41 replies to this topic

[MikeDC]

If you can kill all cancer cells with chemo, then NR is not good since it will help cancer cells to survive. But if you don't kill all the cancer cells, NR actually prevent the growth and migration. So the best strategy is to kill as much cancer cells as you can and then starting taking NR to prevent recurrence of cancer.

This does not maker seems to me. It seems like you would take NR before you had cancer to try and keep errors away which cause cancer but the moment you have a cancer concern, stop NR and don't go near it as it can feed cancer cells and it looks like it would work against many cancer treatments which seek to starve cancer cells which reproduce so much faster. Thoughts?

At least for mice, NR cured liver cancer and prevented breast cancer from spreading. I would say stop NR if you are in chemotherapy and resume after the treatment.

[Michael]

First, let's all note that contrary to Dach's claims, Lisanti's report does not demonstrate that vitamin C can actually kill cancer in vivo: this was entirely an in vitro study on cancer stem cells, looking at mechanisms. The in vivo studies cited do not show killing of cancer or CSC, but slower tumor growth when administered before a cancer is implanted into the animal.

 

If it's similar to antioxidant capacity, then you'd want to increase capacity/NAD+ when you don't have cancer & deplete capacity/NAD+ when you do. The aim is: to fuck cancer cells up with oxidative stress.

 

All well and good, except it assumes that you know whether you have cancer and/or precancerous lesions — which you don't. See the "But it's OK If You Don't ALREADY Have Cancer" thread.

 

If indeed one has slow-growing, undiagnosed cancer whose growth and survival are limited by NAD+ availability, and/or precancerous lesions that are still lacking mutations needed to increase  NAD+ availability for energy production and/or its cofactor function (as with the NAMPT and other mutations discussed earlier in this thread), boosting NAD+ with NR or other strategies might fill in a needed gap, allowing the precancerous lesion cancer cell to continue progressing or turning an indolent cancer aggressive. And the longer such cancers survive or the faster they grow, the more likely it is they'll acquire the mutations to unleash them from their prior dependence on the supplement (although evolutionary drift could also occur in cancers that already have and depend on such mutations).

[stefan_001]

First, let's all note that contrary to Dach's claims, Lisanti's report does not demonstrate that vitamin C can actually kill cancer in vivo: this was entirely an in vitro study on cancer stem cells, looking at mechanisms. The in vivo studies cited do not show killing of cancer or CSC, but slower tumor growth when administered before a cancer is implanted into the animal.

If it's similar to antioxidant capacity, then you'd want to increase capacity/NAD+ when you don't have cancer & deplete capacity/NAD+ when you do. The aim is: to fuck cancer cells up with oxidative stress.

All well and good, except it assumes that you know whether you have cancer and/or precancerous lesions — which you don't. See the "But it's OK If You Don't ALREADY Have Cancer" thread.

If indeed one has slow-growing, undiagnosed cancer whose growth and survival are limited by NAD+ availability, and/or precancerous lesions that are still lacking mutations needed to increase NAD+ availability for energy production and/or its cofactor function (as with the NAMPT and other mutations discussed earlier in this thread), boosting NAD+ with NR or other strategies might fill in a needed gap, allowing the precancerous lesion cancer cell to continue progressing or turning an indolent cancer aggressive. And the longer such cancers survive or the faster they grow, the more likely it is they'll acquire the mutations to unleash them from their prior dependence on the supplement (although evolutionary drift could also occur in cancers that already have and depend on such mutations).

This statement belongs to the same unproven category as statements that say NR cures cancer. I will add my own speculation to this and call Michael's scenario unlikely. If NAD+ was an accelerator of cancer "starts" then that would mean the younger you are the higher cancer risk you have as NAD+ falls strongly with age, stats show otherwise.

Edited by stefan_001, 05 July 2017 - 07:38 PM.

[Razor444]

 

 

If it's similar to antioxidant capacity, then you'd want to increase capacity/NAD+ when you don't have cancer & deplete capacity/NAD+ when you do. The aim is: to fuck cancer cells up with oxidative stress.

 

All well and good, except it assumes that you know whether you have cancer and/or precancerous lesions — which you don't. See the "But it's OK If You Don't ALREADY Have Cancer" thread.

 

 

 

One can know they have cancer to some degree of certainty. When they're diagnosed with cancer. Proving one doesn't have cancer obviously isn't possible today, though. So maybe useful for those already diagnosed.

[Michael]

 

If indeed one has slow-growing, undiagnosed cancer whose growth and survival are limited by NAD+ availability, and/or precancerous lesions that are still lacking mutations needed to increase NAD+ availability for energy production and/or its cofactor function (as with the NAMPT and other mutations discussed earlier in this thread), boosting NAD+ with NR or other strategies might fill in a needed gap, allowing the precancerous lesion cancer cell to continue progressing or turning an indolent cancer aggressive. And the longer such cancers survive or the faster they grow, the more likely it is they'll acquire the mutations to unleash them from their prior dependence on the supplement (although evolutionary drift could also occur in cancers that already have and depend on such mutations).

This statement belongs to the same unproven category as statements that say NR cures cancer.

I'd agree with you that it's unproven — hence my use of the word "might," rather than "will" or "has been shown to" — but there's a rather strong theoretical base for it in the overexpression of NAMPT in many cancers, and other NAD+-increasing genes in others: see Wagner's excellent mini-review on NAD+-boosting mutations in cancer, the recent study on NAMPT mutations in glioblastoma multiforme (paper here).
 

I will add my own speculation to this and call Michael's scenario unlikely. If NAD+ was an accelerator of cancer "starts" then that would mean the younger you are the higher cancer risk you have as NAD+ falls strongly with age, stats show otherwise.

That would be reasonable if the only thing that changed in an aging body were a decline in NAD+, and if that happened globally — but of course, neither of the above is true. The most important reason why cancer incidence rises with age is, of course, that it takes time for precancerous lesions to acquire mutations conferring the full Hallmarks of Cancer; the longer you live, the longer your cells have to acquire the requisite mutations. Other things that predispose the aging body to cancer include the decline in the immune system and the disordering of the extracellular matrix. The issue here is the possibility that boosting NAD+ with NR might allow a precancerous lesion to advance by backstopping its need for more NAD+ without having to acquire a NAMPT or other NAD+boosting mutation.

 

In any case, the issue in cancer is not, of course, what the level of NAD+ is in the body's otherwise-normal aging cells, but the status of the cancer cell. In "normal" aging, NAD+ declines, but many cancers acquire NAMPT or other mutations to boost up their levels. The aging but otherwise normal cells don't get any extra NAD+ out of these mutations, and at this point their lack of NAD+ doesn't hold up the cancer cell one whit. Again, an NR supplement might be expected to give precancerous lesions the NAD+ they need even before they've acquired such mutations, allowing them to proliferate faster and giving them more opportunity to acquire it on an autonomous basis.

[stefan_001]

If indeed one has slow-growing, undiagnosed cancer whose growth and survival are limited by NAD+ availability, and/or precancerous lesions that are still lacking mutations needed to increase NAD+ availability for energy production and/or its cofactor function (as with the NAMPT and other mutations discussed earlier in this thread), boosting NAD+ with NR or other strategies might fill in a needed gap, allowing the precancerous lesion cancer cell to continue progressing or turning an indolent cancer aggressive. And the longer such cancers survive or the faster they grow, the more likely it is they'll acquire the mutations to unleash them from their prior dependence on the supplement (although evolutionary drift could also occur in cancers that already have and depend on such mutations).

This statement belongs to the same unproven category as statements that say NR cures cancer.

I'd agree with you that it's unproven — hence my use of the word "might," rather than "will" or "has been shown to" — but there's a rather strong theoretical base for it in the overexpression of NAMPT in many cancers, and other NAD+-increasing genes in others: see Wagner's excellent mini-review on NAD+-boosting mutations in cancer, the recent study on NAMPT mutations in glioblastoma multiforme (paper here).

I will add my own speculation to this and call Michael's scenario unlikely. If NAD+ was an accelerator of cancer "starts" then that would mean the younger you are the higher cancer risk you have as NAD+ falls strongly with age, stats show otherwise.

That would be reasonable if the only thing that changed in an aging body were a decline in NAD+, and if that happened globally — but of course, neither of the above is true. The most important reason why cancer incidence rises with age is, of course, that it takes time for precancerous lesions to acquire mutations conferring the full Hallmarks of Cancer; the longer you live, the longer your cells have to acquire the requisite mutations. Other things that predispose the aging body to cancer include the decline in the immune system and the disordering of the extracellular matrix. The issue here is the possibility that boosting NAD+ with NR might allow a precancerous lesion to advance by backstopping its need for more NAD+ without having to acquire a NAMPT or other NAD+boosting mutation.

In any case, the issue in cancer is not, of course, what the level of NAD+ is in the body's otherwise-normal aging cells, but the status of the cancer cell. In "normal" aging, NAD+ declines, but many cancers acquire NAMPT or other mutations to boost up their levels. The aging but otherwise normal cells don't get any extra NAD+ out of these mutations, and at this point their lack of NAD+ doesn't hold up the cancer cell one whit. Again, an NR supplement might be expected to give precancerous lesions the NAD+ they need even before they've acquired such mutations, allowing them to proliferate faster and giving them more opportunity to acquire it on an autonomous basis.

Thanks for the links. Sure there is that connection. But I have not seen any literature indicating that cancer cells have increased NRK expression needed to convert NR as a means to increase NAD+. That would also be illogical that such mechanism would have evolved as circulating NAD decreases. What I do agree is that when you try to kill cancer cells using HDAC inhibitors dont take NR, the nrk path may help cancer cells survive.

[Michael]

Thanks for the links. Sure there is that connection. But I have not seen any literature indicating that cancer cells have increased NRK expression needed to convert NR as a means to increase NAD+. That would also be illogical that such mechanism would have evolved as circulating NAD decreases.

The line of argument you're presenting supports my point here. Absent NR (or NMN) supplementation, there's no selective advantage for a cancer cell to increase NRK levels or activity, since (a) even in healthy young organisms, it's not the rate-limiting enzyme on NAD+ synthesis (NAMPT is), and (b) in the older organisms in which cancer normally develops, its alternative source of substrate (extracellular NMN — and NAD⁺, tho' I'm not sure that's relevant) declines with age. So cancer cells that developed such a mutation would lose out by genetic drift and/or selective disadvantage.
 
Supplemental NR would change the game, allowing the cell to boost NAD⁺ levels even without further mutations, and also giving cells with mutations that increase NRK levels and/or activity a selective advantage in the new substrate-rich environment.
 

What I do agree is that when you try to kill cancer cells using HDAC inhibitors dont take NR, the nrk path may help cancer cells survive.

... or NAMPT inhibitors, as has been shown with NMN and nicotinic acid (which latter also validates the 'escape hatch' model):
 

Because of the high rate of NAD degradation, the conversion of NAM into nicotinamide mononucleotide (NMN) is the most effective pathway to maintain NAD levels in most tissues. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme responsible for this conversion, and this enzyme has been shown to be overexpressed in many types of cancer, including lung, prostate, gastric, colorectal, and pancreatic cancer ... [NAMPT] uses nicotinamide (NAM) to generate nicotinamide mononucleotide (NMN). NMN is one of the main precursors of NAD synthesis in cells.
 
Our previous study showed the importance of NAMPT in maintaining NAD levels in pancreatic ductal adenocarcinoma cells (PDAC), and that the NAMPT inhibitor FK866 decreased pancreatic cancer growth. We now tested the effect of STF-118804, a new highly specific NAMPT inhibitor. ... STF-118804 reduced viability and growth of different PDAC lines, as well as the formation of colonies in soft agar. In addition, STF-118804 decreased glucose uptake, lactate excretion, and ATP levels, resulting in metabolic collapse. STF-118804 treatment activated AMPK ... Exogenous NMN blocked both the activation of the AMPK pathway and the decrease in cell viability. Panc-1 cells expressing GFP-luciferase were orthotopically implanted on mice pancreas to test the in vivo effectiveness of STF-118804. Both STF-118804 and FK866 reduced tumor size after 21 days of treatment....

 

PMID:    28733523

The ability of STF-118804 and analogs to inhibit biosynthesis of NAD⁺ from nicotinamide was measured using a coupled in vitro enzyme assay containing NAMPT and nicotinamide nucleotide adenylyltransferase (NMNAT) . STF-118804 and its less active analog STF-118791 prevented NAD⁺ production ..., as did the known NAMPT inhibitor FK866 (all at 10 μM), which was also cytotoxic to MV411 cells. In contrast, the analog STF-118803, which lacked inhibitory activity in cellular assays, did not block NAD⁺ production in vitro. The observed reduction in NAD⁺ biosynthesis was caused by specific inhibition of NAMPT in the coupled reaction, since none of the analogs or FK866 inhibited production of NAD⁺ catalyzed by the downstream enzyme NMNAT in a parallel in vitro assay. ... Overexpression of NAMPT rendered 293T cells more resistant to STF-118804, resulting in a higher IC₅₀ (106 nM; 95% confidence interval [CI], 74–151 nM) compared to control cells (17 nM; 95% CI, 13–23 nM) ... Taken together, the inhibitory activities of STF-118804 and analogs in NAMPT enzymatic assays, which correlate with their structure-activity relationship (SAR) in cellular assays, establish that NAMPT is a molecular target. ...

The Preiss-Handler pathway is an alternative NAD⁺ biosynthesis pathway that bypasses NAMPT by using nicotinic acid as a substrate to form NAD⁺. Addition of nicotinic acid to in vitro viability assays (measured by live cell protease activity) completely abrogated the toxicity induced in leukemia cells by STF-118804 but not idarubicin [which is toxic to cancer cells but whose mechanism of action does not depend on inhibiting NAMPT or lowering NAD+ levels]. The observed rescue of viability via the Preiss-Handler pathway suggested that the cytotoxic effects of STF-118804 were due to depletion of NAD⁺.

PMID 24183972

[stefan_001]

Hi Michael, my impression is that the extra NAD+ you get out of supplementation is very small compared to what is generated via glycosis. It need massive amounts to grow. On the other side you really need to starve the cancer cell into the extreme to kill it, so while supplemenatation can keep the cells alive there is a huge gap to aiding it. Anyways I know that is not your point. I understand the scenario you point at but I would call it very speculative and probably would need testing. I dont see why such mutation towards increased NRK expression in the formation stages towards cancer would then not have occured already especially when you are still younger when levels havent depleted that much?

[Michael]

Hi Michael, my impression is that the extra NAD+ you get out of supplementation is very small compared to what is generated via glycosis.

Glycolysis doesn't generate NAD.
 

On the other side you really need to starve the cancer cell into the extreme to kill it, so while supplemenatation can keep the cells alive there is a huge gap to aiding it.

The issue isn't killing it, but restraining its growth. If you only needed to avoid very severe energy restriction relative to normal cells, there'd be no selective advantage for lines with NAMPT mutations.
 

Anyways I know that is not your point. I understand the scenario you point at but I would call it very speculative and probably would need testing. I dont see why such mutation towards increased NRK expression in the formation stages towards cancer would then not have occured already especially when you are still younger when levels havent depleted that much?

For the reason I gave earlier: "there's no selective advantage for a cancer cell to increase NRK levels or activity, since (a) even in healthy young organisms, it's not the rate-limiting enzyme on NAD+ synthesis (NAMPT is), and (b) in the older organisms in which cancer normally develops, its alternative source of substrate (extracellular NMN — and NAD+, tho' I'm not sure that's relevant) declines with age. So cancer cells that developed such a mutation would lose out by genetic drift and/or selective disadvantage."

 

And it wouldn't happen during the early formation stages when you're young because its growth hasn't yet reached the point where it would need it, which is by definition late in the cancer process.

[Michael]

These are posts from this thread about this paper:
 

These results were partially previewed in their "Battlefield Test" meeting abstract. As I noted at the time, one potential downside of this would be increased risk of cancer growth or invasion via angiogenesis. Flagging angiogenesis with age may be one of the reasons why cancer incidence plateaus late in current lifespans.

 

this is good to know:

The ability of NMN to promote angiogenesis raises the question of whether it might stimulate tumor growth. Mice treated with NMN or NR for extended periods show no evidence of increased tumor burden (Mills et al., 2016; Zhang et al., 2016). Indeed, during the course of our studies, no increase in tumor burden was seen with NMN-treatment or in a DEN-induced model of hepatocarcinoma (Figures S7J and S7K), although more study is warranted.

Additional press over at the excellent health news site STAT. Snips of note:

 

New blood vessels could also be a mixed blessing. They support the growth of tumors, which is why anti-angiogenesis molecules have become cancer drugs. The scientists found no excess cancers in the mice given NMR [sic], but “more study is warranted,” they wrote. ...

 

In the Mills Long-term study, mice were given 100 or 300mg/kg NMN daily for 12 months (mid-life to old age) with no increased mortality. Does that not give a clue to safety or cancer risk?

"It should be noted that NMN administration did not generate any obvious toxicity, serious side effects, or increased mortality rate throughout the 12-month-long intervention period"

[Mind]

I have seen the "cancer spectre" raised in association with many different therapies and supplements. Since cancer is still very hard to cure, a lot of caution is warranted.

 

However, here is my thought on the cancer threat.

 

From a over-arching viewpoint, since cancer cells are your own cells growing out of control, almost any supplement that promotes growth and repair will generally be capable of assisting cancer growth. If I have cancer, I do not want to take a supplement that promotes angiogenesis, upregulates telomerase, etc... If I am healthy then I generally assume that the cancer-protective systems in my body will benefit from the supplements and "win out" over cancer cells.

 

Obviously, this theoretical viewpoint is subject to actual data, which might indicate more cancer risk in some instances.

[Michael]

one potential downside of this [increase in capillary growth in the NMN-exercise-angiogenesis paper] would be increased risk of cancer growth or invasion via angiogenesis. Flagging angiogenesis with age may be one of the reasons why cancer incidence plateaus late in current lifespans.

 

this is good to know:

The ability of NMN to promote angiogenesis raises the question of whether it might stimulate tumor growth. Mice treated with NMN or NR for extended periods show no evidence of increased tumor burden (Mills et al., 2016; Zhang et al., 2016). Indeed, during the course of our studies, no increase in tumor burden was seen with NMN-treatment or in a DEN-induced model of hepatocarcinoma (Figures S7J and S7K), although more study is warranted.

In the Mills Long-term study, mice were given 100 or 300mg/kg NMN daily for 12 months (mid-life to old age) with no increased mortality. Does that not give a clue to safety or cancer risk?

"It should be noted that NMN administration did not generate any obvious toxicity, serious side effects, or increased mortality rate throughout the 12-month-long intervention period"

The mice in the Mills et al long-term NMN paper were not initiated in mid-life, but as young adults (5 mo), and ended in late middle age (17 mo — before the "knee" in the mortality curve), not old age, so this is not a period where you expect to see much cancer anyway:
 

Figure from the Harrison lab at The Jackson Laboratory.

 
An effect sufficient to cause a substantial increase in cancer mortality over this age range would have to be very severe indeed. Additionally, to the extent that the concern raised by the NMN-exercise-angiogenesis paper is that NAD+ precursors could restore flagging angiogenesis with age and thereby facilitate cancer growth and invasion, these mice are too young for such an age-related decline to even set in: in the report, two months of NMN restored more youthful angiogenesis in mice that were 20 months old (well after the end of the Mills et al study), but "NMN did not alter the capillarity or exercise capacity of sedentary animals younger than 12 months (not shown), consistent with overexpression of Nampt, an NAD biosynthetic gene (Frederick et al., 2015)." So there's no reason to expect that you'd see an effect on cancer mediated by renewing angiogenesis in animals like those in Mills et al (though you might still wonder about other effects of NAD+, as discussed elsewhere in this thread).
 
Similarly, their N-nitrosodiethylamine-induced model of hepatocarcinoma is not very useful here: they give what is actually rather stunningly little information about the study, but they do say that the test was initiated at at 14 days of age (before the mice were even weaned!), and continued for 20 weeks: at this age, again, there's no age-related decline in angiogenesis to reverse. I'm also not sure about the expected time-course of cancer in their model, since they don't state the dose of carcinogen (!) and the time-course may be too short.
 
You might more reasonably expect to see an effect in the Zhang et al NR lifespan study, where animals were put on NR commencing at 24 months of age and continuing until death (≤10 months in practice), but somewhat stunningly they didn't do any necropsies, so they don't know if there was an increase in tumors or not. Of course, if there had been a truly massive increase in grossly-visible tumors, you'd expect someone would pick up on it — but not a (say) 30% increase in more typical-sized ones. (They also actually didn't do any necropsies in Mills et al either, but they look at their health in other ways, which again didn't happen in Zhang et al).

 

So, these lines of evidence are, literally, better than nothing, but not really all that reassuring.

Edited by Michael, 23 March 2018 - 06:52 PM.