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Another double-edge sword?

Interacting NAD+ and Cell Senescence pathways complicate anti-aging therapies.

Rejuvenation Res. 2019 May 29. doi: 10.1089/rej.2019.2218. Mendelsohn AR1,2, Larrick J3.
 
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Abstract

During human aging, decrease of NAD+ levels is associated with potentially reversible dysfunction in the liver, kidney, skeletal and cardiac muscle, endothelial cells and neurons. At the same time, the number of senescent cells, associated with damage or stress that secrete pro-inflammatory factors (SASP, Senescence-Associated Secretory Phenotype), increases with age in many key tissues, including the kidneys, lungs, blood vessels, and brain. Senescent cells are believed to contribute to numerous age-associated pathologies and their elimination by senolytic regimens appears to help in numerous preclinical aging-associated disease models including those for atherosclerosis, idiopathic pulmonary fibrosis, diabetes, and osteoarthritis.

A recent report links these processes, such that decreased NAD+ levels associated with aging may attenuate the SASP phenotype potentially reducing its pathological effect. Conversely increasing NAD+ levels by supplementation or genetic manipulation which may benefit tissue homeostasis, also may worsen SASP and encourage tumorigenesis at least in mouse models of cancer. Taken together these findings suggest a fundamental trade-off in treating aging related diseases with drugs or supplements that increase NAD+.

Even more interesting is a report that senescent cells can induce CD38 on macrophages and endothelial cells. In turn increased CD38 expression is believed to be the key modulator of lowered NAD+ levels with aging in mammals.

So accumulation of senescent cells may itself be a root cause of decreased NAD+, which in turn could promote dysfunction. On the other hand, the lower NAD+ levels may attenuate SASP, decreasing the pathological influence of senescence. The elimination of most senescent cells by senolysis before initiating NAD+ therapies may be beneficial and increase safety, and in the best case scenario even eliminate the need for NAD+ supplementation.

 

Edited by Sibiriak

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3 hours ago, Sibiriak said:

Interacting NAD+ and Cell Senescence pathways complicate anti-aging therapies.

I think fasting, exercise and thermal stress may have senolytic effects, boost SIRT1 activation (and NAD+ too?) and should be a foundation for testing NAD+ boosting supplements.

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On 4/29/2016 at 8:28 PM, notmuffy said:

Thanks for this thread - I was seriously considering that "Basis" product before I read this. I won't waste my money.

On Elysium's Basis, I suggest we go to the Elysium web site and read about the science behind Basis. The company has several Nobel winners on it. But the best is, no claim for human benefit is made. Len Guarante's scientists, including himself, discovered that NAD + is necessary for mitochondria health. In mice, old mouse NAD+ levels were significantly lower than younger mice, whose levels were ~40%. The old mice got NAD+ to where their levels were once again ~40%. They then had more energy and lived longer. So Elysium says bring your NAD+ levels up with Basis, and maybe your mitochondria might  maintain health because of NAD+. No claims about human pep and longevity because there is no credible data yet. Elysium doesn't make any claims because FDA approved trials would take a very long time, it was decided to simply market it with mouse data only. 

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Just came across this:

 

Hm, I kind of looked more closely at this Chris Masterjohn and it seems he often enters into quack territory....

But still, even a broken clock show the right time twice a day.

Edited by Ron Put

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I have started taking NMN, but now I am beginning to question the wisdom of it.

Sinclair made a lot of money pushing Resveratrol before the public wised up that the devil was in the (extremely high) dosing. Now I am wondering if he is doing the same with NMN.

The more I read, the less clear it gets. I also haven't seen any studies comparing NR or NMN to just plain Vitamin B3 supplementation (which certainly can have adverse effects if too high).

Then there is this:

"Therefore, while NR or NMN may cause NAD levels to increase in the liver, the increase in NAD measured in other tissues and attributed to NR or NMN supplementation is actually caused by an increase of nicotinamide (NAM).

This suggests that a sublingual nicotinamide, by skipping the biological conversions that take place in the liver, would be more effective for increasing NAD than any form of B3 taken orally."
https://www.legerepharm.com/2018/09/05/nr-vs-nam-vs-nmn/

And then there is the video I posted above, which brings up some reasonable issues with NR and Niacin supplementation.

Any thoughts, especially ones backed up by studies I have not ran across?

I get about 130-140% of Niacin DV% through food, I also exercise some (which also boosts NAD). So, I am wondering if I should reorder NMN? Or switch to NR? Or just stick to making sure I get my DV% from food (non-fortified nutritional and brewer's yeasts and broccoli/broccoli sprouts mostly, as seen below)?

 

1539476874_ScreenShot2019-07-30at17_14_16.thumb.png.0a32a022d8dbb809bb286c3ff51949a8.png

Edited by Ron Put

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Ron, I cannot give you a direct answer, but after listening to numerous podcasts from professor Sinclair and those from Chris Masterjohn and others, presently I decided against the use of NR, NMN, NAD etc., at least pending further ponderation and more clarity and consensus on the subject.

I do take low-dosage B3 (niacin) supplements though, since that's one of the very few nutrients which rarely reaches 100% RDA in my regimen. 50 mg once every other day and fast-release, if taken within a meal no or little flushing is experienced at this dosage.

Slow-release B3 megadoses for lipids regulation may definitely be detrimental in some cases.

One last interesting anecdotal consideration. After some cronometer reconstruction, I have reasonable suspects that prior to following the ortorexic suggestions of this forum I had some slight niacin deficiency.

And that might have been related to a condition of intolerance of the skin to sun radiation. I simply could not tolerate even moderate sun radiation, excluding the tough skin on my face and legs. A very anomalous phenomenon for a subject of mediterranean ancestry (significant skin pigmentation) and accustomed to sunrays exposure since the birth.

After my dietary adjustments, the condition simply dissolved. Maybe one example of the triage principle by bruce Ames. It might have been some other nutrients but not copper nor B6 (involved in the tyrosine-melanine synthesis), B3 is the main suspect.

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Yeah, I mind stop the MNM at the end of this bottle, too. It appears that it may be a repeat of the resveratrol hype, where the effective doses were not practical for humans. But it will make Sinclair and his investors another bundle of cash.

mccoy, do you use nutritional yeast and brewer's yeast? They are both really rich in B vitamins, even when not enriched and add great flavor, too. I prefer non-enriched, because it has has a decent amount of folate, as opposed to the wallop of folic acid found in the enriched versions. But I do take Vitamin B12 daily.

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56 minutes ago, Ron Put said:

mccoy, do you use nutritional yeast and brewer's yeast? They are both really rich in B vitamins, even when not enriched and add great flavor, too.

Thanks for reminding, I'll have to do a specific search since here it's such products are not so easily available. 

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This is from a June 14, 2016 interview from Life Extension Foundation

Fahy interviewing George Church:

Fahy: There are several very exciting stories in aging intervention these days. In 2013, the Sinclair lab at Harvard came out with the revelation that the aging of mitochondria (which are the producers of usable energy within cells) is driven in significant part by reduced levels of one particular molecule in the cell nucleus: oxidized NAD (NAD+).
The team showed that they could correct mitochondrial aging just by giving old mice nicotinamide mononucleotide (NMN), which is a vitamin-like substance that can be converted into NAD+, for one week. This resulted in phenomenal overall rejuvenation, including reversal of signs of muscle atrophy, inflammation, and insulin resistance. Now your lab showed that there is a very exciting gene engineering alternative involving TFAM (Transcription Factor A, Mitochondrial). Why is TFAM important, and what have you done with it?
Church: TFAM is a key regulatory protein that is in this pathway of NMN and NAD+. It allows cells to manufacture the NMN precursor on their own, so you don't have to manufacture it outside the cell and then try to get it into the cell from outside. Ideally, you don't want to have to take NMN for the rest of your life, you want to fix the body's ability to make its own NMN and buy yourself rejuvenation for at least a few decades before you have to worry about NMN again. In order to accomplish this on a single cell level, we've used CRISPR to activate a TFAM activator, and we made it semi-permanent. (See sidebar: Gene Editing with CRISPR)
Fahy: With this technique,
you were able to increase TFAM levels in the cell by 47-fold.
This resulted in restored ATP levels, increased NAD+, and an increased NAD+ / NADH ratio. It also increased total mitochondrial mass and reversed several other age-related changes.
Church: Yes. We have a number of ways to measure mitochondrial function and age-related losses of those functions. When we activated TFAM, these changes returned to what you would expect of a younger cell state. And we built this anti-aging ability into the cell, so it's self-renewing and eliminates the need to take pills or injections.

 

Church stated the above 3 years ago and if this were (actually) avaliable it would seem to be a more upstream and direct way of addressing NAD+ decline than taking exogenous NMN or N(R)

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In order to accomplish this on a single cell level, we've used CRISPR to activate a TFAM activator, and we made it semi-permanent.

 

First U.S. Patients Treated With CRISPR As Human Gene-Editing Trials Get Underway

https://www.npr.org/sections/health-shots/2019/04/16/712402435/first-u-s-patients-treated-with-crispr-as-gene-editing-human-trials-get-underway

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"Every human on the planet should hope that this technology works. But it might work. It might not. It's unknown," says Laurie Zoloth, a bioethicist at the University of Chicago. "This is an experiment. So you do need exquisite layers of care. And you need to really think in advance with a careful ethical review how you do this sort of work."

The researchers conducting the studies say they have conducted careful preliminary research, and their studies have gone through extensive scientific and ethical review.

When might we know whether any of these experimental CRISPR treatments are working?

All of these studies are very preliminary and are primarily aimed at first testing whether this is safe. That said, they are also looking for clues to whether they might be helping patients. So there could be at least a hint about that later this year. But it will be many years before any CRISPR treatment could become widely available.

 

CRISPR Used in Human Trials for the First Time in the US

https://singularityhub.com/2019/05/02/crispr-used-in-human-trials-for-the-first-time-in-the-us/

 

 

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43 minutes ago, Clinton said:

TFAM is a key regulatory protein that is in this pathway of NMN and NAD+. It allows cells to manufacture the NMN precursor on their own, so you don't have to manufacture it outside the cell and then try to get it into the cell from outside.

CR and ketogenic diets have both been suggested to upregulate TFAM by way of SIRT1 & PGC1-alpha.  Here's a paper discussing this with respect to ketogenic diets:

Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health
 

Quote

 

Nutritional ketosis may facilitate PGC-1α activity through multiple mechanisms. Since PGC-1α is activated by AMPK and SIRT1, nutritional ketosis may initiate PGC-1α activity through these enzymes. As previously mentioned, catecholamines and adiponectin facilitate PGC-1α activity by promoting its expression, and insulin inhibits PGC-1α through downstream phosphorylation, all independent of AMPK. As previously discussed, a ketogenic diet may increase catecholamines and adiponectin and is well known to decrease insulin, indicating that nutritional ketosis may directly facilitate PGC-1α activity through these hormones. Supporting these potential mechanisms, a ketogenic or low-carbohydrate diet has increased expression, protein content, and activation of PGC-1α [149, 231, 317], as well as expression of its target PPARα [87, 148]. Furthermore, in skeletal muscle of mice following a ketogenic diet, the resulting increases in O2 consumption and expression of genes related to fat oxidation appear to be dependent on PGC-1α [157]. Ketones likely contribute to this signaling as well based on the recent observation that the increased hepatic expression of PPARα targets induced by a ketogenic diet did not occur with a nonketogenic low-carbohydrate diet [37].

...

NRF-1 and NRF-2 are transcription factors that increase expression of TFAM [342], which is required for full initiation of mtDNA transcription [343–345] and hence mitochondrial biogenesis. PGC-1α induces expression of NRF-1 and NRF-2 and facilitates TFAM expression by coactivating NRF-1 [288]. Oxidative stress increases this signaling [346, 347] in conjunction with increased mitochondrial biogenesis [346]. AMPK also contributes to mitochondrial biogenesis, but by inducing mitochondrial fission through phosphorylation of mitochondrial fission factor (MFF) [348], which is in addition to and independent of AMPK’s role in activating PGC-1α.

 

 

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Interesting - so CRISPR trials have already started and Church has said in an interview from 2017 that in 5-10yrs they'd be 'perfected' ... based on that and some of the timing comment in your post, Sibiriak, I'd guess it should be useful and available by or before 2030.

In the meantime I will try to maintain nutrition, stay hungry, and lift heavy things.

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This is anecdotal, but it may still be of interest to some: I noticed that my homocysteine has jumped from just over 10 to 12 recently. Methinks it may have to do with taking NMN for the last couple of months.

Technically, my homocysteine should have dropped a bit, since when it was just over 10 I was not supplementing with B-12 and was eating fortified nutritional yeast (lots of folic acid), and my folate was close to 20. But now I supplement with B-12, I've switched to non-fortified nutritional yeast and my folate has dropped to just under 12. So, I expected a drop in homocysteine, but instead it went up. And I blame NMN:

"Excess nicotinamide inhibits methylation-mediated degradation of catecholamines in normotensives and hypertensives.
This study demonstrated that excess nicotinamide might deplete the labile methyl pool, increase Hcy generation and inhibit catecholamine degradation. It also revealed that hypertensives had an abnormal methylation pattern, characterized by elevated fasting plasma levels of unmethylated substrates, nicotinamide, Hcy and norepinephrine. Therefore, it seems likely that high nicotinamide intake may be involved in the pathogenesis of Hcy-related cardiovascular disease."

 

I am not overly concerned about homocysteine, since most recent studies appear to discount its contribution to mortality:

Homocysteine and Familial Longevity: The Leiden Longevity Study

Relationship of Homocysteine With Cardiovascular Disease and Blood Pressure


But, still..., once I finish my current supply, I'll stop taking NMN.

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12 minutes ago, Ron Put said:

This study demonstrated that excess nicotinamide might deplete the labile methyl pool, increase Hcy generation and inhibit catecholamine degradation.

I take nicotinic acid and after a while I thought it was aggravating my elevated norepinephrine and related issues such as night sweats.  I found the suggestion to counter the NA with an equal quantity of TMG and my issues resolved.   TMG is inexpensive with a pleasant mildly sweet taste that nicely complements the tartness of NA.   I've taken to storing it in the freezer and putting about 2 weeks worth in a small jar also kept in the freezer to prevent its tendency to develop a fishy odor.

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On 7/31/2019 at 10:22 PM, Ron Put said:

Yeah, I mind stop the MNM at the end of this bottle, too. It appears that it may be a repeat of the resveratrol hype, where the effective doses were not practical for humans. But it will make Sinclair and his investors another bundle of cash.

mccoy, do you use nutritional yeast and brewer's yeast? They are both really rich in B vitamins, even when not enriched and add great flavor, too. I prefer non-enriched, because it has has a decent amount of folate, as opposed to the wallop of folic acid found in the enriched versions. But I do take Vitamin B12 daily.

This charge against Sinclair as being a mere profiteer keeps being repeated here. Do you have proof that he is making illegitimate riches? There are at least some of his (dozens of) patents and products from which he is said to donate the proceeds to research. If a profit motive makes his science less valuable, or even corrupt, that deserves a forum better researched and more costly to him than online gossip and snark.

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