Jump to content


Photo
* * * * * 8 votes

David Sinclair strikes again

aging aging theories david sinclair mitochondria nad sinclair

  • Please log in to reply
505 replies to this topic

#31 niner

  • Member, Moderator
  • 14,556 posts
  • 3,480
  • Location:Philadelphia

Posted 20 December 2013 - 02:53 AM


As far as I can tell, its beta-Nicotinamide mononucleotide. Dr. Sinclair is by no means on the ground floor.


Not at all. It seems almost like a remake of this 2011 study by Yoshino et al (with aging substituted for diabetes).


Wow, Yoshino et al even say:

Furthermore, NAD+ and NAMPT levels show significant decreases in multiple organs during aging, and NMN improves glucose intolerance and lipid profiles in age-induced T2D mice. These findings provide critical insights into a potential nutriceutical intervention against diet- and age-induced T2D.


They do seem to be focused on T2D rather than aging per se, but maybe the real problem is that Yoshino et al just don't have Sinclair's showmanship ability...
  • 3

#32 maxwatt

  • Member, Moderator
  • 4,558 posts
  • 1,415
  • Location:New York

Posted 20 December 2013 - 02:46 PM

It has long been known that increasing the NAD/NADH ratio correlates with longevity. But no one has achieved the results that Sinclair claims.
  • 0

sponsored ad

  • Advert

#33 timar

  • Registered User
  • 549 posts
  • 241
  • Location:Germany

Posted 20 December 2013 - 04:49 PM

What results anyway? Mind you, they didn't report any increased lifespan whatsoever (given the costs for NMN at ~$800/mice/day, they probably didn't have the funding to conduct such a long term study).
  • 0

#34 niner

  • Member, Moderator
  • 14,556 posts
  • 3,480
  • Location:Philadelphia

Posted 20 December 2013 - 10:07 PM

*
POPULAR

You probably don't need to pay Sigma's insane reagent prices. Swanson has nicotinamide riboside for $6.40 per gram. While this isn't nicotinamide mononucleotide (it's missing the phosphate), it looks like it behaves the same way.
  • 4

#35 trance

  • Member
  • 321 posts
  • 111
  • Location:Dallas, Tx

Posted 20 December 2013 - 10:59 PM

Why wouldn't you just supplement with NAD or NADH ?

http://www.iherb.com...60-Lozenges/711

(I see most places are now out of stock, so I guess I wasn't the only one to think of that.)
  • 0

#36 Hebbeh

  • Registered User
  • 1,218 posts
  • 524

Posted 20 December 2013 - 11:09 PM

Sinclair injected massive amounts (500 mg/kg) of NMN to achieve measurable results (over the short term). I question if similar results can be achieved with oral or sublingual dosing (especially lesser amounts) of potential substrates (or NAD) and if supplementation may even lead to down regulation in the pathway causing a net loss over the long term.
  • 0

#37 Darryl

  • Registered User
  • 294 posts
  • 216
  • Location:New Orleans
  • no

Posted 21 December 2013 - 01:48 AM

*
POPULAR

This paper offers some ideas for increasing cellular [NAD+].

Houtkooper, Riekelt H., and Johan Auwerx. "Exploring the therapeutic space around NAD+." The Journal of cell biology 199.2 (2012): 205-209.

Brief literature searches offer these possible interventions:

Precursors:
diet/supplements: nicotinamide, nicotinamide riboside, nicotinic acid, tryptophan
experimental: nicotinamide mononucleotide

AMPK inducers:
lifestyle: caloric restriction, fasting, endurance exercise
diet/supplements: aspirin, berberine, resveratrol, quercetin, anthocyanins, genistein, EGCG, capsaicin, curcumin, garlic oil, hispidulin (Snow Lotus), glabridin (deglycyrrhizinated licorice), gelegine (goats rue)
prescription drugs: metformin, phenformin, rosiglitazone, pioglitazone, troglitazone, salsalate, phenobarbital
experimental: 5-aminoimidazole-4-carboxamide riboside (Acadesine, AICAR), dinitrophenol, oligomycin, 2-deoxyglucose, A23187, A769662, PT1

poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors:
supplements: nicotinamide
experimental: H2O2, 3-aminobenzamide, 1,5-dehydroxyisoquinoline, 5-aminoisoquinolinone, 1,5-isoquinolinediol, N-(6-oxo-5,6-dihydro-phenanthridin-2-yl) -N,N-dimethylacetamide (PJ-34), 5-iodo-6-amino-1,2-benzopyrone; thieno[2,3-c]isoquinolin-5-one, BGP-15, GPI 6150, INO-1001, L-2286

Sirtuin inhibitors (on balance, maybe not a good idea):
supplements: nicotinamide, nicotinamide riboside
experimental: NADH, carbamido-NAD, dihydrocoumarin, splitomicin, 2-OH-napthaldehyde, sirtinol, M15

Another useful review is:

Bogan, Katrina L., and Charles Brenner. "Nicotinic acid, nicotinamide, and nicotinamide riboside: a molecular evaluation of NAD+ precursor vitamins in human nutrition." Annu. Rev. Nutr. 28 (2008): 115-130.

High dose nicotinic acid used to treat dyslipidemia has well known skin flushing side effect. Nicotinamide doesn't cause flushing, but lacks the lipid benefits, and may be hepatotoxic at high doses. Nicotinamide riboside shouldn't cause flushing, and has much greater potential to increase [NAD+] in neurons, but its potential for high-dose hepatoxicity has not been evaluated, and like nicotinamide, its also a potential inhibitor of sirtuins:

Sasaki, Yo, Toshiyuki Araki, and Jeffrey Milbrandt. "Stimulation of nicotinamide adenine dinucleotide biosynthetic pathways delays axonal degeneration after axotomy." The Journal of neuroscience 26.33 (2006): 8484-8491.
Belenky, Peter, et al. "Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD." Cell 129.3 (2007): 473-484.

I suspect one could achieve fairly high [NAD+] with far less than 500 mg/kg of a research reagent by combining high-dose nicotinic acid (if the flushing is tolerable) or more moderate-dose nicotinamide riboside (superior for brain [NAD+], but I'd like to see if it inhibits Sirt1), intermittent fasting + endurance exercise, a high polyphenol diet, aspirin (at AMPK activating dosages), and optionally, berberine or metformin.

Edited by Darryl, 21 December 2013 - 02:10 AM.

  • 4

#38 airplanepeanuts

  • Registered User
  • 122 posts
  • 1
  • Location:Berlin

Posted 21 December 2013 - 02:10 AM

It has long been known that increasing the NAD/NADH ratio correlates with longevity. But no one has achieved the results that Sinclair claims.

Does that mean that taking NADH as a supplement is bad? Sorry if it's a dumb question.
  • 0

#39 Hebbeh

  • Registered User
  • 1,218 posts
  • 524

Posted 21 December 2013 - 02:24 AM


It has long been known that increasing the NAD/NADH ratio correlates with longevity. But no one has achieved the results that Sinclair claims.

Does that mean that taking NADH as a supplement is bad? Sorry if it's a dumb question.


Not necessarily. If you look at the pathways involved in post 28, supplementing NADH may "spare" NAD+ but the pathway is complex and it's difficult to predict. Human biology and metabolism will usually be self correcting to maintain homeostasis and is difficult to "fool" over the long term and why many substances need to be cycled to maintain any degree of effect. I believe the theory behind an increased NAD/NADH ratio is not so much about decreasing NADH as it is about sparing NAD with the assumption that endogenous NADH is derived from NAD+ thus increased endogenous NADH may deplete NAD+.

Edited by Hebbeh, 21 December 2013 - 02:35 AM.

  • 0

#40 bocor

  • Registered User
  • 74 posts
  • 3

Posted 21 December 2013 - 02:29 AM

ok so basically NAD is what we could supplement to mimic these effects.I noticed on iherb.com the sold an NAD supplement from NOW foods it has really good reviews like NADH without the wired feeling it appears NAD from NOW is discontinued!Does anyone know another source for NAD?? thanks
  • 0

#41 Ukko

  • Registered User
  • 141 posts
  • 22
  • Location:In the Multiverse

Posted 21 December 2013 - 02:46 AM

Geez folks. Alpha lipoic (AMPK booster), methylfolate (NAD booster) and NADH (pricey) will get you the results. Well, yeah, maybe with some PQQ and nicotinamide ribo-whatever, will more than suffice...
  • 0

#42 Major Legend

  • Registered User
  • 501 posts
  • 62
  • Location:London

Posted 21 December 2013 - 02:47 AM

http://www.newscient...ml#.UrUAHvQW040

this is a good one.
  • 0

#43 Hebbeh

  • Registered User
  • 1,218 posts
  • 524

Posted 21 December 2013 - 02:51 AM

I did supplement the Enada NADH supplement a number of years ago when it first came out and was all the rage. I remember I bought a bunch of it and trialed it for at least 2-3 months and noticed no effect. Due to the cost and lack of noticed effect, I crossed it off the list. Of course, I don't seem to have any metabolic issues so maybe I wouldn't be able to discern any effect. Most that have reported positive effects, were attempting to correct various apparent metabolic issues I believe.
  • 0

#44 trance

  • Member
  • 321 posts
  • 111
  • Location:Dallas, Tx

Posted 21 December 2013 - 02:55 AM

ok so basically NAD is what we could supplement to mimic these effects.I noticed on iherb.com the sold an NAD supplement from NOW foods it has really good reviews like NADH without the wired feeling it appears NAD from NOW is discontinued!Does anyone know another source for NAD?? thanks


http://www.iherb.com...60-Tablets/1039
  • 0

#45 Hebbeh

  • Registered User
  • 1,218 posts
  • 524

Posted 21 December 2013 - 03:00 AM

Geez folks. Alpha lipoic (AMPK booster), methylfolate (NAD booster) and NADH (pricey) will get you the results. Well, yeah, maybe with some PQQ and nicotinamide ribo-whatever, will more than suffice...


Any references, even anecdotal, to those claims? Most here, I'm sure, have or are using most or all of those (I know I have) and I haven't heard of any miracles. I don't believe any of those are the "bottle neck" or rate limiting substrates impeding the pathway. It's much more complex. Scientists much smarter than me have been pursuing this NAD+ theory of aging for a long time and Sinclair has been the first to report some headway.

Edited by Hebbeh, 21 December 2013 - 03:04 AM.

  • 0

#46 Darryl

  • Registered User
  • 294 posts
  • 216
  • Location:New Orleans
  • no

Posted 21 December 2013 - 03:12 AM

From: Sauve, Anthony A. "NAD+ and vitamin B3: from metabolism to therapies."Journal of Pharmacology and Experimental Therapeutics 324.3 (2008): 883-893.

Two-week treatment of rats with high doses of nicotinic acid and nicotinamide (500 and 1000 mg/kg) 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 to 60% in NAD content for both tissues for either B3. Smaller increases in NADconcentrations not exceeding 15% were observed for 1000 mg kg1 doses of nicotinamide in heart, lung, and kidneys. These findings, on the one hand, appear to confirm that nampt/PBEF activity, which is responsible for recycling nicotinamide to NAD, is typically not rate limited by nicotinamide concentrations in some but not all tissues.

Jackson et al. (1995) also showed that nicotinic acid increases NAD concentrations in liver and blood, similar to nicotinamide. In addition, NAD biosynthesis was increased in heart (50%) and kidney (100%) as well. These results show that nicotinic acid generally has a broader effect than nicotinamide for NAD increases in the body. These results also indicate that the Preiss-Handler pathway is typically operating below saturation in most tissues.


Jackson, Tammy M., et al. "Large supplements of nicotinic acid and nicotinamide increased tissue NAD+ and poly (ADP-ribose) levels but do not affect diethylnitrosamine-induced altered hepatic foci in Fischer-344 rats." The Journal of nutrition 125.6 (1995): 1455-1461.

See also:

Hara, Nobumasa, et al. "Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells." Journal of Biological Chemistry 282.34 (2007): 24574-24582.

Edited by Darryl, 21 December 2013 - 03:31 AM.

  • 1

#47 Hebbeh

  • Registered User
  • 1,218 posts
  • 524

Posted 21 December 2013 - 03:18 AM


ok so basically NAD is what we could supplement to mimic these effects.I noticed on iherb.com the sold an NAD supplement from NOW foods it has really good reviews like NADH without the wired feeling it appears NAD from NOW is discontinued!Does anyone know another source for NAD?? thanks


http://www.iherb.com...60-Tablets/1039


Haha...actually I have 3 bottles of the Source Naturals NAD in front of me. I bought it quite some time back while pursuing this same subject (there have been threads in the past) along with high dose 1500mg Nicotinamide. I started with the high dose Nicotinamide and had intolerable side effects at that dosage which I have discussed several times in other threads and basically terminated my experimentation with high dose Nicotinamide and I throw the unopened bottles of Source Natural NAD into my "failed experiment" box and forgot about them....

Time to continue the experiment to phase 2, I guess.... :cool:
  • 1

#48 bocor

  • Registered User
  • 74 posts
  • 3

Posted 21 December 2013 - 03:30 AM

ok so the NAD+ is basically coenzymated b3 now theres all this talk in the studies about NAD+ precursors reversing malignancy in cancers etc as well as all the positive effects in this latest study are related to now one of these precursors is nicotinamide riboside which is a bit expensive wouldnt this coenzymated b3 which IS ACTUALLY NAD+ be a more direct route? i will reference this study on cancer http://www.ncbi.nlm....pubmed/23426180

which basically says NAD+ prevents cancer and NADH makes cancer more aggressive?I want to make sure that the coenzymated b3 is the NAD+ im not looking to upregulate NADH thanks!
  • 0

#49 Hebbeh

  • Registered User
  • 1,218 posts
  • 524

Posted 21 December 2013 - 03:35 AM

From: Sauve, Anthony A. "NAD+ and vitamin B3: from metabolism to therapies."Journal of Pharmacology and Experimental Therapeutics 324.3 (2008): 883-893.

Two-week treatment of rats with high doses of nicotinic acid and nicotinamide (500 and 1000 mg/kg) 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 to 60% in NAD content for both tissues for either B3. Smaller increases in NADconcentrations not exceeding 15% were observed for 1000 mg kg1 doses of nicotinamide in heart, lung, and kidneys. These findings, on the one hand, appear to confirm that nampt/PBEF activity, which is responsible for recycling nicotinamide to NAD, is typically not rate limited by nicotinamide concentrations in some but not all tissues.

Jackson et al. (1995) also showed that nicotinic acid increases NAD concentrations in liver and blood, similar to nicotinamide. In addition, NAD biosynthesis was increased in heart (50%) and kidney (100%) as well. These results show that nicotinic acid generally has a broader effect than nicotinamide for NAD increases in the body. These results also indicate that the Preiss-Handler pathway is typically operating below saturation in most tissues.


Jackson, Tammy M., et al. "Large supplements of nicotinic acid and nicotinamide increased tissue NAD+ and poly (ADP-ribose) levels but do not affect diethylnitrosamine-induced altered hepatic foci in Fischer-344 rats." The Journal of nutrition 125.6 (1995): 1455-1461.


I would be surprised if anybody could tolerate 1000 mg/kg of nicotinamide. I have experimented with high dose nicotinamide (1500 mg time release...nowhere close to 1000 mg/kg) and wasn't able to make it past a few days due to the side effects which I have discussed in numerous other threads in the past (this NAD issue is really old news and has been discussed many times in past threads).

My main complaint was insatiable and miserable constant feeling of hunger. My girl friend of the time experienced the same effect. It was difficult to work when your mind was constantly consumed with the insatiable gnawing hunger that couldn't be satisfied. Of course we both ate a strictly disciplined moderate carb diet and thus why it was unsustainable...it seemed counter productive to start constantly eating.. :mellow:

Well, I've currently got one of the Source Natural NAD lozenges under my tongue...not sure what to expect...
  • 0

#50 Darryl

  • Registered User
  • 294 posts
  • 216
  • Location:New Orleans
  • no

Posted 21 December 2013 - 03:37 AM

The problem with NAD as a supplement is that its hydrolysed to nicotinamide during digestion. Curiously, both nicotinamide mononucleotide and nicotinamide riboside are intermediaries in this degradation, so its seems likely oral NMN or NR are effectively just expensive nicotinamide.

Gross, Carol J., and Lavell M. Henderson. "Digestion and absorption of NAD by the small intestine of the rat." The Journal of nutrition 113.2 (1983): 412-420

A number of preparations of varying complexity have been used in an effort to elucidate the reactions by which NAD is hydrolyzed to nicotinamide during intestinal digestion. NAD labeled with 14C in the adenine or pyridine moiety was the substrate used with perfused rat intestine, live rats, perfused live rats, with collection of portal flow, intestinal contents, mucosal tissue, or pancreatic juice. The conclusions reached are that a pyrophosphatase present in the intestinal juice and to a much lesser extent in the pancreatic juice releases 5'-AMP and nicotinamide ribonucleotide. The 5'-AMP was rapidly converted to adenosine then to inosine by bacteria-free intestinal contents. Perfused or intact intestine rapidly hydrolyzed NMN to nicotinamide riboside, which accumulated, but was not absorbed. It was slowly cleaved by an enzyme associated with the mucosal cells to nicotinamide, which was the major if not the only labeled compound absorbed.


Maybe sublingual NAD, NMN or NR lozenges would work. Otherwise, get out the hypodermic needles.

Edited by Darryl, 21 December 2013 - 03:51 AM.

  • 2

#51 bocor

  • Registered User
  • 74 posts
  • 3

Posted 21 December 2013 - 03:40 AM

http://www.researchg...cer_progression

another cancer study for NAD+ being helpful or increasing NAD+ to higher balance then NADH
  • 0

#52 Hebbeh

  • Registered User
  • 1,218 posts
  • 524

Posted 21 December 2013 - 03:59 AM

ok so the NAD+ is basically coenzymated b3 now theres all this talk in the studies about NAD+ precursors reversing malignancy in cancers etc as well as all the positive effects in this latest study are related to now one of these precursors is nicotinamide riboside which is a bit expensive wouldnt this coenzymated b3 which IS ACTUALLY NAD+ be a more direct route? i will reference this study on cancer http://www.ncbi.nlm....pubmed/23426180

which basically says NAD+ prevents cancer and NADH makes cancer more aggressive?I want to make sure that the coenzymated b3 is the NAD+ im not looking to upregulate NADH thanks!


I don't think that study says NADH made the cancer more agressive. What I see it saying is...

aberration in mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells


And complex I NADH dehydrogenase is...

http://en.wikipedia....se_(ubiquinone)


Complex I (EC1.6.5.3) (also referred to as NADH:ubiquinone oxidoreductase or, especially in the context of the human protein, NADH dehydrogenase (ubiquinone)) is an enzyme of the respiratory chains of myriad organisms from bacteria to humans. It catalyzes the transfer of electrons from NADH to coenzyme Q10 (CoQ10) and, in eukaryotes, it is located in the innermitochondrial membrane. It is one of the "entry enzymes" of oxidative phosphorylation in the mitochondria.[1]


  • 2

#53 Hebbeh

  • Registered User
  • 1,218 posts
  • 524

Posted 21 December 2013 - 04:09 AM

aberration in mitochondrial complex I NADH dehydrogenase activity can profoundly enhance the aggressiveness of human breast cancer cells


And complex I NADH dehydrogenase is...

http://en.wikipedia....se_(ubiquinone)


Complex I (EC1.6.5.3) (also referred to as NADH:ubiquinone oxidoreductase or, especially in the context of the human protein, NADH dehydrogenase (ubiquinone)) is an enzyme of the respiratory chains of myriad organisms from bacteria to humans. It catalyzes the transfer of electrons from NADH to coenzyme Q10 (CoQ10) and, in eukaryotes, it is located in the innermitochondrial membrane. It is one of the "entry enzymes" of oxidative phosphorylation in the mitochondria.[1]


I wonder if this can help explain the effects of C60/EVOO due to possible positive effects by C60 on the electron transfer chain in the inner mitochondrial membrane? We may have already solved this NAD+ issue with C60/EVOO.....
  • 0

#54 Hebbeh

  • Registered User
  • 1,218 posts
  • 524

Posted 21 December 2013 - 04:19 AM



ok so basically NAD is what we could supplement to mimic these effects.I noticed on iherb.com the sold an NAD supplement from NOW foods it has really good reviews like NADH without the wired feeling it appears NAD from NOW is discontinued!Does anyone know another source for NAD?? thanks


http://www.iherb.com...60-Tablets/1039


Haha...actually I have 3 bottles of the Source Naturals NAD in front of me. I bought it quite some time back while pursuing this same subject (there have been threads in the past) along with high dose 1500mg Nicotinamide. I started with the high dose Nicotinamide and had intolerable side effects at that dosage which I have discussed several times in other threads and basically terminated my experimentation with high dose Nicotinamide and I throw the unopened bottles of Source Natural NAD into my "failed experiment" box and forgot about them....

Time to continue the experiment to phase 2, I guess.... :cool:


Update....just finished one of the Source Natural NAD lozenges under my tongue and did notice a mild but definite mental "buzz" or mild mental energy boost while the lozenge was dissolving quickly followed by subsiding to a feeling of mental clarity. It feels like the effects are subsiding fairly quickly...feels like it may taper over an hour or two...we shall see. I was wondering why I bought these.. :laugh: ..the expiration date was 7/13 but they were sealed and stored in a cool basement closet and sure they are still good. May experiment with higher doses tomorrow.
  • 0

#55 Darryl

  • Registered User
  • 294 posts
  • 216
  • Location:New Orleans
  • no

Posted 21 December 2013 - 04:32 AM

I just missed the edit timeout on my post comparing nicotinic acid and nicotinamide, but believe it would be of interest:

Hara, Nobumasa, et al. "Elevation of cellular NAD levels by nicotinic acid and involvement of nicotinic acid phosphoribosyltransferase in human cells." Journal of Biological Chemistry 282.34 (2007): 24574-24582.

Posted Image

EK293 cells were incubated with indicated concentrations of exogenously added NA (circles) or Nam (squares) for 6 h. After incubation, total cellular contents of NAD (top) and NaAD (bottom) were quantified by ESI-MS assay as described under “Experimental Procedures.” Amounts of NaAD in the presence of Nam were below the limit of detection (bottom).



Nicotinic acid is clearly superior to nicotinamide at inducing NAD production, as it appears the nicotinamide→NAD pathway is saturated at low doses. The level of extracellular nicotinic acid that maximises NAD production is a fairly moderate 5 µm. 500 mg of immediate release nicotinic acid produces plasma peaks of 40-48 µm, above 5 µm for almost 2 hours:

Neuvonen, P. J., et al. "The bioavailability of sustained release nicotinic acid formulations." British journal of clinical pharmacology 32.4 (1991): 473-476.
  • 3

#56 Hebbeh

  • Registered User
  • 1,218 posts
  • 524

Posted 21 December 2013 - 04:42 AM

Nicotinic acid is clearly superior to nicotinamide at inducing NAD production, as it appears the nicotinamide→NAD pathway is saturated at low doses. The level of extracellular nicotinic acid that maximises NAD production is a fairly moderate 5 µm. 500 mg of immediate release nicotinic acid produces plasma peaks of 40-48 µm, above 5 µm for almost 2 hours:


Good Find! But I can't help realizing that many have been supplementing those doses of niacin for cholesterol management for years and benefits of increases of NAD+ have never been reported. Since I don't have cholesterol issues, I've never bothered to high dose niacin and chose nicotinamide in my previous experiments to avoid the flushing.
  • 0

#57 Darryl

  • Registered User
  • 294 posts
  • 216
  • Location:New Orleans
  • no

Posted 21 December 2013 - 06:05 AM

many have been supplementing those doses of niacin for cholesterol management for years and benefits of increases of NAD+ have never been reported.


Keyword searches on NAD and nicotinic acid are a nightmare, but it appears the only human studies on niacin (any form) and NAD+ concentration have been looking for biomarkers of niacin deficiency. Eg

Fu, Casey S., et al. "Biochemical markers for assessment of niacin status in young men: levels of erythrocyte niacin coenzymes and plasma tryptophan."The Journal of nutrition 119.12 (1989): 1949.

It would be easy to run a similar test comparing NAD levels in Niaspan patients with matched patients on other lipid drugs, or crossover studies on volunteers, but it hasn't been done. As far as human aging outcome studies, the closest thing is really:

Canner, Paul L., et al. "Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin." Journal of the American College of Cardiology 8.6 (1986): 1245-1255.

Niacin treatment showed modest benefit in decreasing definite nonfatal recurrent myocardial infarction but did not decrease total mortality. With a mean follow-up of 15 years, nearly 9 years after termination of the trial, mortality from all causes in each of the drug groups, except for niacin, was similar to that in the placebo group. Mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004). This late benefit of niacin, occurring after discontinuation of the drug, may be a result of a translation into a mortality benefit over subsequent years of the early favorable effect of niacin in decreasing nonfatal reinfarction or a result of the cholesterol-lowering effect of niacin, or both.


Of interest, nicotinic acid also showed non-significant benefits of similar magnitude in cancer and other non-vascular disease (most in this cohort still died of CVD). There doesn't appear to be a great deal of interest in nicotinic acid as a longevity drug - maybe the flushing is a deterrant, maybe it has fallen under the shadow of nicotinamide (a potent sirtuin inhibitor).

Interestingly, nicotinamide was the most potent inhibitor (IC50 0.126 mM), while nicotinic acid (IC50 250 mM) was the worst inhibitor, displaying almost a 2000-fold difference in efficiency


Schmidt, Manning T., et al. "Co-enzyme specificity of Sir2 protein deacetylases: Implications for physiological regulation." Journal of Biological Chemistry (2004).

As an aside, given a concurrent thread about high dose aspirin for AMPK induction (which would <<bing>> increase NAD+ synthesis). Concurrent administration of aspirin would both reduce flushing, and impede metabolic clearance of the nicotinic acid:

Wilkin, Jonathan K., et al. "Aspirin blocks nicotinic acid–induced flushing."Clinical Pharmacology & Therapeutics 31.4 (1982): 478-482.
Ding, Reinhard W., et al. "Pharmacokinetics of nicotinic acid–salicylic acid interaction." Clinical Pharmacology & Therapeutics 46.6 (1989): 642-647.

Edited by Darryl, 21 December 2013 - 06:23 AM.

  • 2

#58 Darryl

  • Registered User
  • 294 posts
  • 216
  • Location:New Orleans
  • no

Posted 21 December 2013 - 12:48 PM

Another way to skin this cat: CD38 inhibition by dietary flavonoids

Cantó, Carles, and Johan Auwerx. "Targeting sirtuin 1 to improve metabolism: all you need is NAD+?." Pharmacological reviews 64.1 (2012): 166-187.

The function of CD38 as an intracellular NADase was subsequently proven right when mice lacking CD38 displayed a 30-fold increase in intracellular NAD levels (Aksoy et al., 2006b). This increase in NAD levels is far superior compared with the 2-fold increases generally observed in most genetic (PARP-1 deletion), pharmacological (NAD precursors), or physiological interventions (fasting, calorie restriction) that enhance NAD content. The increase in intracellular NAD elicited by CD38 deletion significantly activated SIRT1 and prompted clinical phenotypes similar to those expected for SIRT1 activation, including protection against diet-induced obesity and a robust deacetylation of SIRT1 targets (Aksoy et al., 2006).



Kellenberger, Esther, et al. "Flavonoids as inhibitors of human CD38." Bioorganic & medicinal chemistry letters 21.13 (2011): 3939-3942.

The dire paucity of CD38 inhibitors, however, renders the search for new molecular tools highly desirable. We report that human CD38 is inhibited at low micromolar concentrations by flavonoids such as luteolinidin, kuromanin (cyanidin-3-O-β-glucoside) and luteolin (IC50 <10 μM).



Escande, Carlos, et al. "Flavonoid apigenin Is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome." Diabetes 62.4 (2013): 1084-1093.

Previously, we reported that CD38 is the primary NAD+ase in mammals. Moreover, CD38 knockout mice have higher NAD+ levels and are protected against obesity and metabolic syndrome. Here, we show that CD38 regulates global protein acetylation through changes in NAD+ levels and sirtuin activity. In addition, we characterize two CD38 inhibitors: quercetin and apigenin. We show that pharmacological inhibition of CD38 results in higher intracellular NAD+ levels and that treatment of cell cultures with apigenin decreases global acetylation as well as the acetylation of p53 and RelA-p65. Finally, apigenin administration to obese mice increases NAD+ levels, decreases global protein acetylation, and improves several aspects of glucose and lipid homeostasis.



It appears the most concentrated source for luteolinidin is black sorghum bran, while the most concentrated source for cyanidin-3-O-β-glucoside is purple corn color, an approved food color which contains some luteolinidin as well. According to the USDA flavonoid database, the best sources for luteolin are oregano, celery seed, juniper berries, thyme, and radicchio. Apigenin (parsley, celery seed, kumquats, celery hearts, oregano) and quercetin (capers, radishes, dill weed, coriander/cilantro, oregano, onions) from the Escande et al paper had slightly lower potency (IC50s of 14.8 and 16.4 μM).

This animal study certainly looks exactly like Sirt1 activation:

Tsuda, Takanori, et al. "Dietary cyanidin 3-O-β-D-glucoside-rich purple corn color prevents obesity and ameliorates hyperglycemia in mice." The Journal of nutrition 133.7 (2003): 2125-2130.

Mice were fed control, cyanidin 3-glucoside-rich purple corn color (PCC), high fat (HF) or HF + PCC diet for 12 wk. Dietary PCC significantly suppressed the HF diet–induced increase in body weight gain, and white and brown adipose tissue weights. Feeding the HF diet markedly induced hypertrophy of the adipocytes in the epididymal white adipose tissue compared with the control group. In contrast, the induction did not occur in the HF + PCC group. The HF diet induced hyperglycemia, hyperinsulinemia and hyperleptinemia. These perturbations were completely normalized in rats fed HF + PCC. An increase in the tumor necrosis factor (TNF)-α mRNA level occurred in the HF group and was normalized by dietary PCC. These results suggest that dietary PCC may ameliorate HF diet–induced insulin resistance in mice. PCC suppressed the mRNA levels of enzymes involved in fatty acid and triacylglycerol synthesis and lowered the sterol regulatory element binding protein-1 mRNA level in white adipose tissue.


Edited by Darryl, 21 December 2013 - 01:08 PM.

  • 2

#59 maxwatt

  • Member, Moderator
  • 4,558 posts
  • 1,415
  • Location:New York

Posted 21 December 2013 - 01:00 PM

http://juvenon.com/j.../Vitamin-NR.pdf

The NAD+Precursor Nicotinamide Riboside
Enhances Oxidative Metabolism
and Protects against High-Fat Diet-Induced Obesity

Carles Canto´,
1,6,7 Riekelt H. Houtkooper,1,6,8 Eija Pirinen,1,2 Dou Y. Youn,3 Maaike H. Oosterveer,1 Yana Cen,3

Pablo J. Fernandez-Marcos,1 Hiroyasu Yamamoto,1 Pe´ne´lope A. Andreux,1 Philippe Cettour-Rose,1 Karl Gademann,4
Chris Rinsch,5 Kristina Schoonjans,1 Anthony A. Sauve,3 and Johan Auwerx1,
DOI 10.1016/j.cmet.2012.04.022

SUMMARY

As NAD+ is a rate-limiting cosubstrate for the sirtuin
enzymes, its modulation is emerging as a valuable
tool to regulate sirtuin function and, consequently,
oxidative metabolism. In line with this premise,
decreased activity of PARP-1 or CD38—both NAD+
consumers—increases NAD+ bioavailability, resulting
in SIRT1 activation and protection against metabolic
disease. Here we evaluated whether similar
effects could be achieved by increasing the supply
of nicotinamide riboside (NR), a recently described
natural NAD+ precursor with the ability to increase
NAD+ levels, Sir2-dependent gene silencing, and
replicative life span in yeast. We show that NR
supplementation in mammalian cells and mouse
tissues increases NAD+ levels and activates SIRT1
and SIRT3, culminating in enhanced oxidative
metabolism and protection against high-fat dietinduced
metabolic abnormalities. Consequently,
our results indicate that the natural vitamin NR could
be used as a nutritional supplement to ameliorate
metabolic and age-related disorders characterized
by defective mitochondrial function.
  • 0

sponsored ad

  • Advert

#60 Ukko

  • Registered User
  • 141 posts
  • 22
  • Location:In the Multiverse

Posted 21 December 2013 - 01:46 PM


Geez folks. Alpha lipoic (AMPK booster), methylfolate (NAD booster) and NADH (pricey) will get you the results. Well, yeah, maybe with some PQQ and nicotinamide ribo-whatever, will more than suffice...


Any references, even anecdotal, to those claims? Most here, I'm sure, have or are using most or all of those (I know I have) and I haven't heard of any miracles. I don't believe any of those are the "bottle neck" or rate limiting substrates impeding the pathway. It's much more complex. Scientists much smarter than me have been pursuing this NAD+ theory of aging for a long time and Sinclair has been the first to report some headway.


Basic common knowledge. Note that Sinclar's dose was insanely high.

E.g. here http://www.ncbi.nlm....pubmed/22456698

Edited by Ukko, 21 December 2013 - 01:46 PM.

  • 0





Also tagged with one or more of these keywords: aging, aging theories, david sinclair, mitochondria, nad, sinclair

1 user(s) are reading this topic

0 members, 1 guests, 0 anonymous users