Nicotinamide Riboside fights aging liver disease in Mice

NR liver disease5Increasing evidence about the importance NAD+ levels in the body continuous to emerge.

This week reseachers in China released a report indicating a link between the onset of nonalcoholic fatty liver disease (NAFLD) and the aging associated decline in NAD+ level.

Further more they found that supplementation with nicotinamide riboside in a NAD+ deficient mice model completely corrected these NAFLD onset symptoms.

Aging is known to be an important risk factor of nonalcoholic fatty liver disease (NAFLD). The researchers wanted to know whether the whether the deficiency of nicotinamide adenine dinucleotide (NAD+) that develops with aging may be the cause or part of the cause.

They setup an experiment that firstly compared NAD+ concentration, together with the protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD+ biosynthesis, between middle-aged and aged mice or human patients.

NR liver diseaseIn addition the influences of NAD+ decline on the steatosis (infiltration of liver cells with fat) and steatohepatitis (type of liver disease, characterized by inflammation of the liver with fat accumulation in liver) was evaluated in wild-type (WT) and H247A dominant-negative enzymatic-dead NAMPT transgenic mice (DN-NAMPT) under normal and high-fat diet (HFD).

The found that hepatic NAD+ level (NAD+ level in the liver) decreased in aged mice and also people. NAMPT-controlled NAD+ salvage, but not de novo biosynthesis pathway, was compromised in the liver of elderly mice and human.

 

NR liver disease3The experiment also revealed that under normal diet, middle-age DN-NAMPT mice displayed systemic NAD+ reduction, and had moderate NAFLD phenotypes, like lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in liver.

A high fat diet worsened these NAFLD sympthoms.

 

A diet that contained nicotinamide riboside however, a natural NAD+ precursor, completely corrected these NAFLD onset sympthoms that were induced by NAD+ deficiency alone or the high fat diet.

From an experiment to evaluate whereas an adenovirus-mediated SIRT1 overexpression would reverse NAFLD phenotypes also it was found that this only partially corrected the disease sympthoms.

NR liver disease2Overall this contributes further to the evidence that aging-associated NAD+ deficiency is a critical risk factor for aging related diseases.

In this study it was shown that supplementation of nicotinamide riboside may be a promising therapeutic strategy to prevent and treat NAFLD.

This article will in the future be updated with dosing related information once that comes available so we can calculate the human equivalent dose.

You can find the article here.

Nicotinamide Riboside helps alleviate problems from diabetes in Mice

NR diabetes1 In a study that perhaps more serves as proof that NAD+ deficiency plays a role in diabetes researchers used high levels of nicotinamide riboside supplementation to demonstrate it protects mice from diabetes complications.

There is an association between prediabetic polyneuropathy (PDPN)1 and obesity, about half of individuals with diabetes will also suffer from diabetic peripheral neuropathy (DPN)2, which makes them insensitive to heat and touch.

This condition can progress to foot ulcers and amputations. Unfortunately there are few treatments that are effective for obesity while there are no known treatments for DPN. Best available care is tight glycemic control, lifestyle changes centered on dietary improvement and exercise, and pain medication when DPN is painful.

The researchers noted that in prior research there are indications that supplementation with nicotinamide riboside (NR), a NAD+ precursor vitamin can improve metabolic health in overfed mice. They also noted that research indicates that NR has an ability to protect damaged neurons.

Because of this dual potential the researchers hypothized that NR may improve prediabetic (PD) and diabetic glucose and lipid metabolism while simulatanuously treating the neuropathic complications that come with DPN. The researchers tested the potential positive effect of NR in mouse models.

NR diabetes2A large cohort of mice was used in the experiment and several comparison groups created, increasing its relevance.

Out of a group of 60 mice 40 were transferred to a HFD and 20 mice stayed on normal diet. Of the 40 mice 20 were given 20 STZ, a chemical that induces type 2 diabetes (T2D). Finally of each group 10 mice were given NR supplementation at a dosing level of 3g/Kg/day. The groups were then studied for various disease indicators.

The study found that NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy.

In type 2 diabetes mice the results showed that NR strongly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The researchers concluded that the neuroprotective effect of NR could not be explained by glycemic control alone.

They therefore used corneal confocal microscopy to analyse deeper. This revealed a protective effect of NR on small nerve structures in living mice. It was established that hepatic NADP+ and NADPH levels were significantly degraded in prediabetes and type 2 diabetes but were largely protected when mice were supplemented with NR.

The dosing, as mentioned earlier, was very high at 3g/Kg/day. Using FDA specified guidelines  we can calculate the Human Equivalent Dose (HED) for the NR diet given to the mice. Using this guideline 3g/kg dosing in mice translates into a HED of approx. 240mg/kg.

Or into approximately 17 gram daily nicotinamide riboside dose for a person weighing 70kg. Typical supplements on the market have serving sizes of 250mg. It should be noted that this dose is well over the limit wrt to side effects and safety.

NR diabetes4Nevertheless the data calls for further investigation e.g. repetition at lower dosing and possibly testing of NR in human models of obesity, type 2 diabetes and associated neuropathies.

Given the current dosing ranges it appears likely that a therapeutic approach will need to be done under medical supervision. It should be noted that there are also alternative supplements that hold promise for treatment of diabetes.

You can find the study here.

Why NAD+ Declines during Aging: It’s Destroyed

NAD+ is required not only for life but for a long life. In this issue, Camacho-Pereira et al. (2016) implicate CD38 in the decline of NAD+ during aging, with implications for combating age-related diseases.

In this issue, Eduardo Chini and col- leagues address an open question in bio- gerontology: why do NAD+ levels fall as we age? They show that the major culprit is an NADase called CD38 whose levels rise during aging. Their results also add to the body of evidence indicating that loss of SIRT3 activity in mitochondria is a cause of age-related metabolic decline (Camacho-Pereira et al., 2016) (Figure 1).

Finally, the authors addressed how CD38 may affect therapies designed to raise NAD+ levels. Currently, the favored approach in mouse and humans is to treat with NAD+ precursors, such as nicotinamide riboside (NR) or nicotin- amide mononucleotide (NMN).

Interest- ingly, CD38 not only degrades NAD+ in vivo, but also NMN. When CD38 knockout mice were given injections of NAD+, NMN, or NR (which is converted to NMN), circulating levels of NAD metab- olites remained stable after 150 min, long after they began to fall in the wild-type animals. Furthermore, when compared to the wild-type, CD38 knockout mice on a high-fat diet exhibited a much larger improvement in glucose tolerance when given NR.

These findings suggest that the efficacy of NAD+ precursors may be enhanced by co-supplementation with CD38 inhibitors, which have been recently identified (Escande et al., 2013; Haffner et al., 2015).

Article published here

Michael B. Schultz1 and David A. Sinclair

 

Do SuperGreens like MetaboGreens 45X really work?

amazing-grass-supergreens-targetBelow is one of the dozens of emails I get everyday pitching some kind of nutrition or weight loss product like garcinia cambogia or some such.

Most are worthless. Some might be useful, but are ridiculously overpriced.  But every now and then I run across one that seems to actually be a good product AND well priced.  This is one of the better ones.

 

“Today I’m going to reveal the exciting details about a brand new, amazingly delicious superfood elixir that fitness professionals, nutritionists, moms and dads, and seniors alike—all over the world—are proclaiming as “the best-tasting greens product on the planet”…and when you savor its delicious & sweet berry flavor for yourself, you’ll understand exactly why that is. It’s called MetaboGreens 45X™, and yes, it really does taste THAT good.

Now, if you’ve ever tasted another greens product, you realize just how big of a deal this is, as almost all other greens powders and supplements taste absolutely horrendous. I mean, just terrible…hard to choke down, even for a “health nut” like me. But with MetaboGreens 45X, we truly formulated this super greens sensation to taste absolutely amazing, enjoyable, and delicious. In fact, it’s sure to be something you actually look forward to drinking every day – what a treat!

But even more important than its incredibly refreshing and delicious taste are the powerhouse ingredients that make up this exotic greens super formula, and what that ultimately means for your health, your longevity, your energy, and your waistline.

With MetaboGreens 45X you will:

**Supercharge your daily energy
**Boost your immune system
**Heighten your mental clarity
**Enhance digestion and your GI health
**Naturally detoxify, flush, and cleanse your body
**Neutralize toxic acidity in your body
**Hydrate and revitalize your skin
**Curb cravings and naturally suppress your appetite, and even better…
**Skyrocket your metabolism (by a whopping 150%!)

A greens product that’s researched-backed (with an actual study) to also burn fat? Try to find that in another greens formula!

But the good news doesn’t stop there. You see, to celebrate this monumental release, today we’re making it even easier to get your hands on this delicious and energizing “super greens miracle” with FREE shipping and huge discounts—all while delivering the antioxidant power of 20 servings of fruits and vegetables in less than 30 short seconds a day…

That’s right, forget the cost, inconvenience, bland taste, and near impossibility of shoveling down 20 servings of fruits and vegetables every single day. Instead, you’ll get all the same antioxidant benefits and then some with our ultra-convenient, mouth-watering synergistic blend of 45 premium superfruits, veggies, greens and exotic herbs—complete with a surplus of health-rejuvenating micronutrients, antioxidants, phytochemicals, prebiotic fiber, digestive enzymes, and more.

This product has literally been over two YEARS in the making, and today’s special offer is only available via this email at what is very likely the lowest pricing we’ll ever make it available at, plus FREE shipping as an added fast-action bonus.

Please read every word we’ve included below, and if you’re as excited about this brand new, truly revolutionary super greens formula as we are, be sure to act quickly as our initial inventory is very limited… and once it’s gone, it’s gone!

Let me ask you a question:

Are you one of the 220+ MILLION Americans who fails to get the recommended servings of fruits and vegetables each day, leaving your body in a dangerously deficient, inflamed and acidic state? You see, most foods in the American diet are highly acidic, and without buffering all that acid with alkalizing fruits and vegetables, you’re sure to experience some rather uncomfortable consequences.

Just think, are you experiencing any of these telltale signs that your body is potentially lacking in many critical nutrients while being in a state of toxic acid overload?

**Fatigue, feeling sluggish, tired and “heavy”
**Increased cravings, especially for sweets
**Excess body fat and trouble losing weight
**Skin issues
**Brain fog
**Weak and frail bones
**Joint discomfort
**Sensitive teeth
**Trouble sleeping
**Digestive distress

And that’s just naming a few! If acid can burn a hole through metal, just think of what excessive acid levels are doing to the inside of your body—your digestive system, your immune system, your joints, and your muscles.

Without a doubt, these sobering concerns of excess internal acid are no laughing matter, and even worse, they’ll only continue to fester and get worse if left unaddressed.

But what specifically causes excess acid, and what can you do about it?For starters, as mentioned, the typical American diet is extremely acidic in nature. Just take a look at all of these common acid-producing foods:

**ALL grains (pastas, breads, pastries, crackers, cereals, rice, oats, etc)
**Refined sugars and sugary foods (the average American consumes 150 POUNDS of sugar annually!)
**ALL meats
**Many types of beans
**Cheese & other dairy
**Many types of nuts & seeds
**Alcohol
**Soft drinks
**Coffee & other caffeinated beverages
**Most sweeteners (both natural & artificial)
**Many condiments such as mustard, ketchup, mayonnaise, and soy sauce

If you’re anything like me, I bet you eat many of these foods each and every day!

Then, there are other causes of excessive acid build up in the body, such as stress, an inactive lifestyle, and not drinking enough water (which hardly anyone gets the recommended 8 glasses a day).

Heck, even a healthy high-protein diet can cause acid overload if not counteracted with enough alkalizing fruits and vegetables!

But there’s one BIG problem: eating enough fruits and vegetables to really make a significant impact on your body’s acid balance is both impractical and inconvenient, not to mention extremely expensive, especially when you have to spend 2 – 3 times the price for organic produce to avoid high levels of pesticides that can easily cancel out the benefits of eating healthy.

For example, recent research conducted by the USDA discovered non-organic kale to contain over 51 different pesticides—the complete opposite of a health food by any standards!

Furthermore, buying premade “green” juices at your local health food store is practically highway robbery (up to $10 for a single drink), and even worse, many of those are loaded with hidden sugars.

How about juicing your own fruits and veggies at home? Well, after spending $250 or more for a decent juicer, along with the cost of POUNDS of organic produce to yield a single glass, there’s the additional “cost” of your time: grocery shopping, washing, cutting, and preparing all that produce – and then cleaning up the mess to boot, and the juicer! Terribly time-consuming and painstakingly inconvenient!

And how many veggies can you really eat every single day, day after day? Cups and cups of broccoli, spinach and kale? It’s just not practical or realistic for us “normal” folks.

Still, there’s no getting around the facts: failing to consume enough fruits and veggies each and every day leads to toxic acid build up in our bodies that plagues the very core of our wellbeing and quality of life in a major way.

I’m sure it all sounds rather overwhelming, and believe me, I can relate. Simply put, getting the recommended amount of fruits & veggies every single day is too impractical, inconvenient, and expensive for the average American to do with any kind of regularity.

The fortunate news, however, is that there IS a much easier, more convenient, considerably cheaper, and incredibly delicious alternative: BioTrust MetaboGreens 45X.

Just a single serving of energizing, revitalizing, and refreshingly delicious MetaboGreens 45X aggressively combats toxic acid overload by providing premium phytonutrients from 45 of the world’s most nutrient-rich veggies, superfruits, herbs and spices, including:

Organic Spirulina
Organic Cracked Cell Wall Chlorella
Organic Wheatgrass
Organic Alfalfa
Organic Barley Leaf
Organic Apple Fruit
Green Coffee Bean
Turmeric
Cinnamon
Basil
Mangosteen
Camu Camu
Tomato
Broccoli
Aronia Berry
Elderberry
Sweet Cherry
Blackberry
Raspberry
Spinach
Kale
Brussels Sprouts
Cranberry
Pomegranate
Blueberry
Goji Berry
Reishi Mushroom
Shiitake Mushroom
Astralagus Root

And more than 15 others!

That’s right, everything you see above and more in one tasty, easy to mix drink.

Furthermore, MetaboGreens 45X also:

**Exterminates free radicals with the antioxidant power of over 20 servings of fruits & vegetables
**Curbs cravings and suppresses appetite
**Boosts metabolism a whopping 150%!
**Eradicates brain fog and increases blood flow 67%
**Supports all-day energy and fights fatigue
**Hydrates and revitalizes your body and skin, from the inside out
**Boosts immune health, digestion, and GI health
**Supports detoxification and internal cleansing
**Alkalizes the body with anti-acidic super nutrients
**Protects against stress & promotes resilience

And again, all in less than 30 delicious seconds each day!

But you may be wondering “How exactly does MetaboGreens 45X translate to all of these amazing benefits for my energy, my vitality, my health, and my waistline?” Well, it’s all made possible through the power of 4 unique and premium superfood blends that can only be found all together in this one first-class greens super formula. Let’s quickly take a look at each:

Superfood Blend #1: Spectra™ TOTAL ORAC

Free radicals are evil, health sabotaging molecules lurking inside your body that can cause accelerated aging and devastating destruction to your body’s fragile cells. Enter Spectra™ TOTAL ORAC, a full-spectrum antioxidant-rich superfood that combines the earth’s most potent, energizing fruit, vegetable, and herb extracts specifically formulated to:

*Combat free radicals
*Boost metabolism
*Curb cravings
*Support cardiovascular health
*Boost energy levels, and
*Defend against cellular aging

Spectra™ has an ORAC value of 10,000 per serving—translating to the same antioxidant power of 20 servings of fruits and vegetables, all in less than 30 seconds a day! Talk about an ultra-simple, incredibly convenient way to get the antioxidant power of 20 whopping servings of fruits & vegetables daily. With MetaboGreens 45X and Spectra™ TOTAL ORAC on your side, you’ll never have to worry about falling short on your fruit & veggie intake, or short-changing your health, ever again.

Now, to further show just how effective Spectra™ is, in a recent study published in the journal Food Science & Nutrition, researchers found that a single serving of this delicious superfood blend reduced ALL FIVE of the most destructive free radicals by up to 45%—with long-lasting free radical protection fully apparent in as little as 1 HOUR after use.

And in yet another groundbreaking, double-blind, placebo-controlled study, researchers discovered that Spectra™ not only decreased total free radicals, but it even prevented them from being generated in the first place—halting free radical production right at the source.

Even more, this same study also found that the participants taking Spectra™ showed significant spikes in their cellular oxygen consumption—to the tune of 2.5 TIMES greater! Why is this so important? Well, more oxygen consumption means several incredibly awesome benefits for you:

**Significantly improved energy levels
**Notably increased focus and reduced brain fog, and even better…
**Radically boosted metabolism and fat burning (a whopping 150% increase in this case!)

Talk about research-backed, metabolism-igniting, health-boosting results—benefits that your body, mind, and waistline will love all the same!

Superfood Blend #2: Organic Spirulina & Organic Chlorella

Chlorella and spirulina are “super sea vegetables” that contain powerful antioxidant phytochemicals, including carotenoids and chlorophyll, providing their rich green color. Specifically, organic cracked cell wall chlorella and organic spirulina (the same type used in MetaboGreens 45X) have been shown to:

**Significantly boost antioxidant activity
**Shield against oxidative stress
**Decrease important biomarkers related to accelerated aging
**Promote immune function
**Increase energy levels
**Fight physical and mental fatigue
**Improve mood
**Increase insulin sensitivity
**Reduce body weight

Furthermore, these two super algaes possess powerful detoxification properties, interfering with the absorption of potentially harmful environmental toxins that we are commonly exposed to via food, water, and even home cleaning products.

Numerous studies have also shown that chlorella and spirulina exert a protective effect on the liver, the body’s primary detox organ—great news for anyone looking to further enhance, detoxify, and cleanse their internal systems.

Superfood Blend #3: Organic Prebiotic “Super Fibers” & Digestive Enzymes

Each serving of MetaboGreens 45X also packs over 5 grams of fiber from 3 unique sources to boost your digestive and GI health; however, organic acacia gum, organic inulin, and beta glucan are anything but your ordinary fibers. Instead, these 3 “super fibers” are gut-friendly prebiotic fibers that help stimulate the growth of critically important healthy bacteria within your GI tract. In the end, these unique fibers support optimal digestion and elimination while at the same time boosting your immune system…a double win for your digestive system and overall health.

MetaboGreens 45X also provides a specialized blend of stomach-soothing superfoods, including the powerful digestive enzymes bromelain and cellulase, to help you optimally digest and absorb a very broad range of foods. Better digestion means less stomach acid is needed to break down the food you eat – further supporting a less acidic, more alkaline environment in your body. True synergy at work!

Superfood Blend #4: Energizing Reishi & Shiitake Mushrooms

If you wake up tired or suffer with regular afternoon energy slumps, you’ll be excited to learn that in addition to Spectra’s energy-boosting properties, MetaboGreens 45X also provides a natural energizing blend of Japanese adaptogenic mushrooms (reishi & shiitake) to help kick-start your day and avoid those afternoon energy lulls, instead of having to resort to stimulant-filled energy shots, coffee and/or caffeinated soft drinks.

Not only that, but both reishi and shiitake mushrooms have also been shown to support immune health, and when you’re feeling good, it’s only natural that you’ll also have more energy.

Now, maybe you’ve tried other greens or “superfood” powders and found that they just didn’t work for you, or maybe that no matter how “good for you” they were supposed to be, you just weren’t going to force down what ultimately tasted like sewer sludge each and every day. Believe me, we understand, and that’s exactly why we created MetaboGreens 45X to be the #1 best-tasting, most effective greens product available anywhere…and here’s how you know that’s exactly what you’re getting:

**It Tastes The BEST: We can’t emphasize enough how much we insisted MetaboGreens 45X be absolutely delicious. It was a must for us, and believe me when I say we made it happen with flying colors. In fact, its sweet, energizing berry flavor won numerous taste tests with expert panels making MetaboGreens 45X the best-tasting greens product on the market today, hands down.

**It Mixes The BEST: When it comes to mixability, other greens supplements are extremely gritty and anything but pleasant to swallow. MetaboGreens 45X, on the other hand, mixes smoothly and evenly with water, tea, juice, or any other beverage you choose—leaving you feeling hydrated, energized and refreshed without the gritty texture.

**It Contains Only The BEST Quality Ingredients, In The Correct Amounts: Another huge issue with other greens supplements is “fairy dusting” – when a company sprinkles a laundry list of popular ingredients into a product in miniscule amounts that are nothing more than window dressing. It’s like trying to bake a loaf of bread with a teaspoon of flour—you’ll never get the results you’re looking for. That said, MetaboGreens 45X contains only the highest quality ingredients, in the correct amounts, to ensure you get the results you absolutely deserve.

**It’s Backed By Real World Research to Prove It Works: Virtually no other greens powder is backed by science to prove it works. Yet MetaboGreens 45X contains Spectra™ TOTAL ORAC, a powerful blend of phytonutrient-rich fruit, vegetable, and herbal extracts that has been shown in human researchto fight free radicals, boost metabolism, and increase energy. In other words, it’s undergone the scientific burden of proof and is shown to actually WORK in the real world.

Remember, just a single serving of this amazingly delicious superfood elixir made with organic ingredients:

**Exterminates free radicals with the antioxidant power of over 20 servings of fruits & vegetables
**Curbs cravings and suppresses appetite
**Boosts metabolism (a whopping 150%!)
**Eradicates brain fog and increases blood flow 67%
**Supports all-day energy and fights fatigue
**Hydrates and revitalizes your body and skin, from the inside out
**Boosts immune health, digestion, and GI health
**Supports detoxification and internal cleansing
**Alkalizes the body with anti-acidic super nutrients
**Protects against stress & promotes resilience

All while aggressively combating toxic acid overload by providing premium phyto and micronutrients from 45 of the world’s most nutrient-rich veggies, superfruits, herbs and spices.

And even better, it does it all in an ultra-convenient, smooth and delicious energizing berry super drink that takes less than 30 short seconds to mix and enjoy each day!

Contrast that with time-consuming, inconvenient, impractical, bland and often downright unappetizing alternatives and you can easily see why MetaboGreens 45X is the #1 solution to get your daily fill of fruits, veggies, antioxidants, phytonutrients, prebiotic fiber, digestive enzymes and more.

In the end, with MetaboGreens 45X you will:

**Supercharge your daily energy
**Boost your immune system
**Heighten your mental clarity
**Enhance digestion and your GI health
**Naturally detoxify, flush, and cleanse your body
**Neutralize toxic acidity in your body
**Hydrate and revitalize your skin
**Curb cravings and naturally suppress your appetite, and even better…
**Skyrocket your metabolism (by a whopping 150%!)

Yes, that’s right: all-day energy, a faster metabolism, improved immune health, a sharper mind, and powerful detoxification in just 30 short and enjoyable seconds each day. It really is that simple.

You’ll also be happy to know that MetaboGreens 45X is also soy-free, vegan-friendly, dairy-free, non-GMO and naturally sweetened (with no added sugar). It really is the best of the best, as that’s what you deserve.

To begin experiencing the delicious, energizing, alkalizing, detoxifying, and metabolism-boosting benefits of MetaboGreens 45X for yourself, simply click on the special link below (only available via this VIP email) and select your money saving package right now:

==> Get MetaboGreens 45X up to 31% OFF + FREE Shipping (very limited inventory)

And of course, like with all BioTrust products, you’re always protected by our industry-best 365 Day Satisfaction Guarantee, where you can get a refund of even empty containers if for any reason you aren’t satisfied — up a full YEAR after securing your order today!

Are we crazy? No, we’re just so incredibly confident that you will see and experience the significant health-rejuvenating, cleansing, and fat-burning benefits of MetaboGreens 45X that we want to make it one of the easiest decisions you’ve ever made to try this premium formula right now before our initial inventory runs out.

Again, this special offer is only currently available to VIP subscribers like you and our initial inventory is limited. Not only that, but today’s discounted packages + FREE shipping fast-action bonus may expire at any time. Act now to secure your savings on this brand new amazingly delicious, energizing superfood elixir and avoid disappointment before this special offer is gone for good.”

Nicotinamide Riboside Reprograms Aging Stem Cells

 

By Mickey Johnston

A study published in the leading academic journal Science in April 2016 showed that supplementation of aged mice with nicotinamide riboside, a form of vitamin B3, resulted in both increased lifespan and enhanced healthspan.1

Scientists found that nicotinamide riboside has the ability to reprogram dysfunctional stem cells to function as they did in youth.(1)

Although this study was done on mice, it suggests enormous promise for nicotinamide riboside to halt and reverse human aging factors.

Nicotinamide riboside functions to boost cell levels of the energy-factor NAD+.

In this article, we will review the implications of this research for human longevity. We’ll also review the beneficial impact of nicotinamide riboside on obesity, fatty liver disease, and cognitive impairment.

Landmark Study

Landmark Study

An international group of researchers investigated the impact of nicotinamide riboside on life-span and functions related to overall health.1 The results, published in mid-2016, were remarkable.

Aged mice (24 months old) treated with nicotinamide riboside for 6 weeks survived, on average, 5% longer than control mice.(1)

While this may seem to be a fairly modest increase, consider two points.

First, the supplementation began when these mice were already fairly advanced in age.

Second, the average human life expectancy today is about 78.8 years.2 A 5% increase in this figure would add nearly 4 years, a significant increase if those years are healthy and rewarding ones.

Perhaps most importantly, this study suggests that the supplemented animals were healthier overall compared with controls.

Here are the highlights of those findings:(1)

  • Aged mice supplemented with nicotinamide riboside demonstrated increases in maximal running times and distances, and in grip strength.
  • Chemically damaged muscle tissue from supplemented mice was regenerated faster, and regenerated muscle was bulkier than in mice fed the control diet.
  • Supplemented mice showed increased proliferation and development of new brain cells, especially in the memory-intensive hippocampus region of the brain, compared with control animals.

Reprogramming Dysfunctional Stem Cells

With aging, adult stem cell function declines (stem cell senescence), causing a loss in tissue homeostasis and regeneration.(1)

Researchers found that nicotinamide riboside increased strength, endurance, and recovery times in aged mice because it increased the number and function of muscle stem cells, providing the mice greater resources for maintaining strong, healthy muscles.(1)

This study showed that supplementation with nicotinamide riboside led to significant improvements in lifespan and factors influencing health. The fact that these changes occurred in aged mice gives hope to older individuals who are looking for viable ways to live longer, healthier lives.

How it Works

How it Works

The reason why nicotinamide riboside is such a potent promoter of healthspan and lifespan is because once it enters the body, it converts to one of the most essential factors in energy production in cells, nicotinamide adenine dinucleotide(NAD+).

NAD+ has two key functions in the body that help combat aging. First, it enhances cellular energy by boosting the function of mitochondria, the body’s cellular “power plants” that convert the food we eat into energy our bodies can use.3 While age-related mitochondrial dysfunction can result in tissue and organ failure, studies show that restoring mitochondrial function slows aging and extends longevity.1

Second, NAD+ activates enzymes called sirtuins that control gene expression. SIRT enzymes “turn off” certain genes that promote aging, such as those involved in inflammation,4,5 in fat synthesis and storage, and in blood-sugar management.6,7

By boosting the body’s levels of NAD+, nicotinamide riboside helps protect the body against some of the most potent age-accelerating processes that threaten longevity. Three of these disorders include obesity, nonalcoholic fatty liver disease, and cognitive decline.

Let’s look at nicotinamide riboside’s impact on each one:

  • Obesity: A 2012 paper showed that nicotinamide riboside supplementation in both cultured cells and tissues activates sirtuins, which boost fat-burning and prevent some of the metabolic changes induced by obesity.8
  • Nonalcoholic fatty liver disease: NAFLD is the most common chronic liver disorder in industrialized nations and one closely related to our obesity epidemic.9 Nicotinamide riboside was found to prevent—and even reverse—NAFLD in mice on a high-fat, high-sugar diet. This effect was due to its ability to increase sirtuin activity, which resulted in sharp increases in mitochondrial fat burning as well as increases in the energy storage molecule ATP, which all cells require to perform their functions.9
  • Alzheimer’s disease: Mitochondrial dysfunction and poor energy management in brain cells are closely associated with the development of Alzheimer’s disease.10 Nicotinamide riboside helps combat both of these factors. A recent study of a mouse model of Alzheimer’s showed that supplementation with nicotinamide riboside for three months significantly slowed cognitive deterioration.10 As expected, these results appeared to arise from the supplement’s ability to improve energy production in brain cells.

Summary

The concept of radical life extension is steadily moving from science fiction to science reality

The concept of radical life extension is steadily moving from science fiction to science reality.

Nicotinamide riboside shows evidence of enhancing the healthspan as well. This is vital, because added years of low-quality life do not represent, for most people, much of a gain.

This landmark study indicates that supplementing with nicotinamide riboside could help one live longer and healthier. More research is urgently needed to corroborate these remarkable findings.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.

References

  1. Zhang H, Ryu D, Wu Y, et al. NAD(+) repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016;352(6292):1436-43.
  2. Available at: https://www.cdc.gov/nchs/fastats/life-expectancy.htm. Accessed December 21, 2016.
  3. Guarente L. CELL METABOLISM. The resurgence of NAD(+). Science. 2016;352(6292):1396-7.
  4. Kotas ME, Gorecki MC, Gillum MP. Sirtuin-1 is a nutrient-dependent modulator of inflammation. Adipocyte. 2013;2(2):113-8.
  5. Galli M, Van Gool F, Leo O. Sirtuins and inflammation: Friends or foes? Biochem Pharmacol. 2011;81(5):569-76.
  6. Li X, Kazgan N. Mammalian sirtuins and energy metabolism. Int J Biol Sci. 2011;7(5):575-87.
  7. Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab. 2014;25(3):138-45.
  8. Canto C, Houtkooper RH, Pirinen E, et al. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 2012;15(6):838-47.
  9. Gariani K, Menzies KJ, Ryu D, et al. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology. 2016;63(4):1190-204.
  10. Gong B, Pan Y, Vempati P, et al. Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer’s mouse models. Neurobiol Aging. 2013;34(6):1581-8.

Whats the TRUTH about Nicotinamide Riboside (NIAGEN)


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 demonstrated that short term supplementation with Nicotinamide MonoNucleotide (NMN) replenished NAD+ and 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 Dr Sinclairs landmark 2013 study, dozens of others have been published investigating the efficacy of supplementation with NMN and Nicotinamide Riboside (NR) 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”

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).

WHAT IS NR


NMN is the immediate precursor to NAD+ in the salvage pathway that constantly recycles NAD+.

Nicotinamide Riboside (NR) is a NAD+ intermediate that is used inside our cells to metabolize NMN and NAD. It is found in natural food sources and broken down in our bodies digestive system to NAM, NMN and other NAD metabolites.

In 2004 Dr Charles Brenner published a paper showing that the enzyme Nrk1 can catalyze NR directly to NMN (100) which can make it a more effective precursor to NAD+ than the previously known NAM, NA, or Tryptophan.

Although NR is unstable by itself, Dartmouth University has patented production methods that combine it with Chloride which makes it stable.

Chromadex has licensed this technology and has been selling NR commercially since 2014 under the brand name “Niagen”.

Tru Niagen is the brand name used by Dr Brenner’s company ProHealthSpan to market their Niagen product.

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 further down the page.

* 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)

NR

  • 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

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 can bypass the Nampt bottleneck, but is not normally available in the bloodstream (see below)

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

MOST NR IS FIRST METABOLIZED 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 (97,98,99).

Quotes from some studies are below:

“This evidence indicates that NR is converted to NAM before absorption occurs and that this reaction is the rate-limiting step ” (98)

“NR has been shown be converted to Nam before being absorbed or reaching tissues” (99)

“oral NR dosing increased circulating NAM ~40-fold while NMN remained unchanged” (97)

“we were surprised to find that NR exerts only a subtle influence on the steady state concentration of NAD in muscles. Our tracer studies suggest that this is largely attributable to breakdown of orally delivered NR into NAM prior to reaching the muscle. ” (97)

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

ORAL NR SUPPLEMENTS NOT DETECTABLE 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).

Finally, this 2017 study did find a trace of NR in the bloodstream briefly, 100 minutes after oral gavage of 200mg/kg.

The Trammell thesis shows that the liver quickly processes any NR to other metabolites such as NAAD, NAM, NaAd, but also failed to find any trace of NR in the bloodstream.

Here are some quotes in the discussion section from the Trammell thesis:

“NR has not been detected in the blood cell fraction nor in plasma

“NR varied and displayed no response to NR administration … but was detected after IP of double labeled NR in liver (Figure 5.7) and muscle (Figure 5.9), revealing NR does circulate”

This research found  that:

  • NR is found in small quantities in the liver
  • NR is normally not detectable in bloodstream
  • Oral supplementation with NR did not show any increase in NR in the body
  • Injection (IP) of NR does result in a detectable increase of NR in muscle and Liver
  • Oral NR does not result in increased NAD+ levels in organs beyond the liver

Any NR supplements that do make it to the blood are quickly cleared by the liver so it is very rarely detected in the bloodstream, and then only at trace levels.

ORAL NR IS NOT AVAILABLE  TO TISSUES BEYOND THE LIVER

The charts below 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 200mg/kg bodyweight of 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.

This is from labelled NR that has been metabolized to NAM and then NMN (likely in the liver) then traveled through the bloodstream to the muscle where it is incorporated to single labeled NAD+

We know this NAD+ was metabolized as NAM and then NMN because these mice lacked Nampt, 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.

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 125mg capsules of 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.

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

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References:

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