13 replies to this topic

[stefan_001]

So seems CD38 may be usefull afterall and is highly active in cancer cells. Looks like one should think twice about inhibitors.

 

http://mcr.aacrjourn...786.MCR-17-0526

[Hebbeh]

The take home message from this study is intracellular NAD+ levels drive prostate cancer.  It has been suggested that all men in time will develop some degree of prostate cancer providing they live long enough.  In light of this, I would be cautious in elevating NAD+ levels in elderly men 60 and above (when prostate cancer risk begins to appear).  Note in the study, inhibition of NAMPT also inversely correlated to prostate cancer by reducing NAD+ with the same positive outcome as elevated CD38.  The downside to exdogenously elevated NAD+ levels beyond "normal" is beginning to appear and suggests reasoning for the body to attempt homeostatic levels in time.  No free lunch.

 

Pharmacological inhibition of nicotinamide phosphoribosyltransferase (NAMPT) mimicked the metabolic consequences of CD38 expression, demonstrating similarity between CD38 expression and NAMPT inhibition.

 

 

Edit:  This study deals with prostate cancer but NAD+ levels feed the metabolism of many other types of cancer in the same model.

Edited by Hebbeh, 07 August 2018 - 11:46 PM.

[stefan_001]

The take home message from this study is intracellular NAD+ levels drive prostate cancer.  It has been suggested that all men in time will develop some degree of prostate cancer providing they live long enough.  In light of this, I would be cautious in elevating NAD+ levels in elderly men 60 and above (when prostate cancer risk begins to appear).  Note in the study, inhibition of NAMPT also inversely correlated to prostate cancer by reducing NAD+ with the same positive outcome as elevated CD38.  The downside to exdogenously elevated NAD+ levels beyond "normal" is beginning to appear and suggests reasoning for the body to attempt homeostatic levels in time.  No free lunch.

 

 

Edit:  This study deals with prostate cancer but NAD+ levels feed the metabolism of many other types of cancer in the same model.

 

That may or may not be the take home message. For me what is clear is that when you target the energy chain in cancer its growth slows. My dad's regular prostate cancer check up (he was at risk) keeps up coming in good after 3.5 years of NR supplementation. Whether boosting NAD+ would make more of it available for cancer growth is not that clear to me as likely there will be an increase of consumers in the cancer cell e.g. CD38. Specifically inhibiting CD38 however s not something I would do.

 

Others feel free to comment.

[ambivalent]

 My dad's regular prostate cancer check up (he was at risk) keeps up coming in good after 3.5 years of NR supplementation.

 

Yes, but if the study in cell magazine is accurate then the chances are your father won't have been raising NAD+ while taking NR during that time (via oral administration).

[stefan_001]

Yes, but if the study in cell magazine is accurate then the chances are your father won't have been raising NAD+ while taking NR during that time (via oral administration).

 

Not sure what study you mean but NR for sure raises NAD+ beyond the liver as studies in humans have shown when taken orally. The debate is whether any NR itself gets into circulation in meaningful amounts.
 

Edited by stefan_001, 08 August 2018 - 03:11 PM.

[Michael]

More evidence on this:

 

 

CD38 is methylated in prostate cancer and regulates extracellular NAD+

Cancer Metab. 2018 Sep 21;6:13. doi: 10.1186/s40170-018-0186-3. eCollection 2018.

Jack Mottahedeh, Michael C. Haffner, Tristan R. Grogan, Takao Hashimoto, Preston D. Crowell, Himisha Beltran, Andrea Sboner, Rohan Bareja, David Esopi, William B. Isaacs, Srinivasan Yegnasubramanian, Matthew B. Rettig, David A. Elashoff, Elizabeth A. Platz, Angelo M. De Marzo, Michael A. Teitell and Andrew S. Goldstein

 

Cancer cell metabolism requires sustained pools of intracellular nicotinamide adenine dinucleotide (NAD⁺) which is maintained by a balance of NAD⁺ hydrolase activity and NAD⁺ salvage activity. We recently reported that human prostate cancer can be initiated following oncogene expression in progenitor-like luminal cells marked by low expression of the NAD⁺-consuming enzyme CD38. CD38 expression is reduced in prostate cancer compared to benign prostate, suggesting that tumor cells may reduce CD38 expression in order to enhance pools of NAD⁺. ...

 

CD38 mRNA expression was reduced in metastatic castration-resistant prostate cancer compared to localized prostate cancer. In a large cohort of men undergoing radical prostatectomy, CD38 protein expression was inversely correlated with recurrence. We identified methylation of the CD38 promoter in primary and metastatic prostate cancer. Over-expression of wild-type CD38, but not an NAD⁺ hydrolase-deficient mutant, depleted extracellular NAD⁺ levels in benign and malignant prostate cell lines. However, expression of CD38 did not significantly alter intracellular NAD⁺ levels in human prostate cell lines grown in vitro and in urogenital tissues isolated from wild-type and CD38 knockout mice.

Conclusions:

... Our study provides support for CD38 as a regulator of extracellular, but not intracellular, NAD⁺ in epithelial cells. These findings suggest that repression of CD38 by methylation may serve to increase the availability of extracellular NAD⁺ in prostate cancer tissues.

PMID: 30258629  PMCID: PMC6150989 DOI:10.1186/s40170-018-0186-3

 

[Phoebus]

so NAD+ pathway also very involved in glioblastoma 

 

 

While a particular metabolic pathway shows potential to slow down the aging process, new research indicates a downside: That same pathway may drive brain cancer.

 

The pathway, known as the nicotinamide adenine dinucleotide (NAD+) pathway, is overactive in a deadly form of brain cancer known as glioblastoma, according to a study by researchers at Washington University School of Medicine in St. Louis. Glioblastoma is the most common and aggressive brain cancer in adults. Over 70 percent of patients with glioblastoma die within two years of diagnosis.

The new research showed that glioblastoma patients with high expression of an NAD+ pathway gene known as NAMPT died sooner. Tumors with elevated expression of the same gene grew rapidly when they were implanted in mice and shrank when NAMPT was inhibited.

The study, published Dec. 5 in Proceedings of the National Academy of Sciences, suggests that inhibiting the NAD+ pathway may improve the outlook for glioblastoma patients but also may affect other biological processes, such as aging.

 

here is what I am wondering 

 

cancer needs energy, so it will steal that energy from wherever it can. Its not choosy, its going to take it from available sources. So in this instance the available source is NAD+. 

 

New research from MIT shows new cancer cells actually feed mostly on amino acids, NOT glucose as most assume 

 

 

The MIT researchers found that glucose accounts for just 10–15% of the carbon found in cancer cells, whereas glutamine contributes about 10% of the carbon. Instead, the researchers found that as a group, amino acids (excluding glutamine) contribute the majority of the carbon atoms found in new cells and 20–40% of the total mass.

Although initially surprising, the findings make sense, Dr. Vander Heiden noted, because cells are made mostly of protein.

https://www.genengne...lucose/81252451

 

So glucose, amino acids, and NAD+ all seem to feed cancer, but of course all of those things are essential to continue to live. 

 

The same things that feed our body's healthy cells also feed cancer cells and thats why this question is so complicated and difficult. Restricting cancer cells sources of energy is also restricting healthy cells sources of energy. And feeding healthy cells the nutrients they need may also be feeding cancer cells the energy they need. 

[Harkijn]

So far I see no reason for worry to those who take NAD precursors, but those who are taking NAD by IV should really think again.

[Phoebus]

So far I see no reason for worry to those who take NAD precursors, but those who are taking NAD by IV should really think again.

 

 

why though? 

 

if precursors work then they are creating NAD

 

why would one type of NAD therapy be more risky than another if the end result if the same?

 

also if you are worried about feeding cancer cells then you shouldn't consume amino acids or glucose either.  

Edited by Phoebus, 02 October 2018 - 01:12 PM.

[Harkijn]

why though? 

 

if precursors work then they are creating NAD

 

 

 

 

No, if precursors are available they give the body the chance to form NAD from them. As discussed in many forums over the years, the several steps in which the various precursors are metabolized provide the body the possibility to 'sidetrack' them for other purposes.

[Mind]

so NAD+ pathway also very involved in glioblastoma 

 

 

here is what I am wondering 

 

cancer needs energy, so it will steal that energy from wherever it can. Its not choosy, its going to take it from available sources. So in this instance the available source is NAD+. 

 

New research from MIT shows new cancer cells actually feed mostly on amino acids, NOT glucose as most assume 

 

 

So glucose, amino acids, and NAD+ all seem to feed cancer, but of course all of those things are essential to continue to live. 

 

The same things that feed our body's healthy cells also feed cancer cells and thats why this question is so complicated and difficult. Restricting cancer cells sources of energy is also restricting healthy cells sources of energy. And feeding healthy cells the nutrients they need may also be feeding cancer cells the energy they need. 

 

I made a similar point here: https://www.longecit...e-2#entry844507

 

I don't want to diminish the incredible dissection of this metabolic discovery, but I do appreciate the higher systems-level thinking about rejuvenation treatments vs. cancer. If we all live long enough and accumulate enough DNA mutations, we will eventually get cancer. Hopefully there will be a cure, but we can't NOT try rejuvenation treatments. I doubt there will ever be a truly risk-free therapy. As always, the questions is "do the benefits outweigh the risks"?

[William Sterog]

why though?

if precursors work then they are creating NAD

why would one type of NAD therapy be more risky than another if the end result if the same?

also if you are worried about feeding cancer cells then you shouldn't consume amino acids or glucose either.

If you don't consume aminos, you die. You can avoid ingesting glucose and NR, though.

[Kevnzworld]

Cancer uses whatever it can to grow...telomerase ( which keeps chromosomes young ), testosterone and estrogen.., glucose and amino acids and of course NAD.
You can’t avoid or limit every natural substance that can be used by cancer.....you might as well just live in fear.

[MikeDC]

Both cancer and normal cells need NAD+.  Until clinical trials are performed for each type of cancer, we don't know the effects of NAD+ precursors on cancer growth. 

In preclinical struies, supplementing NR cured liver cancer in mice.