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Apigenin to Inhibit NAD+ Consumer CD38

nad+ apigenin consumer inhibit cd38

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#1 Nate-2004

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Posted 31 August 2018 - 07:25 PM


So per other discussion threads outlining the problems with NAD+ precursors (not enough NAMPT for salvage, NAM byproduct, salvage cycle dysregulation) there have been notable strides by startups to pursue ways to improve NAD+ levels by indirect means. One of these would be CD38 inhibition and while Apigenin has been discussed off topic in NAD+ threads I don't think it's been discussed in this capacity and context on its own. At least not according to a forum search.

 

Is there harm in CD38 inhibition? Complete inhibition? Probably, but apigenin is likely a weak inhibitor. Quercetin as well.

 

 

Mouse study:

 

 

https://www.ncbi.nlm...les/PMC3609577/

 

 

Abstract

Metabolic syndrome is a growing health problem worldwide. It is therefore imperative to develop new strategies to treat this pathology. In the past years, the manipulation of NAD(+) metabolism has emerged as a plausible strategy to ameliorate metabolic syndrome. In particular, an increase in cellular NAD(+) levels has beneficial effects, likely because of the activation of sirtuins. 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. Our results show that CD38 is a novel pharmacological target to treat metabolic diseases via NAD(+)-dependent pathways.

 

 

 

This article mentions the above in vivo mouse study in passing, perhaps just as an avenue of exploration. No big patent money can be made off apigenin so nobody's paying for the research.

https://www.scienced...550413116302248

 

 

That's it, that's all there is above. Nothing else on apigenin published in this context of research. It's in vitro and both quercetin AND apigenin have absolutely terrible bioavailability problems. The study referenced uses injection to deliver the apigenin. Other studies show 11mg / 100mg at best in terms of absorption. It's fat soluble so ways to improve absorption may be black pepper extract or certain fats taken with or perhaps a liposomal solution.

 

Yet for now, it's all we have. If CD38 is in fact inhibited, in humans, in vivo, with apigenin, then maybe, just maybe it might be a better, cheaper alternative to NAD+ precursors.

 

Anybody on this board aged 60+ want to try washing out and using some agreed upon formulation of apigenin? The only brand that sells this is Swanson, so unfortunately we have to rely on the hope that their labels are accurate.

 

This article mentions the above in vitro study in passing, perhaps just as an avenue of exploration. No big patent money can be made off apigenin so nobody's paying for the research.

https://www.scienced...550413116302248

 

 

That's it, that's all there is above. Nothing else on apigenin published in this context of research. It's in vitro and both quercetin AND apigenin have absolutely terrible bioavailability problems. The study referenced uses injection to deliver the apigenin. Other studies show 11mg / 100mg at best in terms of absorption. It's fat soluble so ways to improve absorption may be black pepper extract or certain fats taken with or perhaps a liposomal solution.

 

Yet for now, it's all we have. If CD38 is in fact inhibited, in humans, in vitro, with apigenin, then maybe, just maybe it might be a better, cheaper alternative to NAD+ precursors.

 

Anybody on this board aged 60+ want to try washing out and using some agreed upon formulation of apigenin? The only brand that sells this is Swanson, so unfortunately we have to rely on the hope that their labels are accurate.

 

 


Edited by Nate-2004, 31 August 2018 - 08:01 PM.

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#2 Oakman

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Posted 31 August 2018 - 09:35 PM

I took Swanson's Apigenin for months, bought lots of bottles (Swanson often has sales), and took it along with Quercetin (EnduraQ - isoquercetin) and other supps daily. This was back when broccoli sprouts were the hot 'thing' of the moment. I wish I could tell you it did everything I was hoping for, but I felt nothing, saw nothing change, and frankly doubt anything really did. Also, nothing negative either, which is good. Thinking the body has a way to equalize out things, esp when taken in such small does. Plus, without multiple suppliers, stuff like this get pretty pricey for the long haul of daily dosing.

 

I have read recently, when investigating the above story, that inhibiting CD38 is not always a good idea. After all it's there for a reason, we simply want to cut it down, not stop it, so there are cautions.


Edited by Oakman, 31 August 2018 - 09:38 PM.

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#3 Michael

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Posted 31 August 2018 - 09:36 PM

Happily, I can disclose that someone (not SENS Research Foundation, and not any of "the usual suspects" in the NAD+ research universe) is doing a human study on apigenin's effects on NAD+. I don't know when we can expect results, but they're coming.


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#4 John250

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Posted 31 August 2018 - 09:41 PM

What are the negatives of CD38 inhibition ?
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#5 Phoebus

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Posted 31 August 2018 - 10:01 PM

I think luteolin is a much better candidate given apigenin's poor bioavailability. 

 

My question is this - do flavonoids like quercetin apigenin and luteolin inhibit cd38 directly or indirectly? Flavonoids are anti inflammatory, and decreases in inflammation are associated with CD38 decreases. So do flavonoids decrease CD38 simply because they decrease inflammation? 



#6 Phoebus

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Posted 31 August 2018 - 10:06 PM

What are the negatives of CD38 inhibition ?

 

here

 

https://www.ncbi.nlm...83294/#S15title

 

 

 

 

 First, it is important to say that it is possible that molecules that inhibit CD38 may also inhibit SIRT1 [71]. In fact, SIRT1 and CD38 have several similarities in their enzymatic and catalytical properties [71], and CD38 has been proposed as a model enzyme for the study of the mechanism of SIRT1 catalysis [71]. Both SIRT1 and CD38 degrades NAD to nicotinamide and an ADPR derivative. Furthermore, both enzymes are capable of base-exchange reaction (Fig. 1B). In this regard, inhibitors of CD38 may also have effects upon SIRT1 activity, a potential undesirable “side-effect”. Secondly, as discussed above CD38 have other functions that are mediated by the generation of calcium regulating second messengers such as smooth muscle contraction, cell death, and apoptosis, neural and hormonal signaling, egg fertilization and others [2921697273]. In this regard, CD38 inhibitors may have beneficial effects upon conditions, where cellular calcium homeostasis is deregulated such as in hypertension, cardiac ischemia, asthma and dysfunctional labor [2921697273]. On the other hand, CD38 has been implicated in the secretion and function of hormones such as oxytocin and ACTH [7475], and may modulate maternal and social behavior [75]. These roles indicate that inhibition of CD38 may have potential deleterious effects. Potential immunologic dysfunction may be one of the worst possible “side-effects” of CD38 inhibitors. It has been shown that CD38 plays a key role in the mechanism by which the organism fights bacterial infection [76], and knockout of CD38 leads to increase susceptibility to lethal bacterial infection [76]. Despite these limitations, the search for CD38 inhibitors and the determination of their potential therapeutic roles will generate key new data that will provide new insights on multiple physiological and pathological conditions, and CD38 inhibitors may hold the key to new therapeutic strategies to multiple metabolic and inflammatory conditions. 

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#7 Nate-2004

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Posted 01 September 2018 - 02:50 PM

What are the negatives of CD38 inhibition ?

 

I honestly don't believe apigenin would completely inhibit CD38 anymore than an anti-inflammatory completely inhibits inflammation, it may just bring it down somewhat, hopefully enough to have an effect on NAD+ consumption.


Edited by Nate-2004, 01 September 2018 - 02:52 PM.


#8 Harkijn

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Posted 01 September 2018 - 04:06 PM

Good idea to take another look  at CD38 Nate.  I suppose the question will be: howmuch inhibition is good and howmuch too much?

Some weeks ago another member posted this and i wondered why his thread didn't make a bigger splash:

https://www.longecit...nd-mayo-clinic/



#9 Nate-2004

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Posted 01 September 2018 - 04:09 PM

Good idea to take another look  at CD38 Nate.  I suppose the question will be: howmuch inhibition is good and howmuch too much?

Some weeks ago another member posted this and i wondered why his thread didn't make a bigger splash:

https://www.longecit...nd-mayo-clinic/

 

Honestly I dunno, but I honestly doubt any drugs developed could inhibit it so completely as to cause dysfunction, maybe, maybe not. Most herbal extracts tend to be weak inhibitors/activators anyway. Especially where enzymes are concerned because they're competitively inhibited.


Edited by Nate-2004, 01 September 2018 - 04:09 PM.


#10 Nate-2004

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Posted 01 September 2018 - 04:54 PM

I took Swanson's Apigenin for months, bought lots of bottles (Swanson often has sales), and took it along with Quercetin (EnduraQ - isoquercetin) and other supps daily. This was back when broccoli sprouts were the hot 'thing' of the moment. I wish I could tell you it did everything I was hoping for, but I felt nothing, saw nothing change, and frankly doubt anything really did. Also, nothing negative either, which is good. Thinking the body has a way to equalize out things, esp when taken in such small does. Plus, without multiple suppliers, stuff like this get pretty pricey for the long haul of daily dosing.

 

I have read recently, when investigating the above story, that inhibiting CD38 is not always a good idea. After all it's there for a reason, we simply want to cut it down, not stop it, so there are cautions.

 

1. I think sprouts and broccoli in general are still a thing lol. I don't tend to eat sprouts, I just put 100g of broccoli in my smoothies and treat it with 60c water and blend before I add other ingredients. I also take broccomax with it whenever I do drink these.

2. You're 69 (awesome age to be lol), so I'm wondering how you took it. Any fats or stuff to make it more bioavailable? There's so little info out there on this but what little there is suggests, as I mentioned in my OP, that it's 11mg/100mg at best. I can't even remember where I read that either.

3. Yeah cutting it down to earlier levels would possibly be good, or better yet, figuring out why it is on the rise conversely with the drop in NAD+. My best guess is SASP but nobody's proven that.


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#11 Oakman

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Posted 01 September 2018 - 11:15 PM

1. I think sprouts and broccoli in general are still a thing lol. I don't tend to eat sprouts, I just put 100g of broccoli in my smoothies and treat it with 60c water and blend before I add other ingredients. I also take broccomax with it whenever I do drink these.

2. You're 69 (awesome age to be lol), so I'm wondering how you took it. Any fats or stuff to make it more bioavailable? There's so little info out there on this but what little there is suggests, as I mentioned in my OP, that it's 11mg/100mg at best. I can't even remember where I read that either.

3. Yeah cutting it down to earlier levels would possibly be good, or better yet, figuring out why it is on the rise conversely with the drop in NAD+. My best guess is SASP but nobody's proven that.

 

I love fresh broccoli and eat it whenever I can, but as a backup supplement I use bulk broccoli sprout extract for convenience and cost.  I cycle it with long off periods, but on it's an AM/PM ~400mgs/dose with a light meal. 

 

It's fun to talk about suppressing CD38, but we know little about how. For 69, I feel like I have an abundance of energy, to a point.  What I already take could help, or maybe my NMN & NR based NAD+ supply just surpasses CD38's capacity to suppress?  I see CD38 suppression w/sups  as a "that would be nice" goal from  perhaps diet, sups, or maybe real drugs or some combo. It seems to be a hot topic right now, if you believe press releases, so it will be interesting going forward. Clarity would be nice!


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#12 Michael

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Posted 01 September 2018 - 11:45 PM

Good idea to take another look  at CD38 Nate.  I suppose the question will be: howmuch inhibition is good and howmuch too much?

Some weeks ago another member posted this and i wondered why his thread didn't make a bigger splash:

https://www.longecit...nd-mayo-clinic/

 

As I've just commented on that thread, I believe the OP in that thread  jumped to a mistaken conclusion. The headline says "Elysium Health™ Announces Exclusive License for Use of Nicotinamide Riboside for the Slowing of Aging and Prevention of Age-Related Diseases from Mayo Clinic and Harvard" — nothing about CD38. The article does discuss Chini's work on CD38 in NAD+ metabolism, but nothing says they're licensing his patents for this. And they say they're licensing a "pending patent," whereas his CD38 inhibitor patents are already approved and published.


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#13 Harkijn

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Posted 02 September 2018 - 06:02 AM

On a side note:

As most will have noticed there is an active Resveratrol thread about RSV and RSV analogues rejuvenating human cells.

Bill Sardi, owner of Longevinex, may have a commercial interest here, but  he does know a bit or two about the subject. His guess is that the analogues are...apigenin.

 

http://www.resveratrolnews.com/


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#14 Phoebus

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Posted 02 September 2018 - 01:35 PM

On a side note:

As most will have noticed there is an active Resveratrol thread about RSV and RSV analogues rejuvenating human cells.

Bill Sardi, owner of Longevinex, may have a commercial interest here, but  he does know a bit or two about the subject. His guess is that the analogues are...apigenin.

 

http://www.resveratrolnews.com/

 

interesting. Can you tell me which of those many articles he speaks about apigenin in ? 

 

thanks 



#15 Phoebus

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Posted 02 September 2018 - 01:44 PM

wow! Look at  this study was to improve the anti-inflammatory activities of apigenin through co-treatment with resveratrol

 

basically resv. helped to increase bioavailability of apigenin. Something to consider 

 

 

Nutrients. 2015 Nov; 7(11): 9650–9661.

Published online 2015 Nov 19. doi:  10.3390/nu7115485
PMCID: PMC4663613
PMID: 26610561
Resveratrol as a Bioenhancer to Improve Anti-Inflammatory Activities of Apigenin
Abstract

The aim of this study was to improve the anti-inflammatory activities of apigenin through co-treatment with resveratrol as a bioenhancer of apigenin. RAW 264.7 cells pretreated with hepatic metabolites formed by the co-metabolism of apigenin and resveratrol (ARMs) in HepG2 cells were stimulated with lipopolysaccharide (LPS). ARMs prominently inhibited (p < 0.05) the production of nitric oxide (NO), prostaglandin E2 (PGE2), interleukin (IL)-1β, IL-6 and TNF-α. Otherwise no such activity was observed by hepatic metabolites of apigenin alone (AMs). ARMs also effectively suppressed protein expressions of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Co-administration of apigenin (50 mg/kg) and resveratrol (25 mg/kg) also showed a significant reduction of carrageenan-induced paw edema in mice (61.20% to 23.81%).

Co-administration of apigenin and resveratrol led to a 2.39 fold increase in plasma apigenin levels compared to administration of apigenin alone, suggesting that co-administration of resveratrol could increase bioavailability of apigenin.

When the action of resveratrol on the main apigenin metabolizing enzymes, UDP-glucuronosyltransferases (UGTs), was investigated, resveratrol mainly inhibited the formation of apigenin glucuronides by UGT1A9 in a non-competitive manner with a Kivalue of 7.782 μM. These results suggested that resveratrol helps apigenin to bypass hepatic metabolism and maintain apigenin’s anti-inflammatory activities in the body.

 


Edited by Phoebus, 02 September 2018 - 01:45 PM.

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#16 Harkijn

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Posted 02 September 2018 - 02:47 PM

interesting. Can you tell me which of those many articles he speaks about apigenin in ? 

 

thanks 

The first one on your screen... ;)


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#17 Nate-2004

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Posted 02 September 2018 - 04:03 PM

wow! Look at  this study was to improve the anti-inflammatory activities of apigenin through co-treatment with resveratrol

 

basically resv. helped to increase bioavailability of apigenin. Something to consider 

 

In mice with *injected* apigenin. It's not even a real test and with absolutely no followup for more realistic scenarios. 


Edited by Nate-2004, 02 September 2018 - 04:13 PM.

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#18 QuestforLife

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Posted 03 September 2018 - 08:57 AM

On a side note:

As most will have noticed there is an active Resveratrol thread about RSV and RSV analogues rejuvenating human cells.

Bill Sardi, owner of Longevinex, may have a commercial interest here, but  he does know a bit or two about the subject. His guess is that the analogues are...apigenin.

 

http://www.resveratrolnews.com/

 

Nope, they weren't - read the paper.

Attached Files


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#19 Phoebus

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Posted 03 September 2018 - 12:54 PM

Nope, they weren't - read the paper.

 

 

here is the fulll study. They simply refer to their compounds as "novel resveralogues" so it looks like something they intend to patent. Whether anything in that study resembles apigenin I cant say. 

 

 

https://bmccellbiol....2860-017-0147-7



#20 QuestforLife

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Posted 03 September 2018 - 03:24 PM

They didn't test Apigenin, but it's molecular structure is not dissimilar (though not the same as) those tested.

 

I'm sure they'd love to patent something, but so far they've not found anything better than resveratrol, atleast according to this paper.

 

 

 

 



#21 Phoebus

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Posted 03 September 2018 - 10:31 PM

They didn't test Apigenin, but it's molecular structure is not dissimilar (though not the same as) those tested.

 

I'm sure they'd love to patent something, but so far they've not found anything better than resveratrol, atleast according to this paper.

 

 

I was noticing that as I read thru the study Res itself performed just as well as the 'novel' resveralogues. IN fact there were several tests where they only test the novel chemicals and didn't bother comparing the novel chemicals to Res itself. Odd. 


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#22 Phoebus

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Posted 04 September 2018 - 12:22 AM

in the other thread we were discussing AMPK's ability to upregulate NAMPT and therefore recycle NAD 

 

apigenin upregulates AMPK in this study 

 

 

Mol Carcinog. 2012 Mar;51(3):268-79.

 

doi: 10.1002/mc.20793. Epub 2011 May 2.

Apigenin, a chemopreventive bioflavonoid, induces AMP-activated protein kinase activation in human keratinocytes.
 
 
Abstract

AMP-activated protein kinase (AMPK) is a cellular energy sensor that is conserved in eukaryotes. Although AMPK is traditionally thought to play a major role in the regulation of cellular lipid and protein metabolism, recent discoveries reveal that AMPK inhibits mammalian target of rapamycin (mTOR) signaling and connects with several tumor suppressors such as liver kinase B1 (LKB1), p53, and tuberous sclerosis complex 2 (TSC2), indicating that AMPK may be a potential target for cancer prevention and treatment.

For the first time, we demonstrated that apigenin, a naturally occurring nonmutagenic flavonoid, induced AMPK activation in human keratinocytes (both cultured HaCaT cell line and primary normal human epidermal keratinocytes).

Through experiments with over-expression of constitutively active Akt and knockdown of LKB1 expression by siRNAs, we further found that the activation of AMPK by apigenin was not dependent on its inhibition of Akt, and was independent of the activation of upstream kinase LKB1. Instead, another upstream kinase of AMPK, calcium/calmodulin-dependent protein kinase kinase-β (CaMKKβ), was required for apigenin-induced AMPK activation. We have demonstrated that knockdown of CaMKKβ expression by siRNA or inhibition of CaMKKβ activity by either CaMKK inhibitor STO-609 or BAPTA-AM (1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester; a chelator of intracellular Ca(2+)) prevented apigenin-induced AMPK activation.

Apigenin-induced AMPK activation inhibited mTOR signaling and further induced autophagy in human keratinocytes. These results suggest that one of the mechanisms by which apigenin exerts its chemopreventive action may be through activation of AMPK and induction of autophagy in human keratinocytes.

https://www.ncbi.nlm...pubmed/21538580


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#23 QuestforLife

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Posted 04 September 2018 - 08:19 AM

I was noticing that as I read thru the study Res itself performed just as well as the 'novel' resveralogues. IN fact there were several tests where they only test the novel chemicals and didn't bother comparing the novel chemicals to Res itself. Odd. 

 

The main reason for making the analogues was to unpick what was going on - the analogues had different effects on the SASP and one did not activate SIRT1 at all, but all had a rejuvenating effect. They focussed their efforts on unpicking splicing factors (that splice together mRNA in slightly different ways to affect gene expression) to explain this. One of the most interesting splicing factors is SRSF2, which is likely important because it is near the telomere and has altered expression levels as the telomere shortens, then possibly having a knock on effect on other genes that are effected by this splicing factor [1]. Indeed the same team that looked at the resveratrol analogues went on to show what only upregulating SRSF2 (with 1 other splicing factor) could do in old cells, by using hydrogen sulphide [2]. This has been discussed further elsewhere on other threads.

 

references:

 

[1] https://onlinelibrar...1111/acel.12646

[2] https://www.ncbi.nlm...pubmed/30026406


Edited by QuestforLife, 04 September 2018 - 08:25 AM.

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#24 Harkijn

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Posted 25 October 2018 - 06:48 AM

Elsewhere in these NAD forums much attention is given to the AMA wiith dr. Sinclair. Here I just want to draw your attention to the fact that in that AMA he rather enthusiastically supports CD38 inhibition.

This doesn't prove or disprove anything about CD38, but he is a leader in this field so it is good to know his thoughts about this.


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#25 HBRU

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Posted 10 December 2019 - 03:00 PM

Inhibiting CD38 still seems a good idea... new study

 

https://www.ncbi.nlm...les/PMC5935140/

 

Its not a free lunch anyway...

http://www.jbc.org/c...4/43/29335.full

 


Edited by HBRU, 10 December 2019 - 03:23 PM.

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#26 osris

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Posted 28 January 2020 - 06:11 PM

Proanthocyanidins (such as grape seed extract) regulate but don't remove CD38. This might be a safer alternative than complete CD38 removal. See the following. You will need to scroll down to find the references to CD38:
 

Edited by osris, 28 January 2020 - 06:13 PM.


#27 Castiel

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Posted 13 February 2020 - 04:53 PM

https://www.youtube....h?v=hggLOXhFRxc

 

I think Rhonda Patrick's comments, on research papers, suggest that neither NR nor NMN boost NAD+ in the brain.    So alternate substances that boost nad+ would be beneficial.



#28 gamesguru

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Posted 13 February 2020 - 09:15 PM

Apigenin definitely sticks out in my mind, can't recollect it all.  But has some interesting glutamate and serotonin effects, mitochondrial health and neurogenesis.

 

I wouldn't be surprised if it was found helpful in studies of depression or dementia.



#29 Michael Lustgarten

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Posted 02 February 2021 - 11:51 PM

Although they didn't measure NAD+, apigenin increases muscle mass in both young and old mice:


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#30 Castiel

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Posted 14 February 2021 - 04:06 PM

Chamomile tea that has apigenin is said to reduce mortality in women by 28%.    Which should result in increased lifespan.

 

A cup of Chamomile tea everyday may extend your lifespan:  Apigenin-based anti-ageing and Lifespan extension therapy:  Apigenin (4′,5,7-trihydroxyflavone), the main constituent of Chamomile tea and others, increases CHIP levels, increases monoubiquitylation of insulin receptor (INSR), decreases INSR protein levels, increases telomerase levels, and enhances lifespan, via up regulation of its target gene, 20/December/2019, 12.47 pm (genomediscovery.org)


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