Nicotinamide Riboside shown to increase NAD+ in first clinical study with humans

screenshot-2016-09-08-09-20-24Nicotinamide Riboside  (Niagen) has shown the ability to elevate the co-enzyme NAD+ levels in clinical studies with Mice many times, but in a series of research described in this PHD thesis, has now been proven to have the same effect in humans.

Several experiments were carried testing response to NAD+ levels in both human and mouse test subjects.

In one, a human subject was given 1000 mg of NR daily for 7 days, and blood NAD+ levels were tested. It was found that the single dose of Nicotinamide Riboside raises NAD+ levels up to 270%.

NAD+ levels were raised approximately 4 hours after ingesting NR, and peaked at approximately 8 hours. NAD+ remained elevated 24 hours later.

screenshot-2016-09-08-09-32-20Further testing involved 6 male and 6 female adults. Subject received 100 (purple), 300 (red), or 1000mg (black) of NR, with a 7 day washout period between doses to monitor the response on NAD+ levels.

Subjects showed the increase to NAD+ levels was dose dependent.

The average NAD+ increases were 30% at 100mg, and 50% at the higher dosages.

The lead researcher, Charles Brenner, PhD, was somewhat surprised that a single dose of 100 mg was able to raise NAD+ levels, however it seems the 300mg dose was much more effective over a 24 hour span.

Optimum dosage of NR?

nr_nad_chartThe 300 and 1000mg dosages resulted in similar maximum increase in NAD+ levels at 24 hours. However the 1,000 mg dose resulted in higher increase at 8 hours.

As participants were given a single dose, with a washout period of 7 days between dosages, it is not known what the cumulative effect of daily dosages would achieve.

It is quite possible the 300 mg dosage would be even higher at the 8 hour point on days 2,3,4 and on.

The optimum dose for maximum NAD+ elevation with minimum NR dosage is likely closer to 300 mg than 1,000 mg. A cost effective guess would be 300 to 500mg per day.

Read more about the optimum dosage of NR here.

Other studies for proper dosage of NR

Among the dozens of studies underway currently, one involves NR  taken daily for eight consecutive weeks  is underway to measure the long term NAD+ increase from NR and determine the most effective dosage.

Why NAD+ levels matter

Prior research has shown supplementation with NMN can raise NAD+ levels and result in  more youthful cellular function thru improved mitochondria health.  NAD+ levels naturally drop as we age and is thought to be a key driver in many age related diseases and health problems.  Restoring NAD+ levels to youthful levels has proven to work in restoring youthful energy and performance in mouse studies.

NAD+ is a key factor in cellular health as it is required to power all activity in every cell of our bodies.

Increased NAD+ levels is key to maintaining healthy cellular activity and mitochondrial function. Besides the decrease in NAD+ levels due to aging, they are also used up when battling chronic problems such as cancer.  When this happens, the mitochondria are less effective which causes many health problems.


One example is shown in a mouse study published in November 2014  that showed  NR was effective at restoring NAD+ levels in mitochondria in mice that suffered from the  accelerated aging disease known as Cockayne Syndrome (CS).  NR was described to show promise as a therapy for the disease in addition to other chronic health problems that result in lower NAD+ levels.

Below are some of the benefits that have been proven to result from increased NAD+ levels in studies with mice.

  • Better Vision
  • Less muscles soreness
  • Improved muscle endurance
  • Improved Hearing
  • Neurological function

human studies

have been completed showing:

  • hearing damage protection
  • NAD+ levels restored to youthful levels

Testing in humans for any potential Anti-Aging benefits is further down the road, due to the extreme cost and time involved.  Also, the FDA does not recognize aging as a disease, so any proof that it may slow or even reverse aging cannot be claimed.

However,  more short term testing for specific age-related disease and conditions is ongoing in Humans and Mice.

About NIAGEN brand Nicotinamide Riboside (NR)

Niagen is manufactured by Chromadex and  is the only supplier of NR, with multiple patents from Dartmouth College, Cornell University and Washington University.

There are many different brands of Nicotinamide Riboside on the market, but all use the same ingredients supplied by Chromadex.

New Study finds Nicotinamide Riboside safe at typical dosages

safetyA clinical study was published January 2016 on the safety and side effects  of Nicotinamide Riboside in the HET Journal (Human and Experimental Toxicology), an international peer reviewed journal.

Although naturally occurring in trace amounts in some foods such as milk and beer, Nicotinamide riboside (NR) is a recently discovered form of vitamin B3.

It is being studied along with Nicotinamide Mono-Nucleotide  for a wide range of potential health benefits due to it’s ability to increase NAD+ levels in human and animal testing.

NAD+ is a co-enzyme found in all animals that enable the mitochondria to perform their role in powering the basic functioning of every cell in our bodies. NAD+ levels naturally drop as we age and is thought to be a key driver in many age related diseases and health problems.

Prior research has shown that increased NAD+ levels in older mice results in improved energy and muscle performance similar to that of young animals.

This study was performed using Niagen, which is the only commercially available brand of Nicotinamide Riboside (NR). They also compared the effects of NR with that of similar dosage of Nicotinamide (also referred to as niacinamide) , a more common and better studied form of B3 vitamin with a long record of safe usage.

In the first phase of the study, mice that were fed 5000 mg per kg of bodyweight exhibited no mortality.

The second phase was a 90 day assessment comparing dosages of 300, 1000, and 3000 mg/kg of bodyweight per day.

Researchers compared the effects on liver, kidneys, ovaries, and testes and found no toxicity at any of the dosages tested.

Their was no adverse effects noted at the 300 mg level. Minor effects at 1000 and 3000 mg levels were similar to that of Nicotinamide.

There are  guidelines used by the FDA to translate the dosages used in mice to the equivalent dosage for the Human Equivalent Dose (HED).

The 300 mg/kg dosage equals 48mg/kg HED, which would be approximately 2880 mg a day for a 132 lb human, which is well over the dosage recommended. However, the FDA requires a 10x safety factor which would result in a dosage of 288 mg, which is at the lower end of recommended dosage.

Comparing results on animals given NR vs Niacinamide, the researchers concluded that NR has a similar toxicity to niaciniamide.

Niacinamide has a long track record of safe use in humans, and is rated as LIKELY SAFE at normal dosages. At dosages above 3 grams per day, Niacinamide can result in serious side effects including liver problems, gout, vision, elevated blood sugar, and other serious problems.

3 grams of Niacinamide per day equals roughly 7 grams per day of Nicotinamide Riboside.

Based partly on the results of this study, Chromadex was able to obtain GRAS status for Niagen.

Niagen (Nicotinamide Riboside) recognized as GRAS (Generally Recognized as Safe)

The company called ChromaDex Corporation, an innovator of nutritional and health ingredients, announced that an independent scientific panel of experts determined that NIAGEN , a patented formula of Nicotinamide Riboside (NR) is Generally Recognized As Safe (GRAS). 

Generally recognized as safe (GRAS) is an American Food and Drug Administration (FDA) designation that a chemical or substance added to food is considered safe by experts, and so is exempted from the usual Federal Food, Drug, and Cosmetic Act (FFDCA) food additive tolerance requirements.

It is a very strong testimony that Nicotinamide Riboside supplementation is safe without side effect. It should be noted here that the GRAS status was only given to Chromadex’s commercially available form of nicotinamide riboside (NR) called Niagen. This formula is protected by five patents issued and several pending and so far it appears this is the only NR form that is known to be commercially available. Hence when buying NR it seems prudent to ensure oneself of the source to avoid buying false formula’s.

Frank Jaksch Jr., founder and CEO of ChromaDex, commented, “Receiving GRAS status immediately allows NIAGEN to be included as an ingredient in both food and beverages –applications that we believe presents a very substantial opportunity for ChromaDex. Coupled with the recent NDI status, we believe the stage is set for widespread commercialization of NIAGEN as an innovative and compelling ingredient across a myriad of consumer products.”

You can find the press release here.

Quercetin, not caffeine is neuroprotective ingredient in coffee

Quercetin3An interesting study was carried out by researchers of the Kinsmen Laboratory of Neurological Research, University of British Columbia. They set out to determine which component of coffee is responsible for its alleged neuroprotective effects.

Several epidemiologic studies have indicated that coffee consumption has a protective effect against Parkinson disease (PD) and Alzheimer disease (AD). This has led to conclusions that on the basis of the Cardiovascular Risk Factors, Aging and Dementia studies that drinking 3-5 cups of coffee at midlife is associated with a decreased risk of dementia/AD in late life.

Several studies also reported this is due to caffeine and/or other mechanisms such as antioxidant capacity by other components. However a study carried out in 2015 found that there was no significant difference between consuming caffeinated or decaffeinated coffee. This indicates that other constituents of coffee rather than caffeine must be responsible for the protective effect.

To shed light on this the team from UBC examined the effects of caffeine and other well-known coffee components, such as quercetin, flavone, and chlorogenic acids (CGAs), on neuroinflammation and neurotoxicity. The test involved prevention of neurotoxicity to SH-SY5Y cells that was induced by lipopolysaccharide plus interferon-g or interferon-g released from activated microglia and astrocytes. SH-SY5Y is a human derived cell line often used as in-vitro models of neuronal function and differentiation.

Previous studies have concluded that in coffee beans, the constituents most likely to exert anti-inflammatory and antioxidative function are caffeine, quercetin, flavonoids, and CGA as well as their derivatives. The researchers measured that the amounts of the 4 compounds included in 100 grams of coffee beans are 280 mg for CGA, 200 mg for quercetin, 60 mg for flavones (a representative of flavonoids), and 40 mg for caffeine.


Therefore in a standard cup of coffee, caffeine occurs in clearly smaller amount than quercetin, CGA, and flavonoids. The experiments showed that only very high concentrations of caffieine are needed to show anti-inflammatory and neuroprotective properties (at least 100 mg/mL), much higher than dosing in coffee.

The results also indicated no significant difference in protective effects in a coffee mixture of compounds with and without caffeine.

On the other hand Quercetin protected against SH-SY5Y cell loss after exposure to LPS/IFNg-stimulated microglia and IFNg-stimulated astrocytes. The effect was concentration and incubation time-dependent.

Quercetin also inhibited activation of proinflammatory pathways such as P38 MAP kinase and NFkB stimulation. It was demonstrated that caffeine has these properties also but only very weakly. The other major coffee components, CGA and flavones, are also more effective than caffeine.

In addition Quercetin showed antioxidative properties which led to a decrease in 8-OHdG, a biomarker of oxidative damage to DNA. Quercetin also attenuated the increase in protein carbonyls, a marker of oxidative damage to amino acids in proteins.

It reduced lipid peroxide, a product of the attack of reactive oxygen species on unsaturated fatty acids in lipids, as well as 3-nitrotyrosine, a product of the attack of reactive nitrogen species. Caffeine did not show any of these antioxidant functions.

The researchers concluded that quercetin protected SH-SY5Y cells not only by reducing the release of proinflammatory factors but also by inhibiting attack by reactive oxygen species and reactive nitrogen species.

CGA and flavones also showed to have antiinflammatory and neuroprotective properties although weaker than quercetin.


In summary the data indicates that quercetin is the major neuroprotective component in coffee against Parkinson’s disease and Alzheimer’s disease. Quercetin is a readily available supplement and this study further confirms its potential. As for drinking coffee to maintain health it may be wise to combine a cup of coffee with the consumption of a quercetin serving.

You can find the study here.

Heart Attack risk cut by Omega 3 fats

Omega 3 Supplements And FoodsThe health benefits of long-chain omega-3 fatty acids — docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) – are well known.

One large trial in patients with heart disease showe
d that supplementing with 1 gram of omega-3 per day reduced their risk of death by 20%. However, not all studies agree (12).

Recently, a large randomized controlled t
rial examined whether supplementing with 4 grams of omega-3 would help repair some of the damage caused by a heart attack. Below is a detailed summary of its findings.


Article Reviewed

This study examined the benefits of high-dose omega-3 supplementation on heart recovery after a heart attack.

Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction. The OMEGA-REMODEL Randomized Clinical Trial.

Study Design

This randomized controlled trial investigated the effects of omega-3 fatty acids on changes in heart function and structure during the first 6 months after a heart attack (acute myocardial infarction).

A total of 358 participants were randomly assigned to one of two groups 14 to 28 days after they had a heart attack:

  • Omega-3: The participants received high-dose omega-3 supplements from fish oil (4 grams per day for 6 months). The supplement contained ethyl esters of EPA (465 mg) and DHA (375 mg).
  • Placebo: The control capsules contained corn oil, providing 600 mg of omega-6 linoleic acid.

During the study, all of the participants were also receiving standard medical therapy to treat heart disease.

At the start and end of the study, the researchers measured heart structure and function using cardiac magnetic resonance imaging. They also measured several markers of inflammation and cardiac fibrosis.

Bottom Line: This was a large randomized controlled trial investigating the effects of high-dose omega-3 supplementation on changes in heart structure and function after a heart attack.

Finding 1: Omega-3 Supplements Improved Heart Function

Left ventricular systolic volume index (LVSVI) is a marker of the heart’s ability to pump blood.

The researchers discovered that high-dose omega-3 supplementation reduced LVSVI by 5.8%, compared to a placebo. This is a beneficial change, indicating improved heart function.

The chart below shows the changes in LVSVI in both groups:

Change In LVSVI

There was a dose-response relationship between these benefits and increases in the omega-3 content of red blood cells (RBC).

Among those participants who achieved the highest increase in the omega-3 content of RBCs, the reduction in LVSVI was much higher at 13%.

Bottom Line: Supplementing with 4 grams of omega-3 for half a year after a heart attack significantly improved heart function, compared to a placebo.

Finding 2: Omega-3 Supplements Reduced Myocardial Fibrosis

Myocardial fibrosis (MF) is a condition characterized by the accumulation of scar tissue in the heart muscle. It reduces the heart’s ability to contract and pump blood.

Increased MF is often seen following a heart attack and increases the risk of heart failure.

The researchers assessed non-infarct myocardial fibrosis (NMF), which is myocardial fibrosis in undamaged areas of the heart.

The researchers were unable to measure NMF directly. Instead, they measured extracellular volume fraction, which is a marker of MF.

On average, the participants experienced a 5.6% improvement in NMF, compared to a placebo. The chart below shows the differences between groups:

Change In NMF

The researchers also measured ST2, a circulating marker of MF. Levels of ST2 are elevated when the heart muscle is dysfunctional or partially dead (3).

They discovered that high-dose omega-3 supplementation reduced ST2 by 7.9%, further confirming its benefits for patients with heart disease. These findings are consistent with previous studies (4).

Both groups also experienced a significant improvement in infarct size (areas of dead heart tissue), but the difference was not statistically significant between groups.

All of these benefits were associated with an increase in the omega-3 content of red blood cells.

Bottom Line: Supplementing with omega-3 decreased heart tissue scarring (myocardial fibrosis), reducing the risk of heart failure.

Finding 3: Omega-3 Supplements Decreased Inflammation

The study found that supplementing with omega-3 reduced circulating levels of myeloperoxidase by 8.1%.

Myeloperoxidase is an enzyme that has been used as a marker of inflammation in the heart (5).

The authors speculated that the anti-inflammatory effects of omega-3 fatty acids explain the health benefits seen in the current study.

These findings are consistent with previous studies in animals and humans (678).

Bottom Line: Omega-3 supplements also decreased inflammation, potentially explaining their benefits for heart function.


This study didn’t have any major limitations.

However, a considerable proportion of the participants couldn’t return for a lab visit at the end of the study.

Additionally, the participants started supplementing with omega-3 two to four weeks after having a heart attack.

Changes in LVSVI and NMF were only modest compared to clinical care guidelines, but much greater benefits could have been achieved if the treatment had started earlier.

Finally, the omega-3 came from a prescription supplement with the brand name Lovaza, which was provided by the pharmaceutical company GlaxoSmithKline. It is unclear if regular omega-3 supplements are as effective.

Bottom Line: This study didn’t appear to have any major limitations. However, if the omega-3 treatment had started immediately after a heart attack, the participants might have achieved much greater benefits.

Summary and Real-Life Application

In short, this study showed that supplementing with 4 grams of omega-3 for 6 months helped repair some of the damage caused by a heart attack.

Many previous studies have confirmed the health benefits of omega-3 supplements, and most health authorities promote adequate dietary intake of omega-3 oils.

The present results strongly support the use of high-dose omega-3 supplements after a heart attack.

But even if you are healthy and fit, regularly eating fatty fish or supplementing with omega-3 might reduce your risk of developing chronic disease later in life.

How Coconut Oil and other MCT’s aid weight loss

How quickly you become hungry after eating not only depends on how much you ate, it also depends on what you ate.

Diet pills like Garcinia Cambogia can help, but its also important to know that some foods are more filling or satiating than others.

A recent study compared the effects of two types of fat — conjugated linoleic acid (CLA) and medium-chain triglycerides (MCTs) — on subsequent appetite and calorie intake.

Here is a detailed summary of its findings, as well as some background information.


Fat is the most calorie-rich nutrient you can find, providing 9 kcal for each gram, exceeding protein and carbs by 5 kcal.

However, fat isn’t necessarily fattening. It all depends on how much you eat, the dietary context and the type of fat.

In fact, some types of fat seem to promote the loss of excess weight. This includes conjugated linoleic acid (CLA) and medium-chain triglycerides (MCTs).

Conjugated Linoleic Acid (CLA)

cla-in-dairyCLA is a type of fat found in the milk and meat of ruminant animals, such as sheep and cows.

Supplementing with CLA is believed to benefit those who wish to lose excess fat. This is supported by a few human trials. However, the effects are small, and the clinical relevance is unclear (1234).

One trial showed that CLA may reduce appetite, while other studies have detected no effects (567).

However, its effects on calorie intake in humans have not been investigated before.

Medium-chain Triglycerides (MCTs)

medium-chain-triglyceridesMCTs are a type of fat mainly found in palm oil, coconut oil, milk fat or supplements. They are more water-soluble and are quickly absorbed into the bloodstream after a meal.

Compared to long-chain triglycerides (LCT), MCTs may reduce appetite, calorie intake and promote weight loss (891011).

This is likely because MCTs are a more readily available calorie source than LCT (12).

However, not all studies agree. Some studies found that supplementing with MCTs did not affect appetite (1314).

Article Reviewed

This study tested the effects of conjugated linoleic acid (CLA) and medium-chain triglycerides (MCTs) on appetite and calorie intake.

Medium-chain triglycerides and conjugated linoleic acids in beverage form increase satiety and reduce food intake in humans.

Study Design

This was a randomized controlled trial examining the effects of different types of fat on appetite and calorie intake.

A total of 19 healthy men and women participated in the study. They were assigned to three test breakfasts on separate days in a random order.

All three breakfasts consisted of 250 ml of a Tesco red berries smoothie (123 kcal), providing 0.8 grams of protein and 29.8 grams of carbs (91% sugar).

Added to the smoothie were 193 kcal of fat, but the type of fat differed between the three breakfasts:

  • Conjugated linoleic acid (CLA): 5 grams of CLA and 16 grams of vegetable oil.
  • Medium-chain triglycerides (MCTs): 25 grams.
  • Control: 22 grams of vegetable oil (unspecified).

After breakfast the participants were told to request a sandwich buffet lunch when they felt hungry enough.

The researchers measured calorie intake at the sandwich lunch. Weighed food diaries were also used to assess food intake for the rest of the day.

They also measured the time between the breakfast and self-requested lunch and assessed appetite using visual analogue scale questionnaires.

Bottom Line: This was a randomized controlled trial comparing the effects of supplementing with MCTs and CLA at breakfast on calorie intake and appetite for the rest of the day.

Finding: CLA and MCTs Reduced Calorie Intake

Supplementing with conjugated linoleic acid (CLA) or medium-chain triglycerides (MCTs) for breakfast resulted in a similar calorie intake at the lunch buffet, compared to supplementing with vegetable oil.

However, calorie intake for the rest of the day (after lunch) was significantly reduced after the participants had supplemented with CLA or MCTs for breakfast, as shown in the chart below.

Calorie Intake CLA MCT Control

Supplementing with CLA for breakfast also delayed the time until the participants requested the lunch buffet. Yet, the researchers detected no significant differences in appetite ratings.

Bottom Line: Eating CLA or MCTs at breakfast reduced calorie intake by roughly 500 kcal for the rest of the day.


3-question-marksThe study’s design doesn’t seem to have had any major flaws, but several limitations should be mentioned.

First, the lunch buffet didn’t have a fixed time. The participants asked for it when they felt hungry enough.

Although this probably didn’t change the study’s overall findings, it probably explains why the researchers didn’t detect any between-group differences in calorie intake at lunch.

Second, calorie intake after lunch was estimated using food diaries, which are often inaccurate. However, this is unlikely to have affected the main results.

Third, five participants reported adverse digestive symptoms after supplementing with MCTs. This discomfort might have reduced their appetite and calorie intake later in the day.

In comparison, only one participant reported digestive discomfort after supplementing with CLA, and there were no adverse symptoms after consuming the control breakfast.

Finally, the calorie content of the two test lipids did not match. The amount of CLA used was 5 grams, whereas the dose of MCTs was 25 grams. As a result, the study didn’t provide an equal comparison of CLA and MCTs.

Bottom Line: The study didn’t have any major limitations to its design. However, there are some limitations to how its results can be interpreted.

Summary and Real-Life Application

This study showed that supplementing with CLA or MCTs for breakfast significantly reduced calorie intake for the rest of the day, compared to vegetable oil.

The reduction in calorie intake amounted to approximately 500 kcal. This calorie reduction should result in considerable weight loss over time, but it is unclear to what extent these effects are sustained when CLA or MCTs are taken regularly.

Some previous studies have indicated that supplementing with MCTs or CLA may help people lose excess weight, although the relevance is still debated (415).

Sleep important for Weight and Fat Loss

Beautiful woman sleeping

Most people know that adequate sleep is one of the cornerstones of good health. But is poor sleep bad for your waistline?

It’s not as flashy as diet products like Garcinia Cambogia, but adequate sleep is important for weight loss.

A recent meta-analysis examined the association of sleep quality and overweight and obesity in young people. Here is a detailed summary of its findings.



obese-man-with-doctorMany previous studies suggest that inadequate sleep makes people more likely to gain weight (12).

However, most of them have investigated sleep duration rather than quality (345).

As opposed to sleep duration, sleep quality is more about the personal experience of sleep, such as difficulties falling asleep or sleep satisfaction. Broken sleep is also an aspect of sleep quality (6).

Some observational studies indicate that light pollution at night might increase weight by disrupting sleep.

However, until now, no meta-analyses have examined the association of sleep quality and overweight or obesity.

Article Reviewed

This was a systematic review and meta-analysis on the association of sleep quality and overweight and obesity.

Sleep quality and obesity in young subjects: a meta-analysis.

Study Design

This was a systematic review and meta-analysis of observational studies.

Its purpose was to examine the association of sleep quality and overweight and obesity in young people and find out if the association is independent of sleep duration.

The researchers selected nine observational studies for the meta-analysis, including a total of 26,553 children, adolescents and young adults.

Most of the included studies had a cross-sectional design, meaning that they examined the association at one point in time. In other words, they didn’t investigate the effect of poor quality sleep on weight changes over time.

Studies were excluded if they didn’t include body mass index as an outcome or the participants had medical or psychological problems.

Additionally, studies were left out if they only focused on sleep duration or all of the participants were overweight or obese.

Poor sleep quality was defined as difficulties falling asleep and sleep disturbances (recurrent awakenings).

Some of the studies assessed sleep using the Pittsburgh Sleep Quality Index or the Children’s Sleep Habits Questionnaire, both of which evaluate sleep duration and quality.

Bottom Line: This was a systematic review and meta-analysis of studies examining the association of sleep quality and overweight or obesity.

Finding: Poor Sleep Quality Was Associated With Overweight and Obesity

This meta-analysis suggests that both short sleep duration and poor sleep quality makes young people more likely to be overweight or obese.

The association of sleep quality and overweight or obesity seemed to be independent of sleep duration (78).

Most of the included studies found that inadequate sleep was significantly associated with overweight and obesity.

However, the studies that used non-validated research methods provided mixed results (7910).

Most of the included studies were cross-sectional, measuring associations at one point in time. In contrast, only two of the studies were longitudinal, measuring sleep quality and changes in weight over time.

The longitudinal studies found no significant links between sleep quality and overweight or obesity (911).

Bottom Line: The study suggests that poor sleep quality is associated with overweight and obesity in young people, independently of sleep duration.

How Could Low Sleep Quality Make People Fat?

Although this study didn’t prove that poor sleep quality may lead to fat gain, it seems plausible that it might.

The potential mechanisms are unclear, but scientists have a few ideas.

  • Disrupted body clock: The body’s timekeeping system regulates many aspects of metabolism. Disrupting this system by sleeping irregularly or poorly may increase weight gain. (1213).
  • Increased appetite: Irregular or low-quality sleep can disrupt the 24-hour fluctuations in appetite hormones, promoting increased calorie intake during the day and at night (14).
  • Food intake at night: Broken sleep or difficulties falling asleep may encourage night-time eating, leading to more weight gain.

Bottom Line: Several plausible ideas explain how poor sleep might promote weight gain. For example, low sleep quality may disrupt the body clock and encourage night-time snacking.


This study had a few important limitations.

First, all of the included studies had an observational design, and all but three were cross-sectional. This means that they couldn’t prove causality and didn’t show that poor sleep was linked with weight gain over time.

It’s plausible that being overweight or obese may reduce sleep quality, rather than the other way around.

Second, only three studies measured sleep quality, using actigraphy. Additionally, most of the included studies used validated questionnaires, whereas three relied on parental or self-reporting.

Finally, most of the studies used body mass index (BMI) as an outcome. Four of the studies used self-reported height and weight for calculating BMI. BMI is an inaccurate measure of overweight, especially when relying on self-reports.

Bottom Line: The meta-analysis included observational studies, which cannot prove a causal relationship. Additionally, most of the studies relied on inaccurate measurements.

Summary and Real-Life Application

In short, this study indicates that poor sleep quality — broken sleep or difficulties falling asleep — are associated with excessive fat mass.

However, the evidence is weak, and the direction of causality is unclear. Obesity, overweight or related factors are plausibly responsible for poor sleep quality, at least in some cases.

Regardless, there is no doubt that getting high-quality sleep is important for maintaining a healthy mind and body.

What are the best No Calorie Sugar replacements

Excessive sugar consumption is suspected to be one of the main causes of obesity.

Rather than making the effort to eat healthy whole foods, many people look for an easy solution like popping some Garcinia Cambogia pills,using zero-calorie (non-nutritive) sweeteners instead of added sugar.

They are supposed to provide a sweet taste without any of the adverse health effects associated with too much sugar. Nonetheless, their safety is debated.

A recent article summarized the available evidence on the effects of non-nutritive sweeteners on glucose metabolism and appetite hormones. Here is a detailed summary.

Article Reviewed

This was a systematic review that included 44 human studies on the effects of non-nutritive sweeteners on glucose metabolism and appetite hormones.

Effects of the Non-Nutritive Sweeteners on Glucose Metabolism and Appetite Regulating Hormones: Systematic Review of Observational Prospective Studies and Clinical Trials.

What Are Non-Nutritive Sweeteners?

Non-nutritive sweeteners (NNS), often referred to as artificial sweeteners, are food additives that imitate the sweet taste of sugar without any calories.

Six NNS are currently approved for use in the US and Europe:

  • Acesulfame-K.
  • Advantame.
  • Aspartame.
  • Neotame.
  • Saccharin.
  • Sucralose.

There is also growing interest in naturally-derived NNS, such as steviol glycosides(stevia) and luo han guo extract.

The following sections summarize the available evidence on the health effects of some of these NNS.

Bottom Line: Non-nutritive sweeteners, most of which are artificial sweeteners, imitate the taste of sugar without any additional calories.

Acesulfame K

Härtel BG, et al. The influence of sweetener solutions on the secretion of insulin and blood glucose level. Ernährungsunschau, 1993.

This crossover study in 14 healthy people compared the effects of 165 mg of acesulfame K mixed in water to water only. Acesulfame K did not affect insulin or blood sugar levels.

Bryant CE, et al. Non-nutritive sweeteners: no class effect on the glycaemic or appetite responses to ingested glucose. European Journal of Clinical Nutrition, 2014.

This crossover study in 10 healthy individuals examined the effects of 85 mg of acesulfame K to 45 grams of glucose.

Consuming acesulfame K did not significantly affect glucose or appetite sensations, compared to glucose only.

Steinert RE, et al. Effects of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal satiety peptides. The British Journal of Nutrition, 2011.

This crossover study in 12 healthy individuals compared the effects of an intragastric infusion to 50 grams of glucose, 25 grams of fructose or 220 mg of acesulfame K.

Acesulfame K did not affect glucose, insulin, glucagon-like peptide 1 (GLP-1), peptide YY, ghrelin or appetite sensations, compared to water.

Olalde-Mendoza L, et al. Modification of fasting blood glucose in adults with diabetes mellitus type 2 after regular soda and diet soda intake in the State of Queretaro, MexicoArchivos Latinoamericanos de Nutricion, 2013.

This randomized trial in 40 people with type 2 diabetes (T2D) showed that drinking 200 ml of diet soda containing a 40 mg mix of aspartame and acesulfame K did not affect glucose levels, compared to a regular soda.

Brown RJ, et al. Effects of diet soda on gut hormones in youths with diabetes.Diabetes Care, 2012.

This crossover study recruited 9 participants with T1D, 10 with T2D and 25 healthy individuals as a control.

The study showed that drinking 240 ml of a diet soda sweetened with sucralose and acesulfame K increased levels of glucagon-like peptide 1 (GLP-1) by 43% in people with T1D and 34% in healthy individuals.

No effects were seen in participants with T2D. Additionally, the diet soda didn’t affect levels of glucose, C-peptidegastric inhibitory polypeptide (GIP) or peptide YY.

Bottom Line: Human trials suggest that acesulfame K has no adverse effects on blood sugar control or appetite.


Nehrling JK, et al. Aspartame use by persons with diabetes. Diabetes Care, 1985.

This study in 62 individuals with type 2 diabetes (T2D) showed that consuming 2.7 grams of aspartame every day for 18 weeks did not affect blood sugar levels or HbA1c, compared to a placebo.

Okuno G, et al. Glucose tolerance, blood lipid, insulin and glucagon concentration after single or continuous administration of aspartame in diabetics. Diabetes Research and Clinical Practice, 1986.

These were two small crossover trials. The first trial showed that a single 500 mg-dose of aspartame lowered blood sugar 2–3 hours afterward, compared to 100 grams of glucose.

The second study found that consuming 125 mg of aspartame for two weeks had no effects, compared to 50 grams of glucose.

In these studies, aspartame did not significantly affect insulin, glucagon, triglycerides, total cholesterol or HDL cholesterol.

Colagiuri S, et al. Metabolic effects of adding sucrose and aspartame to the diet of subjects with noninsulin-dependent diabetes mellitus. The American Journal of Clinical Nutrition, 1989.

This small study in nine diabetics showed that taking 162 mg of aspartame every day for 6 weeks did not affect glucose, HbA1c, body weight, total cholesterol, HDL cholesterol or triglycerides, compared to taking 45 grams of sucrose.

Rodin J. Comparative effects of fructose, aspartame, glucose, and water preloads on calorie and macronutrientintake. The American Journal of Clinical Nutrition, 1990.

This crossover trial included 12 overweight and 12 normal-weight adults. On separate visits, the researchers tested the effects of 50 grams of glucose, 50 grams of fructose or 250 mg of aspartame. They also consumed 500 ml of water.

They detected no significant differences in glucose, insulin, glucagon, free fatty acids or calorie intake (at a subsequent lunch) between groups, or compared to water only.

Melanson KJ, et al. Blood glucose and meal patterns in time-blinded males, after aspartame, carbohydrate, and fat consumption, in relation to sweetness perception. The British Journal of Nutrition, 1999.

This small crossover study in 10 healthy men showed that drinking an aspartame-sweetened beverage reduced blood sugar levels in 40% of the participants, whereas they increased them 20% and remained stable in the rest.

Aspartame did not affect calorie intake at a subsequent meal.

Hall WL, et al. Physiological mechanisms mediating aspartameinduced satiety.Physiology & Behavior, 2003.

This small crossover trial in six participants investigated the effects of taking either 400 mg of aspartame, 176 mg of aspartic acid combined with 224 mg of phenylalanine or 400 mg of corn flour as a placebo.

The researchers found that levels of glucagon-like peptide 1 (GLP-1) were significantly lower after taking either aspartame or the amino acids (aspartic acid and phenylalanine).

However, aspartame did not affect glucose, insulin, gastric inhibitory polypeptide (GIP), cholecystokinin, gastric emptying or appetite.

Maersk M, et al. Satiety scores and satiety hormone response after sucrose-sweetened soft drink compared with isocaloric semi-skimmed milk and with non-caloric soft drink: a controlled trial. European Journal of Clinical Nutrition, 2012.

This crossover study in 24 adults with obesity investigated the effects of drinking a soda sweetened with 500 ml of aspartame.

Consuming an aspartame-sweetened beverage did not affect glucose, insulin, ghrelin, GLP-1, gastric inhibitory polypeptide (GIP), appetite sensations, thirst or calorie intake at a buffet four hours afterward.

Härtel BG, et al. The influence of sweetener solutions on the secretion of insulin and blood glucose level. Ernährungsunschau, 1993.

This crossover study in 14 healthy people compared the effects of 165 mg of aspartame to 330 ml of water.

The study showed that glucose levels were in some cases slightly lower after consuming aspartame, compared to water. However, the differences were not clinically relevant.

Bryant CE, et al. Non-nutritive sweeteners: no class effect on the glycaemic or appetite responses to ingested glucose. European Journal of Clinical Nutrition, 2014.

This crossover study in 10 healthy individuals examined the effects of 150 mg of aspartame to glucose.

Consuming aspartame did not significantly affect glucose or appetite sensations, compared to glucose only.

Steinert RE, et al. Effects of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal satiety peptides. The British Journal of Nutrition, 2011.

This crossover study in 12 healthy individuals compared the effects of an intragastric infusion of 50 grams of glucose, 25 grams of fructose or 169 mg of aspartame.

Aspartame did not affect glucose, insulin, glucagon-like peptide 1 (GLP-1), peptide YY, ghrelin or appetite sensations, compared to water.

Horwitz DL, et al. Response to single dose of aspartame or saccharin by NIDDM patients. Diabetes Care, 1988.

This study compared the effects of a beverage sweetened with 400 mg of aspartame to an unsweetened placebo.

Blood samples were taken regularly for three hours after consuming each beverage. The researchers found no significant differences in the levels of glucose, insulin or glucagon at any point in time.

Temizkan S, et al. Sucralose enhances GLP-1 release and lowers blood glucose in the presence of carbohydrate in healthy subjects but not in patients with type 2 diabetes. European Journal of Clinical Nutrition, 2015.

This crossover study included eight people newly diagnosed with T2D and eight healthy people. It compared the effects of consuming 200 ml of water to water combined with 72 mg of aspartame.

Aspartame did not affect glucose, insulin, C-peptide or glucagon-like peptide 1 (GLP-1), compared to water.

Bottom Line: Aspartame did not adversely affect blood sugar control or appetite. Some studies suggest that aspartame may be useful for diabetics.


Cooper PL, et al. Sucrose versus saccharin as an added sweetener in noninsulin-dependent diabetes: short- and medium-term metabolic effects.Diabetic Medicine: A Journal of the British Diabetic Association, 1988.

This crossover study in 17 people with non-insulin dependent diabetes showed that taking 30 grams of saccharin combined with starch every day for 6 weeks did not affect glucose, insulin or triglycerides.

Suez J, et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature, 2014.

This small trial in seven people showed that taking saccharin (2.3 mg per pound, or 5 mg per kg, of body weight) every day for 6 days, increased blood sugar levels in four of the participants.

When the feces of some of these four participants were transplanted into mice, their blood sugar levels increased as well. However, this study didn’t include a control group and therefore doesn’t prove that saccharin caused these effects.

Härtel BG, et al. The influence of sweetener solutions on the secretion of insulin and blood glucose level. Ernährungsunschau, 1993.

This crossover study in 14 healthy people compared the effects of 75 mg of saccharin to 330 ml of water.

The researchers found that glucose levels were in some cases slightly lower after consuming saccharin, compared to water. However, the differences were not clinically relevant.

Bryant CE, et al. Non-nutritive sweeteners: no class effect on the glycaemic or appetite responses to ingested glucose. European Journal of Clinical Nutrition, 2014.

This crossover study in 10 healthy individuals compared the effects of 20 mg of saccharin to 45 grams of glucose.

Consuming saccharin did not significantly affect glucose or appetite sensations, compared to glucose only.

Horwitz DL, et al. Response to single dose of aspartame or saccharin by NIDDM patients. Diabetes Care, 1988.

This study tested the effects of a beverage sweetened with 135 mg of saccharin to an unsweetened placebo.

Blood samples were taken regularly for three hours after consuming the beverage. The researchers found no significant differences in the levels of glucose, insulin or glucagon at any time point.

Bottom Line: There is limited evidence that saccharin has adverse effects on blood sugar control or appetite. One study suggests that saccharin may increase blood sugar levels by affecting the gut microbiota.


Gregersen S, et al. Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metabolism: Clinical and Experimental, 2004.

This crossover trial in 12 people with type 2 diabetes showed that 1 gram of stevioside added to a 412 calorie breakfast reduced the rise in blood sugar levels in 18% of the participants.

Stevioside also increased the ratio of insulin to glucose (the insulinogenic index). In contrast, stevioside did not affect insulin, glucagon, glucagon-like peptide 1 (GLP-1) or gastric inhibitory polypeptide (GIP).

Barriocanal LA, et al. Apparent lack of pharmacological effect of steviol glycosides used as sweeteners in humans. A pilot study of repeated exposures in some normotensive and hypotensive individuals and in Type 1 and Type 2 diabetics.Regulatory Toxicology and Pharmacology, 2008.

This was a randomized controlled trial in 76 people — 30 with T2D, 16 with T1D and 30 healthy individuals.

It showed that taking 250 mg of steviol glycosides every day for three months did not affect glucose, insulin or HbA1c, compared to a placebo.

Maki KC, et al. Chronic consumption of rebaudioside A, a steviol glycoside, in men and women with type 2 diabetes mellitus. Food and Chemical Toxicology: An International Journal Published for the British Industrial Biological Research Association, 2008.

This randomized controlled trial in 122 people with diabetes examined the health effects of taking 1000 mg of rebaudioside A (a steviol glycoside) for four months.

The study showed that rebaudioside A did not affect glucose, insulin, HbA1c, C-peptide, body weight, blood pressure or blood lipids.

Anton SD, et al. Effects of stevia, aspartame, and sucrose on food intake, satiety, and postprandial glucose and insulin levels. Appetite, 2010.

This crossover study in 19 normal-weight and 12 obese adults examined the acute effects of tea sweetened with sucrose, stevia or aspartame. The quantity of each sweetener was not specified.

Stevia reduced glucose and insulin levels, compared to sucrose. In contrast, there were no significant differences in hunger, satiety or fullness at a subsequent meal.

Bottom Line: Stevia may have benefits for blood sugar control, and there is no evidence of any harmful effects.


Mezitis NH, et al. Glycemic effect of a single high oral dose of the novel sweetener sucralose in patients with diabetes. Diabetes Care, 1996.

This crossover study included 13 people with type 1 diabetes and 13 with type 2 diabetes. On two separate visits, the participants took a single 1000 mg capsule of sucralose or a placebo, followed by a standard liquid breakfast.

Sucralose did not affect the levels of blood sugar or C-peptide for four hours afterward, compared to a placebo.

Grotz VL, et al. Lack of effect of sucralose on glucose homeostasis in subjects with type 2 diabetes. Journal of the American Dietetic Association, 2003.

This large randomized controlled trial recruited 128 participants with T2D. It showed that taking 667 mg of sucralose every day for 13 weeks did not affect glucose, C-peptide or HbA1c, compared to a placebo.

Ma J, et al. Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects. American Journal of Physiology Gastrointestinal and Liver Physiology, 2009.

This small crossover trial in seven healthy adults showed that intragastric infusions of up to 800 mg of sucralose did not affect glucose, insulin, GLP-1, gastric inhibitory polypeptide (GIP) or gastric emptying, compared to a saline solution.

Ma J, et al. Effect of the artificial sweetener, sucralose, on small intestinal glucose absorption in healthy human subjects. The British Journal of Nutrition, 2010.

This study in 10 healthy people tested the effects of injecting 960 mg of sucralose into the duodenum. Sucralose infusion did not significantly affect glucose or glucagon-like peptide 1 (GLP-1), compared to saline.

Ford HE, et al. Effects of oral ingestion of sucralose on gut hormone response and appetite in healthy normal-weight subjects. European Journal of Clinical Nutrition, 2011.

This small crossover study in eight healthy individuals examined the acute effects of 50 ml of water, sucralose or maltodextrin combined with sucralose.

Sucralose did not affect glucose, insulin, GLP-1, peptide YY, food intake, appetite or brain responses, compared to a placebo.

Brown AW, et al. Short-term consumption of sucralose, a nonnutritive sweetener, is similar to water with regard to select markers of hunger signaling and short-term glucose homeostasis in women. Nutrition Research, 2011.

This small crossover study in eight women showed that consuming 6 grams of sucralose did not affect glucose, insulin, glucagon, triglycerides, ghrelin, appetite sensations or general wellbeing, compared to water.

Wu T, et al. Effects of different sweet preloads on incretin hormone secretion, gastric emptying, and postprandial glycemia in healthy humans. The American Journal of Clinical Nutrition, 2012.

This crossover study in 10 healthy individuals showed that consuming 60 mg of sucralose did not affect glucose, insulin, glucagon-like peptide 1 (GLP-1), gastric inhibitory polypeptide (GIP) or gastric emptying, compared to 40 grams of glucose.

Pepino MY, et al. Sucralose affects glycemic and hormonal responses to an oral glucose load. Diabetes Care, 2013.

This study in morbidly obese people showed that 48 mg of sucralose increased blood sugar and insulin levels and impaired insulin sensitivity by 23%.

In contrast, sucralose did not affect GLP-1, gastric inhibitory polypeptide (GIP), glucagon or the pancreatic response.

Steinert RE, et al. Effects of carbohydrate sugars and artificial sweeteners on appetite and the secretion of gastrointestinal satiety peptides. The British Journal of Nutrition, 2011.

This crossover study in 12 healthy individuals compared the effects of an intragastric infusion of 50 grams of glucose, 25 grams of fructose or 62 mg of sucralose.

Sucralose did not affect glucose, insulin, glucagon-like peptide 1 (GLP-1), peptide YY, ghrelin or appetite sensations, compared to water.

Temizkan S, et al. Sucralose enhances GLP-1 release and lowers blood glucose in the presence of carbohydrate in healthy subjects but not in patients with type 2 diabetes. European Journal of Clinical Nutrition, 2015.

This crossover study included eight people newly diagnosed with T2D and eight healthy people. It compared the effects of consuming 200 ml of water to water combined with 24 mg of sucralose.

The researchers found that sucralose lowered glucose levels and increased glucagon-like peptide 1 (GLP-1) in healthy participants, compared to water. In contrast, sucralose did not affect insulin and C-peptide.

Bottom Line: There is no solid evidence that sucralose adversely affects blood sugar control or appetite. One study showed that sucralose impaired insulin sensitivity in severely obese people.

Observational Studies on the Total Intake of Non-Nutritive Sweeteners

Several observational studies have investigated the association of total non-nutritive sweetener intake (NNS) with metabolic disorders, mainly type 2 diabetes (T2D). Here are summaries of their results.

One report using data from a study including more than 70,000 women showed that a high intake of caffeinated, artificially sweetened beverages was associated with an increased risk of T2D (1).

However, this association was lost when the researchers adjusted for body mass index (BMI) and calorie intake. In other words, those who consumed the most NNS from caffeinated beverages had a higher BMI, explaining the links with T2D.

In another study based on data from the Nurses Health Study II, researchers found no significant association between NNS intake and T2D (2).

Similar studies have also investigated this association in men.

Data from the Health Professionals Follow-Up Study, including more than 40,000 men, showed that a high intake of NNS was significantly linked with an increased risk of T2D, but the association was lost after an adjustment for BMI (3).

The largest observational study examining the link between total NNS intake and T2D was the European Prospective Investigation into Cancer and Nutrition (EPIC) study. It was conducted in eight countries and included 340,234 subjects (4).

The study reported a significant association between NNS intake and T2D. But once again, this link was lost after an adjustment for BMI and calorie intake.

Several other smaller observational studies have investigated the links between NNS intake and metabolic disease.

The Black Women’s Health Study, which included 43,960 African American women, found no significant links between NNS intake and T2D (5).

Three studies showed that a high intake of NNS was associated with metabolic syndrome. However, they didn’t take BMI or fat mass into account (678).

One study found that drinking a lot of diet soda was linked with an increased risk of metabolic syndrome and T2D.

Again, the association with metabolic syndrome was lost after adjusting for BMI and waist circumference. However, while the link to T2D weakened after adjustment, it remained significant (9).

Another study in 66,118 French female teachers showed that drinking more than 20 oz of artificially sweetened beverages per week was linked with a higher risk of T2D, even after adjusting for BMI (10).

Among 2,337 Japanese factory workers, consuming one or more servings of diet soda per week was associated with a higher risk of T2D, compared to those who didn’t drink diet soda (11).

The association remained significant after adjusting for multiple variables.

In the EPIC-Norfolk Study, which included 24,653 adults, drinking more than 336 g of artificially sweetened beverages per day was associated with an increased risk of T2D (12).

However, this link was lost after adjusting for BMI and waist circumference.

Other studies looked at the links between obesity and NNS intake. They showed that obese people and those gaining weight were more likely to consume artificially sweetened beverages (13).

Two meta-analyses have examined the connection between drinking artificially sweetened beverages and T2D.

One analysis included four studies with healthy participants. It reported that drinking 330 ml of artificially sweetened beverages a day increased the risk of T2D.

However, the relative risk (RR) was small or only 1.13. In other words, those who consumed 330 ml of artificially sweetened beverages per day were only 1.13 times more likely to develop TD2, compared to those who didn’t consume them (14).

Another analysis included 10 studies. It found artificial sweeteners increased the risk of T2D (RR = 1.48). However, the association was lost after adjusting for BMI (15).

Bottom Line: Studies indicate people who consume NNS are at an increased risk of metabolic disease, but the link is usually lost after adjusting for fat mass.

Summary and Real-Life Application

Although some observational studies show a significant link between high intakes of NNS and type 2 diabetes, the association is generally lost after an adjustment for fat mass or BMI.

People who are overweight or obese and at risk of developing diabetes or metabolic disorders have a tendency to choose diet sodas sweetened with zero-calorie sweeteners. This likely explains the findings of many observational studies.

Accordingly, the majority of randomized controlled trials have not found any signs of adverse effects. However, many trials are small and flawed in design.

One study found that sucralose reduced insulin sensitivity in morbidly obese individuals. Further trials need to confirm its findings.

Additionally, a few trials found that artificial sweeteners lowered blood sugar or insulin levels, compared to sugar, which benefits people with poor blood sugar control.

Taken together, there is currently no strong evidence linking non-nutritive sweeteners (NNS) with adverse changes in glucose metabolism or appetite in humans when they are eaten in acceptable amounts.

Cancer risks linked to body fat

Cancer is one of the leading cauObese Man In Doctors Officeses of death.

Earlier this year, the International Agency for Research on Cancer (IARC) assembled an international group of experts to assess the effects of excess fat on cancer risk.

Recently, they published an overview of their conclusions in The New England Journal of Medicine. Here is a summary of their report.



People’s risk of developing certain types of cancer is largely determined by lifestyle habits, although genetics also play a significant role.

A healthy diet and exercise may reduce the risk of cancer, whereas smoking, excessive alcohol intake and certain types of foods may increase the risk.

For example, the IARC recently concluded that an excessive intake of processed meat increases the risk of cancer.

Article Reviewed

This was a special report from the International Agency for Research on Cancer (IARC), which is a part of the World Health Organization.

The report provides a summary of their conclusions regarding the association of cancer risk with overweight and obesity.

Body Fatness and Cancer — Viewpoint of the IARC Working Group.

Study Design

From April 5–12th, 2016, the IARC working group reviewed more than 1,000 studies investigating the links between excess body fat and cancer.

Most of these studies were observational and used body mass index (BMI) or waist circumference when assessing excess body fat.

Their findings were not based on new research. They simply based their conclusions on the most recent or comprehensive studies and meta-analyses available.

Bottom Line: The IARC working group spent a few days reviewing the available evidence, basing their conclusions on the most recent studies and meta-analyses examining the link between obesity and cancer risk.

What Are Overweight and Obesity?

Overweight and obesity are terms used to describe the excessive accumulation of body fat.

They are generally defined using the body mass index (BMI), which is a marker of fat mass. BMI is calculated by dividing body weight (in kilograms) by body height squared (in centimeters).

Using BMI, normal weight, overweight and obesity are defined as follows:

  • Normal weight: 18.5–24.9.
  • Overweight: 25.0–29.9.
  • Obesity, class 1: 30.0–34.9.
  • Obesity, class 2: 35.0–39.9.
  • Obesity, class 3: More than 40.

BMI is not an accurate measure of excessive fat, given that it can be skewed by high muscle mass. However, it is easy to measure and an adequate proxy for fat mass on a population level.

Bottom Line: Overweight and obesity are terms used to describe the excessive accumulation of body fat. The basic causes are excessive calorie intake and inactivity.

Does Excessive Fat Mass Increase the Risk of Cancer?

In 2002, the previous IARC working group concluded that there was evidence linking weight gain to an increased risk of five types of cancer.

These included cancers in the colon, esophagus (adenocarcinoma), kidneys (renal cell), breasts (postmenopausal) and the uterus (1).

The current working group added eight additional cancers to this list, including cancers in the liver, gallbladder, pancreas, ovaries, thyroids, brain (meningioma), white blood cells (multiple myeloma) and stomach (gastric cardia).

The charts below show the percentage change in risk for each of these cancers, comparing normal-weight people with those in the highest BMI category studied.

Increase In Risk Of 5 Cancers

Increase In Risk Of Various Cancers

For uterine and esophageal cancers, the researchers compared those in the highest obesity category (BMI above 40) with normal-weight people.

For other cancers, the risk increase was based on a comparison of those in the lowest obesity category (BMI above 30) with normal-weight people. Values marked with an asterisk (*) show the risk increase per 5 BMI units above a BMI of 30.

Bottom Line: Obesity increases the risk of many types of cancer. In severely obese people, the risk of esophageal adenocarcinoma increases by 380% and uterine cancer by 610%, compared to normal-weight people.

Why Does Excess Fat Increase Cancer Risk?

In many cases, the excess cancer risk associated with overweight or obesity is due to lifestyle factors.

Overweight and obese people tend to exercise less than normal-weight people. Additionally, their choice of food is often unhealthier (2).

Obesity is also linked with considerable hormonal and metabolic abnormalities, including chronic inflammation, which may promote the formation of cancer (34).

Bottom Line: Unhealthy lifestyle habits and metabolic abnormalities explain why overweight and obese people tend to be at an increased risk of cancer.


The main limitation of the reviewed studies is their observational design.

Even though causality cannot be demonstrated, it is clear that some aspects of obesity and the related lifestyle increase the risk of cancer.

Additionally, the observational evidence is consistent across studies and populations and supported by controlled studies in animals.

Summary and Real-Life Application

In short, the IARC working group concluded that there is sufficient evidence linking overweight and obesity with 13 types of cancer in humans. In fact, the risk is even higher than previously thought.

However, the human evidence is mostly based on observational studies, which cannot prove causality. However, it is clear that some metabolic aspects of obesity or the related lifestyle habits are associated with an increased risk of cancer.

Nicotinic Acid, Nicotinamide, and Nicotinamide Riboside: A Molecular Evaluation of NAD+ Precursor Vitamins in Human Nutrition

This study by Dr Charles Brener published here  in 2008.

As schematized in Figure 1, the reason that a poor diet can produce a requirement for Na and Nam is that Trp, Na, and Nam are all NAD+ precursors (7). Trp is converted to NAD+ through an eight-step de novo pathway (Figure 2), so termed because the Nam base is essentially made from scratch. In contrast, Na and Nam are considered “salvageable precursors” that require only three steps and two steps, respectively, to rebuild NAD+. Nicotinamide riboside (NR) is an additional salvageable NAD+ precursor vitamin with a two-step pathway (14) and a three-step pathway (8) to form NAD+. As schematized in Figures 1 and 2, cells require ongoing NAD+ synthesis because NAD+ and NADP are not only coenzymes, which are recycled back and forth between oxidized (NAD+ and NADP) and reduced (NADH, NADPH) forms by hydride transfer enzymes, but are also substrates of NAD+ -consuming enzymes that break the glycosidic bond between the Nam moiety and the ADPribose moiety. NAD+consuming enzymes transfer ADPribose and/or ADPribose polymers, form signaling compounds from NAD+ and NADP, and reverse the acetyl modification of protein lysine residues. Each of these reactions consumes an NAD+ equivalent to a salvageable Nam product plus an ADPribosyl product (7).

NAD+-consuming enzymatic activities are induced, in part, by stresses such as DNA damage and inflammation. Many of these stresses are accompanied by specifically induced biosynthetic pathways, which appear to function to maintain NAD+ homeostasis. The term NAD+ homeostasis should be used cautiously, however, because it is not clear that cells are always in NAD+ homeostasis. Mammalian NAD+ biosynthesis is not a closed, cell-autonomous system, and there appear to be situations in which cells actively increase and/or reduce the concentration of NAD+ and NAD+ metabolites to promote vital and/or regulatory functions, including cell death.


Despite the fact that the biosynthetic pathways are not the same, in the literature of human and animal nutrition, Nam and Na are collectively termed niacin and/or vitamin B3 . To protect against pellagra that can develop with Trp deficiency, recommended daily allowances (RDAs) of niacin are 16 and 14 mg

per day for adult men and women, respectively (79). Because all plant, animal, and fungal inputs in our diet contain cellular NAD+ and NAD+ metabolites, foods provide NAD+ , NADH, NADP, and NADPH, which are considered nutritional “niacin equivalents,” in addition to Nam and Na. Whereas Nam and Na are the fully broken down NAD+ metabolites from animals and plants/fungi/bacteria respectively, NR and nicotinic acid riboside (NaR) can be considered partly broken down niacin equivalents. In the genetically tractable yeast system, all of the salvageable precursors (Na, Nam, NR, and NaR) support the growth of cells inactivated for de novo NAD+ synthesis (83).

A single yeast cell deficient in de novo synthesis or undergoing a biological process that requires more than the minimum vital concentration of NAD+ must convert an available vitamin precursor to NAD+ in a cell-autonomous fashion. In contrast, humans exhibit the complexity of systemic NAD+ metabolism in which particular cells may utilize an NAD+ precursor to produce an excess of NAD+ and export salvageable precursors to other cells. Accordingly, dietary Trp is also classified as a niacin equivalent. However, because of the protein and other biosynthetic uses of Trp, 60 mg of Trp is considered the equivalent of 1 mg of niacin (79). This physiological fact, that high levels of dietary Trp result in circulation and excretion of Na (9, 10, 60, 70), has resulted in claims in textbooks and reviews that Na is derived from Trp. Whereas this is true in vertebrate organisms, there may not be a vertebrate intracellular pathway that is responsible. As illustrated in Figure 2, Trp can be converted to Nam but not Na in any vertebrate cell expressing a de novo pathway and an NAD+-consuming enzyme such as poly(ADPribose)polymerase (PARP) or a sirtuin. Nam can then be converted in the intestinal lumen by bacterial nicotinamidase to Na. The most reasonable pathway by which a single vertebrate cell might convert Trp to Na was depicted by Magni and coworkers (53). Magni’s scheme of human NAD+ metabolism depicts the activity of Na phosphoribosyltransferase (NAPRT1 gene product) and several other enzymes as bidirectional. Indeed, if there is sufficient pyrophosphate and NaMN in cells, then Naprt1 could catabolize nicotinic acid mononucleotide (NaMN) to Na, thereby creating a cell-autonomous route from Trp to Na. This is an interesting possibility that has not been demonstrated in vivo.

NR is a newly discovered salvageable precursor of NAD+ that occurs in cow’s milk (14). Studies in Saccharomyces cerevisiae have shown that, like Na and Nam, NR is an NAD+ precursor that contributes to maintaining intracellular NAD+ concentration and improves NAD+ dependent activities in the cell including Sir2-dependent gene silencing and longevity (8, 14). NR can either be converted to NAD+ by the Nrk pathway (14), which is induced by axotomy in dorsal root ganglion (DRG) neurons (71), or by the action of nucleoside phosphorylase and nicotinamide salvage (8). It has also been shown that the same two pathways required for NR salvage in yeast cells can also be used for NaR salvage (83). In yeast cells, NR clearly qualifies as a vitamin by virtue of rescuing growth of strains deficient in de novo synthesis (14, 83), improving Sir2 functions (8), and utilizing a dedicated transporter (8a). Additionally, because cells deleted for the NR/NaR salvage enzymes have a significant deficiency in intracellular NAD+ when not supplemented with these compounds, it appears that NR and/or NaR are also normal metabolites (8).

Five lines of reasoning support designation of NR as an authentic NAD+ precursor vitamin in vertebrates. First, Haemophilus influenza, a flu-causing bacterium, which has no de novo pathway and cannot utilize Na or Nam, is strictly dependent on NR, NMN, or NAD+ for growth in the host bloodstream (22). Second, milk is a source of NR (14). Third, NR protects murine DRG neurons in an ex vivo axonopathy assay via transcriptional induction of the nicotinamide riboside kinase (NRK) 2 gene (71). Fourth, exogenously added NR and derivatives increase NAD+ accumulation in a dose-dependent fashion in human cell lines (94). Fifth, Candida glabrata, an opportunistic fungus that depends on NAD+ precursor vitamins for growth, utilizes NR during disseminated infection (51).

It should be realized that not every cell is capable of converting each NAD+ precursor to NAD+ at all times. Expression of the eightstep de novo pathway is required to utilize trp. Expression of the Nampt pathway is required to utilize Nam. Expression of either the Nrk pathway or nucleoside phosphorylase and the Nampt pathway is required to utilize NR. Finally, expression of the Preiss-Handler pathway is required to utilize Na. Because tissue and celltype specific enzyme expression differences exist, the precursors are differentially utilized in the gut, brain, blood, and organs. Understanding the unique aspects of metabolism of each precursor is necessary to define the mechanisms underlying the physiological effects and side effects of each.


NAD+ is classically known as a coenzyme for hydride-transfer enzymes. As a coenzyme, NAD+ is essential to a variety of diverse biological processes including energy production and synthesis of fatty acids, cholesterol, and steroids. NAD+ participates in oxidationreduction (redox) reactions as hydride donor (NADH and NADPH) and acceptor (NAD+ and NADP). NAD+ most commonly functions in energy-producing catabolic reactions, such as the degradation of carbohydrates, fats, proteins, and alcohol, whereas NADP functions in anabolic reactions, such as the synthesis of cellular macromolecules including fatty acids and cholesterol. As depicted in Figure 1, coenzymatic activities of NAD+ and its reduced and phosphorylated derivatives interconvert but do not alter total cellular levels of NAD+.

In recent years, multiple enzyme-mediated, nonredox roles for NAD+ have been discovered. NAD+-consuming enzymes break down NAD+ to Nam and an ADPribosyl product (7). These enzymes fall into three classes. The first class consists of ADPribose transferases (ARTs) and PARPs, which transfer and/or polymerize NAD+-derived ADPribose, frequently as a post-translational modification. PARP activity, which is upregulated by DNA strand breaks (54), may be the major source of intracellular NAD+ consumption. The second class of NAD+-consuming enzymes consists of cADPribose synthases, which are membranebound ecto-enzymes also known as CD38 and CD157, that produce and hydrolyze the Ca2+-mobilizing second messenger cADPribose from NAD+ (38, 39, 43). Additionally, CD38 catalyzes a base exchange between NADP and Na to form nicotinic acid adenine dinucleotide phosphate (NaADP) (1), which is also a hydrolytic substrate (30). The products of these reactions have distinct and important roles in Ca2+ mobilization and signaling. The third class of NAD+-consuming enzymes consists of sirtuins, named for their sequence similarity to the yeast Sir2 genesilencing protein. Sirtuins exhibit protein lysine deacetylase and, occasionally, ADPribose transferase activities. Sirtuin deacetylation reactions proceed by binding an acetyl-modified lysine on a target protein and NAD+ in distinct pockets. Deacetylation of the modified lysine side chain is coupled to the cleavage of the glycosidic bond in NAD+ such that the products are the deacetylated lysine, acetylated ADPribose, and Nam (72). Sirtuin-dependent deacetylation of histones and other proteins results in reprogrammed gene expression, mitochondrial synthesis and function, cell survival, and longevity (91). Sirtuins have been recently reviewed as master switches of metabolism (18a).

Nam regulates the activity of NAD+ consuming enzymes both by direct enzyme inhibition and by its role as an NAD+ precursor. Nam inhibits NAD+ -consuming enzymes by binding a conserved pocket that participates in NAD+ binding and catalysis (4). Recycling of Nam back to NAD+ raises NAD+ levels, increasing substrate availability and relieving Nam inhibition. In systems such as yeast in which NAD+ concentration has been determined carefully, basal intracellular NAD+ concentration is approximately 0.8 mM and can be elevated with vitamin precursors by 1 mM or more (8). At first glance, it would seem that 0.8 mM NAD+ should be saturating for virtually all sirtuins, which exhibit Km values for NAD+ between 5 μM and 500 μM (72). However, the first 0.8–1 mM of intracellular NAD+ concentration may largely be bound by redox enzymes such that salvage-derived synthesis of NAD+ may generate the majority of free NAD+ to drive sirtuin functions.

The first step in Nam salvage is catalyzed by Nam phosphoribosyltransferase (Nampt), which is encoded by the PBEF1 gene. This polypeptide, first identified as an extracellular protein termed pre B-cell colony enhancing factor (PBEF), was characterized as cytokine that enhances the maturation of B-cell precursors in the presence of IL-7 and stem cell factor (69). The same polypeptide was also termed

Visfatin, due to reported insulin mimetic functions and regulation of systemic metabolism (26). However, the intracellular form of the molecule was shown to be induced in activated lymphocytes and function simply as Nampt (68).

Because of the disparate functions ascribed to the same polypeptide, it had been assumed that intracellular Nampt functions as an NAD+ biosynthetic enzyme, whereas extracellular Nampt has cytokine and insulin-mimetic roles. However, it has now been reported that both intraand extracellular Nampt exhibit robust phosphoribosyltransferase activities and that inhibiting NAD+ biosynthesis through the Nampt pathway, either genetically or pharmacologically, causes impaired glucose tolerance and reduced insulin secretion in mice, a defect that can be corrected by administering nicotinamide mononucleotide (NMN) (66). Moreover, murine plasma contains high concentrations of Nampt and NMN, which are reduced in nampt heterozygous animals. These new findings strongly indicate that the primary role for extracellular PBEF/Visfatin/Nampt is to catalyze NMN production from Nam, and that NMN has an important role in maintaining β-cell function (66). In a recent review, we speculated that a partially extracellular NAD+ cycle might consist of a Nampt step, followed by extracellular dephosphorylation of NMN to NR, intracellular transport of NR, and conversion of NR to NAD+ (7).


Consistent with Goldberger’s studies (29), niacin is abundant in meat, eggs, fish, dairy, some vegetables, and whole wheat. Notably, corn contains abundant Na and Nam, largely present in bound forms that are not bioavailable. Treatment with alkali is used to increase bioavailability, a practice that protected native and South American populations from deficiency. Untreated corn is considered “pellagragenic,” causing increased sensitivity to low dietary niacin concentrations in animal studies (46, 47). Milk, now known to be a natural source of NR (14), was shown to counteract the growth defect seen in corn-fed animals (46). In meats, Na and Nam are scarce and NAD+ and NADP are the abundant sources of niacin (34, 86). Nam is produced by mucosal enzymes that cleave NAD+ (86), and Na is produced from Nam by deamination by bacterial nicotinamidase in the gut (13). Both Na and Nam are absorbed from the alimentary canal and enter the bloodstream for distribution to tissues (40, 82, 86). Studies indicate that Nam is the dominant absorbed form of niacin when the dietary sources are NAD+ and NADP (16, 35, 36, 81). However, it has also been reported that NAD+ is digested by pyrophosphatases to NMN and hydrolyzed to NR, which was found in the lumen of the upper small intestine (32). We surmise that NR is incorporated into the cellular NAD+ pool via the action of Nrk pathway (14) or via Nam salvage after conversion to Nam by phosphorolysis (8).


Qprt, Nampt, Naprt1, and Nrk1,2 are the committed enzymes in the synthesis of NAD+ from Trp, Nam, Na, and NR. As such, by examining the expression of each enzyme and by following the metabolic fates of dietary inputs, one can describe tissue-specific pathways of NAD+ biosynthesis.

Animals on diets containing sufficient amounts of both Trp and niacin have a measurable concentration of each in liver (9, 10). Nam and Na, however, are thought to supply only a fraction of the NAD+ produced in the liver, with much niacin circulating to other tissues. Trp is thought to be the principal NAD+ precursor utilized in liver (9). In addition to producing quinolinate for entry into NAD+ biosynthetic pathways, Trp is incorporated into protein, utilized to generate energy through total oxidation, and utilized to form kynurenic acid. Inducible enzymes of Trp utilization regulate the flux of Trp through different pathways depending on diet and cellular metabolic state. Under conditions of low Trp consumption, circulating levels of Trp decrease and enzymes that direct Trp to non-NAD+ biosynthetic routes are down-regulated, suggesting a shift of all possible Trp catabolism to NAD+ generation (75). Supplementing high amounts of Trp allows more flux to the oxidative branch and allows increased levels of Nam to be released into the vasculature (6, 9, 10). All Trp that reaches quinolinate in the liver is thought to be converted to NAD+ via subsequent enzyme reactions of Qprt, Nmnat1-3, and Nadsyn1, which are highly expressed in liver (24, 58).

In addition to liver (27), Qprt is expressed in human and rat brain and plays a critical role in protection against the neurotoxic effects of quinolinate (23, 45, 58, 93). Quinolinate is a potent endogenous neurotoxin, and elevated levels in brain are associated with neurodegenerative disorders including epilepsy and Huntington’s disease (73, 74). The normal concentration of quinolinate in the brain was found to be in the lowto mid-nanomolar range (37), and Qprt activity increases in response to increased levels of quinolinate (25), suggesting a protective role. The highest levels of quinolinate are found in spleen, lymph nodes, thymus, and many specific immune cell types and are increased following stimulation by immune activators (57).

Activated lymphocytes induce expression of Nampt (68), which is also expressed in smooth muscle cells with loss of expression in senescence (87). In the mouse, Nampt has been shown to circulate and to be highly expressed intracellularly in brown adipose tissue, liver, and kidney, with fat as the source of extracellular Nampt. Human fat is also a source of circulating Nampt (66). From classical feeding studies, the testes were found to utilize Nam rather than Na or quinolinate (50), and blood and liver were also found to be major sites of Nam utilization (41). Nam crosses the blood-brain barrier and is converted to NAD+ in brain, though it is not known whether Nam is a precursor of NAD+ in neuronal or non-neuronal cells (78). Studies with DRG neurons suggest that Nampt is not neuronally expressed (71). Nam and NR are also taken up by intestinal epithelial cells and both are utilized by Nam salvage (15).

By global analysis of mRNAs, Naprt1 is expressed in most tissues of the adult mouse, including colon, heart, kidney, and liver, suggesting the presence and utilization of the substrate Na as an NAD+ precursor in these tissues (21). Classical feeding studies showed that exogenously added Na is a better NAD+ precursor than Nam in liver, intestine (16), and kidney (50). Similarly, rats fed Na showed elevated levels of NAD+ in the heart and kidney in addition to blood and liver, which are sites of Na and Nam utilization (41). Classical studies have been corroborated by a recent report that mouse Naprt1 is expressed in intestine, liver, kidney, and heart. In addition, human kidney cell lines are able to use Na to increase intracellular NAD+ concentration in a manner that depends on the NAPRT1 gene. Moreover, Naprt1 expression decreases vulnerability to oxidative damage from NAD+ depletion. The use of Na as an NAD+ precursor in normal and stress conditions implicates the presence of Na as a normal cellular metabolite in humans (33). As discussed earlier, we consider the bacterial flora of the intestinal lumen to be the first major site in a vertebrate for production of Na, though bacterial and fungal degradation of cellular NAD+ in food and direct Na supplementation will also produce supplies of Na in the alimentary canal for distribution to tissues through the vasculature. True intracellular production of Na in a vertebrate cell (53) would require high levels of Trp and/or NAD+ and substantial reverse flux through what are usually considered anabolic pathways.

The use of NR as a precursor in mammalian cell types was first demonstrated in DRG neurons, which induce the NRK2 transcript when damaged by axotomy (71). The ubiquitous expression of Nrk1 in mammalian tissues (80) suggests utilization of NR and/or NaR (83) in a diverse array of cell types. However, Nrk2 is present in heart, brain, and skeletal muscle, and is notably absent in kidney, liver, lung, pancreas, and placenta (48, 71). The fact that DRG neurons cannot be protected from damage

induced neuropathy by Na or Nam without concurrent gene expression of Na or Nam salvage genes suggests that NR is a uniquely useful precursor to the nervous system (71) when de novo synthesis of NAD+ from Trp is not sufficient.

Available data summarizing the system-wide use of NAD+ precursors are summarized in Figure 3. The data are more static than one would like, such that it will be important to determine how gene expression and precursor utilization changes as a function of nutrition, age, stress, and disease state. It is particularly striking that two enzymes, namely Nampt and Nrk2, were first identified as highly regulated proteins involved in immune cell (69) and muscle cell (48) development. Thus, developmental regulation of NAD+ synthesis and utilization remains on the forefront of NAD+ biology.


Caloric restriction (CR) is the most effective intervention to extend the lifespan of multiple model organisms including mammals. CR is defined as a 20% reduction versus ad libitum feeding without compromising adequate nutrition (56). Although the mechanisms of CR remain elusive, it is thought that CR modulates fat and carbohydrate metabolism, attenuates oxidative damage, and activates a stress-induced hormetic response that mediates improved vitality and disease resistance (55). Among these three major mechanisms, modulation of fat and carbohydrate utilization is the most direct response to reduced dietary inputs, and hormesis is potentially the mechanism most influenced by the “signaling” aspect of CR.

The hormetic theory is supported by experiments in which model organisms exhibit extended lifespan when placed in a variety of sublethal stress conditions including high temperature, high salt, or osmotic stress. In yeast, such conditions increase expression of nicotinamidase, thereby altering NAD+ metabolism in a manner that favors Sir2 activity (2). The principal mechanism by which Sir2 extends lifespan in a wild-type yeast cell is repression of formation of aging-associated extrachromosomal ribosomal DNA circles (76). Though this mechanism is unique to yeast, there are substantial data showing that sirtuins are conserved from fungi to metazoans to mediate some of the beneficial effects of CR (77). Sir2 is not the only mediator of CR-induced lifespan extension in yeast (42), nor are sirtuins necessarily the only targets of nicotinamide inhibition (84). Nonetheless, there is excellent evidence that NAD+ metabolism is altered in vertebrate systems by CR and that increased activity of sirtuins may mediate beneficial brain and liver physiology under CR conditions.

In CR-treated mice, brain NAD+ levels are increased and Nam levels are decreased, and these changes accompany neuronal Sirt1 activation, which reduces Alzheimer’s neuropathology (63). In fasted mice, NAD+ levels are increased in liver, which is accompanied by Sirt1 activation, PGC1α deacetylation, and increased mitochondrial biogenesis (67). The mechanisms by which lower food inputs increase NAD+ levels in brain and liver are completely unknown. Two potential mechanisms that may account for this phenomenon are systemic mobilization of NAD+ precursors to the brain and liver and reduced NAD+ breakdown. Among the potential precursors that could mediate this phenomenon, Na and Trp seem unlikely because one would expect that increased food consumption would be required to increase their availability. Analysis of CR-induced systemic metabolites should permit the detection of either Nam or NR as candidate mediators of increased brain and liver NAD+ levels. Reduced NAD+ breakdown is another mechanism by which CR might increase NAD+ levels in particular tissues. This could occur if an NAD+-consuming activity such as PARP is negatively regulated by CR. The pathways that produce NR or NaR at the expense of NAD+ (8) are not known. These, too, might be negatively regulated by CR in order to elevate brain and liver NAD+.


Wallerian degeneration refers to the ordered process of axonal degeneration. Wallerian degeneration occurs when an axon is severed from the cell body, and proceeds via characteristic fragmentation of cellular components initiated by a factor or factors intrinsic to the neuron (28, 31). The distal part of a severed or damaged axon usually undergoes Wallerian degeneration within 24–48 hours of injury (88). This type of axonopathy is thought to be a critical, early event in neurodegenerative conditions including multiple sclerosis, Alzheimer’s, and Parkinson’s diseases and in polyneuropathies associated with diabetes and acute chemotherapy use (64, 90). Remarkably, a mouse mutant, termed wlds, with delayed Wallerian degeneration has been identified in the C57BL/6 background. Axons from the wlds mouse survive several weeks after transection (61, 62).

The dominant neuroprotective gene in the wlds mouse is an in-frame fusion of the Nterminal 70 amino acids of a ubiquitin assembly factor (Ube4b/Uf2a) with the entire coding sequence of Nmnat1 (17). Transgenic mice expressing the Ube4b/Nmnat fusion gene showed that the nuclear protein protected from axonopathy in a manner that depended on the level of protein expression, indicating the activity of a nuclear-derived factor (52). Although Nmnat in flies can protect against degeneration of optic neurons in an active site-independent manner (95, 96), the protective factor for DRG neurons appears simply to be NAD+. The evidence is as follows. Lentiviral expression of Nmnat1 protects DRG neurons from axonopathy in an active site-dependent manner (3). Overexpression of wlds or Nmnat1 prevents NAD+ and ATP decline in response to mechanical and chemical damage (89). Nam and Na also protect against axonopathy as long as Nampt or Naprt1 are concomitantly expressed in DRG neurons, whereas NR protects without engineered gene expression of a biosynthetic gene (71). Nrk2 mRNA levels following axonopathy are induced approximately 20-fold, indicating a preferential use of NR as a precursor in maintaining intracellular NAD+ levels in DRG neurons (71). Whether sufficient oral NR supplementation might protect against diabetic or chemotherapy-induced neuropathy or protect against age-associated neurodegenerative conditions remains to be determined.


Candida glabrata, the second leading cause of candidiasis, does not encode genes for de novo synthesis of NAD+, such that it is a Na auxotroph. Because the C. glabrata Sir2 homolog represses transcription of a set of adhesin genes, Na limitation leads to adhesin gene expression and host colonization (19). Recent data establish that NR is also utilized by C. glabrata as the primary vitamin precursor in disseminated infection in mouse (51). The Nrk pathway (14) and NR to Nam salvage (8) are both components of NR utilization in C. glabrata (51).


Na has been used to treat dyslipidemias in humans since the 1950s. Gram dosages reduce triglycerides and low-density lipoprotein (LDL, i.e., “bad”) cholesterol and raise highdensity lipoprotein (HDL, i.e., “good”) cholesterol levels. As a monotherapy, Na is one of the most effective means to improve cardiovascular risk factors and, in combination with statins and bile acid treatments, can enhance therapeutic effects (18). In addition to lowering circulating cholesterol levels, Na prevents establishment of lipid deposits and the progression of atherosclerosis in a cholesterol-fed rabbit model (59). However, high-dose Na utilization produces a painful flushing response that limits use.

The mechanism of action of Na in treatment of dyslipidemias is not clear. Na is an agonist of the G-protein-coupled receptor Gpr109A (PUMAG in mice) (85, 92). However, it is not

clear that activation of this receptor, which is not expressed in the liver, can account for the clinical efficacy of Na. Activation of Gpr109A in adipocytes inhibits the liberation of free fatty acids from stored triglycerides. However, activation of GPR109A in epidermal Langerhans cells is directly responsible for flushing (11). The lack of expression of Gpr109A in the liver and the finding that Gpr109A mediates flushing cast serious doubt on the receptor model of Na function in dyslipidemia.

We have hypothesized that the beneficial effects of high-dose Na derive simply from NAD+ biosynthesis (7, 14). The fact that Nam is not beneficial in promoting reverse cholesterol transport can be explained in two ways. First, Na is a better NAD+ precursor than Nam in liver (16). Second, if the requirement for elevated NAD+ biosynthesis for improved reverse cholesterol transport depends on sirtuin function, one would expect Nam to be inhibitory.

Sirt1 has been identified as a positive regulator of liver X receptor (LXR), which in turn is a regulator of cholesterol and lipid homeostasis. Sirt1 deacetylates LXR at conserved lysine residues, resulting in LXR activation. sirt1−/− animals show reduced expression of LXR target genes, SREBP1, and ABCA1, in macrophages and in liver, which play important roles in HDL biogenesis (49). These data would appear to make the simple model of Na as an NAD+ precursor highly reasonable.


The most fundamental use of NAD+ precursor molecules, Na and Nam, is in the prevention of pellagra. Like Na and Nam, NR is a natural product found in milk (14), which is incorporated into the intracellular NAD+ pool (94), and thus could be used as a general supplement, potentially for people who have adverse reactions to Na or Nam. More significantly, however, the specific utilization of NR by neurons may provide qualitative advantages over niacins in promoting function in the central and peripheral nervous system.

NR may also find uses related to the pharmacological uses of Na or Nam, which are limited by the side effects of each. Because Gpr109A is specific for the acid and not the amide (85, 92), one would not expect NR to cause flushing. Similarly, the side effects associated with high-dose use of Nam in the prevention and treatment of diabetic disorders (65) raise substantial health and safety concerns (44). In light of the inhibitory effects of Nam on sirtuins and the protective roles of sirtuins in normal cellular metabolism (18a, 91), NR may represent an alternative supplement. Though uncertainties as to the mechanisms of action of therapeutic doses of Na and Nam exist, positive results with NR would clarify the mechanisms of action of Na and Nam.

Because of the prevalence of PARP activation in neuropathies, inflammation, and neurodegeneration and the association of C. glabrata adherence with low NAD+, NR has great potential as a supplement or therapeutic agent that would elevate or maintain NAD+ in specific tissues. Future work will evaluate the pharmacokinetics, safety, and efficacy in animal and human systems to maintain health and to prevent disease.