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NAD+ on physical/aesthetics attributes

physical nad+ aesthetic

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#1 jrnozid

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Posted 30 May 2017 - 09:18 PM


I'm 25 yrs old and I just discvoered NAD+ on abovetopsecret website about an experiment in mice and you know the rest. I tried researching about this topic and actually found the science is sound. But I have also found out that the dosage used on mice was actually enormous for their size and that not much is said about N+ having any effects on physical attributes.

I want to know more about this before trying it myself. Some might say I may be too young for this but that is the reason because I want to slow if not prevent any aging factors as possible as I can. So I hope my questions get answered. Thank you

1. What would be the equivalent dose for humans from the 400mg to mouse? Has anyone ever tried that kind of dose?
2. Are there any effects on physical attributes? Does it stop/slow you from looking old when you take it while you are young?
3. Is it really effective even if you take it at a 250mg dose?
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#2 MikeDC

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Posted 11 June 2017 - 11:30 AM

1. It is well known mouse dose needs to be scaled down significantly for human dose.
2. Definitely. It could even reverse aging for many people. I would recommend 125 mg from age 30.
3. Yes. Even 125mg can be effective
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#3 SearchHorizon

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Posted 11 June 2017 - 04:16 PM

I don't think an optical dosage is easy to determine.

 

I have read most of the posts on NR - but I am as puzzled about this as I was before.

 

 

 

 



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#4 Nate-2004

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Posted 27 June 2017 - 02:12 PM

First off I'm not sure what he needs references for, he's asking questions not making claims.

 

Second, there's no way to answer this question without trying it for 10 years and letting us know, or better yet, conducting a long term experiment on a large group of people taking NR vs some other supplement, track them for 10 or 15 years and then check results. 

 

What you're asking is whether or not you should bet your money on NR. That's unknown still. I think it'll help to have more unbiased research conducted but all we have currently are trials conducted by the manufacturer Chromadex, which isn't exactly reliable in the sense that it's unbiased.

 

You could educate yourself as much as possible on NR, the path it takes, its bioavailability and effects on NAD+, etc. The locked curated thread is a good start. Then decide for yourself on whether it's worth the investment/gamble. You can limit how much you end up spending by buying in large quantities from HPN.

 

You're only 25, you're not losing any NAD+ yet and depending on how well you take care of yourself in the way that is free or cheap (vitamin D3 is cheap, fish oil is relatively cheap, exercise and fasting are free, sauna just needs a gym membership depending where you are), then you probably won't need to start taking it low dose till you're 30. You could buy a whole year's worth at that dosage for $150 and by then who knows what we will know or what the prices will be.

 

 


Edited by Nate-2004, 27 June 2017 - 02:19 PM.


#5 Oakman

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Posted 27 June 2017 - 04:06 PM

No one knows the positive (negative) effects on aging of long term NR supplementation, yet. All we know for sure is it raises serum NAD+ levels. I think this graph shows something like what you might want to imagine happens to NAD+ levels with supplementation over time. But they don't know if this actually will happen at all ages, nor whether the increase actually helps you or not - just yet. These projections take time, often a lot of time, to be proven one way or the other.

 

newsciencechart.gif


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#6 Nate-2004

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Posted 27 June 2017 - 09:08 PM

I wasn't aware that NAD+ fell 50% every 20 years, I thought it was something that only begins falling off around 25 due to a sudden rise in CD38 probably due to an accumulation of senescent cells.



#7 Turnbuckle

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Posted 27 June 2017 - 10:55 PM

I wasn't aware that NAD+ fell 50% every 20 years, I thought it was something that only begins falling off around 25 due to a sudden rise in CD38 probably due to an accumulation of senescent cells.

 

See Fig. 4 in this paper--Age-Associated Changes In Oxidative Stress and NAD+ Metabolism In Human Tissue



#8 jrnozid

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Posted 29 June 2017 - 10:32 AM

@nate-2004 I see thinks for the detailed input. So for now it really is a gamble when taking nad+ since there is not much study about it. Yeah i guess Im pretty young and I just want to start early though so in the future I might not need to cram in taking nad. About HPN, which company is this? And when you say a years worth for 150$, how much dosage are we talking about?

@oakman - thanks for the graph it really helps me understand more on nad levels degradation

#9 bluemoon

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Posted 29 June 2017 - 06:12 PM

No one knows the positive (negative) effects on aging of long term NR supplementation, yet. All we know for sure is it raises serum NAD+ levels. I think this graph shows something like what you might want to imagine happens to NAD+ levels with supplementation over time. But they don't know if this actually will happen at all ages, nor whether the increase actually helps you or not - just yet. These projections take time, often a lot of time, to be proven one way or the other.

 

newsciencechart.gif

 

What is the source of this graph? I don't see how it is close to being correct. First, where is there evidence that NAD+ declines from year 1? More like year 25 or 30. Second, it says "NAIGEN supplementation begins" but does not say at what dose. Using Elysium's study, an 80 year old taking 500 mg of NR may be raising NAD+ levels by 90% but that would not bring his levels up to nearly that of a 20 year old as the graph shows. 

 

We don't know the slope of the downward curve but even with the above made-up graph, it looks like an 80 year old taking 500 mg a day would return to NAD+ levels closer to that of a 65 year old. (Maybe if at 1000 mg a day could move NAD+ levels up to that of a typical 55 year old.)  



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#10 MikeDC

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Posted 29 June 2017 - 06:40 PM

There was another graph with real data that shows NAD+ goes down consistently. Not just after year 20. I am in mid 50s,
I think my NAD+ is above 20s level judging by the skin smoothness. So it is quite possible to raise NAD+ above youthful levels.
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#11 Oakman

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Posted 29 June 2017 - 07:21 PM

 

No one knows the positive (negative) effects on aging of long term NR supplementation, yet. All we know for sure is it raises serum NAD+ levels. I think this graph shows something like what you might want to imagine happens to NAD+ levels with supplementation over time. But they don't know if this actually will happen at all ages, nor whether the increase actually helps you or not - just yet. These projections take time, often a lot of time, to be proven one way or the other.

 

newsciencechart.gif

 

What is the source of this graph? I don't see how it is close to being correct. First, where is there evidence that NAD+ declines from year 1? More like year 25 or 30. Second, it says "NAIGEN supplementation begins" but does not say at what dose. Using Elysium's study, an 80 year old taking 500 mg of NR may be raising NAD+ levels by 90% but that would not bring his levels up to nearly that of a 20 year old as the graph shows. 

 

We don't know the slope of the downward curve but even with the above made-up graph, it looks like an 80 year old taking 500 mg a day would return to NAD+ levels closer to that of a 65 year old. (Maybe if at 1000 mg a day could move NAD+ levels up to that of a typical 55 year old.)  

 

 

The graph appeares to be marketing conjecture based - on the legend words like "Hypothetical projection", or that total lack long term NR data eliminates 20 year projections of anything, and why I said, "something like you might want to imagine". But it is one possible future. The graph appears to be based on a 250mg/d dose, giving a "demonstrated" ~30% increase in NAD+ and is from here. I agree, present scant data seems to show a leveling off and decreasing NAD+ level with continued supplementation, but I don't think the results are settled. Still, why should it keep increasing x5 or x10 or whatever to some higher level over time? One day we might know the truth.


Edited by Oakman, 29 June 2017 - 07:23 PM.


#12 bluemoon

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Posted 29 June 2017 - 09:30 PM

 Maybe I missed something, but I only remember David Sinclair saying in 2013 that the mice he injected with NMN at a dose I don't know, nor know the conversion to humans, turned the human equivalent of a 60 year old mouse's muscles to one in its 30s. Another report said from 80 to 40s in human years. 



#13 Nate-2004

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Posted 03 July 2017 - 04:19 AM

I thought I'd add more about physical attributes and your question in general. While NAD+ is important I just don't think it's going to be the end game. When it comes to physical attributes, especially appearances, these things are going to be better addressed by AGE breakers than anything else. We have yet to discover a means of removing the glucosepane that accumulates in the extra-cellular matrix. (ECM). I really think CR extends lifespan not just because it activates SIRT which feeds off NAD+, repairing DNA, etc, etc, but because more importantly, it greatly reduces the accumulation of AGEs.  A calorie restriction mimetic like NR or any NAD+ booster isn't the whole picture or the whole equation. AGEs are a big part of the problem.  I can't stress enough that if you're limited on funds and want to do something about aging, spend your money on these particular SENS projects rather than supplements. It's cheaper to just fast frequently, drink plenty of green tea and take carnosine. Also don't cook at such high temps. Anything that reduces formation of AGEs is a good thing.

 

A quote from Michael here gives us some idea and some hope:

 

 


So, there's a lot here, of course ... I'm going to address what seem to be the main points of confusion:

First, AH, thanks for engaging here: you're clearly highly knowledgeable in this area, and your input is welcome (as would be direct communication with us, particularly if you're engaged in intervention-oriented research on glucosepane, especially since you're doing so using an approach consistent with the "damage-repair" strategy of SENS).

It is of course correct that glucosepane is actually pretty labile: as you probably know, the reason it went undetected for so long was exactly that the harsh treatments and broad-spectrum proteases normally used to break down aging collagen to look for nonenzymatic crosslinks destroy it in the process. It was only identified through a painstaking process of sequential enzymatic digestion of the native collagen. This is one of the many reasons why having a ready source of synthetic glucosepane is valuable: by incorporating it into collagen peptides, it can be used to generate antibodies for the convenient labeling of glucosepane in vitro and in vivo.

A viable glucosepane-cleaving rejuvenation biotechnology, then, must to selectively cleave glucosepane crosslinks without damaging the native collagen. This would both directly restore its youthful elasticity, and should also allow for normal, physiological turnover of the tissue (such as by restoring MMP1's ability to access to its binding site, which the molecular dynamics simulation of glucosepane formation linked by Slicer suggests is likely impeded by glucosepane because its favorable formation site is only two amino acid residues away).

This is also the resolution of the conundrum highlighted by Slicer: [Since] MMPs, no matter the amount, cannot function on collagen with glucosepane crosslinks ... Can we develop something to finish what the MMPs started? Is there any molecule that can either usurp glucosepane's hold on its binding sites without damaging anything else or simply go around it, unmaking collagen in an entirely different way and breaking off the glucosepane-infested chunks?

Neatly cleaving glucosepane from the native structure will achieve this aim in a more direct and durable way than trying to unbind it or work around it, and (as noted) will not only allow for the turnover of the previously-crosslinked collagen fibril, but also restore its motion and function, likely rendering turnover unnecessary unless other damage has accumulated.

It's quite true that glucosepane accumulates much more slowly in normally-aging and even diabetic rats than it does in human aging. This isn't really an impediment to using them for basic testing of candidate glucosepane-cleaving agents, however. Even if glcosepane's low tissue burden in rats means that cleaving it will not have dramatic rejuvenating effects in these animals (which is a reasonable prediction, but might be happily disproven in the event), its high prevalence in aging and diabetic human collagen, and its implication in the complications of diabetes, will make the mere demonstration of a candidate's ability to cleave glucosepane crosslinks in vivo a sufficient proof-of-concept to spur further work to move it down the therapeutic pipeline into human testing.

(It's perhaps worth noting that even if glucosepane did accumulate in rats in a way that more closely scales to their rate of aging, cleaving it wouldn't necessarily extend their lifespan, because of the "weakest link in the chain" problem: to extend the lives of otherwise-healthy, normally-aging mice or humans by definition requires addressing all of the cellular and molecular damage driging aging to some degree, using a comprehensive panel of rejuvenation biotechnologies. As Chief Science Officer de Grey wrote to address a canard along these lines from critics:

[It is true] that no SENS intervention—in isolation—has ever been shown to extend any organism's lifespan. I do not recall Henry Ford alerting potential customers that the components of a car—in isolation—remain obstinately stationary when burning petrol is poured on them, nor do I recall his being castigated for this omission.

And in the meantime, the free availability of the anticipated glucosepane-detecting antibodies generated by the research that SENS Research Foundation funded at Yale will enable the identification of more suitable animal models for the demonstration of a hard health outcome. It's even conceivable (though not likely) that the mouse might be one such: the 300 pmol/mg figure cited by AH is for rats, and conceivably mice might prove a closer parallel to human aging and diabetes in this regard). On this front:

AH, you noted that Although glucosepane has recently been synthesized in vitro (I assume you mean by Draghici et al), I find it unlikely that work can have applications for animal models. Simply infusing glucosepane will not form the collagen crosslinks in question.

That wouldn't be the idea. The ability to synthesize glucosepane is now enabling the Yale crosslink team to incorporate glucosepane into synthetic, chemically-uniform crosslinked peptides. These can be used to create antigens with which to immunize rabbits, inducing the formation of antibodies targeting glucosepane-containing peptides. Labeled monoclonal antibodies generated from hybridomas derived from B-cells from such animals could then be used for the convenient detection of glucosepane crosslinks in tissue samples, and then evaluate the effects of candidate glucosepane-cleaving rejuvenation therapies in vitro and in vivo.

You (AH) also express concern that bacteria and other microorganisms just need to find something which works [to degrade glucosepane]. It's not their problem if the solution they use won't help us for the odd situation we're trying to solve."

Right ... the idea, however, is to find bacteria that can grow under physiologic conditions (temperature, pH, etc) with glucosepane as the sole available energy source, or alternatively as the sole available source of lysine and arginine for strains auxotrophic for these amino acids. In the wild, a community of bacteria and other microorganisms will often cooperate or compete for energy sources, leading to strains that are specialized in attacking specific bonds within a larger structure to carve out a niche for themselves (or a role within a larger network). It is then trivial to negatively screen candidate enzymes identified through such methods against physiologic collagen and later other proteins.

In addition to wild-derived bacteria, the Yale group is working to construct a cosmid library (see also here) to screen the huge diversity of gut microbe enzymes in easily-cultured E. coli lines, which would then similarly be screened against glucosepane as the sole source of energy and/or lysine and arginine.

Another issue with enzymes is the tight packing of the collagen fibrils, making it questionable if the enzyme will be able to reliably reach its target. A tailored small molecule may be a considerably better option for that reason alone.

Entirely possible, yes. The advantage of a microorganism-based enzyme-discovery program is that the enormous diversity of solutions generated by evolution (both in nature and later through directed enzyme evolution) allows for the hypothesis-neutral testing of an enormous range of candidate therapies generated by the engines of evolution, which are much cleverer than I am ;) . At the moment, I don't think anyone has much of an idea on how to identify good small molecule candidates with conventional medicinal chemistry methods (though I'm intrigued to hear that you have some thoughts, AH!).

I'm a also going to quote from a recent email from Dr. de Grey, from a conversation on this subject in which I was a participant:

the access issue for enzymes reaching crosslinks in tightly-wound collagen is one that has been on our mind since forever, and is in tension with the converse problem of specificity of small molecules. The fact that glucosepane looks so weird, seven-membered ring etc, does not translate as well as I had initially hoped to the conclusion that drugs to cleave it will often be harmless to structures that the body synthesises on purpose. For this reason one approach that we are looking at is organocatalysts, which are small peptides with enzymatic activity - they are a compromise between size and specificity, and thus may be the best of both worlds.

But there is a huge amount not known about all this; it may just be that regular enzymes work fine because breaking the subset of glucosepane that they can get to will loosen things up enough that they can get to a bit more, and so on.

No matter what the strategy one favors for identifying therapeutic candidates, the glucosepane reagents generated by David Spiegel's group through the SENS Research Foundation funding will for the first time provide the soil that will allow a thousand flowers to bloom. Like you, AH, and I'm sure like everyone here, I'd be delighted to make progress toward a viable glucosepane-degrading therapeutic based on on any strategy, though it would sure be nice to claim a part in the bragging rights for that, too ;)Solvitur ambulando!


Edited by Nate-2004, 03 July 2017 - 04:22 AM.


#14 Kirito

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Posted 03 July 2017 - 07:52 AM

According to this, NMN seems to have increased elastin in the aorta. https://www.ncbi.nlm...pubmed/26970090

 

No idea if that could also apply to the skin, though.



#15 Nate-2004

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Posted 03 July 2017 - 02:40 PM

According to this, NMN seems to have increased elastin in the aorta. https://www.ncbi.nlm...pubmed/26970090

 

No idea if that could also apply to the skin, though.

 

No, it can't, see the post just above. That is an glucosepane problem.


Edited by Nate-2004, 03 July 2017 - 02:41 PM.

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#16 jrnozid

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Posted 05 July 2017 - 09:09 PM

 

According to this, NMN seems to have increased elastin in the aorta. https://www.ncbi.nlm...pubmed/26970090

 

No idea if that could also apply to the skin, though.

 

No, it can't, see the post just above. That is an glucosepane problem.

 

 

I'm sorry what are AGE's and SENS again? 



#17 MikeDC

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Posted 05 July 2017 - 09:53 PM

According to this, NMN seems to have increased elastin in the aorta. https://www.ncbi.nlm...pubmed/26970090

No idea if that could also apply to the skin, though.


No, it can't, see the post just above. That is an glucosepane problem.

You are saying skin wrinkles are due to glucosepane. It doesn't mean elastin is not increased by NMN.
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#18 SearchHorizon

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Posted 06 July 2017 - 12:32 AM

Based on my personal experience, one has to exercise or practice fasting of some sort, in combination with NAD precursor administration, to see any effect on wrinkles. To me, this makes sense, because NAD+'s main mechanism of action is to translate stress into physical response. Hence, even if one is taking NR, one still would have to exercise/fast, to see the benefit of taking it.

 

Having said that, I have not seen any benefit whatsoever with respect to my hair color - it is still turning grey, and NAD precursors don't seem to help.

 

-------


One more thing - NAD+ precursors seem to affect sexual function. Not sure if that'd be considered "aesthetics."  


Edited by SearchHorizon, 06 July 2017 - 12:34 AM.


#19 MikeDC

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Posted 06 July 2017 - 01:14 AM

Niagen is fasting and exercise mimic. May not be everything, but most of It. Ofcource exercise will increase NAD+ even more.
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#20 SearchHorizon

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Posted 06 July 2017 - 05:02 AM

Niagen is fasting and exercise mimic. May not be everything, but most of It. Ofcource exercise will increase NAD+ even more

.

 

That seems a bit far-fetched to me.

 

I know that NAD+ does not activate SIRT1 on its own. In addition, I have not seen any paper that supports the notion that NR activates SIRT1. It is possible that I overlooked something, of course.

 

Gven that SIRT1 is a stress-to-physical response transducer, it also would not make any sense to have SIRT1 activated by a NAD+ precursor (given that is represents no stress). 

 

 

 

 

 

 

 

 


Edited by SearchHorizon, 06 July 2017 - 05:25 AM.

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#21 MikeDC

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Posted 06 July 2017 - 12:28 PM

Niagen is fasting and exercise mimic. May not be everything, but most of It. Ofcource exercise will increase NAD+ even more
.


That seems a bit far-fetched to me.

I know that NAD+ does not activate SIRT1 on its own. In addition, I have not seen any paper that supports the notion that NR activates SIRT1. It is possible that I overlooked something, of course.

Gven that SIRT1 is a stress-to-physical response transducer, it also would not make any sense to have SIRT1 activated by a
NAD+ precursor (given that is represents no stress).

Not correct. NAD+ directly regulate Sirt1.
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#22 Harkijn

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Posted 17 July 2017 - 03:23 PM

Search Horizon said::

 

 

 

 I have not seen any paper that supports the notion that NR activates SIRT1. It is possible that I overlooked something, of course.

 

 

A very good way to read up on NR, NAD+ and SIRT1 :

 

https://www.ncbi.nlm...les/PMC3616312/

 

 


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#23 MikeDC

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Posted 17 July 2017 - 04:01 PM

In general, NAD+ levels increase in mammalian tissues in response to energy/nutrient stresses like exercise (Canto et al., 2009; Canto et al., 2010; Costford et al., 2010), fasting (Canto et al., 2010; Rodgers et al., 2005) or calorie restriction (Chen et al., 2008). Accordingly, SIRT1 activity is enhanced by all these conditions.
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