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Human Plasma NAD+ Metabolome Dysregulation with Age

nad+ aging methylnicotinamide

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#31 sthira

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Posted 28 August 2018 - 02:41 PM

Which blood markers though?


Right! Damned if we do, and damned if we don't. The issue raised in this thread seems to sprout the question of if we are more damned if we do than don't. So, erring on the side of safety (and saving money maybe better invested for more accurate future metabolism guesstimations) you can choose to wait. But if I had the money to buy either of these two commercially available self-experiments I'd probably go ahead and check before and after basic panels. I mean, why not?

#32 able

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Posted 28 August 2018 - 03:15 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.

 

 

I see it more as putting a turbocharger on a worn engine.  It will likely  provide a boost for a while, but might not be good long term, depending on how worn the engine is, and how much you turn up the boost. 

 

I think that applies mostly to dumping a lot of NR/NMN in the liver and hoping it can handle the increased fuel.  That is the "NAD+ engine" that Liu study says drives NAD+ metabolism for the rest of the body, but becomes old and worn.

 

The sublingual method bypasses the liver (partly), to deliver it where used elsewhere.  Kind of like fixing the spark plugs, or wires, or other parts of the engine downstream from the carburetor.

 

I agree with Oakmans theories about the exercise also.  The muscles use the NAD+, and activate AMPK, which increases NAMPT, in a virtuos cycle.  But we know  older folks don't get benefit from exercise when they don't have sufficient NAD+.

 

Sinclair study found far more benefit with NMN and exercise combined than either alone.  

 

In fact, it even found the young mice who exercised had much benefit from NMN.  

 

Dumping extra, uneeded NAD+ on young, lazy mice had no benefit, and might build up the NAM/MeNam over time.   But exercise them, and they do indeed become "supermice".   

 

So in my thinking,  smaller sublingual dosages along with exercise spares the massive overload in the liver which results in build up of downstream metabolites that the body cant quite process fast enough.


Edited by able, 28 August 2018 - 03:21 PM.

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#33 stefan_001

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Posted 28 August 2018 - 06:38 PM

My view is oil in leaking engine

#34 stefan_001

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Posted 28 August 2018 - 07:43 PM

@able At what dosing level do you believe this happens: "the massive overload in the liver which results in build up of downstream metabolites"?

 

To me it looks like the build up of 2PY and 4PyTP is dependent of the filter capabilities of the kidneys. So the increase of these products in the blood could also be caused by the aging of the kidneys, they are known to reduce in performance as one ages.It would have been interesting if they had measurements of creatinine that would tell something about the kidney performance.

 


Edited by stefan_001, 28 August 2018 - 08:25 PM.


#35 able

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Posted 28 August 2018 - 09:22 PM

@able At what dosing level do you believe this happens: "the massive overload in the liver which results in build up of downstream metabolites"?

 

To me it looks like the build up of 2PY and 4PyTP is dependent of the filter capabilities of the kidneys. So the increase of these products in the blood could also be caused by the aging of the kidneys, they are known to reduce in performance as one ages.It would have been interesting if they had measurements of creatinine that would tell something about the kidney performance.

 

I have no idea what dosing level might be "too much" for an older person to process and might contribute to MeNam buildup. Am just theorizing that it is possible.  

 

I was concerned to see that NAM and MeNam  more than double with age in this study, and that as Michael pointed out, the Trammel thesis showed Dr Brenners MeNam more than doubled with 1,000 mg a day Figure 4, Trammel & Brenner PMID 27721479

 

But looking at that again, I remembered that the Trammel thesis was measuring NAD+ metabolites in the urine, not plasma as this current study does.

 

Maybe it is not such a concern that 1,000 mg a day results in 2-3x increase of  MeNam in urine.  Does that imply a similar increase in blood plasma, or is it mostly just excreted in urine?

 

Regardless, I don't think dumping a lot of precursors into the liver to have it metabolize and excrete NAM is as effective as putting NR/NMN direct to the bloodstream

 

 


Edited by able, 28 August 2018 - 10:15 PM.


#36 Michael

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Posted 28 August 2018 - 10:25 PM

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

 
You're falling into the usual trap around the healthspan construction, which is to imagine that it will mean that we will have an extended period of healthiness and then just drop dead of  ill-defined asymptomatic mechanisms. Pushing harder on the gas pedal so that the damaged engine pushes runs faster means that the car is still progressively getting worse, not that you "get to" speed into a cliff with no prior engine problems.
 

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 would here invoke Winston Churchill's comments about democracy being the worst of all possible systems of government — except for all the alternatives.
 

I see it more as putting a turbocharger on a worn engine.  It will likely  provide a boost for a while, but might not be good long term, depending on how worn the engine is, and how much you turn up the boost.


I'd say that's really just another phrasing of the same metaphor.
 

The sublingual method bypasses the liver (partly), to deliver it where used elsewhere.


... in theory. We have zero pharmacokinetic data: for all we know, the NMN in those tabs just gets degraded in the mouth, or trickles down your throat instead of going as a bolus to the stomach — let alone pharmacodynamics, which is what's really of interest.
 

Kind of like fixing the spark plugs, or wires, or other parts of the engine downstream from the carburetor.

 
You wouldn't be fixing anything — you'd just be avoiding one of many damaged parts in favor of others. However, I'd agree that there is a theoretical advantage of bypassing the liver even in the young, and more so in the old if the local conversion to NAM and metabolites is even greater.
 

I agree with Oakmans theories about the exercise also.  The muscles use the NAD+, and activate AMPK, which increases NAMPT, in a virtuos cycle.  But we know  older folks don't get benefit from exercise when they don't have sufficient NAD+.

 
Careful. Old people and mice most certainly do benefit from exercise, despite their lower NAD levels (and perhaps one of the reasons they do is exactly by upregulating NAMPT); Sinclair's study and others, as well as theory, does certainly suggest that you'll get better performance out of exercise with NAD+ boosting or reduced disposition, and I'd agree with you that there's a plausible case that they get more actual benefit as well (above & beyond that directly attributable to the performance boost).
 

Sinclair study found far more benefit with NMN and exercise combined than either alone.  
 
In fact, it even found the young mice who exercised had much benefit from NMN.  
 
Dumping extra, uneeded NAD+ on young, lazy mice had no benefit, and might build up the NAM/MeNam over time.   But exercise them, and they do indeed become "supermice".   
 
So in my thinking,  smaller sublingual dosages along with exercise spares the massive overload in the liver which results in build up of downstream metabolites that the body cant quite process fast enough.


That's a quite intriguing hypothesis. I'd add more explicitly that it might also reduce the downstream buildup of metabolites in the muscles themselves, by allowing more NAM to be recycled back to NAD+ by boosting NAMPT.


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#37 LongLife

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Posted 07 September 2018 - 11:20 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.

I agree, there is something missing. ALL of these substances are naturally occuring in our bodies. Science (maybe Dr. Sinclair;s lab) might study groups of young persons before, during and after puberty. Track the urine content for these metobolites, check the blood content, over a period of time and find what the scenario is before "aging" starts to take place. After all, aging is the RESULT of a cause effect. What changes (biochemically) between say age 12 years old and age 32 years old would indicate which substances cause the biochemical changes. What develops (changes) to reduce the elements activity of the Krebs Cycle; causing aging? Some things are missing still yet.


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#38 Nate-2004

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Posted 10 September 2018 - 02:29 PM

So the things that reportedly boost NAMPT are exercise and, hypothetically, sauna use and *maybe* sulforaphane. There are also some claims that AMPK activation upregulates NAMPT.  If resveratrol or pterostilbene activate AMPK, or if they're taking metformin, perhaps that resolves the issue with NAMPT and cycling out excess NAM?

 

I worry about taking metformin because of its reported effects on testosterone and libido.

 

https://www.ncbi.nlm...les/PMC5296448/

 

I also worry because ampk activation isn't exactly great for building muscle and getting the other benefits of exercise.


Edited by Nate-2004, 10 September 2018 - 02:46 PM.

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#39 Phoebus

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Posted 10 September 2018 - 02:45 PM

So the things that reportedly boost NAMPT are exercise and, hypothetically, sauna use and *maybe* sulforaphane. There are also some claims that AMPK activation upregulates NAMPT.  If resveratrol or pterostilbene activate AMPK, or if they're taking metformin, perhaps that resolves the issue with NAMPT and cycling out excess NAM?

 

I worry about taking metformin because of its reported effects on testosterone and libido. I also worry because ampk activation isn't exactly great for building muscle and getting the other benefits of exercise.

 

 

have you seen this thread on NAMPT?

 

https://www.longecit...pt-snps-please/


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#40 Nate-2004

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Posted 10 September 2018 - 03:09 PM

have you seen this thread on NAMPT?

 

https://www.longecit...pt-snps-please/

 

This was very helpful. I have heterozygous alleles for those two SNPs so that's a plus. I'm wondering if response to NR may vary based on these SNPs.

 

I also did not know that NAMPT was upregulated by Rhodiola. I take it every other day for its brain boosting effects (MAO).



#41 Phoebus

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Posted 10 September 2018 - 03:45 PM

circadian clock is crucial in NAMPT production  

 

 

 

 

The circadian clock genes BMAL1 and CLOCK control the production of the NAMPT enzyme which is the final step in the production of NAD+ (R).

The ebb and flow of cellular production due to circadian rhythm will result in the ebb and flow of NAD+ levels.

With aging, there will be lessor of this ebb and flow, which may explain why NAD+ declines with age.

https://www.selfhack...rtant-increase/

 


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#42 Nate-2004

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Posted 10 September 2018 - 05:13 PM

This article here talks about age related circadian rhythm dysregulation. I tend to take 500mcg of melatonin at the same time every night before bed (I don't take it if I'm past that time).  It may help maintain that rhythm if dosage is increased with age, maybe an extra 500mcg each decade past 40. Just a hypothesis based on this idea of sleep, circadian rhythm, and the brain cleaning that goes on with cerebral spinal fluid during sleep, (especially side sleeping position) and aging.  I'm sure this is all connected somehow but for the past several years now I've mastered the rhythm I think. I even wrote a guide on optimizing sleep.

 

Furthermore, in the context of the self-hacked article you linked, in light of this thread and the original post information, he's wrong that precursors like NR don't require NAMPT, because of the excess of NAM from NAD+ use that could result.


Edited by Nate-2004, 10 September 2018 - 05:15 PM.

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#43 StevesPetRat

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Posted 10 September 2018 - 05:50 PM

Just gonna leave this here:

https://www.cell.com...4131(18)30194-3

 

A Potent and Specific CD38 Inhibitor Ameliorates Age-Related Metabolic Dysfunction by Reversing Tissue NAD+ Decline

 

Aging is characterized by the development of metabolic dysfunction and frailty. Recent studies show that a reduction in nicotinamide adenine dinucleotide (NAD +) is a key factor for the development of age-associated metabolic decline. We recently demonstrated that the NADase CD38 has a central role in age-related NAD + decline. Here we show that a highly potent and specific thiazoloquin(az)olin(on)e CD38 inhibitor, 78c, reverses age-related NAD + decline and improves several physiological and metabolic parameters of aging, including glucose tolerance, muscle function, exercise capacity, and cardiac function in mouse models of natural and accelerated aging. The physiological effects of 78c depend on tissue NAD + levels and were reversed by inhibition of NAD + synthesis. 78c increased NAD + levels, resulting in activation of pro-longevity and health span-related factors, including sirtuins, AMPK, and PARPs. Furthermore, in animals treated with 78c we observed inhibition of pathways that negatively affect health span, such as mTOR-S6K and ERK, and attenuation of telomere-associated DNA damage, a marker of cellular aging. Together, our results detail a novel pharmacological strategy for prevention and/or reversal of age-related NAD + decline and subsequent metabolic dysfunction.

 

 


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#44 Phoebus

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Posted 10 September 2018 - 07:26 PM

problem with CD38 inhibitors is that its seems CD38 is important for the immune system and inhibiting it could leave you open for a bacteria/viral infection 

 

but not enough is known now to be sure 


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#45 Nate-2004

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Posted 11 September 2018 - 01:04 PM

problem with CD38 inhibitors is that its seems CD38 is important for the immune system and inhibiting it could leave you open for a bacteria/viral infection 

 

but not enough is known now to be sure 

 

I have said this before but I do think it's important to address why CD38 is on the rise, as well as PARP.

 

Plus, I don't think inhibitors are necessarily a bad thing if the strength of it merely knocks it back to younger levels and it still functions properly.


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#46 Phoebus

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Posted 11 September 2018 - 01:19 PM

reference regarding CD38 and immune system 

 

 

 

CD38, adenosine-5′-diphosphate-ribosyl cyclase 1, is a multifunctional enzyme, expressed on a wide variety of cell types. CD38 has been assigned diverse functions, including generation of calcium-mobilizing metabolites, cell activation, and chemotaxis. Using a murine Listeria monocytogenes infection model, we found that CD38 knockout (KO) mice were highly susceptible to infection. Enhanced susceptibility was already evident within 3 days of infection, suggesting a function of CD38 in the innate immune response. 

https://iai.asm.org/content/81/11/4091


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#47 male_1978

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Posted 13 September 2018 - 09:22 AM

I agree, there is something missing. ALL of these substances are naturally occuring in our bodies. Science (maybe Dr. Sinclair;s lab) might study groups of young persons before, during and after puberty. Track the urine content for these metobolites, check the blood content, over a period of time and find what the scenario is before "aging" starts to take place. After all, aging is the RESULT of a cause effect. What changes (biochemically) between say age 12 years old and age 32 years old would indicate which substances cause the biochemical changes. What develops (changes) to reduce the elements activity of the Krebs Cycle; causing aging? Some things are missing still yet.

 

I am not an expert but my unqualified view on this topic is this:

 

Lets assume the "age" of a cell is in some way the amount of disadvantageous changes within that cell, whatever these changes may be. I assume that these changes naturally occur over time.

 

Cell division creates new, unaged cellular structures and the existing damage will probably divide between the two child cells, reducing their age all the time. That would explain why during growth (until we are 20 or so) we wont accumulate a lot of damage ( i am not talking about telomeres here).

 

After we are adult, there is less growths and hence changes accumulate naturally. 

 

However, the question is whether these changes are cause for more disadvantageous changes or not. If so, over time we should see an exponentially number of changes, else it would only be linear. I assume its exponentially, because lifestyle changes should have much more impact on life expectancy else.

 

However, if its exponential it would be a good thing if we want to cure or treat the condition, because in this case focussing on preventing consequential damages ( e.g. by preventing problems with low Nad+) should have a huge impact.

 

What do you think about this?


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#48 stefan_001

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Posted 13 September 2018 - 11:41 AM

Epigenetic changes are passed on in cell division.


Edited by stefan_001, 13 September 2018 - 11:42 AM.


#49 Oakman

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Posted 13 September 2018 - 01:21 PM

The exponential change of epigenetic dis-function gives one food for thought. However, looking at the animal kingdom, what we see is often apparently quite different, at least in appearance.  Aging animals don't show marked deficits until near end of life, upon which there seems to be a rapid cascade of issues leading to a quick demise. In humans, the situation seems different, although they should not. People seem to start falling apart ever younger and younger. Lifestyle choices condoned and allowed by society likely play a big part in the faster degeneration of the human body over its lifespan. We currently see this problem all around in the general population.

 

This cascade of dis-ease and dis-ability in humans seems to be coming more and more from people literally dis-respecting their own bodies with food, drugs, lack of exercise and movement in favor of the enticement of gluttony, laziness, and self indulgence, sadly. Epigenetic changes in humans seem to be more and more self-inflected, not random. With obesity rates in the US for adults passing through ~35%, and diseases previously not seen until old age appearing in younger populations, what will be the end result if this continues?


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#50 ceridwen

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Posted 13 September 2018 - 01:36 PM

Extinction!
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#51 Oakman

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Posted 13 September 2018 - 01:43 PM

Extinction!

 Guessing more like Wall-E   :wacko:



#52 QuestforLife

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Posted 13 September 2018 - 02:06 PM

I am not an expert but my unqualified view on this topic is this:

 

Lets assume the "age" of a cell is in some way the amount of disadvantageous changes within that cell, whatever these changes may be. I assume that these changes naturally occur over time.

 

Cell division creates new, unaged cellular structures and the existing damage will probably divide between the two child cells, reducing their age all the time. That would explain why during growth (until we are 20 or so) we wont accumulate a lot of damage ( i am not talking about telomeres here).

 

After we are adult, there is less growths and hence changes accumulate naturally. 

 

However, the question is whether these changes are cause for more disadvantageous changes or not. If so, over time we should see an exponentially number of changes, else it would only be linear. I assume its exponentially, because lifestyle changes should have much more impact on life expectancy else.

 

However, if its exponential it would be a good thing if we want to cure or treat the condition, because in this case focussing on preventing consequential damages ( e.g. by preventing problems with low Nad+) should have a huge impact.

 

What do you think about this?

 

I think this is a good, logical analysis done without any preconceptions, which can be very useful sometimes.

 

I would agree that the end of growth of the body (cell division) seems to also be the start of aging. This might operate through a variety of mechanisms. For example:

 

1. The continuing mitotic growth signals in the fully grown adult instead of causing growth (cell division)  in post mitotic (growth-arrested) cells now cause insulin resistance, cell hypertrophy (growth without division) and eventual cellular senescence. This is the basis of the TOR theory of aging and Blagosklonny's work. There is evidence for this theory in the fact obesity and aging seem to be connected. It may also be that various metabolites produced by this process cause epigenetic dysregulation, such as loss of SIRTUINS. If so, this should be relatively simple (if not easy) fix.

 

2.  But not all cells are arrested. Mouth, throat and stomach lining, as well as lungs, skin, blood and immune cells all turnover at various rates in the adult. The telomere and to some extent stem cell theory of aging suggest that this resource is eventually exhausted. There is evidence for this in that fact people with various telomere genetic diseases suffer from often lethal lung and blood diseases. There is also evidence we 'run out' of stem cells in the very old. The are various genetic therapies to re-elongate telomeres in the works, and ex vivo stem cell treatments are also developing rapidly. It is unclear whether this would address other epigenetic changes that occur with aging in the human body, or whether these matter but there is also evidence that gene expression changes for the worse (including, possibly, down-regulation of SIRTUINS and other important epigenetic regulators), as telomeres shorten, but long before they reach a critically short length.

 

3.   There is also the simple fact that the end of (most) cell division in the fully grown adult means any internal 'damage' is no longer divided (as you rightly point out) and that this damage (in the absence of sufficiently well evolved autophagy, etc.) then begins to mount up over time. Obviously as dysfunctional mitochondria and lysosomes, etc mount up, this might cause a loss in turn of proper gene expression and those important self regulating proteins like the SIRTUINS.  This, very simply is the basis of the SENS approach to aging and its resolution. It's definitely not an easy fix if we have to go this way and deal with every last, little problem, but it is probably the most certain to work.


Edited by QuestforLife, 13 September 2018 - 02:13 PM.

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#53 jabowery

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Posted 26 February 2019 - 04:26 PM

problem with CD38 inhibitors is that its seems CD38 is important for the immune system and inhibiting it could leave you open for a bacteria/viral infection 

 

but not enough is known now to be sure 

 

Remember the concern about NAD+ metabolites negating the benefits of NAD+ increase?

Look, the problem is largely C38 increase with age, not NAD+ decrease with age.  This means inhibiting CD38 increase is getting closer to the root cause and should not be so cavalierly discarded over concerns of "over-doing it".

You can over-do water consumption.

78c appears to be a superior intervention pathway given proper administrative protocol.

 

The biggest problem right now is figuring out that administrative protocol, plus the cost of 78c which is $185/10mg.


Edited by jabowery, 26 February 2019 - 04:29 PM.

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#54 Phoebus

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Posted 26 February 2019 - 04:54 PM

Remember the concern about NAD+ metabolites negating the benefits of NAD+ increase?

Look, the problem is largely C38 increase with age, not NAD+ decrease with age.  This means inhibiting CD38 increase is getting closer to the root cause and should not be so cavalierly discarded over concerns of "over-doing it".

You can over-do water consumption.

78c appears to be a superior intervention pathway given proper administrative protocol.

 

The biggest problem right now is figuring out that administrative protocol, plus the cost of 78c which is $185/10mg.

 

 

Again inhibiting CD38 could cripple the immune system. I made a post here about how/why CD38 rises with age and why I dont think inhibiting CD38 is a long term solution. 

 

https://www.longecit...p-death-spiral/


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#55 LawrenceW

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Posted 26 February 2019 - 06:44 PM

From this study: https://www.scienced...550413116302248

 

"The fact that CD38 metabolizes not only NAD, but also NMN, may indicate that CD38 could at least in part decrease the availability of extracellular and intracellular NAD precursors to cells during the aging process."

 

Does the increase in CD38 as we age mean that CD38 consumes a higher percentage of available NAD and NMN? 

 

Does providing the body with more NMN and therefore NAD mean that there is more NAD to fuel both CD38 and the other functions?

 

Therefore is NAD precursor supplementation to sustain the increased activity of CD38 as we age a good thing?



#56 jabowery

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Posted 26 February 2019 - 08:20 PM

Again inhibiting CD38 could cripple the immune system. I made a post here about how/why CD38 rises with age and why I dont think inhibiting CD38 is a long term solution. 
 
https://www.longecit...p-death-spiral/

AGAIN...
 
...inhibiting CD38 increase is getting closer to the root cause and should not be so cavalierly discarded over concerns of "over-doing it".

You can over-do water consumption.

Now, let's try to have a civil dialogue on this, OK?

You believe that age-related degradation of the thymus results in stealth pathogens emerging and that the increase in C38 is a necessary immune response.

That's a plausible hypothesis. I'm being civil in this admission.

Here's another plausible hypothesis that I hope you'll admit must be tested along with yours:

Senolytic therapies demonstrate the senescent cells generate false immune system alarms resulting in age-related inflammatory responses that cause damage associated with aging. This much is not controversial. C38 may be one aspect of that immune response to false alarms.

So we have two hypotheses regarding age-related increase in C38. One of them indicates that 78c in any dose level would increase pathology. The other hypothesis indicates that a 78c dose-response lowering of C38 would, at an appropriate dose, bring C38 levels to a level appropriate to the real immune requirements.
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#57 Phoebus

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Posted 26 February 2019 - 08:54 PM

Lets look at some age related diseases. The big one - Alzheimers 

 

Surely its just that naughty amyloid right? I mean 20 years of amyloid drug research has cured Alzheimers...surely!   Or..... maybe its actually a brain infection from stealth pathogens such as...

 

HSV-1

 

https://theconversat...-a-cause-104943

 

lyme

 

https://www.j-alz.co...-and-alzheimers

 

Staphylococcus aureusStreptococcus pneumoniae and Candida albicans,

 

https://www.chemistr...3002490.article

 

So its possible that the reason the immune system is on high alert, thus driving up CD38 levels, in older folks is that their brains are literally under attack from stealth pathogens. And there is solid research saying so. And suppressing CD38 levels permanently could potentially possibly accelerate the rate of dementia. 

 

 


Edited by Phoebus, 26 February 2019 - 08:56 PM.

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#58 jabowery

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Posted 27 February 2019 - 02:25 AM

Lets look at some age related diseases. The big one - Alzheimers 

 

Surely its just that naughty amyloid right? I mean 20 years of amyloid drug research has cured Alzheimers...surely! ...

 

I've lost track of how many copies of "Plague Time:  How Stealth Infections Cause Cancer, Heart Disease, and Other Deadly Ailments" I've purchased and given away.

 

Your sarcastic tone is quite unnecessary with me, which should have been abundantly apparent from my prior response.


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#59 male_1978

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Posted 27 February 2019 - 09:09 AM

The following post contains pure speculation.

 

If you want to find a balance between the advanatages of NAD+ and possible problems with its metabolites, i would approach it as this:

 

We know that molecular signals in young individuals are somehow optimized by evolution, so if you are 18 its probably not useful to mess around with them.

 

For old people after reproduction this is not the case any more. So there is no reason to assume that their concentrations of molecules and the bodies reaction to them is optimal. It makes sense to use the existing knowledge to improve the molecular state of the body. We know that lack of NAD+ causes a lot of problems and there is little data about too much NAD+ causing similar problems. So with the available knowledge seems reasonable to increase NAD+ to get closer to the optimum. This strategy can be adjusted when we know more.

 

Regarding CD38 i would bring an evolutionary argument. In evolution, changing the NAD-Level in a cell or an area might be a simple strategy  (easily to invent by evolution) to reduce problems: Throw an hairdryer into the water, a fuse blows, energy is gone, damage is limited. The regulation of CD38 however is probably optimized for young persons, where damage is so limited that restricting energy in a few cells has no global impact. It might be different for old people, when free CD38 circulates in the blood.

Based in this hypothesis and the evolutionary optimum in young people i would assume that its best when the blood has a similar amount of NAD+ and CD38 as seen in young to eliminate any global impact of local problems. In some tissues, your old damaged body could then still reduce the NAD+-Level as it would naturally to react to problems. 

 

Ok, thats pure speculation of course, but is there a better approach at the moment?


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#60 jabowery

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Posted 04 August 2019 - 08:20 PM

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.

@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


Paradoxically, apigenin inhibits prostate cancer!  See "Table 1: Effects of apigenin treatment alone on cancer cells", subtable "Prostate cancer" in the paper "Apigenin in cancer therapy: anti-cancer effects and mechanisms of action" by

Xiaohui Yan, et al.

It is reasonable to speculate that apigenin is a magic bullet.

Edited by jabowery, 04 August 2019 - 08:53 PM.

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

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