Can NMN really reverse Aging? (backup)

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

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

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


The quotes below are directly from that research:

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

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

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

According to Dr Sinclair:

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


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

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


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

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


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

  • Tryptophan
  • Nicotinic Acid (NA)

Salvage Pathway

  • NAM – Nicotinamide
  • NR – Nicotinamide Riboside
  • NMN – Nicotinamide MonoNucleotide

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

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


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

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

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

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

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

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

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

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


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


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


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

NA (Niacin)

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


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


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

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

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

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

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

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

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

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

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

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

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

Oral NMN supplements:

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

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


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

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

This quote below is directly from that study.

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


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

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





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

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



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

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

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

Here are some quotes from  the  study:

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

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

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

NMN effectively mitigates age-associated physiological decline in mice


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

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

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

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


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

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

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

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

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

NMN administration has significant preventive effects against age associated physical impairment


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

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

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

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

According to the study:

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

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


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

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


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

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

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

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


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

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

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

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

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

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

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


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

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

DNA Damage

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

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

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

Diabetes & Metabolic disease

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

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

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

Surprisingly, just one dose of NMN normalized impaired glucose tolerance

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

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

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

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

CardioVascular Disease

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

NMN significantly increased the level of NAD+ in the heart

NMN protected the heart from I/R injury

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

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

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

NMN can reduce myocardial inflammation

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

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

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

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

Neurological Injury

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

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

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


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

We now demonstrate that mitochondrial respiratory function was restored

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

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

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

NMN Treatment Rescues Cognitive impairments
NMN Treatment Improves Inflammatory Responses

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

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


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The truth about Salt and high blood pressure

salt3For decades, scientists have suspected that excessive salt intake may cause elevated blood pressure, which is a risk factor for heart disease.

However, studies have provided mixed results, partly because people’s blood pressure responds to salt intake in different ways. Those who are prone to hypertension when eating too much salt are referred to as being salt sensitive.

Recently, the American Heart Association published a comprehensive review of the available evidence on salt sensitivity. Here is a summary of the review’s main points.

Article Reviewed

This was a review of the available evidence regarding salt sensitivity.

Salt Sensitivity of Blood Pressure. A Scientific Statement From the American Heart Association.

What Is Salt Sensitivity?

Salt sensitivity is a measure of how blood pressure responds to changes in dietary salt intake.

The way people’s blood pressure responds to salt intake differs. As a result, not everyone is salt sensitive.

Salt sensitivity is difficult to accurately measure. Additionally, salt sensitivity is not a static variable, and the limit above which people are considered salt sensitive differs depending the definition used.

However, most people who are hypertensive are also salt sensitive, especially when their blood pressure is very high (1).

The physiological mechanisms behind salt sensitivity are incompletely understood. It’s likely that salt sensitivity is caused by abnormalities in the regulation of sodium balance.

One recent study showed that the excretion of excess sodium from the body (in urine) fluctuates according to a 7-day rhythm and is entirely independent of sodium intake (2).

It is possible that disruptions of this natural rhythm may have something to do with salt sensitivity, but further studies are needed.

Bottom Line: Salt sensitivity is a measure of how blood pressure changes in response to the dietary intake of salt (sodium).

Why Is Salt Sensitivity Important?

salt-sensitivityStudies have shown that being salt sensitive is a risk factor for heart disease, independently of blood pressure (34).

There is currently no cure for salt sensitivity itself. However, salt-sensitive individuals may need to take anti-hypertensive medication or limit their dietary salt intake.

The salt intake of most Americans exceeds the recommendations of 3,750–5,750 mg of salt (1,500–2,300 mg of sodium) per day (56).

For those who are salt sensitive, sticking to these recommendations might reduce the risk of hypertension and heart disease (7).

However, some observational studies suggest there is a J-shaped association between salt intake and heart disease. Both too little and too much salt may be harmful (8).

Additionally, meta-analyses of randomized controlled trials suggest that salt restriction causes only a mild reduction in blood pressure, and some even conclude that salt intake does not significantly affect heart disease risk (910).

These findings were based on averages, and the studies didn’t differentiate between salt sensitive and insensitive individuals. Randomized controlled trials comparing salt sensitive and insensitive individuals are needed.

Many observational studies also provide inconsistent results. Individual differences, as well as methodological weaknesses, may be to blame for the controversy.

Bottom Line: Studies on whole populations provide conflicting results regarding the association of salt intake and heart disease risk. However, limiting salt intake is probably important for those who are salt sensitive.

What Causes Salt Sensitivity?

salt-sensitivity-genotypesNot everyone is sensitive to salt intake. It depends on the following factors:

  • Genes: Salt sensitivity depends on people’s genetics. Multiple genes seem to be involved.
  • Race: Black people are more likely to be salt sensitive, compared to white people (11).
  • Age: The blood pressure of older people is more likely to respond to changes in salt intake, compared to young people (12).
  • Gender: Some studies indicate that women are at a greater risk of being salt sensitive than men, but the evidence is inconsistent (13).
  • Hypertension: Those who are hypertensive are more likely to be salt sensitive than people with normal blood pressure (14).
  • Low potassium intake: People’s salt sensitivity is greater when their potassium intake is low (1516).

Bottom Line: People’s sensitivity to salt intake mainly depends on genetic factors. Old age and low potassium intake may also increase the risk.

Summary and Real-Life Application

This review concluded that a high salt intake may result in elevated blood pressure (hypertension) among those who are salt sensitive.

On the other hand, those who are not salt sensitive do not develop hypertension from eating too much salt, although a very high intake may still be unhealthy.

Salt sensitivity is usually associated with hypertension. If your blood pressure is too high, you may benefit from reducing your intake of salted food.

Eat a big breakfast for more weight loss

healthy-fried-breakfastWeight loss supplements like Garcinia Cambogia may help a little, but successful weight loss depends on how much you eat and exercise and perhaps also the timing of your meals.

A recent study examined the relevance of meal timing among overweight or obese women on a weight loss program.

The researchers compared the effects of eating a large number of calories either at lunch or dinner on weight loss. Here is a detailed summary of their findings.


Growing evidence from controlled trials suggests that the timing of your meals may affect your health.

For example, eating most of your daily calories late in the afternoon or evening may adversely affect your blood sugar control(123).
Alarm Clock On Plate
Also, some studies show that eating a lot in the late afternoon or evening, relative to earlier in the day, may reduce calorie expenditure and promote weight gain (456).

These findings are supported by studies indicating that consuming more than half of your daily calorie intake at or before midday is associated with a lower risk of obesity, compared to eating that amount in the late afternoon or evening (7).

Article Reviewed

This study compared the effects of eating a high-calorie meal either at lunch or dinner on weight loss success among obese women.

Beneficial effect of high energy intake at lunch rather than dinner on weight loss in healthy obese women in a weight-loss program: a randomized clinical trial.

Study Design

This 3-month, randomized trial compared the effects of eating a high-calorie meal either at lunch or dinner on weight loss and heart disease risk factors in women.

A total of 80 overweight or obese women who were otherwise healthy participated in the study. 86% of them completed the study.

At the beginning of the study, all of the participants started a weight loss program that was designed to promote 7–10% loss of body weight over a 12-week period.

The program involved both diet and exercise and addressed potential difficulties on an individual basis.

The participants were advised to gradually increase physical activity levels up to 60 minutes of moderate activity five days a week.

Additionally, all participants were told to consume 15% of their daily calories at breakfast and 15% from snacks. Their calorie intake at lunch and dinner differed depending on which experimental group they were randomly assigned to:

  • Main meal at lunch: 50% of daily calorie intake at lunch and 20% at dinner.
  • Main meal at dinner: 50% of daily calorie intake at dinner and 20% at lunch.

To improve adherence to the diet, the participants had a meeting with a dietitian twice a week and recieved a phone call every weekday.

At the start and end of the study, the researchers measured the following:

  • Body weight.
  • Waist circumference.
  • Calorie and macronutrient intakes.
  • Fasting blood lipids – total cholesterol, HDL, LDL and triglycerides.
  • Fasting blood sugar, insulin and glycated hemoglobin (HbA1c).
  • Insulin resistance was calculated using homeostatic model assessment (HOMA).

Bottom Line: This was a randomized trial comparing the health and weight loss effects of eating a high-calorie meal either at lunch or dinner.

Finding 1: A Large Lunch Meal Caused More Weight Loss

The participants lost significant amounts of weight, on average.

However, having a large meal at noon promoted more weight loss (-12.9 lbs or -5.9 kg), compared to eating an equally large meal at dinner (-9.6 lbs or -4.4 kg), as shown in the chart below.

Weight Loss Large Lunch Vs Large Dinner

In contrast, there were no significant differences in waist circumference between groups.

Bottom Line: Eating a large meal at noon led to greater weight loss, compared to an equally large meal at dinner.

Finding 2: A Large Lunch Meal Improved Insulin Sensitivity

The weight loss program improved blood sugar control among all of the participants, but those who ate a large meal at lunch experienced slightly greater benefits.

Fasting insulin levels decreased by 2.01 mIU/mL among those who ate their largest daily meal at noon but only 0.72 mIU/mL among those whose main meal was dinner. Insulin resistance also improved in the lunch group, as shown below.

Insulin Lunch Vs Dinner

On the other hand, there were no significant differences in blood sugar or blood lipid levels between groups.

Bottom Line: Having a large meal at noon had greater benefits for blood sugar control, compared to eating an equally large dinner.

Why Does Eating a Large Meal Early in the Day Promote Weight Loss?

Controlled trials consistently show that eating most of your daily calories early in the day (at breakfast or lunch) may promote weight loss.

Scientists are not entirely sure how this happens, but they have come up with a few plausible theories:

  • Increased fullness: A large early meal may lead to lower calorie intake throughout the day. The current study doesn’t support this hypothesis, as both groups appeared to be eating similar amounts of calories over the day (8).
  • Reduced calorie expenditure: One study showed that an early meal caused a greater increase in metabolic rate and calorie expenditure than an identical meal eaten in the evening (4).

Further studies need to look into the possible physiological mechanisms. Since these effects are time dependent, they might have something to do with the body clock.

Bottom Line: It is incompletely understood why early meals may promote weight loss. Some studies suggest they may increase calorie expenditure.


The study was well designed and doesn’t appear to have had any major flaws. However, the authors pointed out a few limitations.

First, the intervention period was relatively short, or just three months. Longer trials are needed to find out if the effects are sustained in the longer term.

Second, the participants were overweight and obese women. Future studies should confirm these findings in other groups.

Summary and Real-Life Application

This study adds to a growing body of research suggesting that meal timing and daily calorie distribution may affect metabolism.

Specifically, the study showed that eating a large meal early in the day, such as at noon, improves the results of a weight loss program, compared to eating a large meal later in the day.

Eating the day’s main meal for lunch also reduced fasting insulin levels and insulin resistance.

If you are trying to lose weight and want to maximize your chances of success, eating your day’s largest meal for breakfast or lunch might be worth a shot

Honokiol increases Sirt3 which can extend lifespan


In an expansive study, researchers found that Honokiol increases levels of SIRT3. This appears to be the first ever report describing a pharmacological activator of Sirt3. Exercise and calorie restriction are the only other known methods to increase SIRT3.

Sirtuins in general are believed to extend lifespan across species, although the role in nematodes and fruitflies is controversial. Whether sirtuins can truly and broadly reverse aging-associated degeneration is unknown but there are increasing scientific results showing health benefits and improvements. In this recent SIRT3 focused study the findings suggest that bolstering mitochondrial function and cell stress resistance by increasing SIRT3 levels may offer a promising therapeutic target for protecting against age-related cognitive decline and brain diseases. This study found that SIRT3 reverses aging-associated degeneration in mice.


It is known that SIRT3 is suppressed with aging and therefore finding compounds that can offset this decline may be a promising approach to fend off some aspects of age related degeneration.


In the study it was demonstrated that honokiol is firstly present in the mitochondria and secondly enhances SIRT3 expression nearly two-fold. There was also indication that honokiol binds to SIRT3 changing the properties in a way that further increase its activity. The figure on the left shows the schematic pathways of SIRT3 increase effect by honokiol.

It should be noted that the near two fold increase was observed with in-vitro testing. In-vivo testing in mice showed that supplementation with honokiol increased SIRT3 levels in mice with an induced cardiac hypertrophy. Compared to a control group of similar mice without supplementation the SIRT3 levels were markedly higher.

The increased SIRT3 activity was associated in the study with reduced acetylation of mitochondrial SIRT3 substrates, MnSOD and OSCP which stopped the development of cardiac hypertrophy.

Overall these results indicate that honokiol is capable of activating SIRT3 and having health benefits like the blocking of cardiac hypertrophic response in vivo.

The supplementation in the study was done by dissolving honokiol in peanut oil which was injected at a rate of 0.2mg/kg/day intraperitoneally. Therefore it is not easily possible to make translations to human doses.


Nicotinamide Riboside Optimum Dosage

dosageNicotinamide Riboside (NR) is a form of vitamin B3 closely related to Niacin that is showing great promise for it’s ability to raise  NAD+ levels in older humans, back to the levels normally found in youth to prevent and repair damage to various organs in the body.

NAD+   is a key co-enzyme that enables the mitochondria to power and repair damage in every cell of our bodies.


There have been numerous studies of NR and NMN in mice that showed no negative side effects in Human Equivalent Dosages (HED) of 2.1 to 17 grams per day

The FDA recently granted GRAS (Generally Recognized as Safe) status on the basis of this clinical study, which showed “no observed adverse effect level was 300 mg/kg/day.”

screen-shot-2016-10-17-at-2-25-43-pmUsing the chart here from the  FDA guidelines for calculating this to HED of 2880 mg for a 130lb person.

With the FDA required 10x safety factor, that would equate to a dose of 288 mg per day for a 130lb human.

That is likely the limit on what sellers will recommend, but many people have been taking 500-1,000mg a day with no noticeable side effects.

[box]The 10x safety factor required by the FDA results in a safe dosage of 288 mg a day, although many people take much more and few if any side effects are reported at 1,000 mg a day or less[/box]



The first published research to date that measures the NR supplementation increase in NAD+ levels in humans by Dr Charles Brenner is also documented in the Phd dissertation by Samuel AJ Trammel at the University of Iowa.

Experiment #1
In the first experiment, one Human subject was given a single dose 1,000 mg of NR each morning for 7 days. Blood levels of NAD+ and metabolites were 9 times the first day and every 24 hours thereafter.


From the results shown in chart above, we see NAD+ levels did not rise until 4 hours after ingesting, peaked at around 8 hours,  and remained elevated up to 24 hours.

Experiment #2
The second experiment involving human subjects included 12 individuals that were given 100,300, or 1,000 mg of NR with a washout period of 7 days between doses. Blood levels of NAD+ were recorded at 1, 2, 4, 8, and 24 hours.



100 mg per day
This chart shows 100mg per day (purple) elevates NAD+ levels around 4 hours, dropping significantly by 8 hours and continuing to decline throughout the 24 hours.

300 mg per day
The numbers in this line (red) are slightly elevated at 8 hours, then continue rising to 24 hours.

It appears that a dosage of 300mg achieved the same NAD+ increase as 1,000 mg at the 24 hour mark.

1,000 mg per day
This line (black) looks very similar to the first test with one subject given 1,000 mg daily.

Increased NAD+ noted at 4 hours, with maximum increase reached around 8 hour. It appears NAD+ levels remain at that maximum through 24 hours.

We can see that at all dosages the NAD+ levels were elevated somewhat within 4 hours.

It does appear an upper limit was reached after which, additional NR did not raise NAD+ any further.

Dr Brenner points to the increased NAAD levels that coincide with the peak of NAD+ and suggest NAAD acts as an “overflow pool”, that may later be converted to NAD+ if needed.

Do other Metabolites of NAD+ matter?
The author notes that supplementation with Nicotinamide Riboside elevates the level of many NAD+ metabolites at different rates:

“Because every NAD+ metabolite can be converted to one or more other metabolites, snapshots of the levels of NAD+ , nicotinamide (Nam) or any other NAD+ metabolite without assessment of the NAD+ metabolome on a common scale has the potential to be misleading.”

NAAD is much higher in the 1000mg subjects. However, the first study implies there is a limit to the possible increase of NAD+. Despite repeated usage over seven days, NAD+ tops out.

The second study shows that at 24 hours, NAD+ is elevated by approximately the same amount in the 300mg and 1,000mg test subjects.

[box]Conclusion: The maximum effect appears to be achieved at some dosage around 300mg per day.

Note: Subjects in this study were healthy and between 30-55 years of age. Older, sicker subjects might benefit from higher dosages. The Elysium Basis testing with older individuals (below) will hopefully shed more light on this.[/box]


niagen_basis_elysiumResearch to prove Benefits and Safety for Elysium Health Basis brand of Nicotinamide Riboside

This recently complete, but not yet published study tracked 120 elderly subjects (60-80yrs age) over 8 weeks monitored blood and heart parameters to ensure safety.

They also measured NAD+ levels and several physical performance tests.

Completed in July 2016 but not yet published, it was sponsored by Elysium Health, manufacturer of Basis Nicotinamide Riboside.

A single capsule of BASIS is 125 mg of Chromadex NIAGEN brand of Nicotinamide Riboside, along with 50 mg of Chromadex Pterostilbene.

Participants received either placebo, 1, or 2 capsules of BASIS

Elysium Health did issue a press release that states that 125 mg of NIAGEN resulted in a 40% increase in blood NAD+ levels that was maintained throughout the 8 weeks of the study.

The 250 mg dosage resulted in an increase that was “significantly higher” than the 125 mg dose, and reached 90% at one of the 4 checkpoints (4 weeks).

Since the increase from the 250 mg dosages reached a plateau at 4 weeks, and dropped afterwards, implies that a higher dosage probably would not be any more effective.

This rather speculative interpretation agrees with the results in Study #1 that the most effective dosage is higher than 125 mg, but has peaked out at 250mg a day

[box]Conclusion: Most people will likely get the maximum NAD+ increase at 250mg per day



NAD+ is synthesized in humans by several different molecules (precursors), thru 2 different pathways:
De Novo Pathway

  • Tryptophan
  • Nicotinic Acid (NA)

Salvage Pathway

  • NAM – Nicotinamide
  • NR – Nicotinamide Riboside
  • NMN – Nicotinamide MonoNucleotide

The NAD+ supply is not stagnant – it is constantly being consumed and replenished, with the entire NAD+ pool being turned over 2-4 times per day (14).

This recycling is through the salvage pathway, where the enzyme Nampt catalyzes NAM to NMN, which is then metabolized to NAD+.

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

Many studies have confirmed the importance of Nampt in maintaining sufficient NAD+ levels, such as the quote below from a 2016 study that used mice lacking Nampt in muscle fiber:

“NAD content of muscle was decreased by ~85% confirmed the prevailing view that the salvage route of NAD synthesis from NAM sustains the vast majority of the NAD” (97)

These mice exhibited normal muscle strength and endurance while young, but deteriorated rapidly as they aged which confirmed Nampt is critical to maintaining NAD+ levels.

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


NR had been known for decades, but was not thought to be that important until 2004 when Dr. Charles Brenner discovered the enzyme NRK1 can phosphorylate NR directly to NMN, bypassing the Nampt “bottleneck” (100).

This newly discovered “shortcut” in the NAD+ salvage pathway found that NR can be metabolized directly to NMN to boost NAD+ levels more effectively than NAM.


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

Even when taken at very high dosages, NR has not been detected in the bloodstream in any research (97,98,99).

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

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

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

Note:NAM does elevate NAD+, but is on the “wrong” side of the Nampt bottleneck, which limits it’s effectiveness


The following five charts are all from the thesis published by Samuel Alan Trammell in 2016 under supervision by Dr Brenner:

Nicotinamide riboside is uniquely and orally bioavailable in mice and humans

This chart above shows the impact on NAD+ metabolites over time for a 52 year old human after ingesting 1000mg of NR daily for 7 days.

NAD+ levels begin to rise at 4.1 hours, and peak at 8.1 hours.

NAM levels double at .6 hours and have a second peak at 7.7 hours, long before NAD+ levels are elevated.

This chart at right shows metabolites found in urine of the subject from the same experiment as above.

The red box shows NAM  is elevated more than 10x baseline at the same time point that NAD+ is elevated, which implies that NR has elevated NAM to such an extent that excess NAM is excreted in urine.

This chart a left shows impact of NR, NA, and NAM supplementation on blood plasma NAD+ (b), and NAM  (d) levels in 12 human subjects.

The red line at 2 hours shows NR supplementation increases NAM perhaps 3x (d), but has not yet elevated NAD+(b).

The 2 hour mark also is the point at which NAM supplementation begins to increase NAD+ levels (b).

The blue line at 8 hours is when both NR (b) and NAM (d) supplementation reach peak NAD+ increase.

Lastly, the green bar and black bar in chart b show that NAM elevates NAD+ slightly less than NR.

NR elevated NAD+ slightly more than NAM, but is much slower acting


The chart above shows the result on NAD+ metabolism of 15 mice fed NR by oral gavage at a dose of 185 mg/kg of bodyweight.

The NR was synthesized with heavy atoms of deuterium at the ribosyl C2 and 13C on the Nam side, to allow tracking.

The measurement at 2 hours shows 54% of the NAD+ has the single heavy molecule (white bar, M+1). This 54% was likely broken down to NAM first, losing the second labelled heavy atom.

At the same time point, 5% of the NAD+ had both labels (Grey bar, M+2).

This 5% of NR made it through the digestive tract intact and was metabolized through the shortcut from NR -> NMN -> NAD+, vs 54% that had been through NR -> NAM -> NMN -> NAD+.

The chart above shows the impact of the same double labeled NR on mouse liver, but this time after IP (Intraperitoneal) Injection.

Note the dramatic difference in the ratio of labelled M+2 over M+1. IP results in much higher levels of intact NR (M+2) being metabolized to NAD+, whereas Oral NR shows far more M+1 labelled NR to NAD+.

This different behavior in IP vs oral NR supplementation also implies oral NR is partially metabolized to NAM before conversion to NAD+.

The above chart shows the resultant increase in select NAD+ metabolites of mice fed NR (unlabeled) at 185 mg/kg of bodyweight.

As noted by the authors, NR and NAR are the only NAD+ precursors tested that did NOT result in elevated levels of the precursor in the liver.

Here is one last quote in discussion section from the Trammell thesis:

“NR has not been detected in the blood cell fraction nor in plasma …NR varied and displayed no response to NR administration … but was detected after IP of double labeled NR in liver (Figure 5.7) and muscle (Figure 5.9), revealing NR does circulate”

They are saying that NR is found in small quantities in the liver, but is not detectable in bloodstream.  Oral supplementation with NR did not show any increase in NR in the body.  However, Injection (IP) of NR does result in a detectable increase of NR in muscle and Liver. So NR does circulate in the bloodstream when injected, but has not yet been detected upon oral supplementation.

The timing and amplitude of the increases in metabolites noted above imply that:

  • Oral NR does not result in a detectable increase of NR in the body
  • It’s likely a majority of the increase in NAD+ is due to NR->NAM->NAD+.

Note: NAM does elevate NAD+, but is on the “wrong” side of the Nampt bottleneck, which limits it’s effectiveness


Further testing with larger sample sizes and more data points is underway that will give a much better estimate on the most effective dosage. For now, some conclusions on dosage we see are:

  • A single dose of NR does increase NAD+ levels
  • NAD+ levels remain elevated 24 hours after a single dose.
  • There is an upper limit on the increase of NAD+ levels with NR supplementation
  • Maximum NAD+ elevation is maintained at a dosage higher than 125 mg per day – likely close to 250mg per day
  • It appears that a single daily dose may be just as effective as 2  smaller dosages.

Most NR ends up as NAM after digestion, so is much slower and less effective than NMN.

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Lycopene a great natural sunscreen

lycopeneSunscreen is not only applied to your skin, your body also makes its own. It’s called melanin.

But that’s not all. Growing evidence indicates that carotenoids, the antioxidants responsible for the vivid colors of many fruits and vegetables, may provide added protection from the sun.

A recent study investigated the effects of taking carotenoid supplements — lycopene and lutein — on skin protection at the molecular level. Here is a detailed summary of its findings.



Carotenoids are a diverse group of antioxidant plant compounds that are responsible for the red, orange and yellow colors of many fruits and vegetables.

Several studies show that they may protect the skin against harmful sunlight.

Beta-carotene, which can be converted to vitamin A, is the most extensively studied carotenoid. A meta-analysis of seven controlled trials concluded that taking beta-carotene supplements may protect against sunburns and reduce their severity (1).

Carotenoids other than beta-carotene may also act in a similar way.

One study showed that taking 24 grams of a mixed carotenoid supplement containing equal amounts of beta-carotene, lycopene and lutein protected the skin as much as 24 grams of beta-carotene alone (2).

Another 10-week trial found that consuming tomato paste, providing 16 mg per day of lycopene, significantly reduced sunburns, compared to a placebo (3).

However, lycopene may not be the only plant compound in tomatoes providing benefits. Taking a supplement containing a combination of plant compounds from tomatoes led to better protection against sunburns than lycopene alone (4).

Article Reviewed

This was a randomized controlled trial investigating the effects of lycopene and lutein supplements on genes associated with sunburns.

Molecular evidence that oral supplementation with lycopene or lutein protects human skin against ultraviolet radiation: Results from a double-blinded, placebo-controlled, cross-over study.

Study Design

This randomized, double-blind crossover trial examined the capacity of the carotenoids lycopene and lutein to protect the skin against harmful sun radiation.

It was divided into two parts:

Part 1: Lycopene

A total of 29 people (25 men and 4 women) completed part 1. They were assigned to two 3-month treatment periods in a random order.

  • Lycopene: Every day the participants took four capsules containing a lycopene-rich tomato extract providing 5 mg of lycopene, as well as other plant compounds, such as phytoene, phytofluene, tocopherols and phytosterols.
  • Placebo: Capsules containing soy bean oil were taken instead of lycopene.

Part 2: Lutein

A total of 30 people (23 men and 7 women) completed the lutein arm of the study. They were assigned to two 3-month treatment periods in a random order.

  • Lutein: Every day the participants took two capsules containing 10 grams of lutein stabilized by 10% carnosic acid.
  • Placebo: Capsules containing soy bean oil were taken instead of lutein.

Before each study period, there was a 2-week washout period to reduce any possible carry-over effects from the previous period or the participants’ regular diets.

To investigate the carotenoids’ effects on the skin’s ability to protect itself against harmful light, the following procedure was conducted at the start and end of each treatment period.

  1. The researchers started by irradiating a patch of each participant’s skin with two types of ultraviolet light — ultraviolet B (UVB/A-) and ultraviolet A (UVA1) — using a solar simulator.
  2. 24 hours later, they took a skin biopsy from the irradiated area. For comparison, they also took a biopsy from a skin area that was not exposed to ultraviolet light.
  3. Finally, they analyzed the skin samples for the expression of genes that are associated with oxidative stress and sunburns.
  4. These genes were heme oxygenase-1 (HO-1), intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase-1 (MMP-1).

In addition, the researchers measured the carotenoid levels in the participants’ blood.

Bottom Line: This was a randomized controlled trial examining the effects of supplements containing a lycopene-rich tomato paste or lutein on the expression of genes associated with sunburns.

Finding: Lycopene and Lutein May Protect Against Sun-Induced Skin Damage

Supplementing with lycopene or lutein significantly increased blood levels of these carotenoids.

Additionally, exposure to ultraviolet light increased the activity of genes linked to oxidative stress and sunburns (HO-1, ICAM-1 and MMP-1).

However, the researchers discovered that taking lycopene or lutein supplements reduced the activity of these genes, compared to placebo.

The findings indicate that these carotenoids may protect the skin against damage and premature aging caused by sun exposure. The protective effect was similar after both types of ultraviolet light (UVB/A-and UVA1).

It also didn’t matter if the lycopene was given in the first or second phase of each study arm.

However, the protective effect of lutein was significantly weaker, compared to lycopene, if it was given in the second phase. That is, after a placebo period.

On the other hand, there were no differences between lycopene and lutein when they were given in the first phase.

These findings are supported by controlled trials showing that lycopene may reduce sunburns, as well as the harmful effects of sunlight on the molecular level (356).

Why carotenoids work in this way is currently unknown, but some scientists believe it may have something to do with their antioxidant properties.

Bottom Line: The study found that the carotenoids lycopene and lutein may protect the skin against harmful ultraviolet sunlight.


This study had an excellent design. However, it had one fault — the short washout periods between treatments.

The purpose of washout periods is to prevent carry-over effects from a previous treatment or the participants’ habitual diets. Their insufficient length is often a weakness of crossover trials.

In the current study, the length of the washout periods appeared to be reasonably long, based on previous studies (78).

However, the protective effects of lutein were significantly weaker when it was given after 16 weeks of a lutein-restricted diet, indicating that the washout periods might not have been long enough.

Summary and Real-Life Application

In short, this study showed that dietary intake of lutein and lycopene may protect the skin against harmful sunlight, possibly slowing skin aging and reducing the risk of skin cancer.

Although the findings are very promising, further studies are needed before any definite health claims can be made.

Nevertheless, eating tomatoes, watermelons, bell peppers, kale or other carotenoid-rich fruits and vegetables is definitely a good idea if you spend a lot of time in the sun.

Keto diet proven effective for diabetics

ketogenic-dietMany nutritionalists and dietitians are joining the chorus of fans of ketogenic diet. And certainly it is more effective that even the best diet pills like Garcinia Cambodia.

However, there are some health professionals concerned about the use of ketogenic diets for diabetics.

Addressing this concern, a recent randomized controlled trial investigated the safety, tolerability and effectiveness of a 4-month, very low-calorie ketogenic diet in 89 obese people with type 2 diabetes.

Here is a detailed summary of its findings, in addition to some background information.



low-carb-snacks-1200x509The ketogenic diet contains minimal amounts of carbs.

This forces the body to burn fat and leads to ketosis, which is characterized by elevated levels of ketone bodies in the blood. The ketone bodies partially replace glucose (blood sugar) as fuel for cells.

Reducing sugar intake has multiple health benefits, especially for diabetics.

Additionally, eating sugar, especially sugar-sweetened beverages, may promote overeating. Sugar may also be addictive for some people, making them susceptible to cravings and overeating.

For these reasons, high sugar intake is probably one of the main causes of weight gain and obesity.

A ketogenic diet eliminates most dietary sugar, as well as the health problems associated with it. However, eliminating dietary carbs means that you have to eat more fat or protein instead.

Increasing fat intake doesn’t seem to be a problem if the diet is also calorie-reduced. Studies indicate that high-fat diets are more effective for weight loss than low-fat diets. This is probably because high-fat diets contain much fewer carbs (1).

Additionally, limiting carbs is more beneficial for weight loss and blood sugar control, compared to a low-fat diet or high-carb diet (23).

Yet, some researchers are concerned that a high protein intake on a very low-carb diet may adversely affect diabetic people with kidney problems (diabetic nephropathy) (45).

Others have pointed out that very low-carb or high-protein diets may not be feasible in a real-life setting (6).

In 2008, the American Diabetes Association even concluded that very low-carb diets were of limited use for people with diabetes and should only be considered as part of a structured weight loss program (7).

However, few studies have examined the safety and effectiveness of a calorie-reduced, very low-carb ketogenic diet, compared to a standard weight loss diet.

Article Reviewed

This study examined the safety and effectiveness of a low-calorie ketogenic diet in obese diabetics.

Short-term safety, tolerability and efficacy of a very low-calorie-ketogenic diet interventional weight loss program versus hypocaloric diet in patients with type 2 diabetes mellitus.


Study Design

This randomized controlled trial evaluated the safety, tolerability and effectiveness of a low-calorie ketogenic diet in obese people with type 2 diabetes.

A total of 89 men and women, aged 30–65, participated in the study. They followed a 4-month weight loss program, which included lifestyle and behavioral modification support.

The participants were randomly assigned to one of two groups:

1. Very Low-Calorie, Ketogenic Diet (VLCK)

This was a commercial weight loss program (DiaproKal Method) based on specific protein supplements provided by Pronokal Protein Supplies in Spain.

The program consisted of three stages:

  1. Active phase: Very low-calorie diet (600–800 calories per day) containing less than 50 grams of carbs from vegetables and 10 grams of olive oil. Protein intake ranged between 0.36–0.55 grams per pound of body weight (0.8–1.2 g per kg).
  2. Metabolic stabilization: When the participants had reached a pre-specified weight loss target, they began a low-calorie diet and gradually started to incorporate different food groups.
  3. Maintenance phase: Finally, the participants went on a weight maintenance diet that was balanced in carbs, protein and fat and ranged between 1,500–2,250 calories per day.

2. Standard Low-Calorie Diet (Control)

This was a standard weight loss diet based on the American Diabetes Association Guidelines (8).

It aimed at reducing calorie intake by 500–1,000 calories per day, depending on the participants’ basal metabolic rate.

The diet provided 10–20% of calories from protein, 45–60% from carbs and less than 30% of calories from fat.

In both groups, the participants attended nine individual support sessions with a dietitian and were contacted by telephone twice a month.

The researchers measured the participants and took blood samples on four occasions: 1) at the start of the study, 2) after 2 weeks, 3) after 2 months, and 4) at the end of the study (after 4 months).

They measured the following parameters:

  • Renal function: Biomarkers of kidney function were measured in blood samples.
  • Liver function: Biomarkers of liver function were measured in blood samples.
  • Ketones: Levels of ketone bodies in blood samples were measured to confirm that those in the VLCK reached ketosis.
  • Body weight, body mass index and waist circumference.
  • Blood sugar control: Fasting blood sugar, insulin and HbA1c were measured in blood samples. Insulin resistance was calculated using the homeostasis model assessment (HOMA).
  • Blood lipids: Fasting triglycerides, total cholesterol and LDL cholesterol.
  • Dietary adherence: Assessed using the Eating Self-Efficacy Scale.

Conclusion: This was a randomized controlled trial examining the safety and effectiveness of a calorie-reduced, very low-carb ketogenic diet in obese people with type 2 diabetes.

Finding 1: The Ketogenic Diet Caused Greater Weight Loss

The participants in the VLCK group lost an additional 22 lbs (10 kg) of body weight, compared to the control group.

Specifically, they lost 32 lbs (15 kg) in the VLCK group and 11 lbs (5 kg) in the control group.

They also experienced a greater decrease in waist circumference, as shown in the chart below.


Some researchers have speculated that the ketogenic diet helps people lose weight only because it’s much higher in protein than the standard weight loss diet.

Eating high amounts of protein is known to reduce appetite and increase the amount of calories burned.

One study suggests that going on a ketogenic diet without increasing protein intake has no lasting effect on the amount of calories burned and doesn’t lead to additional weight loss, compared to a standard, high-carb weight loss diet.

Conclusion: The ketogenic diet led to significantly greater weight loss than the standard low-calorie diet.

Finding 2: The Ketogenic Diet Led to Greater Improvements in Blood Sugar Control

Insulin resistance decreased significantly more in the VLCK group, compared to the control, as shown in the chart below.


Fasting blood sugar levels reduced similarly in both groups.

However, the decrease in HbA1c was significant only in the VLCK group. HbA1c is a marker of blood sugar control that represents the previous 3-month average of blood sugar levels.

These findings are supported by previous studies showing that very low-carb diets improve blood sugar control in diabetics (910).

Conclusion: The ketogenic diet significantly improved blood sugar control, compared to a standard weight loss diet.

Finding 3: Self-Reported Adverse Effects Were More Common on the Ketogenic Diet

The researchers detected no significant differences in safety parameters between groups. However, self-reported adverse effects were more common in the VLCK group.

Mild adverse effects were reported by 80% of the participants in the VLCK group but only 41% of those in the control group. These included headache, nausea, vomiting and weakness.

Additionally, constipation and low blood pressure when standing up (orthostatic hypotension) were more common in the VLCK group at the end of the study. No serious adverse effects were reported.

Adverse effects became less frequent as the study progressed. The authors concluded that the ketogenic diet is a safe, well-tolerated weight loss method for people with type 2 diabetes.

The adverse effects reported in this study are similar to those generally associated with very low-carb diets (11).

Conclusion: Blood analyses revealed no significant differences in biomarkers of liver and kidney function between groups. However, self-reported adverse effects were more common in the VLCK group.


Participants in the VLCK group received protein supplements provided by Pronokal Protein Supplies in Spain.

Additionally, five of the nine authors received research grants and advisory board fees from the company, creating a conflict of interest.

Otherwise, the study appears to have been well designed.

Summary and Real-Life Application

In conclusion, a weight loss program based on the ketogenic diet was significantly more effective than a standard weight loss program.

It appeared safe and reasonably well tolerated by people with type 2 diabetes and caused greater weight loss and improvements in blood sugar control.

Supplementation to correct NAD+ deficiency repairs vision damage in Mice


Nicotinamide adenine dinucleotide (NAD+) is a coenzyme found in the cells of all living creatures (3,4) and is critical for communication between the cell nucleus and the mitochondria that power the cells (5,6,7)


Everyone experiences lower NAD+ levels throughout the body as we age, effecting the communication within every cell of our bodies.

Scientists have known for some time that this loss of NAD+ leads to many different age related diseases as the cells lose ability to perform basic tasks and repair damage due to oxidative stress. (8)


  • Neural cognitive dysfunction (1,2,3)
  • Decreased Energy and muscle strength (23,24)
  • Higher Blood Sugar Levels and Increased Insulin resistance (20,21,22)
  • Chronic Inflammation resulting in hypertension and heart disease( 12,13,14)
  • Fatty Liver Disease (NAFLD and AFLD)(15,16,17)
  • Increased belly fat (18,19)

[box]Conclusion: Declining NAD+ levels are implicated in many age related disease and chronic conditions[/box]


In addition to the chronic age related diseases found to be related to declining NAD+ levels, the study below finds impaired NAD+ biosynthesis in many diverse retinal diseases among young and older mice.

NAMPT-Mediated NAD+ Biosynthesis Is Essential for Vision In Mice

This study published in cell magazine published sep 27, 2016 found that

  • Limiting the natural NAD+ synthesis in the photoreceptors in Mice results in loss of vision
  • Supplementation to increase NAD+ reverses the damage and restores vision
  • Mouse models of retinal dysfunction exhibit early retinal NAD+ deficiency
  • NAD+ deficiency causes retinal metabolic dysfunction

Vision depends on the 2 classes of photoreceptors the rods and cones. Many different diseases such as Retinitis Pigments (RP), Age-Related Macular Degeneration (AMD), Rod and Cone Dystrophies, and Leber Congenital Amaurosis (LCA) all attack the photoreceptors thru diverse pathways that lead to photoreceptor death and blindness.

Photoreceptors are known to have high energy requirements, but limited reserves so are dependent on constant synthesis of NAD+ to meet energy needs. (Ames et al., 1992, Okawa et al., 2008)

The authors theorized that NAD+ biosynthesis plays a key role in healthy vision. They noted that the leading cause of blindness in children, LCA, is caused by a mutation in the enzyme NMNAT1 which results in impaired synthesis of NAD+.(Falk et al., 2012, Koenekoop et al., 2012, Sasaki et al., 2015)

In mammals, NAM is catalyzed by nicotinamide phosphoribosyltransferase (NAMPT) as the first step in biosynthesis of NAD+.

In this study, researchers created knockout mice that lack NAMPt in rod photoreceptors which disrupts the normal NAD+ biosynthesis, resulting in a 26-43% reduction in retinal NAD+ levels.

Within 6 weeks, these mice exhibited significant photoreceptor death and vision loss. The results very closely matched the degeneration seen in patients with Retinitis Pigments and other degenerative vision disease.

According to the authors:

NAD+ deficiency caused metabolic dysfunction and consequent photoreceptor death…these findings demonstrate that NAD+ biosynthesis is essential for vision


To confirm the cause of vision loss, researchers supplemented knockout mice with daily injections of NMN, bypassing the need for NAMPT in the first step of NAD+ synthesis. Those mice receiving NMN experienced significant recovery of retinal function.
(Figures 3A–3C).

These data clearly demonstrate that NAMPT-mediated NAD+ biosynthesis is necessary for the survival and function of both rod and cone photoreceptors, as promoting NAD+ biosynthesis in the retina with NMN supplementation can compensate for Nampt deletion, thereby reducing photoreceptor death and improving vision.



Researchers were able to determine that NAD+ deficiency is common in many vision problems.

Mice subjected to light exposure retinal damage had significant reduction in NAD+ levels (Figure 3H)

Similar reductions in NAD+ levels were found in mice with streptozotocin (STZ)-induced diabetic retinal dysfunction compared to non-hyperglycemic controls (Figure 3I).

Lastly, they compared 18-month-old vs 6 month old mice. As with the light exposed and diabetic induced mice, the older mice exhibited diminished vision along with decreased retinal NAD+ levels (Figure 3J).

These findings support the idea that NAD+ deficiency may be a shared feature of retinal dysfunction.


screen-shot-2016-10-04-at-10-12-49-amAfter demonstrating that light induced retinal dysfunction was linked to decreased NAD+ levels, researchers were able to show that supplementation to increase NAD+ could protect against retinal damage.

Mice that were given injections of NMN for 6 days prior, and 3 days after light exposure exhibited improved retinal function vs those that did not receive NMN injections (Figures 4A–4C).

[box]Conclusion: Results from this study suggest that supplementation to increase NAD+ deficiencies can help repair macular damage and may be an effective treatment for many common degenerative vision problems.[/box]


This study was very specific for the impact of NAD+ on Retinal disease in Mice, but is also further evidence that the absence of sufficient NAD+ has dire consequences, and that replacement of NAD+ can repair damage.

Researchers are experimenting with various techniques for raising NAD+ levels in mice and humans such as:

The 2013 study by Dr David Sinclair that demonstrated increased levels of NAD+  reverses age related degeneration in mice also used injections of NMN (25).

You can read more about Nicotinamide Mono-Nucleotide (NMN) here.

Other studies with mice and human subjects use supplementation with Nicotinamide Riboside (NR) to raise NAD+ levels.

NR is a precursor the body can use to manufacture NAD+. It has been shown to be safe and effective at raising NAD+ levels in humans in dosages of around 250mg a day.

Another approach to boosting NAD+ levels is preventing the drop in NAD+ levels in the first place.

Recent studies have demonstrated that the enzyme CD38 becomes elevated as we age, possibly in response to increasing inflammation levels, and corresponds with declining NAD+ levels.

Flavonoids such as Quercetin are proving effective at lowering CD38 levels which results in higher circulating levels of NAD+ in the bloodstream.

Dr Sinclair recently published this article on CD38 and concluded that:

    • Combating the rise of CD38 is a promising approach to protect NAD+ levels.
    • The efficacy of NAD+ precursors may be enhanced by co-supplementation with CD38 inhibitors
Conclusion: Inhibiting CD38 to prevent NAD+ destruction AND supplementing with NAD+ precursors so the body can create more NAD+ is a promising new avenue in the anti-aging battle