99 replies to this topic

[Logic]

 

 

Logic,

 

I take supplemental B-6 & B-12 but don't worry about the other B's as I am meeting the RDA for the other B's. Is a proper balance of B important in general or just for your regime? 

 

For a start, there is a big difference between RDA and the optimal dosages mkp6019

 

I need to re-investigate this subject myself but I dont have the inclination atm and dont remember all the details offhand.  Probably due to a lack of B vits!  

it's also somewhat of a moot point: unless you go with separate Bs, you end up taking whatever is in the multi...

 

The info is in the NAD+ and homocysteine threads IIRC.

Personally I think staying away from any form of B3 ending with amide is the most important thing as it downregulates SIRT etc and you get (...more than?) enough of the amidated B3 from food.

Large doses increase homocysteine.

Methyl donors, such as B12, (in the methylcobalamin form) and B6 counteract this.

 

So different forms have greatly different effects.

See Bentafontamine, P5P, Pyridoxamine etc.

 

As niacin/nicotinic acid causes a flush; good luck finding a multi that uses this non amidated form!

I have no idea why they don't use Inositol Hexanicotinate and/or Chromium polynicotinate and kill 2-3 birds with one stone.

Cost probably?
 

 

 

Are you sure about Niacinamide... because: http://www.life-enha...protective-role

 

 

 

Here is Pubmed's list of papers wit D A Sincliar's name on them:

http://www.ncbi.nlm....or_uid=12297502

 

Note the 1st one:

Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1.

...We show that physiological concentrations of nicotinamide noncompetitively inhibit both Sir2 and SIRT1 in vitro. The degree of inhibition by nicotinamide (IC(50) < 50 microm) is equal to or better than the most effective known synthetic inhibitors of this class of proteins...

 

Now in your link its obvious he's aware of this paper:

"“We should entertain the possibility that nicotinamide is activating SIRT1 in vivo, not inhibiting it..."

 

Now the early 2002 study was in vitro, but as we are interested in the level of NAM inside the living cell, as it also is in vivo, the in vitro/vivo point is moot IMHO..?

 

But to fair; the in vitro study is old and a look at the newer evidence is warranted.

Anti-Aging-Firewalls does just that with their 2015 summary:

 

5.  Nicotinamide (Nam)

Nicotinamide is a direct inhibitor of both the SIRT enzymes and the PARP enzymes.

 

The accumulation of excess nicotinamide in cells is probably a major cause of aging.  Whereas we typically associate “NAD deficiency” with aging, “Nam excess” may have a similar effect.  To no one’s surprise, the levels of the two compounds are inversely related in aging.

 

Nam plays a role in both aging and in disease.   In hypertension and in aging individuals with normal blood pressure, Nam inhibits the methylation-mediated degradation of catecholamines.  Thus Nam excess plays a role in hypertension (see references below).

 

Nicotinamide also has an epigenetic effect. When SIRT1 is inhibited, cells age and cancer oncogenes are re-activated.  SIRT1 silences these genes  by histone deacetylation of H3K9 and H4K16 residues on the histones of these oncogenes.

 

A recent article showed that in rats, nicotinamide supplementation during pregnancy causes global DNA hypomethylation in rat fetuses.  Nicotinamide has detrimental effects in development, detrimental metabolic effects, and detrimental epigenetic effects when given to young rats.  Low dose nicotinamide increased weight gain in developing rats.  High dose nicotinamide did not, however.  The livers of nicotinamide-fed young rats had more DNA damage (8oxoG), impaired glucose tolerance, and increased insulin resistance.  Nicotinamide increased the levels of N-methylnicotinamide in the blood and decreased betaine levels in the blood.  This resulted in a global hypomethylation of DNA in the rat genome.  Nicotinamide also had “gene-specific effects” on CpG islands within the promoters of the following genes:

1. NNMT gene – this was down-regulated
2. DNMT genes – these were down-regulated
3. Homocysteine metabolism genes – these were down-regulated
4. Antioxidant genes and oxidative stress protection genes – these were down-regulated

Since niacin is converted into nicotinamide in human tissues, high dose niacin probably produces all of the above effects.  A recent paper called niacin and nicotinic acid “methyl consumers” and strongly suggested that high niacin/nicotinic acid intake is bad.

 

Excess nicotinamide has also been shown to increase plasma serotonin and histamine levels in humans, due to disrupting the metabolism of these neurotransmitters.  This is probably due to the fact that methyl donors and methylation enzymes are needed for serotonin/histamine metabolism.   Most importantly, nicotinamide is a direct inhibitor of the Sirtuin enzymes (SIRT1-7) and the PARP enzymes (all 17 of the PARPs).

 

The molecular mechanism by which Nam works is very straightforward. Nam acts as a direct inhibitor of the SIRT1 enzyme pocket where NAD binds.  Thus Nam is a “competitive inhibitor” of NAD and is “bad” when it comes to most cancers, aging, and most diseases.

On the other hand, inhibition of SIRT1 by Nicotinamide may be a “good thing” in the brain, where it may prevent NAD+ depletion and thereby protect neurons against excitotoxicity and neuronal cell death induced by PARP1.

 

As the cell consumes NAD (by SIRT1-7, PARP1, PARP2, Tankyrases, CD38, CD157, ARTs, and other enzymes), the NAD is consumed, leaving the by-product, Nam.   There are two primary ways  of “disposing of Nam”.  They are methylation/excretion or recycling of Nam into NMN (and subsequently NAD) via the “NAD salvage cycle”. 

 

Here are the problems with both of these methods of reducing Nam levels in the cell.  (see #2 and #3 below).

 

References:

1. 2002 Inhibition of Silencing and Accelerated Aging by Nicotinamide, a Putative Negative Regulator of Yeast Sir2 and Human SIRT1
2. 2006 Inhibition of SIRT1 Reactivates Silenced Cancer Genes without Loss of Promoter DNA Hypermethylation
3. 2009 Nicotinamide Prevents NAD+ Depletion and Protects Neurons Against Excitotoxicity and Cerebral Ischemia: NAD+ Consumption by SIRT1 may Endanger Energetically Compromised Neurons
4. Nicotinamide supplementation induces detrimental metabolic and epigenetic changes in developing rats
5. 2013 Association of Nicotinamide-N-Methyltransferase Gene rs694539 Variant with Patients with Nonalcoholic Steatohepatitis
6. 2013 Excess nicotinamide increases plasma serotonin and histamine levels
7. 2013 Excessive nicotinic acid increases methyl consumption and hydrogen peroxide generation in rats
8. 2014 Metabolism: Targeting a fat-accumulation gene

Conclusion:  It is now clear that high concentrations nicotinamide are harmful to health.  HIgh doses of dietary niacin probably produce the same effects, despite the many benefits of high dose niacin.  With aging, nicotinamide levels already go up.  Adding more nicotinamide is probably not going to “cure” aging.  Adding a methyl donor to eliminate nicotinamide (such as betaine) may be a good thing.

http://www.anti-agin...life-extension/

 

The only fault I can find with James P Watson or Vince Giuliano's reasoning is that Niacin does not seem to have quite the same effect as Nicotinamide as it seems to feed into the de-novo NAD+ synthesis pathway, leaving NAM levels alone until after the synthesis of SIRT etc:

http://www.longecity...ndpost&p=693619

 

So I'm "entertaining the possibility that" the sale of Nicotinamide Riboside "is activating" Sinclair's bank balance, since that 2002 study!?

Edited by Logic, 13 February 2016 - 12:02 PM.

[normalizing]

so should one stop nicotinamide riboside or just stop plain niacin supplementation as that is the one most obvious to detrimental effects? the entry for wikipedia should be edited because nicotinamide riboside is flooded with positive references!

Edited by normalizing, 13 February 2016 - 08:04 PM.

[Logic]

so should one stop nicotinamide riboside or just stop plain niacin supplementation as that is the one most obvious to detrimental effects? the entry for wikipedia should be edited because nicotinamide riboside is flooded with positive references!

 

1st:

Anything ending in amide (niacinamide = nicotinamide = NAM) are different names for the same thing.
The non amidated forms of B3 are Niacin = Nicotinic acid = NA.

(I may have missed some other obscure names, but basically there are 2 forms; one amidated, the other not)

 

This is a very difficult subject to to a miriad feedback loops and different intracellular and extracellular effects etc, but its the amidated form you need to avoid IMHO:

 

The end product of SIRT, PARP, CD38, etc is NAM and it is NAM that downregulates their production.

Now NA isn't the end product of SIRT, PARP, CD38 production but feeds into the de-novo NAD+ production pathway.

(A pathway that declines with age and starts in the gut btw)

 

 

Nuclear ADP-Ribosylation Reactions in Mammalian Cells: Where Are We Today and Where Are We Going?

http://mmbr.asm.org/...t/70/3/789.full

 

It eventually ends up as NAM after SIRT, PARP etc production, but doesn't just add to the SIRT, PARP etc downregulating, end product...

 

Now note the NAM salvage pathway involving NAMPRT. (=NAMPT)

This is where NR feeds into the NAD+ production process.
What I don't like is that it looks like taking NR would make it less necessary to salvage, and thus lower, intracellular NAM levels, which would lead to more SIRT. PARP etc downregulation..?

 

Do note  that that the above diagram is from a 2006 study, which makes it a bit old and newer studies may have made it somewhat obsolete?

The fact is we have a NAD+ salvage pathway capable of making good use of extracellular NR and 

NR is proven to transiently increase  NAD+ levels.

Many are seeing/feeling great benefit from it.
From my old reading I think it may have been conserved as a means of salvaging a valuable resource from surrounding cells that have undergone necrosis.

ie: During times of emergency.

I don't know if it will actually downregulate the salvage of NAM and lead to lower levels of SIRT etc, but I am wary of the possibility.

 

We generally get plenty of NAM from our food, so I would/do choose to supplement NA in stead.
 

Don't lose sight of where this all started which is the necessity of balancing (high or low) all B intake and the importance of B6 and 12. folate etc, with B3.

[Never_Ending]

I'm sure context is a factor in this but it brings up some concerns   , articles like these.

 

http://www.ncbi.nlm....pubmed/12297502

 

Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1.

 

 

I'm sure there is a case for either side but looks a bit unclear at the moment

[mkp6019]

Logic and Nikolay,

 

So many contradictions or lack of certainty in these studies. I do take Resveratrol and feel it helps improve cognition for me.  The reason I started taking it though was due to possible longevity benefits (SIRT1 activation) and would be hesitant to adding any supplements in amidated forms. If and when I add Niacin I will expect a flush and see if it can be tolerated until I am more certain about niacinamide.

[Logic]

Logic and Nikolay,

 

So many contradictions or lack of certainty in these studies. I do take Resveratrol and feel it helps improve cognition for me.  The reason I started taking it though was due to possible longevity benefits (SIRT1 activation) and would be hesitant to adding any supplements in amidated forms. If and when I add Niacin I will expect a flush and see if it can be tolerated until I am more certain about niacinamide.

 

Yes; the myriad feedback loops and different intra and extracellular effects for NAM etc make it very confusing,
I think that if one were able to hold all the relevant research in memory and really give it all a good think one may be able to figure it all out, but my mind just doesn't seem to have the required huge amount of working memory for it and that drives me nutZ!  

 

There is some light at the end of the tunnel though.
see:
http://www.longecity...ndpost&p=762337

http://www.longecity...ndpost&p=762440

[nikolay]

 

Logic and Nikolay,

 

So many contradictions or lack of certainty in these studies. I do take Resveratrol and feel it helps improve cognition for me.  The reason I started taking it though was due to possible longevity benefits (SIRT1 activation) and would be hesitant to adding any supplements in amidated forms. If and when I add Niacin I will expect a flush and see if it can be tolerated until I am more certain about niacinamide.

 

Yes; the myriad feedback loops and different intra and extracellular effects for NAM etc make it very confusing,
I think that if one were able to hold all the relevant research in memory and really give it all a good think one may be able to figure it all out, but my mind just doesn't seem to have the required huge amount of working memory for it and that drives me nutZ!  

 

There is some light at the end of the tunnel though.
see:
http://www.longecity...ndpost&p=762337

http://www.longecity...ndpost&p=762440

 

 

So, NADH should be avoided, too? How about NR, which has bold claims in regards to life extension?

[Logic]

So, NADH should be avoided, too? How about NR, which has bold claims in regards to life extension?

It's all about increasing the NAD+ to NADH ratio and then steering the NAD+ to be used for SIRT activation.

There is a lot of info in the previously linked thread.
http://www.longecity...ndpost&p=762337

[Graviton]

Here are a number of things that don't work (in rodents)--

 

The data presented here suggest that the consumption of complex mixtures of dietary supplements do not provide the same lifespan and health benefits as their whole food sources. Extracted or isolated botanical components or chemicals with antioxidant or anti-inflammatory properties did not increase the longevity of the mice in this study. The results are not likely related to the dosages used. We tested multiple commercial compilations at the mouse equivalent of the human dosages recommended, two published supplement combinations at the dosages reported to have longevity or cognitive benefits in rodents, and a highly complex, high dosage supplement combination. These combinations either had no effect or a negative effect on lifespan. Together our results are not consistent with the view that the consumption of complex mixtures of extracts and isolated components of whole foods is effective at extending lifespan. These results are instead consistent with a large body of epidemiological evidence indicating that the consumption of dietary supplements is associated either with no effect or an increase in morbidity and mortality.

 

http://www.ncbi.nlm....les/PMC4039264/

 

 

And one that does--

 

Fullerene C60 Increases Lifespan by +90% 

 

http://suppversity.b...lerene-c60.html

 

 

You can find many threads on C60 here.

 

Protandim(Some herbal extract combinations with curcumin, milk thistle, green tea, bacopa, ashwagandha) extends mean lifespan although maximum lifespan extension study fails to reach the significant level.

http://www.ncbi.nlm....pubmed/27312235

 

The study you quote also include curcumin, milk thistle, green tea, bacopa, but it didn't influence a significant change of lifespan.

http://www.ncbi.nlm....les/PMC4039264/

 

Edited by Graviton, 01 July 2016 - 01:24 PM.

[kurdishfella]

No but probably just  help keep you healthy.  It will be interesting when we can calculate age via blood tests.