179 replies to this topic

[mag1]

I am interested in this thread's topic of mitochondrial autophagy from the perspective of possible anti-cancer applications.

Many of the comments posted to this thread would seem to have anti-cancer potential. For example, the idea of changing

the NAD+/NADH ratio is noted in the cancer literature and on this thread it is specifically related to a signal to induce mitophagy.  

 

Might someone comment on how an anti-mitochondrial strategy might be combined with other anti-cancer strategies?

 

As an example, the article below found that ccRCC cells had a pronounced reduction in mitochondria and were more vulnerable to treatment with 3-BP. Might a combination of anti-mitochondrials and anti-glycolytics make for a sensible anti-cancer treatment? 

 

 

https://www.ncbi.nlm...les/PMC4669744/

Edited by mag1, 13 October 2016 - 11:34 PM.

[BieraK]

Perhaps an off-topic question.

As I know NAM inhibits Sirt1
What its the function that Nicotinamide (NAM) plays here? 

NAM inhibits or activates SIRT1?

Nicotinamide-induced Mitophagy EVENT MEDIATED BY HIGH NAD⁺/NADH RATIO AND SIRT1 PROTEIN ACTIVATION*

http://www.jbc.org/c...7/23/19304.long

I'm using Niacin for now, but I don't like the effects on reducing insulin sensivity, thats why I prefer to take it first thing in the morning and skipping breakfast.
 

[maxwatt]

While the types of gut bacteria responsible for production of UA are not definitively known, the species that show promise are not those found in common probiotics.

• “Pomegranate extract induces ellagitannin metabolite formation and changes stool microbiota in healthy volunteers” (2015) http://www.ncbi.nlm.nih.gov/pubmed/26189645 http://www.vitafoods.eu.com/visiting/poster-presentations/poster-presentations/poster-pomx-pomegranate-extract-stimulates-growth-of-gut-bacteria-implications-for-prebiotic-and-metabolic-effects
• “Description of urolithin production capacity from ellagic acid of two human intestinal Gordonibacter species” (2014) http://www.ncbi.nlm.nih.gov/pubmed/24909569
• “Gut Microbiota Conversion of Dietary Ellagic Acid into Bioactive Phytoceutical Urolithin-A Inhibits Heme Peroxidases” (2016) http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0156811

 

Pterostilbene-induced changes in gut microbiota composition in relation to obesity.

The above study surmises that pterostilbene encourages the kind of gut bacteria that convert ellagitanins to Urolithin A.  I expect that resveratrol would have a similar effect on the microbiome. Use of these polyphenols might then increase the population of desirable gut bacteria, resulting in a more efficient conversion of pomegranate extract into Urolithin A.  For the past month I have taken 300 mg of pomegranate extract, 40% ellagitanins (nightly), with 400 mg of resveratrol (divided dose, AM and PM) or 30 mg pterostilene.  I perceived about a 10% improvement in strength and approximately 10% improvement in aerobic capacity (time over a known course on a bicycle).  I cannot rule out a training effect nor placebo.  The improvement was not spectacular.  In 10 years if I make like Dorian Grey that might prove something...
 

[Nate-2004]

 

 

While the types of gut bacteria responsible for production of UA are not definitively known, the species that show promise are not those found in common probiotics.

• “Pomegranate extract induces ellagitannin metabolite formation and changes stool microbiota in healthy volunteers” (2015) http://www.ncbi.nlm.nih.gov/pubmed/26189645 http://www.vitafoods.eu.com/visiting/poster-presentations/poster-presentations/poster-pomx-pomegranate-extract-stimulates-growth-of-gut-bacteria-implications-for-prebiotic-and-metabolic-effects
• “Description of urolithin production capacity from ellagic acid of two human intestinal Gordonibacter species” (2014) http://www.ncbi.nlm.nih.gov/pubmed/24909569
• “Gut Microbiota Conversion of Dietary Ellagic Acid into Bioactive Phytoceutical Urolithin-A Inhibits Heme Peroxidases” (2016) http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0156811

 

Pterostilbene-induced changes in gut microbiota composition in relation to obesity.

The above study surmises that pterostilbene encourages the kind of gut bacteria that convert ellagitanins to Urolithin A.  I expect that resveratrol would have a similar effect on the microbiome. Use of these polyphenols might then increase the population of desirable gut bacteria, resulting in a more efficient conversion of pomegranate extract into Urolithin A.  For the past month I have taken 300 mg of pomegranate extract, 40% ellagitanins (nightly), with 400 mg of resveratrol (divided dose, AM and PM) or 30 mg pterostilene.  I perceived about a 10% improvement in strength and approximately 10% improvement in aerobic capacity (time over a known course on a bicycle).  I cannot rule out a training effect nor placebo.  The improvement was not spectacular.  In 10 years if I make like Dorian Grey that might prove something...
 

 

 

I've been doing the same with the 40% ellagic acid from bulksupplements, minus the resveratrol (it's just not all that bioavailable much less stable), except I've been doing it over the past 2 months. I am seeing similar effects. You're right, it's either placebo, or I'm seeing similar gains. It's cheap in bulk, I'll be keeping at it. I also include glutamine and N-A-G for mucin eating akkermansia.

[Fafner55]

Fafner55, thanks for the pomegranate extract report.  Although I'm not certain that a Human Equivalent Dose calculation is called for in this particular case, it probably is.  If that's the case, then the HED for a mouse getting 4mg/kg/d in a 70kg human is 280/12 = 23 mg UA.  Using the same assumptions as you have above, that would translate to about one half to one gram per day, which is a lot easier to stomach.   I think it's unlikely that the pomegranate extract caused your diverticulitis.  I think it's more likely that it was coincidental, although you did take a lot of extract, so it's not like we can rule it in or out as a cause. 

 

If you did have a higher level of mitophagy, how would you know?  A sudden change in apparent cardiovascular fitness?  What sort of time course would one expect in such an improvement?

 

ps:  Just saw the NR post.  Very interesting!  We need better ways to quantify the effects.

 

Niner, I mistyped in post #58 when I stated "4 mg/kg/day in mice". The authors of Urolithin-A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents wrote "Notably, the in vivo results were obtained after administration of UA at a dose of 50 mg/kg/d in mice, which is equivalent to 4 mg/kg/d in humans ..."  (not 4 mg/kg/day in mice as I wrote).  

 

At 4 mg/kg/day, the dose for a 70 kg individual is 280 gm.  It follows that the amount of pomegranate extract needed to get the equivalent dose of UA (if the right gut bacteria is present) is likely in the range of 5.6  to 11.2 gm.

 

Regarding the diverticulitis, it was most likely caused by the large amounts of pomegranate extract I was taking.  Consider, if you were to empty a capsule of Jarrow Formulas PomeGuard brand extract into a cup of water and stir it with a spoon, you would find that small pieces of ground pomegranate would glue to the spoon.  They are quite difficult to get off.  I can guess that in the same way particles of pomegranate adhered to my colon and led to an infection.

[Adam1]

Urolithin A is only one of the dibenzo-α-pyrones biosynthesized as a metabolite of plant-derived ellagitannins and ellagic acid. Supplementing ellagitannins likely involves a spectrum of such metabolites. Dibenzo-α-pyrones can carry toxicity, although toxicity is infrequent, and this may need to be considered with high doses. Also extract purity and hormetic dose response curve may be factors. This is aside from the significant issues you pointed to Fafner55. Thus, ellagitannins may be best used within a synergistic regimen at a lower dose.

 

Ellagitannins are present in a variety of plants aside from pomegranate, such as walnuts (among other nuts), strawberry, raspberry, blackberry, cloudberry, tea, persimmon, peach, plum, muscadine grapes and wine, oak-aged red wine (from the oak – a further French paradox factor?)

 

Urolithins can be supplemented directly without mediation of gut microbes (although caveat emptor with animal products):

 

 

Urolithins are not common molecules in nature, but they have been reported in plants rich in ellagitannins, as it is the case of Tamarix nilotica flowers and Punica granatum leaves that contain urolithin M-5 (3,4,8,9,10-pentahydroxydibenzo[b,d]pyran-6-one). They have also been found in some herbivore-derived products, such as the castoreum produced by beavers, a product of interest for the perfume industry, and the Pteropi faeces (faeces of the squirrel Trogopterus xanthipes) that are used in traditional Chinese medicine. Urolithins are also relevant constituents of shilajit, a soil-derived medicinal product used in Ayurvedic medicine.

 

It cannot be excluded that urolithins in pomegranate leaves are metabolites of endophytes residing in the leaves rather than being plant-produced compounds, although I am not aware of any studies. Preliminary research suggests urolithins could be produced by culture outside the gut so there is potential for biosynthesis, although they can be extracted from plants, e.g. the invasive water chestnut or Tamarix nilotica flowers.

 

As mentioned earlier in the thread, ellagitannins may be happily consumed by some common probiotics, and not just by the mucin-dwellers, as lactobacilli and bifidobacteria gain competitive advantage on a diet of ellagitannins. I wonder if the traditional food pomegranate kefir would selectively culture the microbes that metabolize ellagitannins.

Edited by Adam1, 20 October 2016 - 11:35 PM.

[gamesguru]

It's not clear how effective Lactobacillus plantarum  and L. rhamnosus are compared to Clostridium leptum or Gordonibacter.  But at least you can buy it, i.e. https://www.google.c...arum&tbm=shop. According to Wiki it's present in saliva (chewing) but also along the whole digestive track(?), and anaerobic plant material, such as  kimchi ^[1] or fermented oatmeal gruel. 

 

Based on Adam's post, I bet you could do it with a compote of pomegranate leaves.

Am J Clin Nutr. 2001 Feb;73(2 Suppl):380S-385S.

Probiotics in foods not containing milk or milk constituents, with special reference to Lactobacillus plantarum 299v.

Molin G¹.

 

Abstract

Lactic acid fermentation is the simplest and safest way of preserving food and has probably always been used by humans. Species such as Lactobacillus plantarum, Lactobacillus rhamnosus, Lactobacillus paracasei, Lactobacillus acidophilus, and Lactobacillus salivarius are common in the human mucosa, from the mouth to the rectum. In food, L. paracasei and L. rhamnosus are usually associated with dairy products whereas L. plantarum is found in fermented foods of plant origin. A probiotic food product containing no milk constituent was launched in Sweden in 1994. The product is a lactic acid fermented oatmeal gruel that is mixed in a fruit drink. It contains approximately 5 x 10(10) colony-forming units of L. plantarum 299v/L. The strain L. plantarum 299v originates from the human intestinal mucosa and has been shown in rats to decrease translocation, improve mucosal status, improve liver status, improve the immunologic status of the mucosa, and reduce mucosal inflammation. In humans, L. plantarum 299v can increase the concentration of carboxylic acids in feces and decrease abdominal bloating in patients with irritable bowel disease. It can also decrease fibrinogen concentrations in blood. Should probiotics be administrated through foods, the probiotic organism must remain vigorous in the food until consumption and the food must remain palatable, ie, the food carrier and the organism must suit each other. L. plantarum 299v not only affects the bacterial flora of the intestinal mucosa but may also regulate the host's immunologic defense. The mechanisms involved need to be clarified.

 

Nutr J. 2015; 15: 52.

Three week dietary intervention using apricots, pomegranate juice or/and fermented sour sobya and impact on biomarkers of antioxidative activity, oxidative stress and erythrocytic glutathione transferase activity among adults

Mostafa Gouda, Amr Moustafa, Laila Hussein, and Mohamed Hamza

Discussion

 

Plasma ellagic acid (EA) peaked after one hour of oral ingestion of 180 mL PGJ with mean concentration of 31.9 ng / mL plasma [14]. Identical results were obtained following the daily consumption of capsules (800 mg) containing 330.4 mg pomegranate punicalagins and 21.6 mg EA [44]. According to the authors, the (EA) peak reached 33.8 ± 12.7 ng/mL plasma. This finding presents evidence that pome granate ellagic acid (EA) was absorbed in humans. The increase in pomegranate ellagic acid (EA) was associated with significant increases in plasma AEAC averaging 31.8, 1.62 and 1.43 %, after 0.5, one and two hours post ingestion, respectively [44]. Furthermore, urinary urolithin metabolites persisted for 48 hours after PGJ ingestion [45].

In the present study, the three week dietary intervention with PGJ was quite appropriate to raise and maintain the body pools of phenols. The high AEAC of plasma and urine of our subjects is in good agreement with other studies reporting high plasma antioxidant capacity in human volunteers after PGJ consumption [44].

 

It is suggested that the gastrointestinal tract plays an important role in the first-pass metabolism of dietary flavonoids [46], whereby, during phase I metabolism, intestinal bacteria reductases convert pomegranate flavonoids into the urolithins and enabling reuptake [47]. Urolithin A and urolithin B are the PGJ metabolites detected in the plasma of volunteers following 5 day intakes of one liter of PGJ daily containing 4.37 g/L punicalagins and 0.49 g/L anthocyanins [48]. Their persistence in plasma and tissues suggest that they account for some of the health benefits of PGJ [14]. Specific strains of L. plantarum possess enzyme tannase (tannin acyl -hydrolase) and are able to degrade hydrolyzable tannins and tannic acid, to the monomeric antioxidant derivatives gallic acid and pyrogallol [49]. Eubacterium ramulus is one of the key colonic bacteria implicated in the biotransformation of the polyphewnolic compounds quercetin, apigenin and naringenin [50]. In phase II metabolism, polyphenols and their reductive metabolites are then conjugated with glucuronic acid and sulfate. by intestinal microsomes [47].

 

The probiotics are good for other things too.

Food Science and Biotechnology

 

 

December 2014 , Volume 23, Issue 6, pp 1951–1957
The probiotic characteristics and GABA production of Lactobacillus plantarum K154 isolated from kimchi

Sun-Young Park, Ji-Won Lee, Sang-Dong Lim (Email author), Sang-Dong Lim (Email author), et al.

Abstract

In order to identify strains with a high GABA production ability and glutamate decarboxylase activity, 273 bacteria were isolated from kimchi. K154 produced 154.86 μg/mL of GABA in an MRS broth containing 1% MSG, 170.42 μg/mL of GABA in an MRS broth containing 2% MSG, and 201.78 μg/mL of GABA in an MRS broth containing 3% MSG. K154 was identified as Lactobacillus plantarum based on API carbohydrate fermentation pattern testing. The 16s rDNA sequence was investigated in order to determine physiological characteristics. The optimum growth temperature of K154 was 37°C. K154 was more sensitive to novobiocin and bacitracin than to other antibiotics, and exhibited greater resistance to polymyxin B and vancomycin. K154 was comparatively tolerant to bile juice and acid, and displayed resistance to Escherichia coli, Salmonella Typhimurium, and Staphylococcus aureus at rates of 19.0, 18.9, and 13.6% respectively.

 

Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

Javier A. Bravo, Paul Forsythe, Marianne V. Chew, Emily Escaravage, et al.

 

L. rhamnosus (JB-1) induced region-dependent alterations in GABA_B1b mRNA in the brain with increases in cortical regions (cingulate and prelimbic) and concomitant reductions in expression in the hippocampus, amygdala, and locus coeruleus, in comparison with control-fed mice. In addition, L. rhamnosus (JB-1) reduced GABA_Aα2 mRNA expression in the prefrontal cortex and amygdala, but increased GABA_Aα2 in the hippocampus. Importantly, L. rhamnosus (JB-1) reduced stress-induced corticosterone and anxiety- and depression-related behavior.

[maxwatt]

Wow.

 

I would be cautious about randomly increasing ellagitanins and various forms of Urolithin into one's diet:

 

 

J Agric Food Chem. 2014 Jul 16;62(28):6535-8. doi: 10.1021/jf5024615. Epub 2014 Jul 1.

Ellagic acid metabolism by human gut microbiota: consistent observation of three urolithin phenotypes in intervention trials, independent of food source, age, and health status.

Tomás-Barberán FA¹, García-Villalba R, González-Sarrías A, Selma MV, Espín JC.

Author information

Abstract

Three phenotypes for urolithin production after ellagitannin and ellagic acid intake are consistently observed in different human intervention trials. Subjects can be stratified into three urolithin-producing groups. "Phenotype A" produced only urolithin A conjugates, which included between 25 and 80% of the volunteers in the different trials. "Phenotype B" produced isourolithin A and/or urolithin B in addition to urolithin A, this being the second relevant group (10-50%). "Phenotype 0" (5-25%) was that in which these urolithins were not detected. The three phenotypes were observed independently of the volunteers' health status and demographic characteristics (age, gender, body mass index (BMI)) and of the amount or type of ellagitannin food source ingested (walnuts and other nuts, strawberries, raspberries, and other berries or pomegranates). Interestingly, a higher percentage of phenotype B was observed in those volunteers with chronic illness (metabolic syndrome or colorectal cancer) associated with gut microbial imbalance (dysbiosis). These urolithin phenotypes could show differences in the human gut microbiota and should be considered in intervention trials dealing with health benefits of ellagitannins or ellagic acid. Whether this phenotypic variation could be a biomarker related to differential health benefits or illness predisposition deserves further research.

PMID: 24976365 DOI: 10.1021/jf5024615

 

Urolithin B production by gut bacteria correlated with metabolic syndrome and colorectal cancer. 

 

I really don't know enough about the metabolic processes involved to know where to begin to influence them for certain.  Lots of nuts, probiotics on the uncertain theory that a healthy gut microflora will be a favorable environment for those bacteria that do produce Urolithin A, supplementation with ellagic acid....    It's a shot in the dark.

 

[Adam1]

That is eye opening. What I find perplexing in the study is that the results were independent of dietary ellagitannin. If the phenotype were purely based on genetic factors and the composition of the microbiome, you would expect the more ellagitannin for the bacteria to metabolize, the bigger the positive or negative effect. Perhaps factors such as other phytochemicals in the diet mitigate effects to a limited degree to support homeostasis. Certainly megadoses of elligatanins or urolithins would be a bad idea as this may overwhelm the homeostasis in a positive or negative direction.

 

We are influenced by a paradigm of one drug for one target for all people, and we don’t know enough.

[Adam1]

Reading through the above study, it suggests caution for anyone with a health condition associated with phenotype B:

 

 

The ratio between phenotypes A and B changed in patients with illness associated with gut dysbiosis such as metabolic syndrome or colorectal cancer, where phenotype B gained increasing relevance

 

Otherwise, it seems that the prudent way to supplement would be to test whether you excrete both urolithins A and B after a challenge of ellagitannins and ellagic acid. If you do, you are phenotype B and should be emphasizing a protocol for prevention of colorectal cancer and metabolic syndrome. If you don’t excrete urolithins you could then consider Gamesguru’s recommended probiotics to increase microflora diversity and possibly to increase urolithin production. Then test for urolithins again. I am not aware of where one would obtain this urinary excretion test, but it would be useful to share if anyone pursues this.

 

But… More details from the above study:

 

 

In healthy volunteers as well as in those patients with illnesses that are not characterized by gut dysbiosis (prostate cancer or benign hyperplasia), phenotype A was the main urinary profile (Table 1; Figure 3). In this regard, phenotype A was also the most abundant profile in patients with chronic obstructive pulmonary disease (age 60 ± 11 years) that consumed pomegranate juice for 5 weeks

 

[Fafner55]

Experiment #2: Inducing Mitophagy with NR

The improvements to my skin from personal Experiment #1 have persisted. It is clear at this point that the benefits from that experiment are not transitory.  

 

This experiment repeats Experiment #1 to determine the extent further improvement is possible.

 

2016-10-19  Day 1. Begin taking 10 capsules (1250 mg) three times per day. I have not taken C60-OO or any supplements or medications  for a two weeks.

2016-10-20  Day 2. Like Experiment #1, my face feels very slightly flushed, as if I were taking a niacin.  There is no apparent difference in my skin.

2016-10-21  Day 3. Mid-day: My muscles feel more toned than usual but not stronger.  There is a slight feeling of flushing soon after I take NR.  Otherwise, I feel no symptoms.  PM: the skin on my arms appears smoother.

2016-10-22  Day 4. There is continued improvement to the skin on my arms, with fewer bumps and less discoloration. I feel normal, without muscle aches or other symptoms.

2016-10-23  Day 5. I feel colder and low energy, and otherwise without symptoms.  

2016-10-24  Day 6. Feeling a bit low energy and possibly have some weakness in my legs, but otherwise about normal.  There is no muscle ache like there was with Experiment #1. Remarkably, many of the smaller stucco keratoses on my hands and wrists have disappeared. The larger ones are flatter.  I noticed some recession of these keratoses in Experiment #1 but was not certain and didn't document it. I have had these keratoses for about 20 years; they resisted all attempts at treatment until now. Incidentally, my skin still has about the same degree of fine wrinkles and crepe-like appearance as before, from which I can infer that large doses of NR have little if any effect on collagen production.

2016-10-25  Day 7.  Yesterday was the last day of the treatment.  I’m pleased with the improvement to the appearance of my skin.  Today I feel good and more energetic.  IMHO, there is no benefit in following this treatment with PQQ.

2016-10-26  Day 8.  Following the pattern of Experiment #1, I feel normal.  There is substantial improvement to the appearance of skin on my hands, wrists and arms.  On close inspection, while the larger stucco keratoses on my hands are still present, they are flatter than before. 

2016-10-27  Day 9. I feel  normal.

 

The effects of NR are so wide reaching that I can't see that it is possible to assign these observations positively to mitophagy.  However, low energy is consistent with a reduction in mitochondrial mass.

[stefan_001]

 

Experiment #2: Inducing Mitophagy with NR

The improvements to my skin from personal Experiment #1 have persisted. It is clear at this point that the benefits from that experiment are not transitory.  

 

This experiment repeats Experiment #1 to determine the extent further improvement is possible.

 

2016-10-19  Day 1. Begin taking 10 capsules (1250 mg) three times per day. I have not taken C60-OO or any supplements or medications  for a two weeks.

2016-10-20  Day 2. Like Experiment #1, my face feels very slightly flushed, as if I were taking a niacin.  There is no apparent difference in my skin.

2016-10-21  Day 3. Mid-day: My muscles feel more toned than usual but not stronger.  There is a slight feeling of flushing soon after I take NR.  Otherwise, I feel no symptoms.  PM: the skin on my arms appears smoother.

2016-10-22  Day 4. There is continued improvement to the skin on my arms, with fewer bumps and less discoloration. I feel normal, without muscle aches or other symptoms.

2016-10-23  Day 5. I feel colder and low energy, and otherwise without symptoms.  

2016-10-24  Day 6. Feeling a bit low energy and possibly have some weakness in my legs, but otherwise about normal.  There is no muscle ache like there was with Experiment #1. Remarkably, many of the smaller stucco keratoses on my hands and wrists have disappeared. The larger ones are flatter.  I noticed some recession of these keratoses in Experiment #1 but was not certain and didn't document it. I have had these keratoses for about 20 years; they resisted all attempts at treatment until now. Incidentally, my skin still has about the same degree of fine wrinkles and crepe-like appearance as before, from which I can infer that large doses of NR have little if any effect on collagen production.

2016-10-25  Day 7.  Yesterday was the last day of the treatment.  I’m pleased with the improvement to the appearance of my skin.  Today I feel good and more energetic.  IMHO, there is no benefit in following this treatment with PQQ.

2016-10-26  Day 8.  Following the pattern of Experiment #1, I feel normal.  There is substantial improvement to the appearance of skin on my hands, wrists and arms.  On close inspection, while the larger stucco keratoses on my hands are still present, they are flatter than before. 

2016-10-27  Day 9. I feel  normal.

 

The effects of NR are so wide reaching that I can't see that it is possible to assign these observations positively to mitophagy.  However, low energy is consistent with a reduction in mitochondrial mass.

 

 

This is an interesting experiment and I think I will repeat that for myself. Wrt this one:

 

#1 ....... from which I can infer that large doses of NR have little if any effect on collagen production.

 

I have seen improved collagen production from long term use. Skin epidermal cells renew every 10-30 days. So if there is less collagen due to lower amount of fibroblast cells it may take a while before those are back upto youthfull levels.Will be interesting to hear how the situation is in a few weeks.

 

If I may ask, have you noticed any other improvements:

- gray hair portion in beard which is easy to track if you regularly shave and then stop couple days

- eye sight

- eye whiteness (amount of redness)

- skin elasticity e.g. the skin between thumb and finger is a good place to track that.

- size of pories- you write that face in skin is smoother. Have you seen pories size shrink?

[Turnbuckle]

 

Experiment #2: Inducing Mitophagy with NR

 

 

Thanks for your excellent experiments and reporting. I have a few questions:

 

1. Have you any evidence that NR works better than nicotinamide?

2. When you say on day 9 that you felt normal, does that mean you felt better or worse than days 7-8?

3. Was the overall gain less than the first experiment (as one might expect)? And was the benefit from the second experiment additive with the first experiment?

 

As for the positive effects even before you finished the week, that could be due to the removal of dysfunctional mitochondria that were spewing toxins but not adding anything to ATP production. 

Edited by Turnbuckle, 28 October 2016 - 11:20 AM.

[Fafner55]

This is an interesting experiment and I think I will repeat that for myself. Wrt this one:

 

#1 ....... from which I can infer that large doses of NR have little if any effect on collagen production.

 

I have seen improved collagen production from long term use. Skin epidermal cells renew every 10-30 days. So if there is less collagen due to lower amount of fibroblast cells it may take a while before those are back upto youthfull levels.Will be interesting to hear how the situation is in a few weeks.

 

If I may ask, have you noticed any other improvements:

- gray hair portion in beard which is easy to track if you regularly shave and then stop couple days

- eye sight

- eye whiteness (amount of redness)

- skin elasticity e.g. the skin between thumb and finger is a good place to track that.

- size of pories- you write that face in skin is smoother. Have you seen pories size shrink?

 

 

I have never had a problem with eye redness and don't give it any attention.  As for eye sight and the others, I do monitor them and noticed no change.

 

Skin elasticity in particular is something I track.  Crepey skin on the inside of my arm (an area with less sun damage) gives me an easy measure. I watch it daily.  There was no change.

[Fafner55]

 

 

Experiment #2: Inducing Mitophagy with NR

 

 

Thanks for your excellent experiments and reporting. I have a few questions:

 

1. Have you any evidence that NR works better than nicotinamide?

2. When you say on day 9 that you felt normal, does that mean you felt better or worse than days 7-8?

3. Was the overall gain less than the first experiment (as one might expect)? And was the benefit from the second experiment additive with the first experiment?

 

As for the positive effects even before you finished the week, that could be due to the removal of dysfunctional mitochondria that were spewing toxins but not adding anything to ATP production. 

 

 

1. I have not compared NR with nicotinamide and have no opinion.

2. "Normal" is vague.  Here it means that I did not feel adverse symptoms such as low energy or less strength. 

3. In terms of effect on muscles, the effect was less as evidenced by the near absence of aches.  As to skin problems/keratoses, I judge the effect to be additive, perhaps due to a larger accumulation of dysfunctional mitochondria in the affected skin, and I expect further improvements to my skin in a future experiment #3.  Time will tell.

[maxwatt]

 

Fafner55, thanks for the pomegranate extract report.  Although I'm not certain that a Human Equivalent Dose calculation is called for in this particular case, it probably is.  If that's the case, then the HED for a mouse getting 4mg/kg/d in a 70kg human is 280/12 = 23 mg UA.  Using the same assumptions as you have above, that would translate to about one half to one gram per day, which is a lot easier to stomach.   I think it's unlikely that the pomegranate extract caused your diverticulitis.  I think it's more likely that it was coincidental, although you did take a lot of extract, so it's not like we can rule it in or out as a cause. 

 

If you did have a higher level of mitophagy, how would you know?  A sudden change in apparent cardiovascular fitness?  What sort of time course would one expect in such an improvement?

 

ps:  Just saw the NR post.  Very interesting!  We need better ways to quantify the effects.

 

Niner, I mistyped in post #58 when I stated "4 mg/kg/day in mice". The authors of Urolithin-A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents wrote "Notably, the in vivo results were obtained after administration of UA at a dose of 50 mg/kg/d in mice, which is equivalent to 4 mg/kg/d in humans ..."  (not 4 mg/kg/day in mice as I wrote).  

 

At 4 mg/kg/day, the dose for a 70 kg individual is 280 gm.  It follows that the amount of pomegranate extract needed to get the equivalent dose of UA (if the right gut bacteria is present) is likely in the range of 5.6  to 11.2 gm.

 

Regarding the diverticulitis, it was most likely caused by the large amounts of pomegranate extract I was taking.  Consider, if you were to empty a capsule of Jarrow Formulas PomeGuard brand extract into a cup of water and stir it with a spoon, you would find that small pieces of ground pomegranate would glue to the spoon.  They are quite difficult to get off.  I can guess that in the same way particles of pomegranate adhered to my colon and led to an infection.

 

 

I am looking at various pomegranate extracts availabe.  Apparently Fafner, you use one lableled as 40% elligitanins.  I find there are some, including one I use, that is 40% ellagic acid.  As you assumed 25% of the elligitanins converted to ellagic acid, that would imply one quarter of the dose you calculated should suffice.  so a dose between 2 grams and 3 grams  (rounding the fractions)  is called for.  Actually it could be less than that, as the remaining 60% of the extract likely consists mostly of elligitanins.  

 

Edited by maxwatt, 28 October 2016 - 04:37 PM.

[Adam1]

Maxwatt, it appears there may be direct conversion of elligitanins to urolithins:

 

 

Whether these metabolites can be formed directly from ETs or the presence of free EA is a necessary step needs further research, although our preliminary observations (unpublished results) suggest that human fecal samples can directly convert pure ETs to urolithin B derivatives (Figure 1).

 

Cerdá, Begoña, Francisco A. Tomás-Barberán, and Juan Carlos Espín. "Metabolism of antioxidant and chemopreventive ellagitannins from strawberries, raspberries, walnuts, and oak-aged wine in humans: identification of biomarkers and individual variability." Journal of agricultural and food chemistry 53.2 (2005): 227-235.

 

[Fafner55]

I am looking at various pomegranate extracts availabe.  Apparently Fafner, you use one lableled as 40% elligitanins.  I find there are some, including one I use, that is 40% ellagic acid.  As you assumed 25% of the elligitanins converted to ellagic acid, that would imply one quarter of the dose you calculated should suffice.  so a dose between 2 grams and 3 grams  (rounding the fractions)  is called for.  Actually it could be less than that, as the remaining 60% of the extract likely consists mostly of elligitanins.  

 

 

Maxwatt,

Your product said to have 40% ellagic acid may be mislabeled.

 

Standardized pomegranate extract contains 40% punicalagins.  This value is consistent with concentrations reported in literature.  From

"Absorption, metabolism, and antioxidant effects of pomegranate (Punica granatum L.) polyphenols after ingestion of a standardized extract in healthy human volunteers" (2006) http://www.ncbi.nlm.nih.gov/pubmed/17090147

https://examine.com/supplements/punicalagins/

 

Pomegranate Extract Polyphenol Concentrations

                                    Concentration (mg/g) 

Anthocyanins                                 ?

Punicalagins                                413

Ellagic acid (EA)                             27

Other hydrolyzable tannins            ?

EA/Punicalagins ratio              0.0654

 

 

800 mg pomegranate extract has been shown to contain 318 mg punicalagins (anomeric isomers of the punicalagin molecule).  Punicalagins are are type of ellagitannins, which gut bacteria metabolize into ellagic acid which is further metabolized into end products Urolithin-A, B, C and D.  Pomegranate ellagitannins are native in high concentrations and unique to the pomegranate fruit.

• https://examine.com/supplements/punicalagins/
• "Pomegranate Juice and Extracts Provide Similar Levels of Plasma and Urinary Ellagitannin Metabolites in Human Subjects" (2008) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196216/

 

You might also consider pomegranate juice.  Pomegranate juice has been found to contain the composition of polyphenols shown below.  It is seen that as a first order approximation the proportions of polyphenols found in juice is about the same as that found in extract.

"Pomegranate juice ellagitannin metabolites are present in human plasma and some persist in urine for up to 48 hours" (2006) http://www.ncbi.nlm.nih.gov/pubmed/16988113

 

Pomegranate Juice Polyphenol Concentrations

                                     Concentration (mg/L)    

Anthocyanins                               387              

Punicalagins                               1561            

Ellagic acid (EA)                            121            

Other hydrolyzable tannins           417          

EA/Punicalagins ratio               0.0775

 

Pomegranate juice has a density of 1052 mg/mL.  http://www.aqua-calc.com/page/density-table/substance/pomegranate-blank-juice-coma-and-blank-bottled

 

"Pomegranate Juice and Extracts Provide Similar Levels of Plasma and Urinary Ellagitannin Metabolites in Human Subjects" (2008) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3196216/

Pomegranate juice (PJ), a rich source of polyphenols including ellagitannins, has attracted much attention due to its reported health benefits. This has resulted in the consumption of liquid and powder pomegranate extracts as alternatives to PJ. Therefore establishing the bioavailability of polyphenols from these extract preparations is necessary. Sixteen healthy volunteers sequentially consumed, with a 1-week washout period between treatments, PJ (8 ounces, Wonderful fruit variety), a pomegranate polyphenol liquid extract (POMxl, 8 ounces), and a pomegranate polyphenol powder extract (POMxp, 1,000 mg). The three interventions provided 857, 776, and 755 mg of polyphenols as gallic acid equivalents, respectively. Plasma bioavailability, judged based on ellagic acid levels over a 6-hour period, did not show statistical differences in area under the curve for the three interventions: 0.14 ± 0.05, 0.11 ± 0.03, and 0.11 ± 0.04 μmol · hour/L for PJ, POMxl, and POMxp, respectively. The time of maximum concentration was delayed for POMxp (2.58 ± 0.42 hours) compared to PJ (0.65 ± 0.23 hours) and POMxl (0.94 ± 0.06 hours). Urolithin-A glucuronide, a urinary metabolite of ellagic acid, was not significantly different with the three interventions, reaching levels of approximately 1,000 ng/mL.

 

If you choose to ingest pomegranate extract, I suggest first dissolving it in water, then run it through a coffee filter to remove particulate matter that could cause diverticulitis.

[APBT]

Not to devolve this excellent thread into"pomegranate talk", but here are two extract powders;

 

40% ellagic acid:  https://purebulk.com...0-ellagic-acid/

90% ellagic acid:  https://purebulk.com...90-ellagic-acid/

Edited by APBT, 29 October 2016 - 07:15 PM.

[Fafner55]

Not to devolve this excellent thread into"pomegranate talk", but here are two extract powders;

 

40% ellagic acid:  https://purebulk.com...0-ellagic-acid/

90% ellagic acid:  https://purebulk.com...90-ellagic-acid/

 

Nice find.  Please keep us posted.

[stefan_001]

 

This is an interesting experiment and I think I will repeat that for myself. Wrt this one:

 

#1 ....... from which I can infer that large doses of NR have little if any effect on collagen production.

 

I have seen improved collagen production from long term use. Skin epidermal cells renew every 10-30 days. So if there is less collagen due to lower amount of fibroblast cells it may take a while before those are back upto youthfull levels.Will be interesting to hear how the situation is in a few weeks.

 

If I may ask, have you noticed any other improvements:

- gray hair portion in beard which is easy to track if you regularly shave and then stop couple days

- eye sight

- eye whiteness (amount of redness)

- skin elasticity e.g. the skin between thumb and finger is a good place to track that.

- size of pories- you write that face in skin is smoother. Have you seen pories size shrink?

 

 

I have never had a problem with eye redness and don't give it any attention.  As for eye sight and the others, I do monitor them and noticed no change.

 

Skin elasticity in particular is something I track.  Crepey skin on the inside of my arm (an area with less sun damage) gives me an easy measure. I watch it daily.  There was no change.

 

 

I still think that the effects cannot be immediate on items like elasticity and collagen recovery. Any changes for better or worse since ending the session last week if I may ask?

[Fafner55]

I still think that the effects cannot be immediate on items like elasticity and collagen recovery. Any changes for better or worse since ending the session last week if I may ask?

 

 

Not to digress very far from the topic of upgrading dysfunctional mitochondrial, while on the surface it seems reasonable to assume that the accumulation of senescent cells and accumulation of dysfunctional mitochondria contribute to the decline in collagen and elastin production, I can't reconcile the exponential declines in those conditions with the linear declines in collagen production and skin thickness.

 

The many articles on age-related decline in collagen production published by cosmetic companies appear to derive from a single study (attached), “The influence of age and sex on skin thickness, skin collagen and density” (1975), which clearly shows a linear decline after the age of 20 at a rate of about 1.0% / year for men and 1.2% / year for women.

 

Furthermore, figure 2 of “Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders” (2011) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323/ shows unchanged dermis thickness after clearing senescent cells.

 

IMHO, from the lack of correlation with dysfunctional mitochondria or senescent cells, or other evidence, there is not much chance that treating either condition will improve wrinkles caused by intrinsic aging.

Attached Files

•  The influence of age and sex on skin thickness, skin collagen and density.pdf   1.3MB   6 downloads

[maxwatt]

we'll need an effective pentosidine crosslink breaker for wrinkles. ALT-711 did not affect collagen crosslinks.

[Nate-2004]

we'll need an effective pentosidine crosslink breaker for wrinkles. ALT-711 did not affect collagen crosslinks.

Probably off topic for this thread but I agree. Neither does rosmarinic acid apparently, topically or orally so far. Not sure what to expect from that though since I'm only 42 and my skin only has wrinkles (deep around the eyes) when I smile. I'm more concerned about regrowing the subcutaneous fat tissue and bone loss around the upper cheeks and eyes that causes the sunken look and darker circles, another age telling factor that happens first for those with better skin.

[Rocket]

we'll need an effective pentosidine crosslink breaker for wrinkles. ALT-711 did not affect collagen crosslinks.

 

Where is the empirical evidence that wrinkles are caused by AGEs? There isn't any. There is however evidence that wrinkles are caused by the thinning of the skin. 

 

Even *if* AGEs caused wrinkles and there was an effective AGE breaker, then you would be left with soft and drooping saggy skin because the skin would still thin. That's a big if.

[Turnbuckle]

This thread is seriously derailed.

[Fafner55]

Safety of 3750 mg / day NR for 6 days

Relating my experiments with large doses of NR to the study on mice described in http://www.ergo-log.com/safe-dose-of-nicotinamide-riboside.html, and given my 70 kg mass and daily dose of 3750 mg, the comparable rat equivalent dose (RED) is given by

 

RED (mg/kg) = Human Dose (mg/kg) x [Human Km/Animal Km ]

= (3750/70) (37/3)

= 660 mg/kg

 

A RED dose of 660 mg/kg/day falls about halfway between the 300 and 1000 mg/kg published results.  At the end of 90 days male rats in this range experienced about a 10% drop in weight (due to higher metabolism) and a slight increase in weight of the brain, kidney, liver and thymus.  I judge these changes to be positive.  At a higher dose of 1000 mg rats showed an increase in the concentration of white blood cells, which can be a sign of tissue damage.

 

From these results, it is likely that a dose of about 4000 mg per day for a week is safe in humans who weigh 70 kg. There may also be benefits to the brain, kidney, liver and thymus.

 

 Results of feeding rats large doses of NR for 90 days.jpg   91.68KB   15 downloads

Edited by Fafner55, 03 November 2016 - 10:29 PM.

[stefan_001]

 

Safety of 3750 mg / day NR for 6 days

Relating my experiments with large doses of NR to the study on mice described in http://www.ergo-log.com/safe-dose-of-nicotinamide-riboside.html, and given my 70 kg mass and daily dose of 3750 mg, the comparable rat equivalent dose (RED) is given by

 

RED (mg/kg) = Human Dose (mg/kg) x [Human Km/Animal Km ]

= (3750/70) (37/3)

= 660 mg/kg

 

A RED dose of 660 mg/kg/day falls about halfway between the 300 and 1000 mg/kg published results.  At the end of 90 days male rats in this range experienced about a 10% drop in weight (due to higher metabolism) and a slight increase in weight of the brain, kidney, liver and thymus.  I judge these changes to be positive.  At a higher dose of 1000 mg rats showed an increase in the concentration of white blood cells, which can be a sign of tissue damage.

 

From these results, it is likely that a dose of about 4000 mg per day for a week is safe in humans who weigh 70 kg. There may also be benefits to the brain, kidney, liver and thymus.

 

Results of feeding rats large doses of NR for 90 days.jpg

 

 

I think you may interpret the table wrongly. The relative organ weight is up but in absolute terms they shrink. 

[Fafner55]

 

 

Safety of 3750 mg / day NR for 6 days

Relating my experiments with large doses of NR to the study on mice described in http://www.ergo-log.com/safe-dose-of-nicotinamide-riboside.html, and given my 70 kg mass and daily dose of 3750 mg, the comparable rat equivalent dose (RED) is given by

 

RED (mg/kg) = Human Dose (mg/kg) x [Human Km/Animal Km ]

= (3750/70) (37/3)

= 660 mg/kg

 

A RED dose of 660 mg/kg/day falls about halfway between the 300 and 1000 mg/kg published results.  At the end of 90 days male rats in this range experienced about a 10% drop in weight (due to higher metabolism) and a slight increase in weight of the brain, kidney, liver and thymus.  I judge these changes to be positive.  At a higher dose of 1000 mg rats showed an increase in the concentration of white blood cells, which can be a sign of tissue damage.

 

From these results, it is likely that a dose of about 4000 mg per day for a week is safe in humans who weigh 70 kg. There may also be benefits to the brain, kidney, liver and thymus.

 

Results of feeding rats large doses of NR for 90 days.jpg

 

 

I think you may interpret the table wrongly. The relative organ weight is up but in absolute terms they shrink. 

 

 

stefan_001, as you point out, the table of organ weights shows organ weight ratio relative to body weight at day 91.  While relative organ weights are generally shown to increase, they decrease in absolute terms.  At doses of up to 1000 mg/kg/day in rats, these absolute decreases were, in the words of the authors, “considered to be treatment related, but mild and potentially adaptive in nature due to prolonged exposure.”

 

Excerpts from the publication should help clarify interpretation of the results.

 

“Safety assessment of nicotinamide riboside, a form of vitamin B3” (2016) http://het.sagepub.c...tent/35/11/1149

Abstract

Nicotinamide riboside (NR) is a naturally occurring form of vitamin B3 present in trace amounts in some foods. Like niacin, it has been shown to be a precursor in the biosynthesis of nicotinamide adenine dinucleotide (NAD+). The safety of Niagen™, a synthetic form of NR, was determined using a bacterial reverse mutagenesis assay (Ames), an in vitro chromosome aberration assay, an in vivo micronucleus assay, and acute, 14-day and 90-day rat toxicology studies. NR was not genotoxic. There was no mortality at an oral dose of 5000 mg/kg. Based on the results of a 14-day study, a 90-day study was performed comparing NR at 300, 1000, and 3000 mg/kg/day to an equimolar dose of nicotinamide at 1260 mg/kg/day as a positive control. Results from the study show that NR had a similar toxicity profile to nicotinamide at the highest dose tested. Target organs of toxicity were liver, kidney, ovaries, and testes. The lowest observed adverse effect level for NR was 1000 mg/kg/day, and the no observed adverse effect level was 300 mg/kg/day.

 

Excerpts

At 1000 mg/kg/day of Niagen, increases in liver and kidney weights were statistically significant. All other relative to body weight organ weight changes, which reached statistical significance were likely secondary to decrease in terminal body weight and/or random biological variation and not considered treatment related.

 

Relative to brain weight, at 3000 mg/kg/day, there were statistically significant reductions in heart, epididymides, prostate and thyroid/parathyroid in males; liver, heart, ovaries and kidney were increased in females. In the nicotinamide-treated group, there were statistically significant reductions in weights of spleen, epididymides, testes and heart in males; liver weight was increased. At 1000 mg/kg/day there were no changes in organ weights relative to brain weight in males and a statistically significant increase in liver weight in females. No changes in organ weights relative to brain weights were seen in either males or females treated with 300 mg/kg/day of Niagen.

 

At 1000 mg/kg/day, there were statistically significant reductions in absolute organ weights of thyroid/parathyroid, pituitary and heart in males; no effects on absolute organ weights were seen in females. At 300 mg/kg/day, there were statistically significant reductions in absolute organ weights of brain and heart in males; no effects on absolute organ weights were seen in females.

 

Treatment-related histopathological changes were observed in liver, thyroid, kidneys, testes, epididymides, ovaries, and adrenals in both the 3000 mg/kg/day Niagen-treated and nicotinamide-treated groups.

 

NR administration at 1000 mg/kg/day dose level resulted in treatment-related organ weight changes in liver and kidney and increases in neutrophils, ALT and triglycerides, which were statistically significant in female rats only. Although these changes were considered adverse, based on their dose-dependent responsiveness, the increases in ALT and triglycerides occurred only in one gender and were below the twofold increase that is typically used as the cutoff for a biologically significant effect in the absence of histological results. The kidney weight increases at this dose also occurred in the absence of corresponding histopathology. Therefore, the liver and kidney effects at 1000 mg/kg/day were considered to be treatment related, but mild and potentially adaptive in nature due to prolonged exposure to this form of niacin. There were no treatment-related adverse effects noted at 300 mg/kg/day, although there was a slight decrease (8%) in overall body weight (day 90) at 300 mg/kg/day, which was considered adaptive. The NOAEL (no observed adverse effect level) and LOAEL (lowest observed adverse effect level) for NR were determined to 300 and 1000 mg/kg body weight/day, respectively.

[stefan_001]

 

 

 

Safety of 3750 mg / day NR for 6 days

Relating my experiments with large doses of NR to the study on mice described in http://www.ergo-log.com/safe-dose-of-nicotinamide-riboside.html, and given my 70 kg mass and daily dose of 3750 mg, the comparable rat equivalent dose (RED) is given by

 

RED (mg/kg) = Human Dose (mg/kg) x [Human Km/Animal Km ]

= (3750/70) (37/3)

= 660 mg/kg

 

A RED dose of 660 mg/kg/day falls about halfway between the 300 and 1000 mg/kg published results.  At the end of 90 days male rats in this range experienced about a 10% drop in weight (due to higher metabolism) and a slight increase in weight of the brain, kidney, liver and thymus.  I judge these changes to be positive.  At a higher dose of 1000 mg rats showed an increase in the concentration of white blood cells, which can be a sign of tissue damage.

 

From these results, it is likely that a dose of about 4000 mg per day for a week is safe in humans who weigh 70 kg. There may also be benefits to the brain, kidney, liver and thymus.

 

Results of feeding rats large doses of NR for 90 days.jpg

 

 

I think you may interpret the table wrongly. The relative organ weight is up but in absolute terms they shrink. 

 

 

stefan_001, as you point out, the table of organ weights shows organ weight ratio relative to body weight at day 91.  While relative organ weights are generally shown to increase, they decrease in absolute terms.  At doses of up to 1000 mg/kg/day in rats, these absolute decreases were, in the words of the authors, “considered to be treatment related, but mild and potentially adaptive in nature due to prolonged exposure.”

 

Excerpts from the publication should help clarify interpretation of the results.

 

“Safety assessment of nicotinamide riboside, a form of vitamin B3” (2016) http://het.sagepub.c...tent/35/11/1149

Abstract

Nicotinamide riboside (NR) is a naturally occurring form of vitamin B3 present in trace amounts in some foods. Like niacin, it has been shown to be a precursor in the biosynthesis of nicotinamide adenine dinucleotide (NAD+). The safety of Niagen™, a synthetic form of NR, was determined using a bacterial reverse mutagenesis assay (Ames), an in vitro chromosome aberration assay, an in vivo micronucleus assay, and acute, 14-day and 90-day rat toxicology studies. NR was not genotoxic. There was no mortality at an oral dose of 5000 mg/kg. Based on the results of a 14-day study, a 90-day study was performed comparing NR at 300, 1000, and 3000 mg/kg/day to an equimolar dose of nicotinamide at 1260 mg/kg/day as a positive control. Results from the study show that NR had a similar toxicity profile to nicotinamide at the highest dose tested. Target organs of toxicity were liver, kidney, ovaries, and testes. The lowest observed adverse effect level for NR was 1000 mg/kg/day, and the no observed adverse effect level was 300 mg/kg/day.

 

Excerpts

At 1000 mg/kg/day of Niagen, increases in liver and kidney weights were statistically significant. All other relative to body weight organ weight changes, which reached statistical significance were likely secondary to decrease in terminal body weight and/or random biological variation and not considered treatment related.

 

Relative to brain weight, at 3000 mg/kg/day, there were statistically significant reductions in heart, epididymides, prostate and thyroid/parathyroid in males; liver, heart, ovaries and kidney were increased in females. In the nicotinamide-treated group, there were statistically significant reductions in weights of spleen, epididymides, testes and heart in males; liver weight was increased. At 1000 mg/kg/day there were no changes in organ weights relative to brain weight in males and a statistically significant increase in liver weight in females. No changes in organ weights relative to brain weights were seen in either males or females treated with 300 mg/kg/day of Niagen.

 

At 1000 mg/kg/day, there were statistically significant reductions in absolute organ weights of thyroid/parathyroid, pituitary and heart in males; no effects on absolute organ weights were seen in females. At 300 mg/kg/day, there were statistically significant reductions in absolute organ weights of brain and heart in males; no effects on absolute organ weights were seen in females.

 

Treatment-related histopathological changes were observed in liver, thyroid, kidneys, testes, epididymides, ovaries, and adrenals in both the 3000 mg/kg/day Niagen-treated and nicotinamide-treated groups.

 

NR administration at 1000 mg/kg/day dose level resulted in treatment-related organ weight changes in liver and kidney and increases in neutrophils, ALT and triglycerides, which were statistically significant in female rats only. Although these changes were considered adverse, based on their dose-dependent responsiveness, the increases in ALT and triglycerides occurred only in one gender and were below the twofold increase that is typically used as the cutoff for a biologically significant effect in the absence of histological results. The kidney weight increases at this dose also occurred in the absence of corresponding histopathology. Therefore, the liver and kidney effects at 1000 mg/kg/day were considered to be treatment related, but mild and potentially adaptive in nature due to prolonged exposure to this form of niacin. There were no treatment-related adverse effects noted at 300 mg/kg/day, although there was a slight decrease (8%) in overall body weight (day 90) at 300 mg/kg/day, which was considered adaptive. The NOAEL (no observed adverse effect level) and LOAEL (lowest observed adverse effect level) for NR were determined to 300 and 1000 mg/kg body weight/day, respectively.

 

 

Yes I read that, I also looked at the ALT changes there were some reasonable large outliers at 1000mg. Vehicle 85+/-26, 1000mg 106+/-45. For a weeks experiment probably not a big worry but typically ALT up indicates potentially some liver damage.

Edited by stefan_001, 05 November 2016 - 09:04 PM.