30 replies to this topic

[Bryan_S]

Role of CD38 in age-related NAD+ depletion: implication for age-related metabolic dysfunction and NAD+ replacement therapy.

 

http://www.sbbq.org....os/R08029-1.pdf

 

Juliana Camacho-Pereira 1,2 , Veronica Nin 2 , Claudia Chini2 , Mariana Tarrago 2 , Antonio Galina 1 , Eduardo Chini2

 

1Federal University of Rio de Janeiro, UFRJ, Rio de Janeiro, RJ, Brazil; 2Mayo Clinic College of Medicine, Kogod Aging Center and Anesthesiology Department, Rochester, MN, EUA

 

A decrease in intracellular levels of nicotinamide adenine dinucleotide (NAD+) has been shown to occur during the aging process. This decrease in NAD+ levels has a causal role on the development of age-related mitochondrial dysfunction and metabolic decline. To date, the mechanisms responsible for the age-related NAD+ decline have not been identified. It has been proposed that accumulation of DNA damage driven PARP activation may be involved. However, we identify that PARP levels and activity decline with aging. In contrast, we demonstrate for the first time that the expression and activity of the enzyme CD38 increases with aging and plays an active role in the age-related NAD+ decline in vivo and the subsequent development of age related mitochondrial dysfunction. In addition, we also identify CD38 as the main enzyme involved in the degradation of NAD+ precursors such as nicotinamide mononucleotide (NMN) in vivo and to have a role in the modulation of the response to NAD+ replacement therapy in aging. These data demonstrates the key role of CD38 in age-related NAD+ and metabolic decline, and highlights the potential role of CD38 inhibition for the development of an effective ìNAD+ replacement therapy" for aging and other metabolic diseases.

 

Keywords: Age-related metabolic diseases, mitochondrial dysfunction, NAD+ replacement therapy

 

 

[albedo]

Role of CD38 in age-related NAD+ depletion: implication for age-related metabolic dysfunction and NAD+ replacement therapy.

 

http://www.sbbq.org....os/R08029-1.pdf

 

...

 

That is informative also because there are studies looking at genotype profiles in healthy humans which can tell about the CD38 activity and possibly therapeutic interventions. E.g.:

 

Population variability in CD38 activity: Correlation with age and significant effect of TNF-α -308G>A and CD38 184C>G SNPs

http://www.mgmjourna...0656-1/abstract

 

CD38 (EC 3.2.2.6, NAD(+)-glycohydrolase) is a multifunctional enzyme catalyzing the synthesis and hydrolysis of cyclic ADP-ribose from NAD⁺ to ADP-ribose. The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications. Notably, it has been linked to HIV infection, leukemias, myelomas, solid tumors, Type II Diabetes mellitus, bone metabolism, as well as Autism Spectrum Disorder. Taking into account the crucial role played by CD38 in many diseases and in clinical practice, here we assessed the distribution of CD38 NADase activity in a healthy population (104 sex-matched unrelated individuals, 12–98 years) and determined its main predictors among genetic and physiological factors (age and sex). The mean value of CD38 NADase activity was 0.051±0.023 mU/mg (0.010–0.099 mU/mg), following a normal distribution in the study population (Kolmogorov–Smirnov test P=0.200). The TNF-α -308G>A (rs1800629) resulted the main predictor (β=0.364, P=0.00008), followed by Age (β=0.280, P=0.002) and the CD38 184C>G (rs6449182) (β=0.193, P=0.033). Our study contributes to understanding CD38 enzyme physiological functions, by reporting, for the first time, its activity distribution in healthy individuals and demonstrating a significant positive correlation with age. Moreover, the possible use of TNF-α -308G>A (rs1800629) and the CD38 184C>G (rs6449182) SNPs as predictive genetic markers of CD38 activity, clearly point toward possible pharmacogenomic applications and to a more refined use of CD38 in clinical settings.

[albedo]

 

Role of CD38 in age-related NAD+ depletion: implication for age-related metabolic dysfunction and NAD+ replacement therapy.

 

http://www.sbbq.org....os/R08029-1.pdf

 

...

 

That is informative also because there are studies looking at genotype profiles in healthy humans which can tell about the CD38 activity and possibly therapeutic interventions. E.g.:

 

Population variability in CD38 activity: Correlation with age and significant effect of TNF-α -308G>A and CD38 184C>G SNPs

http://www.mgmjourna...0656-1/abstract

 

CD38 (EC 3.2.2.6, NAD(+)-glycohydrolase) is a multifunctional enzyme catalyzing the synthesis and hydrolysis of cyclic ADP-ribose from NAD⁺ to ADP-ribose. The loss of CD38 function is associated with impaired immune responses, metabolic disturbances, and behavioral modifications. Notably, it has been linked to HIV infection, leukemias, myelomas, solid tumors, Type II Diabetes mellitus, bone metabolism, as well as Autism Spectrum Disorder. Taking into account the crucial role played by CD38 in many diseases and in clinical practice, here we assessed the distribution of CD38 NADase activity in a healthy population (104 sex-matched unrelated individuals, 12–98 years) and determined its main predictors among genetic and physiological factors (age and sex). The mean value of CD38 NADase activity was 0.051±0.023 mU/mg (0.010–0.099 mU/mg), following a normal distribution in the study population (Kolmogorov–Smirnov test P=0.200). The TNF-α -308G>A (rs1800629) resulted the main predictor (β=0.364, P=0.00008), followed by Age (β=0.280, P=0.002) and the CD38 184C>G (rs6449182) (β=0.193, P=0.033). Our study contributes to understanding CD38 enzyme physiological functions, by reporting, for the first time, its activity distribution in healthy individuals and demonstrating a significant positive correlation with age. Moreover, the possible use of TNF-α -308G>A (rs1800629) and the CD38 184C>G (rs6449182) SNPs as predictive genetic markers of CD38 activity, clearly point toward possible pharmacogenomic applications and to a more refined use of CD38 in clinical settings.

 

 

I got hold of the paper and tried to look at my genotype for the SNP which are indicated therein, trying to answer, even if only qualitatively though, the question if I could benefit or not from NR.

 

I assume understanding correctly that higher CD38 activity would mean decreased intracellular NAD (as confirmed by CD38-/- mouse having 10-20x higher NAD). CD38 also looks reducing SIRT1.

 

Looking at table with the best predictors of CD38 activity, I found out that being GG for TNF-α -308G>A (rs1800629) which is the 1^st best predictor (p=0.00008) tells me basically nothing useful to reply my question.

 

 CD38.PNG   56.58KB   1 downloads

 

However, my age (2^nd best predictor) and being CG for CD38 184 C>G (rs6449182) (3^rd best predictor), therefore bringing the G allele which increases the CD38 expression, would presumably imply together a benefit with NR supplementation. Moreover, not bringing the rs1800561 SNP (I am CC) for which the paper reports a 50% decrease in CD38 activity, would add to the argumentation.

 

Of course, this is qualitative as age and the effect of the second part of the rs6449182 genotype (the C allele) should be disentangled and quantitatively assessed. It might also be that, again qualitatively, the C allele of rs6449182 would make high doses are not required as the activity of CD38 is already partially reduced. Just for the record I am running today at 200 mg of NR (with 250 mg t-resveratrol and 25 mg of pterostilbene).

 

To me this looks like another good example of a “personalized nutrition” intervention, here with NR and I will also post it in my own thread.

 

 

 

 

 

[Harkijn]

Bryan, I assume you have an communication channel to Dr. Brenner open , so you might pose an additional question to him. Sometime ago some of us were puzzled about CD38 which seemed to need a lot of NAD+ as a substrate. Does he think this is a relevant concern?

[Bryan_S]

Bryan, I assume you have an communication channel to Dr. Brenner open , so you might pose an additional question to him. Sometime ago some of us were puzzled about CD38 which seemed to need a lot of NAD+ as a substrate. Does he think this is a relevant concern?

 

It was a topic I wished to raise with him. I don't think we need to raise the question of relevant concern and I believe its firmly on his radar.

 

When you get into time contained interviews you sometimes have to prioritize your questions. Plus this was a topic published from another Lab and his first hand lab findings were the priority on his 2 recent publications.(Human Clinical testing and the NMN pathway) I also wanted to gain his perspective on dosing for our group.

 

So twice daily was my take. Your milage may very.

 

I was able to get comments from him on what others have done with his NMRK1 and NMRK2 findings. I'd felt the gene expression mapping was throwing down the Bread crumbs for all these other researchers chasing disease/injury specific research. You could tell how excited he was that so many were following this approach and asking why this NMRK2 expression is happening in instances of tissue stress and injury. This was one of those questions that builds a base for further interviews across other researchers should we be so lucky.

 

I've asked Dr. Brenner in email that they include this CD38 side of the NAD story on their website but keep in mind this research was generated from a 2nd Lab and the Brenner Lab hasn't publicly reviewed it "yet" and if they have, it hasn't been published that I've seen.

 

CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism

http://www.cell.com/...4131(16)30224-8

Juliana Camacho-Pereira, Mariana G. Tarragó, Claudia C.S. Chini, Veronica Nin, Carlos Escande, Gina M. Warner, Amrutesh S. Puranik, Renee A. Schoon, Joel M. Reid, Antonio Galina, Eduardo N. Chini

 

It was peer reviewed by Michael B. Schultz and David A. Sinclair. "NAD+ is required not only for life but for a long life. In this issue, Camacho-Pereira et al. (2016) implicate CD38 in the decline of NAD+ during aging, with implications for combating age-related diseases."

 

At this point the Brenner Lab has not weighed in but its a pretty sure bet this will be an area of peer review and comment.

 

As always JMHO

Edited by Bryan_S, 25 October 2016 - 07:58 AM.

[Oakman]

CD38 inhibitors definitely look to be an intriguing avenue to explore to increase NAD+, especially in older people. Symbiosis with other compounds may lead to improved efficacy of NR supplementation. Any questions you could pose regarding encouraging study of this in older individuals would be appreciated. It seems elder specific studies are not being done, yet and this is an age group that could most benefit from this approach (and one in which I find myself).

 

 

 

Why NAD+ Declines during Aging: It’s Destroyed > http://pubs.acs.org/....1021/jm502009h

Michael B. Schultz, David A. Sinclair

 

Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds

http://www.nature.com/nrm/journal/v17/n11/full/nrm.2016.93.html >

Michael S. Bonkowski & David A. Sinclair

 

There are many more similar articles. One could postulate that if CD38 is a major contributing factor to reduced NAD+ later in life, that supplementation with NR would not be as effective as we age to increase NAD+ levels. Even higher levels of supplemental NR might be required to reach effective levels, or perhaps the effect of CD38 is limiting overall NAD+ levels entirely, and is an overriding factor as we age.  Reducing CD38 appears to take on ever increasing importance the older one gets.

 

To that end, and as an adjunct to NR supplementation, any way to reduce CD38 production would seem to be beneficial. Both Quercetin and Apigenin supplementation to do just that, thereby allowing higher overall NAD+ levels. There seems to be considerable research in these compounds.

 

Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38 >

http://diabetes.diab...ntent/62/4/1084

 

Flavonoid Apigenin Is an Inhibitor of the NAD+ ase CD38, Implications for Cellular NAD+ Metabolism, Protein Acetylation, and Treatment of Metabolic Syndrome >

https://dash.harvard....pdf?sequence=1

 

Quercetin and Apigenin slow down the escalating NAD+ consumption by CD38 as we age >

http://www.timelesslifemag.com/index.php/2016/06/29/quercetin-apegenin-may-slow-down-the-escalating-nad-consumption-by-cd38-as-we-age/

 

I’ve recently added both of these to my NR stack. I’m trying to figure what amounts are therapeutic toward reducing CD38. I’ve only found one source of apigenin tablets, but have settled on using readily available EMIQ over standard Quercetin due to Quercetin’s poor bioavailability vs. EMIQ that shows 40x Cmax and 15x-17x AUC.

 

Enzymatically modified isoquercitrin, alpha-oligoglucosylquercetin 3-O-glucoside, is absorbed more easily than other quercetin glycosides or aglycone after oral administration in rats. >
https://www.ncbi.nlm.nih.gov/pubmed/19952424

EMIQ Activated Quercetin 40 Times Greater Absorption than Quercetin >

http://bioclinicnaturals.com/WebsiteImages/BioClinicNaturalsUSA/BulkGeneric/Documents/50280_9411U_BCNPS_EMIQ_LRz.pdf

 

Another explaination > https://www.enduraq.com/pages/benefits Much more can be found with a quick search.

 

[Harkijn]

CD38 inhibitors definitely look to be an intriguing avenue to explore to increase NAD+, especially in older people. Symbiosis with other compounds may lead to improved efficacy of NR supplementation. Any questions you could pose regarding encouraging study of this in older individuals would be appreciated. It seems elder specific studies are not being done, yet and this is an age group that could most benefit from this approach (and one in which I find myself).

 

 

 

Why NAD+ Declines during Aging: It’s Destroyed > http://pubs.acs.org/....1021/jm502009h

Michael B. Schultz, David A. Sinclair

 

Slowing ageing by design: the rise of NAD+ and sirtuin-activating compounds

http://www.nature.com/nrm/journal/v17/n11/full/nrm.2016.93.html >

Michael S. Bonkowski & David A. Sinclair

 

There are many more similar articles. One could postulate that if CD38 is a major contributing factor to reduced NAD+ later in life, that supplementation with NR would not be as effective as we age to increase NAD+ levels. Even higher levels of supplemental NR might be required to reach effective levels, or perhaps the effect of CD38 is limiting overall NAD+ levels entirely, and is an overriding factor as we age.  Reducing CD38 appears to take on ever increasing importance the older one gets.

 

To that end, and as an adjunct to NR supplementation, any way to reduce CD38 production would seem to be beneficial. Both Quercetin and Apigenin supplementation to do just that, thereby allowing higher overall NAD+ levels. There seems to be considerable research in these compounds.

 

Flavonoid Apigenin Is an Inhibitor of the NAD+ase CD38 >

http://diabetes.diab...ntent/62/4/1084

 

Flavonoid Apigenin Is an Inhibitor of the NAD+ ase CD38, Implications for Cellular NAD+ Metabolism, Protein Acetylation, and Treatment of Metabolic Syndrome >

https://dash.harvard....pdf?sequence=1

 

Quercetin and Apigenin slow down the escalating NAD+ consumption by CD38 as we age >

http://www.timelesslifemag.com/index.php/2016/06/29/quercetin-apegenin-may-slow-down-the-escalating-nad-consumption-by-cd38-as-we-age/

 

I’ve recently added both of these to my NR stack. I’m trying to figure what amounts are therapeutic toward reducing CD38. I’ve only found one source of apigenin tablets, but have settled on using readily available EMIQ over standard Quercetin due to Quercetin’s poor bioavailability vs. EMIQ that shows 40x Cmax and 15x-17x AUC.

 

Enzymatically modified isoquercitrin, alpha-oligoglucosylquercetin 3-O-glucoside, is absorbed more easily than other quercetin glycosides or aglycone after oral administration in rats. >
https://www.ncbi.nlm.nih.gov/pubmed/19952424

EMIQ Activated Quercetin 40 Times Greater Absorption than Quercetin >

http://bioclinicnaturals.com/WebsiteImages/BioClinicNaturalsUSA/BulkGeneric/Documents/50280_9411U_BCNPS_EMIQ_LRz.pdf

 

Another explaination > https://www.enduraq.com/pages/benefits Much more can be found with a quick search.

I think the consensus here on CD38 still is that mildly inhibiting it by means of quercetin and apigenin will be okay ( I take some apigenin every now and then). However, CD38 is essential to a surprising variety of vital functions and AFAIK it is not yet known what it is that regulates its actions (and upregulates its actions as we grow older).

Also: the fact that inhibiting CD38 raises NAD+ levels does not necessarily mean that this is healthy or longevity inducing downstream from CD38 . A real solution woud be to find out when to inhibit and not to inhibit CD38. As Bryan righly notes CD38 is not the main focus of Dr. Brenner's research but I would be very interested to hear him speculate on this issue.

[Harkijn]

In my modest experience CD38 has always remained an elusive player in the game of of raising NAD+. I hope some knowledgeable posters are able to analize this recent study which I am still reading myself:

http://www.cell.com/...4131(17)30618-6

[TMNMK]

Good question and I've also been looking for a longitudinal murine study that tracks CD38 expression during NR or NMN supplementation but have not yet found that. So I don't know if CD38 is down-regulated or whether expression continues to rise through age.

[recon]

Good question and I've also been looking for a longitudinal murine study that tracks CD38 expression during NR or NMN supplementation but have not yet found that. So I don't know if CD38 is down-regulated or whether expression continues to rise through age.

Assuming that CD38 consumes NAD+, then it would be more plausible that an increase in NAD+ due to NR or NMN supplementation will up-regulate CD38 rather than down-regulate.

[Harkijn]

 

Good question and I've also been looking for a longitudinal murine study that tracks CD38 expression during NR or NMN supplementation but have not yet found that. So I don't know if CD38 is down-regulated or whether expression continues to rise through age.

Assuming that CD38 consumes NAD+, then it would be more plausible that an increase in NAD+ due to NR or NMN supplementation will up-regulate CD38 rather than down-regulate.

 

We can safely assume that CD38 is able to consume NAD+ (see earlier NR threads). However,  how much and at what moment in which tissues we simply don't know. If we speculate from homeostasis, CD38 will only be upregulated if NAD+ exceeds a certain max limit and calm down if NAD+ sinks below a certain minimal level. Of course, PARPs have their own role to play in this balance....

[TMNMK]

 

Good question and I've also been looking for a longitudinal murine study that tracks CD38 expression during NR or NMN supplementation but have not yet found that. So I don't know if CD38 is down-regulated or whether expression continues to rise through age.

Assuming that CD38 consumes NAD+, then it would be more plausible that an increase in NAD+ due to NR or NMN supplementation will up-regulate CD38 rather than down-regulate.

 

 

Perhaps, and there is also mention that "CD38 not only degrades NAD+ in vivo, but also NMN." 

https://www.ncbi.nlm...les/PMC5088772/

[Phoebus]

Inhibiting CD 38  raises NAD measurably and multiple studies show this.

 

Another way to rasie NAD+ is by inhibiting NADPH, which is the enzyme that breaks down NAD. NADPH has an inverse relationship with NAD. 

 

 

Luteolin, apigenin, quercetin, are flavonoid compounds that supress CD38 and have good track record of being safe to consume.

 

 

Meanwhile Fisetin inhibits NADPH.

 

Here is the evidence and studies to show this.

 

 

 

 

http://alivebynature...actor-in-aging/

 

Sinclair article points to new approach to raise NAD+ levels

 

Why NAD+ Declines during Aging: It’s Destroyed 

 

https://www.cell.com...?code=cell-site

 

This recently published article in cell magazine by David Shultz and David Sinclair reviews several recent studies, including the June 2016 study by also published in Cell magazine by Camacho-Yeriera and colleagues

https://www.cell.com...?code=cell-site

 

The study implicates CD38 as a consumer of NAD+ that becomes overactive as we age  and destroys significant amounts of NAD+, resulting in increased age related disease and loss of function.

Their results also add to the body of evidence indicating that loss of SIRT3 activity in mitochondria is a cause of age-related metabolic decline.

• CD38 levels increase in tissues with age and correlate with NAD decline
•  
• NAD and mitochondrial function are preserved in old CD38 knockout mice
•  
• CD38 metabolizes NMN in vivo and modulates the response to NAD-replacement therapy

The Sinclair article concludes:

 

These findings suggest that the efficacy of NAD+ precursors may be enhanced by co-supplementation with CD38 inhibitors.

 

 

what are some natural/safe CD38/NADPH inhibitors? 

 

here 

 

 

https://www.ncbi.nlm...pubmed/21641214

 

We report that human CD38 is inhibited at low micromolar concentrations by flavonoids such as luteolinidin, kuromanin and luteolin (IC(50) 

 

and 

 

 

https://onlinelibrar...1111/acer.13172

 

In addition, fisetin supplementation remarkably reduced hepatic NADPH oxidase 4 levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4‐hydroxynonenal levels after alcohol exposure.

 

and 

 

 

 

 

CD38 inhibition by apigenin increases NAD + and decreases protein acetylation in vivo .

 

https://www.research..._fig2_233746160

 

and 

 

 

 

 

CD38 inhibition by quercetin and apigenin increases NAD⁺ levels in cells.

 

 

http://diabetes.diab...ntent/62/4/1084

 

 

 

tldr: Taking NR/NMN with CD38/NADPH inhibitors (luteolin, apigenin, quercetin, fisetin) is likely to raise NAD+ levels higher than taking NR/NMN alone

 

 

 

[orion22]

do you know if  quercetin, fisetin supliments stress the kidneys,if to much of these is excreated true urine?

[Phoebus]

do you know if  quercetin, fisetin supliments stress the kidneys,if to much of these is excreated true urine?

 

yeah great question, I do not know,

 

also some say quercetin is cytotoxic in large amounts, but I dont think you reach that level through normal supplementation. 

 

I take all these on a regular basis and can only say good things about them, (N=1 and all that jazz)

[Phoebus]

 

 

https://www.ncbi.nlm...pubmed/24060679

 

 

The CL assay demonstrated that curcumin efficiently inhibited the O2(-) production and easily entered into PMNs or interacted with their membrane. Cell-free assay showed that curcumin acted on the reconstitution of NADPH oxidase even at 10(-5)M, while resveratrol appeared to be an O2*- scavenger rather than an inhibitor of NADPH oxidase activity, since it acted from outside the cell in CL and after the complex assembly in cell-free assay. By acting directly on NADPH oxidase, curcumin should be a good candidate for the treatment of acute or inflammatory diseases involving an excessive ROS production.

 

 

curcumin, but not resveratrol, inhibits NADPH 

[Harkijn]

Hi Phoebus,

I encourage you to read back in the various NAD threads, where you will find these issues discussed.

Edited by Harkijn, 27 May 2018 - 05:19 PM.

[Oakman]

IMHO it's good to bring these effects to light once again and made a focus point, as past threads aren't the easiest things to interrogate. Plus any new research can be posted and noticed by new and old viewers alike.

 

 

[Phoebus]

Hi Phoebus,

I encourage you to read back in the various NAD threads, where you will find these issues discussed.

 

 

I searched the forum for CD38 references and found a few but didn't see any of the studies i llisted here. This thread for instance is pretty bare 

 

https://www.longecit...-cd38-nad-axis/

 

also Fisetin and curcumin as NADPH inhibitors has never been discussed here near as I can tell

Edited by Phoebus, 27 May 2018 - 06:49 PM.

[Nate-2004]

See Michael's post here on this issue. 

 

https://www.longecit...ne/#entry847892

[Harkijn]

See Michael's post here on this issue. 

 

https://www.longecit...ne/#entry847892

Yes, and there is quite a lot of information to be found in many other recent threads, too.

One implication of the title of the present thread is that (permanently) maximizing NAD+ levels is 'good'. As moderator Michael has insisted in many other threads this is unlikely and at least unproven.

[Turnbuckle]

Yes, and there is quite a lot of information to be found in many other recent threads, too.

One implication of the title of the present thread is that (permanently) maximizing NAD+ levels is 'good'. As moderator Michael has insisted in many other threads this is unlikely and at least unproven.

 

 

 

 

There is a potential long term problem associated with maintaining a high NAD+ level. A higher NAD+/NADH ratio drives mitochondria to fission, while fission biases stem cell proliferation to asymmetric rather than symmetric (self-renewal) division. By reducing self-renewal, a constant state of fission would tend to deplete the stem cell pool.

 

Removal of dysfunctional mitochondria requires the activation of autophagy coupled with ongoing mitochondrial fission (7). Our current and previous studies show that both of these processes can be induced by NAM treatment. The earlier part of this study showed that the effect of NAM was exerted through an increase of [NAD+]/[NADH] ratio.

https://www.ncbi.nlm...les/PMC3365962/

 

 

and,

 

… we present a model whereby changes in mitochondrial structure direct the fate of stem cells. In this model, elongated [fused] mitochondria in NSCs [neural stem cells] maintain low ROS levels and promote self-renewal, while a transition of mitochondria to a more fragmented state [fissioned] results in a modest increase in ROS levels, thereby inducing the expression of genes that inhibit self-renewal and promote commitment and differentiation.

https://www.scienced...934590916300820

 

[Phoebus]

 

 

By reducing self-renewal, a constant state of fission would tend to deplete the stem cell pool.

 

but would a permanent increase in NAD+ actually create a 'constant state of fission'?

 

and can the 'stem cell pool' really be exhausted via higher fission rates? maybe the body would just create more stem cells? 

[Turnbuckle]

but would a permanent increase in NAD+ actually create a 'constant state of fission'?

 

and can the 'stem cell pool' really be exhausted via higher fission rates? maybe the body would just create more stem cells? 

 

 

It's not clear if NAD+ per se will increase fission, but increasing the ratio of NAD+/NADH is known to do that. As for stem cells, the body creates more stem cells through symmetric division --  self-renewal. This is associated with fusion, not fission.

Edited by Turnbuckle, 28 May 2018 - 06:56 PM.

[Phoebus]

It's not clear if NAD+ per se will increase fission, but increasing the ratio of NAD+/NADH is known to do that. As for stem cells, the body creates more stem cells through symmetric division --  self-renewal. This is associated with fusion, not fission.

 

I see

 

well in the study above fisetin decreased NADPH in the liver after alcohol consumption. I doubt it does this directly, its likely its an indirect affect of hepato protective actions. 

 

same with luteolin. I dont think it just randomly depresses CD38 levels, its likely a secondary affect possible as a result of luteolin's anti inflammatory properties or maybe its anti oxidant properites. 

 

i dont think you can compare those compounds, found in plentiful amounts in plants we regularly consume, to novel chemicals created in a lab that are specifically designed to inhibit CD38 and/or NADPH directly 

 

I doubt very much fisetin for example is going to throw the NAD+/NADH  ratio way in the favor of NAD+ by directly suppressing NADPH. But a novel chemcal designed to directly inhibit NADPH might do this, I dont know. 

[Nate-2004]

Yes, and there is quite a lot of information to be found in many other recent threads, too.

One implication of the title of the present thread is that (permanently) maximizing NAD+ levels is 'good'. As moderator Michael has insisted in many other threads this is unlikely and at least unproven.

 

The only reason I continue reiterating the point about apigenin's lack of bioavailability is that people keep perpetuating the implication that it's effective orally in vivo, in humans, regardless of what they're claiming it does. I'm not trying to waste people's time I'm trying to save people's time and more importantly, money.

Edited by Nate-2004, 29 May 2018 - 01:19 PM.

[Harkijn]

The only reason I continue reiterating the point about apigenin's lack of bioavailability is that people keep perpetuating the implication that it's effective orally in vivo, in humans, regardless of what they're claiming it does. I'm not trying to waste people's time I'm trying to save people's time and more importantly, money.

 I  fully appreciate  your point Nate, here as well as in other threads. I hope I did not give rise to any other impression.

[Michael]

First: Phoebus, with your permission, I'd like to merge this thread in with this earlier one — agreed?
 

Inhibiting CD 38 raises NAD measurably and multiple studies show this.
 

http://alivebynature...actor-in-aging/

Sinclair article points to new approach to raise NAD+ levels

Why NAD+ Declines during Aging: It’s Destroyed

https://www.cell.com...?code=cell-site

 

While I'd agree with you that "Inhibiting CD 38 raises NAD measurably and multiple studies show this," the fingering of increased CD38 activity with age as the (or even the dominant) driver of the age-related decline in NAD+, and several of the details of the Chini study underlying the Sinclair editorial, is actually contradicted by other studies. There's more work needed in this space.
 

what are some natural/safe CD38/NADPH inhibitors?
Inhibiting CD 38 raises NAD measurably and multiple studies show this.

Luteolin, apigenin, quercetin, are flavonoid compounds that supress CD38 and have good track record of being safe to consume.

Luteolin, apigenin, quercetin, are flavonoid compounds that suppress CD38 in vitro. I'm aware of no evidence that luteolin or quercetin inhibit CD38 in vivo — can you cite any?

Apigenin has been reported to inhibit CD30 in vivo — but as I've indicated, all it's so far been shown to do is "to partially normalize the excessive CD38 in young (20-week-old), high-fat-fed obese, likely diabetic mice (PMID 23172919), and the dose was 100 mg/kg by intraperitoneal injection, which is not the ideal test for an orally-administered compound, particularly if it's a phenolic compound and particularly if it's a phenolic compound being administered to a mouse (since rodents metabolize many phenolics very heavily). We have no peer-reviewed data showing it lowers CD38 in otherwise normal aging mammals... let alone that it does so after oral administration and to metabolic benefit."

Additionally, you say that these compounds "have good track record of being safe to consume." I'm aware of no evidence to support this, unless you mean it's safe to consume them at the levels in and in the form of onions, apples, and celery. Do you have any evidence that long-term use of isolated supplements at the kind of supra-dietary doses that would be required to plausibly have a meaningful effect on CD38 activity "have good track record of being safe to consume"? Eg, can you cite a 2-y toxicology report for any of them?

Writing in 2000, scientists with the National Toxicology Program's Chemical Selection Working Group said that "Apigenin is brought to the attention of the CSWG because of a recent scientific article citing this flavonoid as a substance that can be metabolically activated to produce toxic prooxidant phenoxyl radicals", and that "No 2-year carcinogenicity studies of apigenin were identified in the available literature. The only acute toxicity value found in the available literature reported an LD25 of 1 mg/kg when apigenin 8-C-glucoside was administered to mice via intraperitoneal injection (NLM, 1999)." More recently:
 

Subchronic Exposure of Apigenin Induces Hepatic Oxidative Stress in Male Rats
Jiawei Liu, Yuhong Wang, Wencai Chen, Sheng Li, Lingfei Liu, Yuhui Dang, Zhilan Li
DOI: 10.4236/health.2014.610124
Health. 2014 Apr;6(10):989-997.

... 48 SD male rats were randomly divided into control group (saline, 1 ml/100g·bw), low-dose group (AP, 234 mg/kg·bw), middle-dose group (AP, 468 mg/kg·bw) and high-dose group (AP, 936 mg/kg·bw). The rats were administered with apigenin or saline via intragastriation [ie, gavage] once a day, 6 days per week, and 5 consecutive weeks. ... Total protein (TP), albumin (ALB) and globulin (GLO) in apigenin treatment groups were significantly lower than those in the control group (P < 0.05). SOD in the middle-dose group (AP, 468 mg/kg·bw) and high-dose group (AP, 936 mg/kg·bw) were significantly higher than that in the control group (P < 0.05). [Total antioxidant capacity (T-AOC)], catalase (CAT), and glutathione peroxidase (GSH-Px)] in apigenin treatment groups were significantly lower than those in the control group (P < 0.05). In high-dose AP group (AP, 936 mg/kg·bw), apigenin can result in the reduction of T-AOC, thus leading to the oxidative damage of liver tissues. In contrast, in middle-dose AP group (AP, 468 mg/kg·bw), apegenin can reduce the elimination capacity of oxygen free radicals.

Cayman Chemicals' MSDS on luteolin states that "To the best of our knowledge, the toxicological properties have not been thoroughly investigated."

The exception is quercetin, and there I'd say the evidence leans in the opposite direction. Two rodent lifespan studies using quercetin have come to less than promising results: there was no effect in a study using 62 mg/kg quercetin in one study,[1] while it shortened life rather than lengthening it in the other,[2] using about twice that dose.
 

https://www.ncbi.nlm...pubmed/21641214

We report that human CD38 is inhibited at low micromolar concentrations by flavonoids such as luteolinidin, kuromanin and luteolin (IC(50)

The  "human CD38" here was recombinant CD38 enzyme in vitro — not in vivo, and not even in the presence of cells or plasma. We have no idea if this would happen under physiological conditions after oral administration.
 

CD38 inhibition by apigenin increases NAD + and decreases protein acetylation in vivo .
https://www.research..._fig2_233746160

CD38 inhibition by quercetin and apigenin increases NAD⁺ levels in cells.

http://diabetes.diab...ntent/62/4/1084

I've consolidated these. From the way you originally posted them, I'm guessing that you thought (and readers will think) that they are from three different studies. In fact, you've posted two excerpts from the same study (PMID 23172919, which I cited above) from two different websites. To repeat, the study was done in "teenaged" obese, high-fat-fed mice, using i.p. injected apigenin; we don't know how this relates to the use of oral apigenin supplements to counteract age-related rise in CD38 activity, or (more importantly) the associated metabolic derangement.
 

Another way to rasie NAD+ is by inhibiting NADPH, which is the enzyme that breaks down NAD. NADPH has an inverse relationship with NAD.
Meanwhile Fisetin inhibits NADPH.
 

In addition, fisetin supplementation remarkably reduced hepatic NADPH oxidase 4 levels along with decreased plasma hydrogen peroxide and hepatic superoxide and 4‐hydroxynonenal levels after alcohol exposure.

https://onlinelibrar...1111/acer.13172

 

 
You have here conflated NADPH with NADPH oxidase 4 (NOX4), and are possibly actually confusing both of them with NADH. And this study is in the use of fisetin  to counteract the elevation of NOX4 resulting from alcohol intoxication. I'm aware of no evidence that inhibiting NOX4 elevates NAD+, or that doing so counteracts the age-related fall in NAD+ — can you point to any?
 
Putting that somewhat to one side: NOX4 certainly does some Bad Things under some conditions (like alcohol intoxication (above) and probably diabetes), but I'd be cautious about inhibiting it: as usual, Evolution Don't Make No Junk.

NADPH Oxidases Are Essential for Macrophage Differentiation
NADPH oxidase Nox4 has anti-atherosclerotic functions
NADPH oxidase 4 deficiency increases tubular cell death during acute ischemic reperfusion injury
Nox4 Is a Protective Reactive Oxygen Species Generating Vascular NADPH Oxidase

References
1: Spindler SR, Mote PL, Flegal JM, Teter B. Infuence on longevity of blueberry, cinnamon, green and black tea, pomegranate, sesame, curcumin, morin, pycnogenol, quercetin, and taxifolin fed iso-calorically to long-lived, F1 hybrid mice. Rejuvenation Res. 2013 Apr;16(2):143-51. doi: 10.1089/rej.2012.1386. PubMed PMID: 23432089.

2: Jones E, Hughes RE. Quercetin, flavonoids and the life-span of mice. Exp Gerontol. 1982;17(3):213-7. PubMed PMID: 7140862.

[Phoebus]

sure, merge away

[male_1978]

I am not an expert, but if CD38 consumes NAD+ then more NAD+ will probably also upregulate everything downstream CD38 as a side effect,right? In that case a CD38-Inhibitor would maybe just compenate this effect. Your thoughts?