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Human Plasma NAD+ Metabolome Dysregulation with Age

nad+ aging methylnicotinamide

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#1 Michael

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Posted 25 August 2018 - 07:24 PM


The Plasma NAD+ Metabolome is Dysregulated in ‘Normal’ Ageing
Rejuvenation Res. 2018 Aug 19. doi: 10.1089/rej.2018.2077. [Epub ahead of print]
Mr. James Clement, Mr. Matthew Wong, Dr. Anne Poljak, Prof. Perminder Sachdev, Dr. Nady Braidy

We quantified changes in the NAD+ metabolome in plasma samples collected from consenting healthy human subjects across a wide age range (20-85 years [9-10 subjects in age groups 20-40, 41-60, and 60+]) using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS).

Our data shows a significant decline in the plasma levels of NAD+, NADP+, and other important metabolites including nicotinamide mononucleotide (NMN) and nicotinic acid adenine dinucleotide (NAAD) with age. ... NAD had the steepest age decrease, averaging 4% SD units decline per year, ...


However, an age-related increase in ... NADH and NADPH - and nicotinamide (NAM), N-methyl-nicotinamide (MeNAM), and the products of adenosine diphosphoribosylation, including ADP-ribose (ADPR) was also reported. ... MeNAM and NADPH had the average increases of 2.8 and 2.7% SD units per year, respectively. Individual models explained up to 86% of the variance in metabolite levels with age. ...


normal.img-001.jpg
Figure 1. Scatterplots of NAD+ metabolites normalised abundance across age groups

 

normal.img-003.jpg

Figure 2. Boxplots of NAD+ metabolite abundances across age groups.

 
In mammalian cells, NAM is methylated by the enzyme, nicotinamide N-methyltransferase (NNMT) to form N-methyl-nicotinamide (MeNAM), which is further metabolised to Nmethyl- 2-pyridone-5-carboxamide (2PY) [66]. ... One study showed that knockdown to NNMT protected against high fat-diet induced obesity. ... Our data also shows that the level of MeNAM was correlated with BMI (Supplementary table 2), and MeNAM has been strongly associated with obesity and diabetes [70]. Therefore, a higher level of MeNAM is likely to predispose individuals to a greater risk of obesity or insulin resistance in adulthood. Increased NNMT activity and elevations in MeNAM and 2-PY levels have also been reported in type-2 diabetes [71]. [MeNAM has also been implicated in Parkinson's disease,(1,2) and coronary artery disease.(3). -MR]. Increased NNMT activity in tumor cells has been shown to impair polyamine flux [72]. Therefore, increased NNMT activity and upregulated levels of MeNAM can alter individual methylation capacity, with epigenetic consequences.

Recently, it has been shown that metabolites of NAM may serve as uremic toxins at high amounts [73]. These findings originated from findings of interventional trials using NAM to manage end-stage renal disease [74]. In the context of uremia, increased plasma levels of MeNAM, as we have reported, may inhibit NAD-dependent processes. Our current findings can there provide additional mechanisms to explain poor outcomes in the elderly, and the potential effects of impaired NAD+ anabolism on the epigenome due to potentially reduced methylation capacity in the aged individuals. ...

No significant differences were reported across age for nicotinic acid (NA) and nicotinic acid mononucleotide (NAMN).

Taken together, our data cumulatively suggests that age-related impairments may also be associated with alterations in the extracellular plasma NAD+ metabolome.


PMID: 30124109 DOI:10.1089/rej.2018.2077

It's notable that both NAM and MeNAM rise with age: NAM presumably as a result of increased consumption (contributing to the decline in NAD+ and NAD:NADH), and MeNAM due to some combination of the sheer rise in NAM requiring greater engagement of its disposal metabolism, and a decline in methylation capacity. Both of these are also elevated at high levels and longer durations of NAD+ precursor supplementation, with NAM ≥ NR > NA for MeNAM and NR > NAM > NA for NAM (eg. Figure 4, Trammel & Brenner PMID 27721479).  In this respect, then, higher dose and/or uninterrupted use of NAD+ precursors actually exacerbates rather than opposes age-related changes in the NAD+ metabolome.
 
References
1: Williams A, Ramsden D. Nicotinamide: a double edged sword. Parkinsonism Relat Disord. 2005 Nov;11(7):413-20. Epub 2005 Sep 23. Review. PubMed PMID: 16183323.

2: Fukushima T. Niacin metabolism and Parkinson's disease. Environ Health Prev Med. 2005 Jan;10(1):3-8. doi: 10.1265/ehpm.10.3. PubMed PMID: 21432157; PubMed Central PMCID: PMC2723628.

3: Liu M, Chu J, Gu Y, Shi H, Zhang R, Wang L, Chen J, Shen L, Yu P, Chen X, Ju W, Wang Z. Serum N1-Methylnicotinamide is Associated With Coronary Artery Disease in Chinese Patients. J Am Heart Assoc. 2017 Feb 7;6(2). pii: e004328. doi: 10.1161/JAHA.116.004328. PubMed PMID: 28174167; PubMed Central PMCID: PMC5523749.

4:


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#2 stefan_001

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Posted 25 August 2018 - 07:50 PM

Nice study, confirms what we already know. Aging leads to a futile (?) increase of NAD+ consumption with as consequence that beneficial activity e.g. SIRTs is decreased. Good case for long term NAD+ boosting as the deficit only grows. Yes NAD+ boosting is a workaround but the best we have to age healthier.


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#3 able

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Posted 26 August 2018 - 06:45 AM

Looks like they provide more evidence that the NAD+ molecule itself crosses the cell membrane, and may be a good candidate for supplementation, whether IV, transdermal, intranasal, or whatever.

 

 

emerging evidence suggests that exogenous NAD+ may cross the plasma membrane and replenish intracellular NAD+ levels in mammalian cells [24] 

 

On the contrary to previous reports, this study provides strong evidence for the availability of the extracellular NAD+ and its related metabolites in plasma. 

 

upregulation of intracellular NADusing NAD+ and related precursors, may therefore be important in ameliorating some of the age-related cellular degeneration.

 

Our data suggests that it is primarily NAD+ that decreases with age to drive this ratio down, since NADH levels do not appear to be significantly changed across age groups. 

 

 

 

 

 


Edited by able, 26 August 2018 - 06:46 AM.

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#4 Harkijn

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Posted 26 August 2018 - 09:14 AM

Also interesting that they take a favourable view of inhibiting CD38s. And apparently they have no doubts about the effectivity of apigenin for achieving this:

 

CD38 also appears to be a major consumer of NAD+ during the ageing process. Given that 100 molecules of NAD+ must be hydrolysed to generate one molecular of cADPR, it is highly likely that CD38 is a major regulator of intracellular NAD+ levels [58]. Accordingly, we previously found a 5 fold increase in NAD+ levels in CD38 knockout neuronal cells compared to controls [4]. Therefore, CD38 may not only represent an inefficient secondary messenger enzyme, but also as a NADase which primarily regulates intracellular levels of NAD+ and its physiological processes Inhibition of CD38 using the natural phytochemical inhibitor, apigenin increased NAD+ levels and protected against degeneration in mice exposed to a high-fat diet [59]. Interestingly, CD38 has been shown to degrade NAD+ and its precursor NMN in vivo [60]. One study showed that the plasma levels of NAD+ remained stable when CD38 knockout mice were administered intraperitoneal injections of NAD+ , NMN, or NR after 3 hours, long after they began to fall in the wild-type animals [61]. This suggests that the efficacy of NAD+ precursors may be enhanced by combination therapy with CD38 inhibitors such as apigenin.


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#5 Mind

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Posted 26 August 2018 - 05:22 PM

Very quick look at the graphs seems to show a very good correlation between NAD+ molecules and aging (going down dramatically). The correlations between NAM-type molecules and aging is quite weak.


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#6 stefan_001

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Posted 26 August 2018 - 07:25 PM

@ ill informed x 4 ratings -> perhaps you could explain what you believe is wrong with what I wrote. The graphs are clear for NAD+ levels go down, so you need to supplement forever to compensate making NAD+ boosting a workaround. An yes NR/NMN are the best ones out there, feel free to post better options that boost NAD+.

 

EDIT: @ ill informed rater, its a pity/sad you don't contribute by writing a quick reply. Then there would be something to learn.


Edited by stefan_001, 26 August 2018 - 07:39 PM.

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#7 stefan_001

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Posted 26 August 2018 - 07:28 PM

@harkijn It would be interesting to know whether CD38 activity is in general selective or not. There was a recent study showing increased CD38 in prostate cancer cells, as the CD38 consumed NAD+ it slowed down cancer development.

 

EDIT: @ ill informed rater wonderfull you did a rating to this post too. Again,its a pity/sad you don't contribute by writing a quick reply. Here is the study. Feel free to share your knowledge:

CD38 Inhibits Prostate Cancer Metabolism and Proliferation by Reducing Cellular NAD+ Pools

"CD38 expression inversely correlates with PCa progression. Expressing CD38 in PCa cells lowered intracellular NAD+, resulting in cell cycle arrest and expression of p21Cip1 (CDKNA1)."

http://mcr.aacrjourn...786.MCR-17-0526


Edited by stefan_001, 26 August 2018 - 07:47 PM.

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#8 Michael

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Posted 26 August 2018 - 10:20 PM

Nice study, confirms what we already know. Aging leads to a futile (?) increase of NAD+ consumption with as consequence that beneficial activity e.g. SIRTs is decreased. Good case for long term NAD+ boosting as the deficit only grows. Yes NAD+ boosting is a workaround but the best we have to age healthier.

 

@ ill informed x 4 ratings -> perhaps you could explain what you believe is wrong with what I wrote. The graphs are clear for NAD+ levels go down, so you need to supplement forever to compensate making NAD+ boosting a workaround. An yes NR/NMN are the best ones out there, feel free to post better options that boost NAD+.

 

EDIT: @ ill informed rater, its a pity/sad you don't contribute by writing a quick reply. Then there would be something to learn.

 

So, I am not one of the people who tagged your post "Ill-informed," or anything else — but I would say that you're not thinking carefully about this, and are ignoring what I noted in my opening post (emphasis added):

 

 

It's notable that both NAM and MeNAM rise with age: NAM presumably as a result of increased consumption (contributing to the decline in NAD+ and NAD:NADH), and MeNAM due to some combination of the sheer rise in NAM requiring greater engagement of its disposal metabolism, and a decline in methylation capacity. Both of these are also elevated at high levels and longer durations of NAD+ precursor supplementation, with NAM ≥ NR > NA for MeNAM and NR > NAM > NA for NAM (eg. Figure 4, Trammel & Brenner PMID 27721479).  In this respect, then, higher dose and/or uninterrupted use of NAD+ precursors actually exacerbates rather than opposes age-related changes in the NAD+ metabolome.

 

That is: if aging causes a decline in NAD+, and simultaneously causes a rise in potentially deleterious metabolites or pathway usage, then while throwing more and more precursors  at the problem may oppose the rise in NAD+, it will simultaneously further exacerbate the other aspects of age-related NAD+ metabolome dysregulation — and likely disproportionately so, since even in young people you get a nonlinear increase in these with increasing dose. It's not at all clear that that's a good tradeoff. The available data in "normally" aging rodents is  favorable and thus reassuring, but it's also limited and mostly of short duration, and at some level, we still don't know what we don't know.


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#9 Phoebus

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Posted 27 August 2018 - 01:42 AM

So, I am not one of the people who tagged your post "Ill-informed," or anything else — but I would say that you're not thinking carefully about this, and are ignoring what I noted in my opening post (emphasis added):

 

 

That is: if aging causes a decline in NAD+, and simultaneously causes a rise in potentially deleterious metabolites or pathway usage, then while throwing more and more precursors  at the problem may oppose the rise in NAD+, it will simultaneously further exacerbate the other aspects of age-related NAD+ metabolome dysregulation — and likely disproportionately so, since even in young people you get a nonlinear increase in these with increasing dose. It's not at all clear that that's a good tradeoff. The available data in "normally" aging rodents is  favorable and thus reassuring, but it's also limited and mostly of short duration, and at some level, we still don't know what we don't know.

 

 

are you speaking specifically of NAM? As in because NR/NMN  eventually get metabolized into NAM these precursors are raising overall NAM levels and higher NAM levels are associated with aging. There fore NR/NMN supplementation is exacerbating this specific age marker. Is that your point? 



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#10 Mind

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Posted 27 August 2018 - 11:23 AM

are you speaking specifically of NAM? As in because NR/NMN  eventually get metabolized into NAM these precursors are raising overall NAM levels and higher NAM levels are associated with aging. There fore NR/NMN supplementation is exacerbating this specific age marker. Is that your point? 

 

That seems to be the point, to me.

 

Also, the greater point is: not enough data. Were the subjects in this study tested for other aging biomarkers? I am guessing not. So we are missing some context.


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#11 stefan_001

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Posted 27 August 2018 - 01:22 PM

@michael okay thats what you are thinking. I saw the increase in metabolites simply as indication of an increase in NAD+ consumers.



#12 Oakman

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Posted 27 August 2018 - 01:51 PM

Does anyone have a link to the full study or where the various quotes & graphs come from shown above?



#13 LawrenceW

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Posted 27 August 2018 - 01:53 PM

Does anyone have a link to the full study or where the various quotes & graphs come from shown above?

 

 [EDIT: Lawrence, others: please do not post links to illegal websites].


Edited by Michael, 27 August 2018 - 02:23 PM.

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#14 Harkijn

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Posted 27 August 2018 - 01:56 PM

Here it is. The researchers cautiously mention the many limitations of the study. But that does not detract of the possible value of Michael's observation.

Attached Files


Edited by Harkijn, 27 August 2018 - 01:56 PM.

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#15 Phoebus

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Posted 27 August 2018 - 02:10 PM

yet another reason i wish there were actual NAD+ therapies readily available to the public

 

Not precursors, actual NAD+ therapies in whatever form might be affective, as that will not get metabolized to NAM and thus the problem noted here will not be an issue. 


Edited by Phoebus, 27 August 2018 - 02:10 PM.


#16 Michael

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Posted 27 August 2018 - 02:37 PM

are you speaking specifically of NAM? As in because NR/NMN  eventually get metabolized into NAM these precursors are raising overall NAM levels and higher NAM levels are associated with aging. There fore NR/NMN supplementation is exacerbating this specific age marker. Is that your point? 

 

If you read what I quoted from the paper and my actual comments, you'll see that it's not just NAM (which could suppress sirtuins, particularly intracellularly), but also MeNAM (obesity? Metabolic syndrome? Parkinson's?), and a rise in NADPH (and thus possibly oxidative stress).

 

@michael okay thats what you are thinking. I saw the increase in metabolites simply as indication of an increase in NAD+ consumers.

 

Well, in a sense it is simply an indication of an (age-related) increase in NAD+ consumers; the point is that those metabolites are metabolically active, and potentially deleterious.

 

yet another reason i wish there were actual NAD+ therapies readily available to the public

 

Not precursors, actual NAD+ therapies in whatever form might be affective, as that will not get metabolized to NAM and thus the problem noted here will not be an issue. 

 

There's no such thing: every time NAD+ is used by sirtuins, PARPs, or CD38, you get NAM as a product — and part of the response to rising NAM is increased disposition thru' methylation (and also nicotinamide-N-oxide and 6-hydroxy-nicotinamide, tho' they didn't look at those in this report). In an older organism, there is greater (over)activity of CD38 and possibly PARPs to generate NAM from what NAD+ is available, and less capacity for that NAM to be salvaged back to NAD+ via NAMPT; merely increasing levels of NAD+ (directly or via its precursors) does nothing to undo those underlying age-related metabolic changes.


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#17 Nate-2004

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Posted 27 August 2018 - 04:55 PM

@ ill informed x 4 ratings -> perhaps you could explain what you believe is wrong with what I wrote. The graphs are clear for NAD+ levels go down, so you need to supplement forever to compensate making NAD+ boosting a workaround. An yes NR/NMN are the best ones out there, feel free to post better options that boost NAD+.

 

EDIT: @ ill informed rater, its a pity/sad you don't contribute by writing a quick reply. Then there would be something to learn.

 

I strongly agree with your point in the edit. I hate the way this message board system works. It's frustrating, cumbersome, limited in accessible information that's already been discussed, and strongly discourages friendly conversation.

 

I don't agree that continuous NAD+ precursor supplementation is needed, forever, but perhaps cyclical, at least for now until better alternatives arise.


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#18 Nate-2004

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Posted 27 August 2018 - 05:06 PM

If you read what I quoted from the paper and my actual comments, you'll see that it's not just NAM (which could suppress sirtuins, particularly intracellularly), but also MeNAM (obesity? Metabolic syndrome? Parkinson's?), and a rise in NADPH (and thus possibly oxidative stress).

 

 

Well, in a sense it is simply an indication of an (age-related) increase in NAD+ consumers; the point is that those metabolites are metabolically active, and potentially deleterious.

 

 

There's no such thing: every time NAD+ is used by sirtuins, PARPs, or CD38, you get NAM as a product — and part of the response to rising NAM is increased disposition thru' methylation (and also nicotinamide-N-oxide and 6-hydroxy-nicotinamide, tho' they didn't look at those in this report). In an older organism, there is greater (over)activity of CD38 and possibly PARPs to generate NAM from what NAD+ is available, and less capacity for that NAM to be salvaged back to NAD+ via NAMPT; merely increasing levels of NAD+ (directly or via its precursors) does nothing to undo those underlying age-related metabolic changes.

 

Ok so perhaps then the real issue is falling NAMPT due to NAD+ overconsumption by CD38 and PARPs?

 

If the issue is that NAD+ gets converted into NAM and there is not enough NAMPT to salvage that NAM, then this either leads to or *is* part of the dysregulation we're talking about in the cycle.

 

What happens if you upregulate NAMPT?


Edited by Nate-2004, 27 August 2018 - 05:06 PM.


#19 able

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Posted 27 August 2018 - 05:25 PM

Ok so perhaps then the real issue is falling NAMPT due to NAD+ overconsumption by CD38 and PARPs?

 

If the issue is that NAD+ gets converted into NAM and there is not enough NAMPT to salvage that NAM, then this either leads to or *is* part of the dysregulation we're talking about in the cycle.

 

What happens if you upregulate NAMPT?

 

 

There is research showing both increased NAD+ consumption by CD38, and falling NAMPT recycling  as reasons why NAD+ levels fall as we age.

 

It seems like some exogenous NAD+/NR/NMN might help to keep NAD+ levels up, but too much could overwhelm an older bodies ability to get rid of the NAD+ metabolites (NAM, MeNam, etc).

 

The Trammel thesis showed that higher NR input results  in more NAD+ metabolites in the urine, so there is some capacity to process it, but this current study is showing that they do build up, and Michael is pointing out they could have negative impact.  

 

Perhaps that is a good reason for cycling NAD+ precursors - to allow the body to get rid of downstream NAD+ metabolites?

 

I'm wondering if that is why my personal experience was better when taking 1-2 days off every week.   (I posted elsewhere that dosages of sublingual NMN over 1.5 gram a day made me a bit groggy after a week or so and taking some days off really help)


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#20 stefan_001

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Posted 27 August 2018 - 08:01 PM

I looked up the referenced study and I think mainly in case of  mega dosing (>500mg) or when having renal issues/failure its a concern:

http://www.mdpi.com/...51/8/11/339/htm

 

also as the half life is about 12 hours one could wonder whether continuous dosing is a good thing

 

 

 


Edited by stefan_001, 27 August 2018 - 08:10 PM.

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#21 stefan_001

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Posted 27 August 2018 - 08:09 PM

I strongly agree with your point in the edit. I hate the way this message board system works. It's frustrating, cumbersome, limited in accessible information that's already been discussed, and strongly discourages friendly conversation.

 

I don't agree that continuous NAD+ precursor supplementation is needed, forever, but perhaps cyclical, at least for now until better alternatives arise.

 

Happy I am not alone on that.

 

Sure cycling is a small effort, I am not against that at all. Better safe than sorry. But its a usefull debate to have.
 


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#22 Oakman

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Posted 27 August 2018 - 09:08 PM

All this speculation about whether too much precursor is good or bad, causes to many metabolites, etc. is great - but how do we account for the perceived benefits and boosts of energy by so many older NAD+ enthusiasts? (myself included). Has a group placebo effect taken hold? Is there some future reckoning when the over-produced NAD+ metabolites take us old folks all down? What's wrong with this picture?

 

There just seems to be something missing here - theory vs. reality.


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#23 Phoebus

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Posted 28 August 2018 - 02:57 AM

All this speculation about whether too much precursor is good or bad, causes to many metabolites, etc. is great - but how do we account for the perceived benefits and boosts of energy by so many older NAD+ enthusiasts? (myself included). Has a group placebo effect taken hold? Is there some future reckoning when the over-produced NAD+ metabolites take us old folks all down? What's wrong with this picture?

 

There just seems to be something missing here - theory vs. reality.

 

 

well the theory is that perhaps its beneficial in the short term and medium term but possibly detrimental in the long term 

 

Personally I cant think of any supplement that fits that description and would be interested if someone could give an example of such 



#24 Michael

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Posted 28 August 2018 - 03:23 AM

well the theory is that perhaps its beneficial in the short term and medium term but possibly detrimental in the long term 
 
Personally I cant think of any supplement that fits that description and would be interested if someone could give an example of such

 
Vitamin A, active vitamin D (1,25-dihydroxycholecalciferol), iron, or selenium. If you're actually deficient in any of these, a high dose will be beneficial in the short term by rapidly repleting your stores. However, long-term on the first two are toxic, iron may be implicated in a number of diseases of aging, and common doses of selenium are at this point strongly linked from multiple clinical trials and extensive epidemiology with increased risk of diabetes (and possibly some cancers) with no benefit for cancer except possibly in the (very uncommon in N. America) case of outright deficiency.


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#25 Nate-2004

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Posted 28 August 2018 - 12:06 PM

@Michael so hypothetically would boosting NAMPT be better, long term, than boosting NAD+?



#26 sthira

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Posted 28 August 2018 - 12:27 PM

All this speculation about whether too much precursor is good or bad, causes to many metabolites, etc. is great - but how do we account for the perceived benefits and boosts of energy by so many older NAD+ enthusiasts? (myself included). Has a group placebo effect taken hold? Is there some future reckoning when the over-produced NAD+ metabolites take us old folks all down? What's wrong with this picture?

There just seems to be something missing here - theory vs. reality.


It could be something like putting higher octane fuel into a worn engine. It may run better in the short term, but if the damages aren't fixed, it'll break on schedule. The perceived NR and NMN anecdotal benefits not accompanied by objective measures have seemed pretty murky to me.
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#27 Oakman

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Posted 28 August 2018 - 12:58 PM

It could be something like putting higher octane fuel into a worn engine. It may run better in the short term, but if the damages aren't fixed, it'll break on schedule. The perceived NR and NMN anecdotal benefits not accompanied by objective measures have seemed pretty murky to me.

 

That sounds suspiciously like improved quality of life aka improved health span - which sounds good to me - even if I break on schedule :)


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#28 sthira

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Posted 28 August 2018 - 01:16 PM

That sounds suspiciously like improved quality of life aka improved health span - which sounds good to me - even if I break on schedule :)


Yeah except hopefully it's not speeding demise of the worn. If you're looking to jump kick energy, coffee makes me do backflips, seems a cheap and reliable drug for me. This preliminary NAD+ precursor tweaking just seems kinda --preliminary. I like people experimenting on their own and reporting their feelings, though, I think this this is important. Wish y'all would get down with some blood markers or something, though.

#29 Nate-2004

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Posted 28 August 2018 - 01:22 PM

Which blood markers though? Reports from older individuals, 70 and up, on the experience threads should be better than they are, were it to improve blood flow and exercise capacity as theorized. Sinclairs mice seem to respond better but then again mice rarely if ever translate (making them almost useless as a model imo).

 

I still would like to know if boosting NAMPT is possible and whether that would solve the problem.


Edited by Nate-2004, 28 August 2018 - 01:23 PM.


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#30 Harkijn

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Posted 28 August 2018 - 01:33 PM

In the 'Rats thread' I just posted new info about too much NADPH in healthy young rats.







Also tagged with one or more of these keywords: nad+, aging, methylnicotinamide

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