13 replies to this topic

[lucid]

About Sirtuins:
I will discuss SIR2p (Human Analog is SIRT1) which I am most familiar with:
*SIR2p protiens bind to DNA near the telomeres: silencing genes there. In order to bind each SIR2 protien must use NAD+ as a cofactor.
*SIR2p protien levels in a cell are regulated by NAD+ levels.
Hence, Sirtuin levels in a cell as well as individual each protiens catalytic rate is regulated by NAD+.

Resveratrol's MOA
*Resveratrol increase sirtuin biochemical functions by decreasing the apparent Km for the peptide substrate and NAD+.
*Does or does not upregulate sirtuin protien levels??? (It seems no?)
*Does not regulate NAD+ levels??

My Conculsions:
*Resveratrol would work well in synergy with NAD+ enhancing products: Benagene and Niacin (Niacin has the other perk of decreasing nicitinomide levels)
*Too much Sirtuin activity may begin to be non-beneficial as sirtuins silence more genes than were meant to be silenced in natural CR. This is evidenced by studies showing worse results from CR + Resveratrol than CR alone.
*Ultimately, it may be better to control the genes which sirtuins regulate rather than the sirtuins.

A great (and long) read:
http://www.aapspharm...art=aapsj080472

I'll go back and provide citations later though you can find most citations in above website.

[maxwatt]

If I recall SIRT1 increases NAD deacetylization, which might decrease NAD levels, while increasing its utliization.

[lucid]

It would seem that any method for increasing NAD+ should work especially well in concert with resveratrol. Where as increased NAD+ levels will increase sirtuin expression and activity, and resveratrol will futher increase activity.

I was particularly surpised when reading this: where as it seems that resveratrol would not increase sirtuin expression. (Hence the lack of studies testing sirtuin protien levels in humans cells)

[curious_sle]

Thanks for posting Lucid, i'm keeping an eye on combining Oxaloacetic Acid and Resveratrol but thus far it is still too unclear to warrant the expense. Still no one supplying Oxaloacetic Acid besides the Benagene folks?

[health_nutty]

Anyone notice any difference when combining niacin with resveratrol?

[edward]

snip...
Resveratrol would work well in synergy with NAD+ enhancing products: Benagene and Niacin (Niacin has the other perk of decreasing nicitinomide levels)
snip...

Lucid, do you have references for this? I was under the impression that it was more complicated than this. I am very interested in this possibility.

[lucid]

snip...
Resveratrol would work well in synergy with NAD+ enhancing products: Benagene and Niacin (Niacin has the other perk of decreasing nicitinomide levels)
snip...

Lucid, do you have references for this? I was under the impression that it was more complicated than this. I am very interested in this possibility.

Well I believe what they say about commenting when coding a program also applies to citing when you make a post:
"Always comment your code when programming so that those who are unfamiliar with your code can read it, because in 6 months, that person will be you!"
So yes, I spent a while looking for why I said this and can't come up with much... Nicotinamide is a Nicotinic acid precurssor and hence I thought that increasing NA levels would decrease NAM levels. It is more complicated than that, I'm not sure how NAM levels are effected by exogenous NA supplementation.


At any rate here is the source for increasing NAD+ levels:

EFFECTS NA AND NAM ON NAD+ IN TISSUES

Nicotinamide and nicotinic acid obtained at low doses are readily absorbed and retained by the body, whereas at high doses they are transiently absorbed, and rapidly eliminated from the body, albeit with transient increases in NAD+ levels in tissues such as the liver. Two week treatment of rats with high doses of nicotinic acid and nicotinamide (500 mg kg-1 and 1000 mg kg-1) has been evaluated on NAD+ levels in various tissues (Jackson et al., 1995). Both blood (packed red blood cells) and liver were responsive to increased dosages of nicotinamide or nicotinic acid, leading to increases of 40-60 % in NAD+ content for both tissues for either B3.

Full version available:
http://www.ncbi.nlm....Pubmed_RVDocSum
The 40-60% increased levels of NAD+ are equivilent to fasting levels of NAD+ which is note worthy. I'm tired now, I'll read more of the paper later.

Edited by lucid, 01 February 2008 - 07:45 AM.

[lucid]

Anyone notice any difference when combining niacin with resveratrol?

I make sure to take them at the same time. It works out well since I take a baby aspirin an hour before my 1g of niacin to avoid the flush, the aspirin may have some marginal effects in delaying resveratrol sulfonation. I can't say that I notice that the Resv is more effective on days that I take niacin though...

One important thing to consider is that Resveratrol + CR = less LE than CR alone. If CR is mediated primarily through NAD+ concentrations, then very high doses of niacin + Resv could easily 'over-activate' sirtuins (the effect is multiplicative not additive) and yeild less LE benefit. The dose given mice to increase NAD+ levels was absurdly huge though: 1g/kg, so this likely isn't too much of a worry. Its seems reasonable that 1g of niacin may increases resveratrol effectiveness in the order of 5%-10% or so, but the increase in NAD+ levels from 1g of niacin may be almost nill. (Note: all of that was pure speculation)

[health_nutty]

Anyone notice any difference when combining niacin with resveratrol?

I make sure to take them at the same time. It works out well since I take a baby aspirin an hour before my 1g of niacin to avoid the flush, the aspirin may have some marginal effects in delaying resveratrol sulfonation. I can't say that I notice that the Resv is more effective on days that I take niacin though...

One important thing to consider is that Resveratrol + CR = less LE than CR alone. If CR is mediated primarily through NAD+ concentrations, then very high doses of niacin + Resv could easily 'over-activate' sirtuins (the effect is multiplicative not additive) and yeild less LE benefit. The dose given mice to increase NAD+ levels was absurdly huge though: 1g/kg, so this likely isn't too much of a worry. Its seems reasonable that 1g of niacin may increases resveratrol effectiveness in the order of 5%-10% or so, but the increase in NAD+ levels from 1g of niacin may be almost nill. (Note: all of that was pure speculation)

Do you take your resveratrol and niacin in the morning or at night?

I"ve been taking my resveratrol in the morning because it is stimulating and my niacin at night because it is calming.

[lucid]

Histamine is released as a neurotransmitter. The cell bodies of neurons which release histamine are found in the posterior hypothalamus, in various tuberomammillary nuclei. From here, these histaminergic neurons project throughout the brain, to the cortex through the medial forebrain bundle. Histaminergic action is known to modulate sleep. Classically, antihistamines (H1 histamine receptor antagonists) produce sleep. Likewise, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain vigilance. Finally, H3 receptor antagonists (which stimulate histamine release) increase wakefulness.

It has been shown that histaminergic cells have the most wakefulness-related firing pattern of any neuronal type thus far recorded. They fire rapidly during waking, fire more slowly during periods of relaxation/tiredness and completely stop firing during REM and NREM (non-REM) sleep. Histaminergic cells can be recorded firing just before an animal shows signs of waking.

http://en.wikipedia.org/wiki/Histamine

I take them both in the morning. I have taken niacin before bed and never had much trouble sleeping, I figured I was probably getting better quality of sleep on nights when I take niacin during the morning.

[health_nutty]

Histamine is released as a neurotransmitter. The cell bodies of neurons which release histamine are found in the posterior hypothalamus, in various tuberomammillary nuclei. From here, these histaminergic neurons project throughout the brain, to the cortex through the medial forebrain bundle. Histaminergic action is known to modulate sleep. Classically, antihistamines (H1 histamine receptor antagonists) produce sleep. Likewise, destruction of histamine releasing neurons, or inhibition of histamine synthesis leads to an inability to maintain vigilance. Finally, H3 receptor antagonists (which stimulate histamine release) increase wakefulness.

It has been shown that histaminergic cells have the most wakefulness-related firing pattern of any neuronal type thus far recorded. They fire rapidly during waking, fire more slowly during periods of relaxation/tiredness and completely stop firing during REM and NREM (non-REM) sleep. Histaminergic cells can be recorded firing just before an animal shows signs of waking.

http://en.wikipedia.org/wiki/Histamine

I take them both in the morning. I have taken niacin before bed and never had much trouble sleeping, I figured I was probably getting better quality of sleep on nights when I take niacin during the morning.

Interesting. I thought that the theory that the niacin flush is due to histamine release is debunked.

It doesn't make you tired?

[lucid]

You may be right healthynut,
Here is one of drmz's old posts:

For people interested in a good study about niacin and flushing >> READ THIS ARTICLE

Maciejewski-Lenoir D, Richman JG, Hakak Y, Gaidarov I, Behan DP, Connolly DT.
Arena Pharmaceuticals Inc., San Diego, California 92121, USA. dlenoir@arenapharm.com

Nicotinic acid, used for atherosclerosis treatment, has an adverse effect of skin flushing. The flushing mechanism, thought to be caused by the release of prostaglandin D(2) (PGD(2)), is not well understood. We aimed to identify which cells mediate the flushing effect. Nicotinic acid receptor (GPR109A) gene expression was assessed in various tissues and cell lines. Cells expressing GPR109A mRNA were further assayed for PGD(2) release in response to nicotinic acid. Of all samples, only skin was able to release PGD(2) upon stimulation with nicotinic acid. The responsive cells were localized to the epidermis, and immunocytochemical studies revealed the presence of GPR109A on epidermal Langerhans cells. CD34+ cells isolated from human blood and differentiated into Langerhans cells (hLC-L) also showed GPR109A expression. IFNgamma treatment increased both mRNA and plasma membrane expression of GPR109A. IFNgamma-stimulated hLC-Ls released PGD(2) in response to nicotinic acid in a dose-dependant manner (effector concentration for half-maximum response=1.2 mM+/-0.7). Acifran, a structurally distinct GPR109A ligand, also increased PGD(2) release, whereas isonicotinic acid, a nicotinic acid analog with low affinity for GPR109A, had no effect. These results suggest that nicotinic acid mediates its flushing side effect by interacting with GPR109A on skin Langerhans cells, resulting in release of PGD(2).

Nicotinic acid (niacin) is a B vitamin which is also a potent hypolipidemic agent. However, intense flushing occurs following ingestion of pharmacologic doses of niacin which greatly limits its usefulness in treating hyperlipidemias. Previous studies have demonstrated that niacin-induced flushing can be substantially attenuated by pre-treatment with cyclooxygenase inhibitors, suggesting that the vasodilation is mediated by a prostaglandin. However, the prostaglandin that presumably mediates the flush has not been conclusively determined. In this study we report the finding that ingestion of niacin evokes the release of markedly increased quantities of PGD2 in vivo in humans. PGD2 release was assessed by quantification of the PGD2 metabolite, 9 alpha, 11 beta-PGF2, in plasma by gas chromatography mass spectrometry. Following ingestion of 500 mg of niacin in three normal volunteers, intense flushing occurred and plasma levels of 9 alpha, 11 beta-PGF2 were found to increase dramatically by 800, 430, and 535-fold. Levels of 9 alpha, 11 beta-PGF2 reached a maximum between 12 and 45 min. after ingesting niacin and subsequently declined to near normal levels by 2-4 hours. Levels of 9 alpha, 11 beta-PGF2 in plasma correlated with the intensity and duration of flushing that occurred in the 3 volunteers. Release of PGD2 was not accompanied by a release of histamine which was assessed by quantification of plasma levels of the histamine metabolite, N tau-methylhistamine. This suggests that the origin of the PGD2 release is not the mast cell. Only a modest increase (approximately 2-fold) in the urinary excretion of the prostacyclin metabolite, 2,3-dinor-6-keto-PGF1 alpha, occurred following ingestion of niacin and no increase in the excretion of the major urinary metabolite of PGE2 was found. These results indicate that the major vasodilatory PG released following ingestion of niacin is PGD2. The fact that markedly increased quantities of PGD2 are released suggests that PGD2 is the mediator of niacin-induced vasodilation in humans.

Nicotinic acid is a safe, broad-spectrum lipid agent shown to prevent cardiovascular disease, yet its widespread use is limited by the prostaglandin D(2) (PGD(2)) mediated niacin flush. Previous research suggests that nicotinic acid-induced PGD(2) secretion is mediated by the skin, but the exact cell type remains unclear. We hypothesized that macrophages are a source of nicotinic acid-induced PGD(2) secretion and performed a series of experiments to confirm this. Nicotinic acid (0.1-3mM) induced PGD(2) secretion in cultured human macrophages, but not monocytes or endothelial cells. The PGD(2) secretion was dependent on the concentration of nicotinic acid and the time of exposure. Nicotinuric acid, but not nicotinamide, also induced PGD(2) secretion. Pre-incubation of the cells with aspirin (100muM) entirely prevented the nicotinic acid effects on PGD(2) secretion. The PGD(2) secreting effects of nicotinic acid were additive to the effects of the calcium ionophore A23187 (6muM), but were independent of extra cellular calcium. These findings, combined with recent in vivo work, provide evidence that macrophages play a significant role in mediating the niacin flush and may lead to better strategies to eliminate this limiting side effect.

Facial flushing is the most commonly-reported side-effect.[10] It lasts for about 15 to 30 minutes, and is sometimes accompanied by a prickly or itching sensation. This effect is mediated by prostaglandins and can be blocked by taking 300 mg of aspirin half an hour before taking niacin, or by taking one tablet of ibuprofen per day. Taking the niacin with meals also helps reduce this side-effect. After 1 to 2 weeks of a stable dose, most patients no longer flush. Slow- or "sustained"-release forms of niacin have been developed to lessen these side-effects.[11][12][13] One study showed the incidence of flushing was 4.5x lower (1.9 vs. 8.6 episodes in the first month) with a sustained-release formulation.

Looks like the aspirin still works to mediate the effect, I am presently on a roll for being mis-informed.

[health_nutty]

Lucid, does niacin make you tired?

[lucid]

I haven't noticed it before, so I guess no.