OR DR SINCLAIR

This is not the first time NMN made headlines in anti-aging circles. The lead author for this study, Dr. David Sinclair, published research in 2013 that demonstrating:

Raising NAD+ levels in old mice restores mitochondrial function and homeostasis to that of young mice

Key biochemical markers of muscle health in 22-month-old mice returned to levels similar to 6-month-old mice

The 2013 study prompted more research on the benefits and safety of NMN, including this 2016 study, in which mice were treated with NMN for 12 months. The results showed:

NMN was able to mitigate most age-associated physiological decline in mice

Treatment of old mice with NMN reversed all of the biochemical aspects of aging

In a paper published in Science in 2017, Dr. Sinclair identified that the metabolite NAD+, which is naturally present in every cell of our body, has a key role as a regulator in protein-to-protein interactions that control DNA repair. Treating old mice with NMN improved their cells’ ability to repair DNA.

WHY THIS STUDY STANDS OUT

The potential of NMN has been known for over 5 years now, but this most recent study stands out because it:

Shows NEW growth (Angiogenesis) of blood vessels in OLD animals, which is very different than improvement in some metabolic markers that may be temporary.
Is the first time we have seen such a significant improvement in physical performance that actually allowed very old animals to perform as they did when young.
Renewed capillary growth and increased blood flow “reversed vascular aging” and may help reverse heart and neurological problems in addition to sarcopenia.

Remember, as we age, our arteries harden and atrophy resulting in decreased endurance and muscle loss.

Here, the process was not just halted, but REVERSED, with new growth. The number and density of capillaries was the same as in young animals. This is not a temporary phenomenon that might disappear as the body adjusts and homeostasis kicks in.

According to Dr. Sinclair, the same mechanism could also spur the creation of blood vessels in the brain, where “the lack of oxygen and buildup of waste products” (resulting from capillary loss) “sets off a downward spiral of disease and disability,” such as Parkinson’s and Alzheimer’s. This may be why studies with NMN and NR have proven effective in early studies of such neurological diseases.

Sinclair and his team are now studying whether increasing NAD+ levels will also spur the creation of blood vessels in the brain.

“Anything that contributes to muscle health through vascular health is likely to be quite important,” said the Buck Institute’s Verdin, who takes a daily NAD+ precursor.

There is great interest in anything that can improve angiogenesis and treat heart disease. Pharmaceutical companies have spent BILLIONS over the last 10 years testing various products. So far, all have failed. It’s interesting that the FDA insists any such medication must improve exercise performance in patients. It’s easy to see why Dr. Sinclair has plans for gaining approval for NMN as a pharmaceutical drug.

WHY WE THINK THESE RESULTS WILL BE REPLICATED IN HUMAN TESTING

Both NMN and NR boost NAD+ and have overlapping effects in studies. At least four clinical studies with humans given NMN supplements are ongoing or completed but not yet published. There have been three human studies published with NR that show results in humans that are similar to experiments in mice (r,r,r).

A study conducted by Elysium Health in 2017 using their product, Basis (NR + Pterostilbene), found improvements in mobility. 120 individuals aged 60-80 were given 250 mg or 500 mg of Basis daily for eight weeks. Those receiving the larger dose experienced: “7.8% improvement in chair stand and 7.5% improvement in distance walked.”

I wrote at the time that it is nice, but not overwhelming, especially since we don’t know if this increased mobility is at a plateau or may improve. Now, with these results from Dr. Sinclair’s latest research in mice over two months old, we see increased endurance on a much larger scale.

However, the improved capillary growth and blood flow behind the increased endurance would not occur quickly. Two months is a long time to a mouse that live around three years.

As humans live 30-40 times longer than mice, two months in mice time is like six years or so in humans.

If the improved endurance already found in human studies is due to the same increase in NAD+, Sirt1 and capillary growth, it would seem likely to continue and over six years might be similar to that of the 2-month experiment with mice.

We are awaiting results that show NMN works the same in humans, but we do have research that makes it plausible NMN could restore blood flow and physical performance as it does with mice.

Completed or in process human studies with NMN:

Japanese study with 100 mg and 200 mg per day
Dr. Sinclair company Metrobio study completed late 2017, with Phase 2 trials late 2018
University of Washington
Keio University

CONCERNS

Neovascularization—the formation of new blood vessels—should be treated with caution, the researchers say, because increased blood supply could inadvertently fuel tumor growth.

“The last thing you want to do is provide extra blood and nourishment to a tumor if you already have one,” said study co-author Lindsay Wu, at the University of New South Wales School of Medical Sciences.

Sinclair and Wu point out that experiments done provide no evidence treatment with NMN stimulated tumor development in animals treated with the compound.

MAXIMIZE BIOAVAILABILITY OF NMN

We do not believe the best answer is large dosages of oral supplements (capsules), but rather taking Sublingual NMN, as it is a more direct route to the blood and avoids the “first pass” metabolism (stomach, intestines, liver) that degrade a very large percentage of NMN and NR supplements.

From studies on sublingual absorption rates on other molecules, we are convinced sublingual NMN is much more effective, but it is difficult to assign a percentage to how much more.

There is no data on how much more effective NMN is in sublingual form. It’s also difficult to study sublingual absorption with mice as they don’t cooperate when trying to put substances under their tongue.

Our friends and customers do report MUCH better results from taking our NMN powder under the tongue.

We are confident humans will benefit from a more effective delivery method such as sublingual to increase bioavailability and experience the same benefits the mice did in this study at a more affordable dosage of 500-1000 mg per day. We are in contact with dozens of people that are using 1,000 mg per day sublingual.

DOSAGE

This study used 400 mg/kg a day, which equates to more than two GRAMS a day for a 70 kg human!

It is a little higher than most other studies with mice that use 100-300 mg/kg per day.

We don’t know if a smaller dose would be as effective as this large dose, so it’s possible that one gram a day in humans may also reverse aging in blood vessels and prompt new growth such as this study, but even one gram is a lot more than most people are taking.

The most recently published study of NR in humans by the University of Colorado Boulder found two dosages of 500 mg to be safe. They also found wide variation in the effect on NAD+ levels between individuals as shown in the chart at right.

So clearly, its impossible to recommend the exact dose needed for everyone. We base our recommendations on the sum total of all the research to date on NR and NMN, and take into consideration the anecdotal evidence we have from talking to hundreds of our users.

We believe Sublingual delivery is much more effective, so a smaller dose will provide the same benefit of a much larger dose of oral capsules.

With oral supplements (capsules) 1,000 mg is the most common estimate of the maximum amount that is useful, after which any additional precursor is excreted as NAM in the urine.

What we recommend:

Capsules: 500 – 1000 mg per day
Sublingual: 250 – 2,000 mg per day

We believe 1,000 mg sublingual will be MUCH more effective at reaching tissues throughout the body as opposed to capsules.

However, we don’t believe the same upper limit of 1,000 Mg applies to sublingual NMN, as it is not subject to the GI tract and first pass metabolism in the liver, so doesn’t end up as “expensive urine”

We hear reports from people using higher dosages of 1,500 to 2,000 Mg per day with phenomenal results.

Of course the cost is prohibitive for most people. We just mention it so people are aware of the potential. If you can afford it, we believe you don’t bump into the same ceiling on maximum effective dosage with Sublingual administration.

TIMING

Research studies provide great proof, but we also learn A LOT from chatting with customers.

Many users report increased performance in the gym, but we were surprised to hear that competitive runners and bodybuilders taking very large dosages (1,000 mg or more), before, during or just after training, felt it was much more effective.

We were skeptical ourselves, and didn’t actually try larger dosages until the last 45 days or so, when some of us started taking 375-500 mg SUBLINGUAL, just before exercise.

This is anecdotal evidence, but all reported such a significant effect that we now recommend taking NMN just before and after exercise.

Sublingual

50% of your daily dosage immediately before exercise
50% of your daily dosage immediately after exercise

Capsules

50% of you daily dosage one hour before exercise
50% of your daily dosage immediately after exercise

Ideally, take on days you will exercise, or likely to be more active. If you walking is the most exercise you are capable of, thats fine – just take NMN before and after.

We recommend taking NMN 5 days a week, with 2 days off.

CONCLUSION

According to Dr Wu:
“If these findings translate from mouse to human, we could have a revolutionary impact on the quality of life of older people, and not to mention the benefits of avoiding diseases of aging.”

“This new study adds to the body of work showing that the restoration of NAD+ in mammals can delay and reverse many of the effects of aging.”

Even Dr. Sinclair takes NMN to boost NAD+ levels. “In someone my age [49], it’s probably harder to see immediate benefits,” he said, though he said he feels sharper and younger from it. After his 78-year-old father began taking NMN, “he started climbing mountains and going whitewater rafting and looking forward to the next five years.”

There have been numerous studies documenting improvements from NMN and NR for a wide range of age-related issues, but this is the FIRST evidence that shows actual NEW GROWTH in OLD ANIMALS. NMN enabled them to perform as they did when young.

We are excited about the massive benefits this could bring to hundreds of millions of people. NMN is available now in capsules, and in powder form, which is perfect for what we believe is the more effective sublingual delivery method.

The post Research with NMN Demonstrates Age Reversal in Mice That May Apply to Humans appeared first on Alivebynature - Evidence Based Reviews.

HUMAN NAD+ METABOLISM

NAD+ is constantly being consumed and replenished through the Salvage Pathway, with approximately 3g of NAM metabolized to NMN and then to NAD+ 2-4 times per day (14).

The salvage pathway sustains 85% or more of our NAD+ (14)
Nampt is the rate-limiting step in the salvage process (97).
As we age, Nampt enzyme activity is lower, resulting in less NAM recycling, less NAD+, more disease and aging (97, 101).

Chromadex recently published a page (here) listing 16 reasons they think NR is superior to NMN. It’s really more like 2 or 3 points that they restate over and over in slightly different form.

We list those 16 reasons here, and provide a little context (in blue).

1. NMN is not a vitamin

NMN is not yet an established form of vitamin B3 because there are no clinical trials to prove it increases NAD in humans. NMN is also not the type of molecule that would ever be considered as a vitamin because it contains a phosphate.

Huh??? Has absolutely nothing to do with how it works.

2. NR is a vitamin

NR is a proven form of vitamin B3 which is required in small amounts to sustain healthy living. NR is shown in human studies to effectively increase NAD levels.

Huh??? Has absolutely nothing to do with how it works.

3. NMN contains a phosphate

NMN is really just an NR molecule with a phosphate. But that affects how efficiently NMN can create NAD. This phosphate makes it impossible for NMN to get into cells where NAD is created and used.

NR MUST be converted to NMN before it can become NAD+ – see the NAD+ Metabolism diagram below
Oral NMN is very quickly taken up and utilized by tissues throughout the body (below). Many studies show it does this MUCH FASTER than NR.
Dr Brenner showed that NMN does need to be converted to NR in a test tube, in 1 type of liver cell. This has not been demonstrated in the body, or in any other cells, and is contested by Dr Sinclair and other NAD+ researchers.

4. NR does not contain a phosphate

NR is the largest part of NAD that can enter the cell, which is why NMN supplements will turn into NR first before they are able to make NAD.

NR MUST be converted to NMN before it can become NAD+ – see the NAD+ Metabolism diagram above
Oral NMN is very quickly taken up and utilized by tissues throughout the body (below). Many studies show it does this MUCH FASTER than NR.
Dr Brenner showed that NMN does need to be converted to NR in a test tube, in 1 type of liver cell. This has not been demonstrated in the body, or in any other cells, and is contested by Dr Sinclair and other NAD+ researchers.

5. NMN requires 3 steps to make NAD

In its supplement form, NMN must lose its phosphate first before entering the cell. Then once inside the cell, it converts back into NMN to make NAD. In total this is a 3-step process.

NR MUST be converted to NMN before it can become NAD+ – see the NAD+ Metabolism diagram above
Oral NMN is very quickly taken up and utilized by tissues throughout the body (below). Many studies show it does this MUCH FASTER than NR.
Dr Brenner showed that NMN does need to be converted to NR in a test tube, in 1 type of liver cell. This has not been demonstrated in the body, or in any other cells, and is contested by Dr Sinclair and other NAD+ researchers.

6. NR starts making NAD in only 2 steps

NR can directly access the cell, so it only requires two steps to begin creating NAD.

NR MUST be converted to NMN before it can become NAD+ – see the NAD+ Metabolism diagram above
Oral NMN is very quickly taken up and utilized by tissues throughout the body (below). Many studies show it does this MUCH FASTER than NR.
Dr Brenner showed that NMN does need to be converted to NR in a test tube, in 1 type of liver cell. This has not been demonstrated in the body, or in any other cells, and is contested by Dr Sinclair and other NAD+ researchers.

7. NMN has 0 published human clinical studies

As of April 2018, NMN’s only published trials are in mice and rats.

Clinical Trials with NMN by Dr Sinclair and others have been completed and will be published soon – see below

8. NR has 3 published human clinical studies

NR has completed 5 clinical trials. 3 of them are published and the other 2 are pending publication. All 3 published clinical trials confirm NR is a safe and efficient way of increasing NAD in people.

Clinical Trials with NMN by Dr Sinclair and others have been completed and will be published soon – see below

9. NMN is mostly studied by injection

Despite NMN being sold as a pill, NMN is frequently studied through injections in rodents.

Not True – Early studies with NMN were done by injection. Since 2013, most studies with NMN have been done with oral supplements.
Studies using oral supplementation with NMN have shown far more dramatic results than those using NR (below)

10. NR is taken orally

In all 5 clinical trials, NR was administered in capsule form, which represents the recommended way of taking NR as a vitamin.

Clinical Trials with oral supplementation of NMN by Dr Sinclair and others have been completed and will be published soon – see below

11. NMN increases NAD by about 170%

In a 2016 study, NMN and NR were administered to mice in equal doses. NMN increased liver NAD levels by about 170% over baseline.

ONLY IN THE LIVER NR elevates NAD+ in the liver slightly more. NMN elevates NAD+ in the kidney slightly more. They have different effects on NAD+ in different cells throughout the body.
NAM (another form of B3) in that same study is shown to increase NAD+ in the liver more than NR. MANY supplements increase NAD+ in the liver

12. NR increases NAD by about 220%

In the same study, NR increased NAD levels by about 220% over baseline.

ONLY IN THE LIVER NR elevates NAD+ in the liver slightly more. NMN elevates NAD+ in the kidney slightly more. They have different effects on NAD+ in different cells throughout the body.
NAM (another form of B3) in that same study is shown to increase NAD+ in the liver more than NR. MANY supplements increase NAD+ in the liver

13. NMN has 0 safety studies in humans

As of April 2018, there are no data available stating whether or not NMN is safe for human consumption.

Clinical Trials with NMN by Dr Sinclair and others have been completed and will be published soon – see below

14. NR has 3 published clinical trials confirming it is safe for human consumption

Careful analysis of all the preclinical and clinical information available on NR confirm it is safe and well-tolerated.

Clinical Trials with NMN by Dr Sinclair and others have been completed and will be published soon – see below

15. NMN has no known safety status

As of April 2018, NMN has no safety notifications from the United States FDA.

Clinical Trials with NMN by Dr Sinclair and others have been completed and will be published soon – see below

16. NR has 2 FDA safety notifications

NIAGEN® has twice been successfully reviewed under FDA’s new dietary ingredient (“NDI”) notification program, and has also been successfully notified to the FDA as generally recognized as safe (“GRAS”).

Clinical Trials with NMN by Dr Sinclair and others have been completed and will be published soon – see below

SOME FACTS ABOUT NMN

Below are the clinical trial on NMN along with some of the reasons we agree with DR Sinclair that NMN is more effective than NR, with references and direct quotes from some of the research.

Digested to NAM

When taken orally as a supplement, most NR does not make it through the digestive system intact, but is broken down to NAM. This quote below is from the most recent review of Therapeutic Potential of NMN and NR.

Substantial fraction of orally administered NR is likely converted into nicotinamide by first-pass metabolism in the liver or by hydrolysis in the blood circulation before its uptake into other tissues (102)

For more info on how NR is converted to NAM in the body.

Not found in bloodstream

In both mice and humans, studies repeatedly failed to find any NR in the bloodstream at any time, even after very high dosages of NR (97, 98, 99).

The following quote from this Dr Brenner study also did not find NR in bloodstream after oral supplements, but was found in trace amounts after Injection

NR varied and displayed no response to NR administration… but was detected after IP of double labeled NR

A small fraction makes it intact to muscle
and other tissues outside Liver

The charts at left are from this 2016 study which used mice that have had the gene for Nampt ‘knocked out’ in quadricep muscle, so are unable to process NAM. As a result, the NAD+ levels drop to 15% of normal.

These mice were fed double labelled NR to track the movement of the NR through the body.

Any NR that makes it through digestion intact would be incorporated as double labelled NAD (M+2). NR that has been metabolized to NAM loses 1 heavy tracking molecule and would be found as M+1.

Chart D shows both single and double labelled NAD+ (green and red) are abundant in roughly equal amounts in the liver.

Chart C shows quite a lot of single labelled NAD+ in the muscle which is from NR that has been metabolized to NAM and then NMN.

We know this NAD+ was metabolized as NAM and then NMN because these mice lacked Nampt in muscle, so can not process NAM.

At the same time, there is only a tiny fraction of double labelled NAD+ in the muscle.

This demonstrates that NMN, but not NR was readily available for use in the Salvage Pathway inside the muscle.

Very Fast to Liver and muscle tissue

After oral NMN supplementation, levels of NMN in the bloodstream are quickly elevated and remain high longer than NAM, NA, or NR (18, 22, 97, 98, 99)

The chart at left shows levels of a double labeled NAD+ (C13-d-nad+) in liver and soleus muscle at 10 and 30 minutes after oral administration of double labeled NMN.

This clearly shows that NMN makes it way through the liver intact, through the bloodstream, into muscle, and is metabolized to NAD+ in 30 minutes (22).

Orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+in major metabolic tissues (22).

Elevates NAD+ quickly throughout the body

In this 2016 study, mice were given a single dose of NMN in water.

NMN levels in blood showed it is quickly absorbed from the gut into blood circulation within 2’“3 min and then cleared from blood circulation into tissues within 15 min

Increases NAD+ and Sirt1 Dramatically in organs

The charts at left from 2017 study, NMN supplementation for 4 days significantly elevated NAD+ and SIRT1, which protected the mice from Kidney damage.

NAD+ and SIRT1 levels were HIGHER in OLD Mice than in YOUNG Mice that did not receive NMN.

Research on NMN with Humans has been completed, but for various reasons none are yet published.

2016 Keio University Study – UMIN000021309
2017 Keio University Study – UMIN000030609 Phase 2, 8 weeks, 30 subjects
2017 Hiroshima University Study – UMIN000025739 24 weeks, 20 subjects, 100 & 200mg
2017 University of Washington Study – 8 weeks, 50 subjects
2017 Sinclair Metrobio study – Phase 1
2018 Sinclair Metrobio study – Phase 2

The Phase 1 study by Dr Sinclair has been completed, and they are ready to go forward with the Phase 2 study, so we can conclude there were positive results, and no negative side effects, else they would have to publish those immediately.

Studies listed on clinicaltrials.org such as that by the University of Washington provide more insight in advance. It appears to be much larger than the Japanese studies and investigates more health parameters. In that study, participants are 50 healthy women between 55 and 70 years of age with slightly high blood glucose,BMI and triglyceride levels.

Using a dose of 2 capsules of 125mg NMN per day over a period of 8 weeks, researchers are testing for:

change in beta-cell function
works to control blood sugar
blood vessels dilate
effects of NMN on blood lipids
effects of NMN on body fat
markers of cardiovascular and metabolic health

According to that study:

“Data from studies conducted in rodents have shown that NMN supplementation has beneficial effects on cardiovascular and metabolic health, but this has not yet been studied in people”

The active supplementation portion of this study has ended, but testing of metabolic parameters will continue for 2 years after supplementation has ended. So researchers know the immediate effects and preliminary results are expected to be announced in 2018, with final results expected in 2020.

The post Some FACTS about NR and NMN appeared first on Alivebynature - Evidence Based Reviews.

Since mid 2016, we’ve been noticing that Research with Nicotinamide Mononucleotide (NMN) seemed to have more dramatic results than studies using Nicotinamide Riboside (NR), and wondered why.

Recently published research with NMN and NR are good examples of the difference.

In Dr Sinclairs latest study, the mice that received NMN had nearly twice the endurance of the control mice, and actually grew NEW blood vessels. This was after 60 days, in 20 month old mice (equivalent to 90 year old humans).

In Nov 2017 Elysium Health published a study using Basis brand NR on 60-80 year old humans that showed a 7% improvement in endurance after 60 days. Not bad at all – but a long way from near 100% improvement in the Sinclair study using NMN.

In looking at the details from these 2 studies we notice another stark difference.

The NAD+ increase measured in the liver using Basis started out over 90%, but dropped to 40-55% by the end of the trial. It appears that Homeostasis is limiting the long term increase of NAD+ using NR.

The Single dose of 250 Mg NR results in 40% NAD+ increase at 60 days. With the double dose of 500 Mg NR, NAD+ increase is down to 55% at 60 days, and isis likely to continue dropping down to the 40% level.

Older humans such as those in this study generally have about half the NAD+ they did when young, so would need to see around 100% increase to return to youthful levels.

In contrast, the Sinclair study shows over 500% increase in NAD+ levels at 60 days – homeostasis is NOT limiting the effectiveness of NMN in restoring NAD+ levels.

This may be the reason NMN is effective in this long term (12 month) study.
* Note: There have been NO similar studies with NR longer than 3 months

40-55% NAD+ increase with NR

A single dose of NR has been shown to increase NAD+ by 270%. However, homeostasis soon kicks in and this declines after a few weeks. Increasing the dosage of NR does not provide any further benefit.

The chart at left shows this increase of 270% combined with data from this study by Elysium Health published in 2017.

This shows that with NR, homeostasis kicks in around 30 days and the NAD+ increase drops from 90% to 55% .

OVER 500% NAD+ increase with NMN ?

The chart at right shows NAD+ increase measured in the liver (and soleus muscle) after 60 days of supplementation with NMN (Sinclair, 2018).

We doubt that other studies will confirm a 500% increase as this study shows, but whatever the true value is, it does seems that the HUGE increase in liver indicates homeostasis is not limiting the NAD+ increase from NMN supplementation in this study.

FAR more increase of NAD+ from NMN

Homeostasis refers to the ability of the body or a cell to seek and maintain a condition of equilibrium or stability within its internal environment when dealing with external changes.

Although NR and NMN are very similar in their effect on NAD+ levels from a single dose, homeostasis appears to impact NR much more quickly than NMN, impacting its ability to maintain increased levels of NAD+.

Homeostasis limits the long-term increase of NAD+ with NR.
NMN is effective at much higher dosages for much longer than NR.

ANTI-AGING RESULTS WITH NMN

Dozens of research studies have been published showing benefits of NR and NMN supplementation in various disease and illness, with much overlap in their effects (5,6,7,9,10,11,13,14,15,16).

However, the most dramatic results have been those showing old mice that look and perform the same as young mice.

Below are the three studies that made the biggest splash’s about the potential for reversing aging by restoring NAD+ to youthful levels.

These have ALL been accomplished using NMN

Their have been NO studies with NR showing comparable improvements in strength, endurance, vascularity, and muscle growth, with normal, healthy subjects (There are successful studies with NR where mice are genetically modified to replicate disease models).

We don’t believe that is a coincidence, but a result of the homeostasis effect with NR that limits its long term effectiveness.

After 6 days of NMN, 22 month old mice had the muscle capacity, endurance and metabolism of 6 month old mice (2013 Sinclair study)

NMN effectively mitigates age-associated physiological decline in mice (2016 Mills Long Term study)

“The old mice became as fit and strong as young mice” (Sinclair, 2018)

We found the 2018 study the most impressive, as the old mice actually grew new, and more, blood vessels that led to double the endurance of those that did not receive supplements. Read more about this latest study.

Treating Heart Disease

2 separate studies to treat a form of heart disease called Friedreich’s Ataxia with NR and NMN were published in 2017. Treatment with NMN was successful, while NR did not improve cardiac function.

“Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. “(Martin, 2017)

“In conclusion, NAD+ supplementation with NR in the FRDA model of mitochondrial heart disease does not alter SIRT3 activity or improve cardiac function.”(Stram, 2017)

COMBATTING ALZHEIMERS DISEASE

Alzheimer’s disease (AD) pathogenesis is widely believed to be driven by the production and deposition of the β-amyloid peptide (Aβ). Evidence now indicates that the solubility of Aβ, and the quantity of Aβ in different pools is related to disease state (r).Researchers believe that flaws in the processes governing production, accumulation or disposal of beta-amyloid are the primary cause of Alzheimer’s (r).

In studies published in 2017 and 2018 NMN decreased β-amyloid buildup, while NR did not.

“NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polβ+/− mice but had no impact on amyloid β peptide (Aβ) accumulation”(Hou, 2018)

“NMN decreased β-amyloid production, amyloid plaque burden, synaptic loss, and inflammatory responses in AD-Tg mice” (Yao, 2017)

NMN was able to mitigate most age-associated physiological declines in mice Treatment of old mice with NMN reversed all of these biochemical aspects of aging

Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice (mills, 2016)

Raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse

Restore the mitochondrial homeostasis and key biochemical markers of muscle health in a 22-month-old mouse to levels similar to a 6-month-old mouse

Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (Gomes, Sinclair,2013)

DNA Repair

This study showed supplementation with NMN was able to repair the DNA in cells damaged by radiation

The cells of old mice were indistinguishable from young mice after just one week of treatment.

A conserved NAD+ binding pocket that regulates protein-protein interactions during aging (Sinclair, 2017)

WEIGHT

NMN was immediately utilized and converted to NAD+ within 15 min, resulting in significant increases in NAD+ levels over 60 min

Administering NMN, a key NAD+ intermediate, can be an effective intervention to treat the pathophysiology of diet- and age-induced T2D

Surprisingly, just one dose of NMN normalized impaired glucose tolerance

Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice (Yoshino, 2011)

NAD(+) levels were increased significantly both in muscle and liver by NMN

NMN-supplementation can induce similar reversal of the glucose intolerance

NMN intervention is likely to be increased catabolism of fats NMN-supplementation does mimic exercise

Head to Head Comparison of Short-Term Treatment with the NAD(+) Precursor Nicotinamide Mononucleotide (NMN) and 6 Weeks of Exercise in Obese Female Mice (Uddin, 2016)

NMN treatment reduces brain cell death and oxidative stress These results further support the neuroprotection of NMN/NAD+

Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway (Wei, 2017)

We now demonstrate that mitochondrial respiratory function was restored

Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model (Long, 2015)

NMN could restore cognition in AD model rats

Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death (Wang, 2016)

NMN Treatment Rescues Cognitive impairments

Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease (Yao, 2017)

NMN significantly increased the level of NAD+ in the heart

NMN protected the heart from I/R injury

Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and repercussion (Yamamoto, 2014)

NMN reduces vascular oxidative stress

NMN treatment normalizes aortic stiffness in old mice

NMN represents a novel strategy for combating arterial aging

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice (de Picciotto, 2016)

NMN can reduce myocardial inflammation NMN thus can cut off the initial inflammatory signal, leading to reduced myocardial inflammation

Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure (Zhang, 2017)

ENERGY

Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels.

Restoration of cardiac function and energy metabolism upon NMN supplementation

Remarkable decrease in whole-body EE and cardiac energy wasting

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

VISION

Exogenous NMN prevents photoreceptor degeneration and restores vision

NMN rescues retinal dysfunction in light-induced degeneration

NAMPT-mediated NAD+ biosynthesis is essential for vision in mice (lin, 2016)

Completed and pending publication

2016 Keio University Study – UMIN000021309
2017 Keio University Study – UMIN000030609 Phase 2, 8 weeks, 30 subjects
2017 Hiroshima University Study – UMIN000025739 24 weeks, 20 subjects, 100 & 200mg
2017 University of Washington Study – 8 weeks, 50 subjects
2017 Sinclair Metrobio study – Phase 1

Beginning 2018

2018 Sinclair Metrobio study – Phase 2

In the University of Washington study, participants are 50 healthy women between 55 and 70 years of age with slightly high blood glucose,BMI and triglyceride levels.

Using a dose of 2 capsules of 125mg NMN per day over a period of 8 weeks, researchers are testing for:

change in beta-cell function
works to control blood sugar
blood vessels dilate
effects of NMN on blood lipids
effects of NMN on body fat
markers of cardiovascular and metabolic health

Very Fast to Liver and muscle tissue

After oral NMN supplementation, levels of NMN in the bloodstream are quickly elevated and remain high longer than NAM, NA, or NR (18, 22, 97, 98, 99)

The chart at left shows levels of a double labeled NAD+ (C13-d-nad+) in liver and soleus muscle at 10 and 30 minutes after oral administration of double labeled NMN.

This clearly shows that NMN makes it way through the liver intact, through the bloodstream, into muscle, and is metabolized to NAD+ in 30 minutes (22).

Orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+in major metabolic tissues (22).

Elevates NAD+ quickly throughout the body

In this 2016 study, mice were given a single dose of NMN in water.

NMN levels in blood showed it is quickly absorbed from the gut into blood circulation within 2’“3 min and then cleared from blood circulation into tissues within 15 min

Increases NAD+ and Sirt1 Dramatically in organs

The charts at left from 2017 study, NMN supplementation for 4 days significantly elevated NAD+ and SIRT1, which protected the mice from Kidney damage.

NAD+ and SIRT1 levels were HIGHER in OLD Mice than in YOUNG Mice that did not receive NMN.

REFERENCES:

The post WHY NMN IS MORE EFFECTIVE THAN NR appeared first on Alivebynature - Evidence Based Reviews.

Dr. David Sinclair, Co-Director of the Biological Mechanisms of Aging at Harvard Medical School was named to the Times Magazine list of “Most Influential People in the World” after his research found a key cause of aging and a potential weapon to reverse it.

He and his team found that as we age, our cells become less and less efficient due to the lack of an essential metabolite called Nicotinamide Adenine Dinucleotide (NAD+).

WHAT IS NAD+

NAD+ is a key co-enzyme that the mitochondria in every cell of our bodies depend on to fuel all basic functions. (3,4)

NAD+ play a key role in communicating between our cells nucleus and the Mitochondria that power all activity in our cells (5,6,7)

Scientists have now confirmed a direct link between falling NAD+ levels and aging in both animal and in human subjects.

Read more about NAD+

NAD+ DECLINES WITH AGE

As we age, our bodies produce less NAD+ and the communication between the Mitochondria and cell nucleus is impaired. (5,8,10).

Over time, decreasing NAD+ impairs the cell’s ability to make energy, which leads to aging and disease (8, 5) and perhaps even the key factor in why we age (5).

Read more about NAD+

NAD+ METABOLISM IN HUMANS

NAD+ can be synthesized in humans from several different molecules (precursors), thru the De Novo and Salvage Pathways.

The salvage pathway sustains 85% or more of our NAD+ (14), with approximately 3g of NAM metabolized to NMN and then to NAD 2-4 times per day (14).

Nampt is the rate-limiting step in the salvage process (97).

NMN BYPASSES THE NAMPT BOTTLENECK

As we age, Nampt enzyme activity is lower, resulting in less NAM recycling, less NAD+, more disease and aging (97,101).

All NAD+ supplements can restore NAD+ in the Liver but does not solve NAD+ deficiency throughout the body as NAD+ cannot readily pass through the cellular membrane.

Muscle tissue, for example, depends on cells internal recycling of NAD+ through the salvage pathway which is controlled by intercellular Nampt.

WHY NMN

Since mid 2016, we’ve been noticing that Research with Nicotinamide Mononucleotide (NMN) seemed to have more dramatic results than studies using Nicotinamide Riboside (NR), and wondered why.

Recently published research with NMN and NR are good examples of the difference.

In Dr Sinclairs latest study, the mice that received NMN had nearly 100% increased endurance vs the control mice, and actually grew NEW blood vessels. This was after 60 days, in 20 month old mice (equivalent to 90 year old humans).

In Nov 2017 Elysium Health published a study using Basis on 60-80 year old humans that showed a 7% improvement in endurance with NR after 60 days. Not bad at all – but a long way from near 100% improvement in the Sinclair study using NMN.

In looking at the details from these 2 studies we notice another stark difference.

The Single dose of 250 Mg NR results in 40% NAD+ increase at 60 days. With the double dose of 500 Mg NR, NAD+ increase is 55% at 60 days, and is likely to continue dropping down to the 40% level.

Older humans such as those in this study generally have about half the NAD+ they did when young, so would need to see around 100% increase to return to youthful levels.

In contrast, the Sinclair study shows NAD+ increase is over 500% at 60 days
– clearly, homeostasis is NOT limiting the effectiveness of NMN in restoring NAD+ levels in this study.

This may be the reason NMN is effective in this long term (12 month) study.
* Note: There have been NO similar studies with NR longer than 3 months

40-55% NAD+ increase with NR

A single dose of NR has been shown to increase NAD+ by 270%. However, homeostasis soon kicks in and this declines after a few weeks. Increasing the dosage of NR does not provide any further benefit.

The chart at left shows this increase of 270% combined with data from this study by Elysium Health published in 2017.

This shows that with NR, homeostasis kicks in around 30 days and the NAD+ increase drops from 90% to 55% .

OVER 500% NAD+ increase with NMN ?

The chart at right shows NAD+ increase measured in the liver (and soleus muscle) after 60 days of supplementation with NMN (Sinclair, 2018).

FAR more increase of NAD+ from NMN

Homeostasis refers to the ability of the body or a cell to seek and maintain a condition of equilibrium or stability within its internal environment when dealing with external changes.

Homeostasis limits the long-term increase of NAD+ with NR.
NMN is effective at much higher dosages for much longer than NR.

ANTI-AGING RESULTS WITH NMN

Dozens of research studies have been published showing benefits of NR and NMN supplementation in various disease and illness, with much overlap in their effects (5,6,7,9,10,11,13,14,15,16).

However, the most dramatic results have been those showing old mice that look and perform the same as young mice.

Below are the three studies that made the biggest splash’s about the potential for reversing aging by restoring NAD+ to youthful levels.

These have ALL been accomplished using NMN

We don’t believe that is a coincidence, but a result of the homeostasis effect with NR that limits its long term effectiveness.

After 6 days of NMN, 22 month old mice had the muscle capacity, endurance and metabolism of 6 month old mice (2013 Sinclair study)

NMN effectively mitigates age-associated physiological decline in mice (2016 Mills Long Term study)

“The old mice became as fit and strong as young mice” (Sinclair, 2018)

Treating Heart Disease

2 separate studies to treat a form of heart disease called Friedreich’s Ataxia with NR and NMN were published in 2017. Treatment with NMN was successful, while NR did not improve cardiac function.

“Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. “(Martin, 2017)

“In conclusion, NAD+ supplementation with NR in the FRDA model of mitochondrial heart disease does not alter SIRT3 activity or improve cardiac function.”(Stram, 2017)

COMBATTING ALZHEIMERS DISEASE

In studies published in 2017 and 2018 NMN decreased β-amyloid buildup, while NR did not.

“NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polβ+/− mice but had no impact on amyloid β peptide (Aβ) accumulation”(Hou, 2018)

“NMN decreased β-amyloid production, amyloid plaque burden, synaptic loss, and inflammatory responses in AD-Tg mice” (Yao, 2017)

NMN was able to mitigate most age-associated physiological declines in mice Treatment of old mice with NMN reversed all of these biochemical aspects of aging

Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice (mills, 2016)

Raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse

Restore the mitochondrial homeostasis and key biochemical markers of muscle health in a 22-month-old mouse to levels similar to a 6-month-old mouse

Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (Gomes, Sinclair,2013)

DNA Repair

This study showed supplementation with NMN was able to repair the DNA in cells damaged by radiation

The cells of old mice were indistinguishable from young mice after just one week of treatment.

A conserved NAD+ binding pocket that regulates protein-protein interactions during aging (Sinclair, 2017)

WEIGHT

NMN was immediately utilized and converted to NAD+ within 15 min, resulting in significant increases in NAD+ levels over 60 min

Administering NMN, a key NAD+ intermediate, can be an effective intervention to treat the pathophysiology of diet- and age-induced T2D

Surprisingly, just one dose of NMN normalized impaired glucose tolerance

Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice (Yoshino, 2011)

NAD(+) levels were increased significantly both in muscle and liver by NMN

NMN-supplementation can induce similar reversal of the glucose intolerance

NMN intervention is likely to be increased catabolism of fats NMN-supplementation does mimic exercise

Head to Head Comparison of Short-Term Treatment with the NAD(+) Precursor Nicotinamide Mononucleotide (NMN) and 6 Weeks of Exercise in Obese Female Mice (Uddin, 2016)

NMN treatment reduces brain cell death and oxidative stress These results further support the neuroprotection of NMN/NAD+

Nicotinamide mononucleotide attenuates brain injury after intracerebral hemorrhage by activating Nrf2/HO-1 signaling pathway (Wei, 2017)

We now demonstrate that mitochondrial respiratory function was restored

Effect of nicotinamide mononucleotide on brain mitochondrial respiratory deficits in an Alzheimer’s disease-relevant murine model (Long, 2015)

NMN could restore cognition in AD model rats

Nicotinamide mononucleotide protects against β-amyloid oligomer-induced cognitive impairment and neuronal death (Wang, 2016)

NMN Treatment Rescues Cognitive impairments

Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease (Yao, 2017)

NMN significantly increased the level of NAD+ in the heart

NMN protected the heart from I/R injury

Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and repercussion (Yamamoto, 2014)

NMN reduces vascular oxidative stress

NMN treatment normalizes aortic stiffness in old mice

NMN represents a novel strategy for combating arterial aging

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice (de Picciotto, 2016)

NMN can reduce myocardial inflammation NMN thus can cut off the initial inflammatory signal, leading to reduced myocardial inflammation

Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure (Zhang, 2017)

ENERGY

Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels.

Restoration of cardiac function and energy metabolism upon NMN supplementation

Remarkable decrease in whole-body EE and cardiac energy wasting

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

VISION

Exogenous NMN prevents photoreceptor degeneration and restores vision

NMN rescues retinal dysfunction in light-induced degeneration

NAMPT-mediated NAD+ biosynthesis is essential for vision in mice (lin, 2016)

Completed and pending publication

2016 Keio University Study – UMIN000021309
2017 Keio University Study – UMIN000030609 Phase 2, 8 weeks, 30 subjects
2017 Hiroshima University Study – UMIN000025739 24 weeks, 20 subjects, 100 & 200mg
2017 University of Washington Study – 8 weeks, 50 subjects
2017 Sinclair Metrobio study – Phase 1

Beginning 2018

2018 Sinclair Metrobio study – Phase 2

In the University of Washington study, participants are 50 healthy women between 55 and 70 years of age with slightly high blood glucose,BMI and triglyceride levels.

Using a dose of 2 capsules of 125mg NMN per day over a period of 8 weeks, researchers are testing for:

change in beta-cell function
works to control blood sugar
blood vessels dilate
effects of NMN on blood lipids
effects of NMN on body fat
markers of cardiovascular and metabolic health

Very Fast to Liver and muscle tissue

After oral NMN supplementation, levels of NMN in the bloodstream are quickly elevated and remain high longer than NAM, NA, or NR (18, 22, 97, 98, 99)

The chart at left shows levels of a double labeled NAD+ (C13-d-nad+) in liver and soleus muscle at 10 and 30 minutes after oral administration of double labeled NMN.

This clearly shows that NMN makes it way through the liver intact, through the bloodstream, into muscle, and is metabolized to NAD+ in 30 minutes (22).

Orally administered NMN is quickly absorbed, efficiently transported into blood circulation, and immediately converted to NAD+in major metabolic tissues (22).

Elevates NAD+ quickly throughout the body

In this 2016 study, mice were given a single dose of NMN in water.

NMN levels in blood showed it is quickly absorbed from the gut into blood circulation within 2’“3 min and then cleared from blood circulation into tissues within 15 min

Increases NAD+ and Sirt1 Dramatically in organs

The charts at left from 2017 study, NMN supplementation for 4 days significantly elevated NAD+ and SIRT1, which protected the mice from Kidney damage.

NAD+ and SIRT1 levels were HIGHER in OLD Mice than in YOUNG Mice that did not receive NMN.

REFERENCES:

The post CAN NMN REALLY REVERSE AGING? appeared first on Alivebynature - Evidence Based Reviews.

The main ingredient in Elysium Health’s Basis is Nicotinamide Riboside.

Elysium Health is only one of several companies selling Nicotinamide Riboside. Their main selling point is the 6 Nobel Prize winning scientists they have signed up as advisors to their company.

However, these scientists have had no significant role in researching or creating the Nicotinamide Riboside or the Pterostilbene they combine with it to form their Basis product.

WHY BASIS – IS IT BETTER THAN OTHER BRANDS OF NICOTINAMIDE RIBOSIDE?

You won’t find any mention of Niagen in the sales and marketing literature about Basis.

Elysium would like you to think that Basis is some exclusive formula created by their founders.

In fact, until recently, they purchased Nicotinamide Riboside AND Pterostilbene from Chromadex like several other brands.

In mid 2017, a nasty lawsuit between Chromadex and Elysium Health resulted in a new formulation for Basis that uses Nicotinamide Riboside they manufacture themselves.

Conclusion: There is no reason to believe Basis is any more effective than any other Nicotinamide Riboside.

SUPPLEMENTS TO RESTORE NAD+

NMN is not patented and is available to purchase from several different brands. Both Elysium Health and Chromadex market NR capsules.

All have shown great promise in research with mice. While we are still awaiting publication of the first studies of humans with NMN supplements, research has shown NR is effective at elevating NAD+ levels in humans.

However, it is a question if oral supplementation with NAD+ precursors will result in some of the same health benefits demonstrated in studies with mice.

Dr Sinclair’s 2013 study used IP Injections to deliver NMN directly to the bloodstream, enabling it to reach tissues throughout the body more effectively.

In the most recent study by Dr Sinclair, they put NMN in the drinking water of mice at a dosage of 400 mg per kg of bodyweight. This would equate to several grams per day in humans and be extremely expensive.

Limited bioavailability of oral supplements is a big problem. Recent research confirms that oral supplementation of NR and NMN is subject to digestion and first pass metabolism in the liver. Very little actually makes it outside the liver to reach other tissues directly.

SUBLINGUAL DELIVERY

Injections are not feasible for most people, so a more effective delivery method is needed. Introduced in late 2017, a popular option is a Pure NMN powder that users take under the tongue (Sublingually) where it is quickly absorbed directly into the bloodstream, avoiding the digestive system entirely.

Soon you will also be able to purchase a fast dissolve tablet designed for sublingual administration, providing the same benefits as the pure powder, in a more convenient form.

THE PROBLEM with CAPSULES – DIGESTED IN STOMACH

It has also long been suspected that most NR is digested to NAM in the Gastro-Intestinal tract intact (r).

More recently, this research published in 2018 confirms that most oral supplements of NMN and NR are digested to NAM in the GI tract or the liver.

Future pharmacological and nutraceutical efforts to boost NAD will need to take into account the minimal oral bioavailability of NR and NMN (R)

We also showed that intravenous, but not oral administration of NR or NMN delivered intact molecules to multiple tissues (R)

Unlike in cell culture where NR and NMN are readily incorporated into NAD, oral administration fails to deliver NR or NMN to tissues (R)

Interestingly, we found that neither compound was able to enter the circulation intact in substantial quantities when delivered orally (R)

The most recent studies showing tremendous health benefits with NMN were accomplished by feeding mice very large dosages of NMN in water (r). However the dosage of 300-400 mg per kg of bodyweight used in many of these studies would equate to approximately 2,000 Mg per day for a 70 kg human. A more effective delivery method is needed !

SUBLINGUAL VS CAPSULES

Sublingual (under the tongue) delivery can provide rapid absorption via the blood vessels under the tongue rather than via the digestive tract. (r,r)

The absorption of the different molecules delivered through the sublingual route can be 3 to 10 times greater than oral route and is only surpassed by direct IV injection (r).

SUBLINGUAL CAN BE MORE BIOAVAILABLE THAN INJECTION !

With intraperitoneal injection, the primary route of absorption is via the mesenteric vessels, which drain into the portal vein and pass through the liver before reaching the bloodstream.

This means, IP avoids the GI tract, but is still sent directly to the Liver, where much of it is converted to NAD+. Elevated NAD+ in the liver is good, but its far better to reach the bloodstream with intact NMN.

Sublingual delivery is not filtered by the Liver and can reach systemic circulation intact, so can actually result in greater bioavailability that direct injection! Some examples are:

A sublingual formulation of zol… exhibited a faster rate of absorption and higher drug exposure as compared to subcutaneous injection (r)
sublingually administered epin… results in more rapid absorption and a higher peak plasma concentration compared to injected epin… .(r)
40mg of sublingually administered pir.. was found to be as effective as a 75 mg intramuscular injection of dicl… (r)

NMN PERFECT FOR SUBLINGUAL

Depending on the molecule, Sublingual delivery can substantially improve the speed and bioavailability. Smaller molecules that are hydrophilic such as NMN are well-suited.

a drug which has been formulated for sublingual should ideally have a molecular weight of less than 500 (r)

NMN is very hydrophilic, with a molecular weight of 324, making it a perfect fit for sublingual delivery.

New research shows that NMN and NR are mostly digested to Nicotinamide when taken as oral supplements (r). Sublingual delivery of small, hydrophilic molecules such as NMN bypass the digestive system and can be quickly absorbed to the bloodstream making it far more bioavailable than capsules.

CONCLUSION

Elysium Health produces a top quality product, and is a very reputable company.

However, they did not develop Nicotinamide Riboside and there is no evidence the addition of Pterostilbene makes their Basis product any more effective.

The distinguished scientists on their advisory board lend great credibility to the reputation of the company and are a great advantage for marketing purposes.

REFERENCES:

The post Is Basis by Elysium Health a Hoax? appeared first on Alivebynature - Evidence Based Reviews.