Im not sure to agree with that and resveratrol I think was shown to activate sirt1 in an independent manner. Im not sure more NAD+ wil influence it.
However, a point interesting enough is that sirt1 block parp1. Bryan can you confirm this ?
Im trying to connecting the dots, and would like to make a pics the more complete as we can where we show the main pathways
EDIT: about sirt1 activity while we age: http://journals.plos...ne.0042357.t001 as you can see there is no strong difference and we can even say no statistical difference. Female do not have decrease in sirt1..
However, its even more clear that the main problem remain the loss of NAD+ due to PARP1 activity. Again and again, this is the main problem: DNA damage.
Resveratrol increases sirt1 activity indirectly, that doesn't mean sirt1 can function adequately(benefit from substances that increase it activity to levels were it might positively affect lifespan) with suboptimal NAD+.
From that linked graph, if I'm reading it correctly, it seems sirt1 activity drops from around 30 to 11, though it seems the level of variability also increases with age. Which would suggest some appear to retain more youthful levels of sirt1 activity. But again regards elderly, some drop dead at 80, while others live to 100 or more, so it is to be expected that if sirt1 contributed to increased lifespan there might be increased variability in the elderly population given the variability in remaining lifespan.
yes this is true regarding suboptimal NAD+ level. But age-induced reduction in SIRT1 activity can also be due to increasing levels of Nicotinamide (from diet), and increasing levels of DBC1.
As you can read in the full study which i think is the most reliable however, even if conflicting result on mice exist, is that the sirt1 activity on female is not a matter while they still age.. and sirt1 remain statistically stimilar for new born, younf adult and adult while only a group of male elerdy have a real decrease as you mentioned. The real marker you have to consider are dna damade (though ph2aX), PARP over expression with aging and NAD+ depletion. All linked: If we fix DNA damage we probably fix PARP, and then NAD+..
We should focus on:
-does sirt1 really block parp1 in healthy cells ? if so by which mechanism ?
- is supplementing with NR will break down into nicotinamide metabolites into the blood AND within the cells (causing on the long run a very bad health effect, knowing the role of sirt1): I want to know if accumulation can be increased here because this case is already maybe done via normal niacin diet). Im sure its possible to have this info. Actually we must have, because here we advice to supplement always more and often with NR without considering that point. I point again the fact we will have to make a strict difference between blood plasma nicotinamide AND accumulation within the cells wich is far more complicated to proof. Then only I would feel safeto consume NR but still have to fix the loop and the DNA damage (maybe the theory of massive inflammation is legit)
yes this is true regarding suboptimal NAD+ level. But age-induced reduction in SIRT1 activity can also be due to increasing levels of Nicotinamide (from diet), and increasing levels of DBC1.
As you can read in the full study which i think is the most reliable however, even if conflicting result on mice exist, is that the sirt1 activity on female is not a matter while they still age.. and sirt1 remain statistically stimilar for new born, younf adult and adult while only a group of male elerdy have a real decrease as you mentioned. The real marker you have to consider are dna damade (though ph2aX), PARP over expression with aging and NAD+ depletion. All linked: If we fix DNA damage we probably fix PARP, and then NAD+..
We should focus on:
-does sirt1 really block parp1 in healthy cells ? if so by which mechanism ?
- is supplementing with NR will break down into nicotinamide metabolites into the blood AND within the cells (causing on the long run a very bad health effect, knowing the role of sirt1): I want to know if accumulation can be increased here because this case is already maybe done via normal niacin diet). Im sure its possible to have this info. Actually we must have, because here we advice to supplement always more and often with NR without considering that point. I point again the fact we will have to make a strict difference between blood plasma nicotinamide AND accumulation within the cells wich is far more complicated to proof. Then only I would feel safeto consume NR but still have to fix the loop and the DNA damage (maybe the theory of massive inflammation is legit)
I cant post links or smilies atm but
SIRT1 Promotes Cell Survival under Stress by Deacetylation-Dependent Deactivation of Poly(ADP-Ribose) Polymerase 1
PMC2715814
Will help as it explains nicely how SIRT controls PARP by deacetylation and tells you what, besides DNA damage (over?) activates PARP:
phosphorylation,
high levels of Mg2+, Ca2+
polyamines
PCAF. Also known as K(lysine) acetyltransferase 2B (KAT2B)
Can't link to the other graph in the paper(forum restrictions), but there's a graph for the sirt1 changes in females and males in that paper.
Well looking at the graph there is one outlier in this graph, that might skew it, as it seems there are only like 3 people in the last female age group. There are also quite few, involved. Also I'm going off of the numbers in the table you linked, going by it there is a decrease, and it might not show given the outlier in the graph with only 3 people.
Regards rodents here's the relevant quote from that same article(relevant as it may elucidate resveratrol's failure in normal rodents to increase lifespan)
However, it should be remembered that SIRT1 activity is dependent on adequate NAD+ availability. Recently, our laboratory reported a significant decline in SIRT1 activity consistent with a decline in NAD+ levels in the heart, lung, liver and kidney in an aging rat model [36]. This was consistent with the hypothesis that NAD+ levels impact on SIRT1 activity
plos 0042357
Consistent with this prediction we report for the first time a significant decline in SIRT1 activity with age in post pubescent males (Fig. 5A, line b), though surprisingly, not in females (Fig. 5B)
I think too few individuals were used at the greater ages, and the outlier affected the results. Also I should note, that normal levels of sirt1 activity need not be indicative of how NAD+ might limit enhanced or increased activity through substances such as resveratrol. While, it might or might not affect normal levels of activity it may or may not impede increased activity from being facilitated.
All linked: If we fix DNA damage we probably fix PARP, and then NAD+..
IIRC, I think the reason DNA damage is likely increasing is likely due to altered gene expression that downregulates protein turn over and probably dna repair. I think Michael Fossel suggested restoring telomeres to more youthful levels reverses the gene expression and protein turn over age related adverse effects, restoring cells to more youthful states, or something like that in his latest book.
EDIT
Several studies point out age-related decrease in expression of DNA repair enzymes or their activities...Why do levels of DNA repair enzymes decline with age, and why are all the DNA repair systems affected?...- paper
My research has me conflicted on the role of nicotinamide riboside in treating or preventing cancer. New cancer therapies are exploring the inhibition of NAMPT(
It seems that increasing NAD+ may help tumor cells proliferate and strategies to inhibit the formation of NAD+ may serve to shrink tumor cells.
On the other hand you have the study that came out that showed increasing levels of NAD+ in liver cancer reversed the disease in those mice that had it as well as prevented in the mice.
My research has me conflicted on the role of nicotinamide riboside in treating or preventing cancer. New cancer therapies are exploring the inhibition of NAMPT(
On the other hand as energy is produced within the mitochondria, in the form of ATP, free radicals are emitted—the same free radicals that are a common byproduct of radiation as mentioned above. In essence, the power produced by the mitochondria comes with a certain amount of cellular destruction. This is why the cell has moved critical DNA out of the mitochondria and into the nucleus for better protection.
I've had this discussion with others before, when we are young we are well equipped to deal with the daily damage and all of our repair mechanisms are set to maximum. There are rare cases where cancer can develop in our youth do to other factors but statistically these numbers are rather low in comparison to the average population/age and when cancers become a higher risk. We've evolved as a species in an environment where we receive external radiation and internal chemical factors that both produce cellular damage. (we were built with the ability/tools to perform the necessary maintenance) So if we turn off our NAD pathways we also starve our repair mechanisms but there are times when this may be appropriate and warranted under a doctor's care.
In the Cancer therapy arena they have found that attacking NAD pathways can be a target to stress and help kill "some" cancers and this type of approach may involve other chemotherapies as the final death blow to wipe out that mutant cell. This study came to mind but there are many others.
Now I'm not an Oncologist but this approach is a way to weaken the NAD energy pathways Cancer needs to survive, so this can be a beneficial treatment approach as suggested. Keep in mind it also affects healthy tissue as well, reducing the ability of those cells to perform DNA maintenance thru the NAD dependent PARP enzymes.
It's not unheard of to hear about unrelated "separate" cancers developing after weakening the cells DNA maintenance and repair with these chemo's. "Chemotherapy Can Inadvertently Encourage Cancer Growth" So the primary cancer can get help from the surrounding tissue and secondary cancers can develop within the healthy tissues as collateral damage. Within this strategy PARP inhibitors may also be employed by keeping cancer cells from repairing themselves once they've been damaged by chemotherapy. So this is why several approaches are often used together to block the recovery of the targeted cells. If you are a cancer patient I would openly discuss NAD boosting with your Oncologist because they can let you know when and when not to use the NAD precursors and there might be an appropriate time to resume them after the chemo treatment.
So for most of us we want our cells to keep vigilant in repairing our daily NAD lesions and this ability slowly drops with age and our NAD levels. This one reason out of many why we follow NAD boosting. But if we are in the situation of being under the care of an Oncologist and they are trying to cripple or slow-down a cancer making it more susceptible to another chemotherapy or radiation I would follow their instructions to the letter to ensure success but I would still ask a lot of questions regarding the known risks to my healthy tissue.
Hope that helps.
For those walking this path my heart goes out to you but this should be a discussion with your Doctor. My opinions should really only be used to stimulate these questions. One area many of us have begun to look into for cancer prevention and as a supplement to chemo is honokiol. This is why I believe honokiol could be the Swiss Army knife in cancer treatment. Not an inticment/recommendation as a cure but the research is well worth reading.
Sorry I didn't see the start of these questions but I'm on the road and away from my keyboard.
Edited by Bryan_S, 22 February 2016 - 02:59 AM. background radiation and mitochondrial energy damage update, How Sirtuin Deacetylation Impacts Genetic Expression, David Sinclair defends nicotinamide
"SIRT 1 is NAD dependent, just raising SIRT levels will not increase their activity unless there is sufficient NAD to perform the work."
Agreed, except you mean 'trying to raise SIRT'
NAD+ will raise levels of everything dependant in it.
ie: SIRT, PARP, CD38 etc.
(Upregulating NAMPT is the best way of doing this IMHO as it will keep intracellular NAM levels down and NAM downregulates SIRT, PARP etc.)
Then SIRT1 will control PARP levels by de-acetylation of PARP activated by things other than DNA breaks.
See my previous post.
As there are things, besides DNA damage, that raise PARP to dangerous levels; increasing SIRT with R and/or Pt is a very important consideration IMHO!
See my previous post and google the study title/s you lazy buggers!
Now in vivo Pt is likely to give the results seen in vitro with R due to a much longer half life and much better bioavailability IMHO.
Ask yourself: WTF did Sinclair et-al added Pt to their NR tablets.........!?
The in vitro/vivo research results have been the source of much confusion and argument here.
Keeping the difference in mind and reading about PT and R and their metabolites cleared that up for me. Try it!
Just a thought, but if certain cancers thived on NAD, wouldn't they be more prevalent in our youth when we have higher levels of NAD?
Not if other factors of youthful cells overcame that.
But NAD is in all cells, and we're lead to believe in larger amounts when we are younger...
IMHO:
You don't have the buildup of:AGEs, lipofuscin, etc.
You arent full of low level chronic infections. (Ever notice the link between viral infection and cancer? Think HPV vaccine and Cervical cancer and then see how many cancers you can find that aren't somehow linked to a virus. They change your DNA to do what they want...)
Your gut isn't leaking toxins and pathogens into the rest of you.
ie: Conditions are optimal for the use of optimal epigenetics, so the body does not have to compromise to avoid cancer. Hence the high NAD+ levels. IMHO.
Slaying Two Dragons with One Stone – How to Prevent Cancer and Aging with the Same Strategy
"Basis [NR and pterostilbene] was first released for sales in February 2015 after initial human trials, additional trials for safety and efficacy began in January 2016. Run by an independent group, these trials will result in a report, slated to be published in late 2016, that is expected to expand the safety data and begin to test efficacy in humans."
"The trials, placebo-controlled and double-blind, will measure markers of good health like blood glucose, lipids, levels of inflammation, sleep and energy, as well as tests based on physical capacity."
---
If I'm reading this correctly, then the efficacy results have been pushed back about a half a year to a year.
"SIRT 1 is NAD dependent, just raising SIRT levels will not increase their activity unless there is sufficient NAD to perform the work."
Agreed, except you mean 'trying to raise SIRT'
NAD+ will raise levels of everything dependant in it.
ie: SIRT, PARP, CD38 etc.
(Upregulating NAMPT is the best way of doing this IMHO as it will keep intracellular NAM levels down and NAM downregulates SIRT, PARP etc.)
Then SIRT1 will control PARP levels by de-acetylation of PARP activated by things other than DNA breaks.
See my previous post.
As there are things, besides DNA damage, that raise PARP to dangerous levels; increasing SIRT with R and/or Pt is a very important consideration IMHO!
See my previous post and google the study title/s you lazy buggers!
Now in vivo Pt is likely to give the results seen in vitro with R due to a much longer half life and much better bioavailability IMHO.
Ask yourself: WTF did Sinclair et-al added Pt to their NR tablets.........!?
The in vitro/vivo research results have been the source of much confusion and argument here.
Keeping the difference in mind and reading about PT and R and their metabolites cleared that up for me. Try it!
Is Sinclair even connected to Elysium which adds pterostilbene to NR?
Note that Sinclair said a few months ago in a WaPo interview that he takes 1000 mg of resveratrol a day yet also said in a Q&A in late 2014 that while he takes resveratrol, he thought it was "old technology and that there is better, the NAD route." [paraphrase]
The plot thickens as Guarente said in an interview that he takes NR/pterostilbene [Elysium] but in another interview said that he also 250 mg of resveratrol a day. I wonder why both resveratrol and pterostilbene.
I found the following interesting (bold is mine) in relation to the NR protective role and the PARP inhibition, in particular for prostate cancer.
Nicotinamide Riboside Delivery Generates NAD+ Reserves to Protect Vascular Cells Against Oxidative Damage
“…This study determines if nicotinamide riboside (NR) delivery can augment NAD+ stores and fuel resistance to oxidative stress. I established that oxidative-stress insult on vascular cells decreased NAD+ levels, accompanied by a striking increase in nuclear PAR-chain accumulation. PARP inhibition abolished PAR-chain formation and preserved NAD+ levels, establishing PARP in NAD+ consumption in this model. NR delivery protected against cell-shrinkage and cell death and promoted DNA repair efficiency. PARP inhibition mimicked NR’s beneficial effects on cell-shrinkage and viability but at the cost of DNA repair efficiency…”
In another article titled “Scientists unveil prostate cancer’s ‘Rosetta Stone’”, “ … Researchers analysed the genetic codes of metastatic tumors from the bone, soft tissues, lymph nodes and liver of 150 patients with advanced prostate cancer. Nearly two thirds of the men in the study had mutations in a molecule that interacts with the male hormone androgen which is targeted by current standard treatments – potentially opening up new avenues for hormone therapy. Mutations in the BRCA1 and BRCA2 genes – most famous for their roles in breast cancer – were found in nearly 20% of patients. Recent work at the ICR and The Royal Marsden has shown that these patients can be treated effectively by drugs called PARP inhibitors. Researchers also discovered new mutations, never detected before in prostate cancer, but which do occur in other cancers. These include mutations in the PI3K and RAF gene families which can also be targeted by existing drugs, either currently in trials or approved for use in the clinic…”
ChromaDex Announces Commencement of an Obesity-Related Clinical Study of NIAGEN® in Collaboration With the University of Copenhagen and Aarhus University
Dr. Jonas Treebak, a Researcher With The Novo Nordisk Foundation Center for Basic Metabolic Research (University of Copenhagen, Denmark) Will, in Collaboration With Researchers at Aarhus University, Investigate the Metabolic and Insulin Sensitizing Effects of NIAGEN® in Obese Healthy Adults Aged 40-70 Years
Thanks for the Grape seed info on modulating NAMPT. "In conclusion, PAs modulate the molecular clock in the liver even though their effectiveness depends largely on the time of administration." As we look for activators of NAMPT to heighten NAD+ this one appears to signal to modulate the molecular clock in the liver. So overall the timing of its ingestion can heighten the production of NAMPT but not so much when taken during off hours.
Did I read this right, it had its greatest effect when administered at the beginning of the active wake cycle. Which for the rats was at dusk. Can we pin this down to a human 24-hour circadian cycle? I assume this equates to when we wake up?
Some of us already take this for blood pressure and I take it in my AM stack and again in my PM stack before bed. Sounds like some of us can optimize our efforts by choosing the correct time of day for its administration boosting NAD+.
ChromaDex Announces Commencement of an Obesity-Related Clinical Study of NIAGEN® in Collaboration With the University of Copenhagen and Aarhus University
Dr. Jonas Treebak, a Researcher With The Novo Nordisk Foundation Center for Basic Metabolic Research (University of Copenhagen, Denmark) Will, in Collaboration With Researchers at Aarhus University, Investigate the Metabolic and Insulin Sensitizing Effects of NIAGEN® in Obese Healthy Adults Aged 40-70 Years
Is Sinclair even connected to Elysium which adds pterostilbene to NR?
Note that Sinclair said a few months ago in a WaPo interview that he takes 1000 mg of resveratrol a day yet also said in a Q&A in late 2014 that while he takes resveratrol, he thought it was "old technology and that there is better, the NAD route." [paraphrase]
The plot thickens as Guarente said in an interview that he takes NR/pterostilbene [Elysium] but in another interview said that he also 250 mg of resveratrol a day. I wonder why both resveratrol and pterostilbene.
I'm sure we will know more soon... by 2021.
Here are my two cents: I have known Lenny Guarante for almost 10 years, I know David somewhat, having interviewed him and gone back and forth over some years. David is not involved in Elysium that I know of, although Lenny's group did use Sitris's insights for delivery of Basis into the body. So maybe
there was some financial recompense. Last July (ish) David emailed me and asked in response to something I had brought up about beta lapachone:
' Beta Lapachone is very interesting. Do you have a trusted source for beta lapachone; do you take it?' That is close to a quote. Another aging researcher
I know had also zeroed in on the NAD rationed beta lapachone. Bottom line here is that I think they think beta lapachone could be the missing link. I actually didn't tell Lenny or David, but I have been having beta lapachone synthesized since September, a small amount has been rendered, they will finish building top material by early April, test it etc - my intention is to try it in different combinations (resveratrol, rapamycin etc) on mice. I may give David and Lenny some. It will be independently tested again after the chemists turn it over to me. Robert Kane Pappas
because they have been generous sources for my film research.
Is Sinclair even connected to Elysium which adds pterostilbene to NR?
Note that Sinclair said a few months ago in a WaPo interview that he takes 1000 mg of resveratrol a day yet also said in a Q&A in late 2014 that while he takes resveratrol, he thought it was "old technology and that there is better, the NAD route." [paraphrase]
The plot thickens as Guarente said in an interview that he takes NR/pterostilbene [Elysium] but in another interview said that he also 250 mg of resveratrol a day. I wonder why both resveratrol and pterostilbene.
I'm sure we will know more soon... by 2021.
Here are my two cents: I have known Lenny Guarante for almost 10 years, I know David somewhat, having interviewed him and gone back and forth over some years. David is not involved in Elysium that I know of, although Lenny's group did use Sitris's insights for delivery of Basis into the body. So maybe
there was some financial recompense. Last July (ish) David emailed me and asked in response to something I had brought up about beta lapachone:
' Beta Lapachone is very interesting. Do you have a trusted source for beta lapachone; do you take it?' That is close to a quote. Another aging researcher
I know had also zeroed in on the NAD rationed beta lapachone. Bottom line here is that I think they think beta lapachone could be the missing link. I actually didn't tell Lenny or David, but I have been having beta lapachone synthesized since September, a small amount has been rendered, they will finish building top material by early April, test it etc - my intention is to try it in different combinations (resveratrol, rapamycin etc) on mice. I may give David and Lenny some. It will be independently tested again after the chemists turn it over to me. Robert Kane Pappas
because they have been generous sources for my film research.
Sorry for the typos. It's the NAD ratio Vis a vis NQO1 that they feel is key.
Sorry for the typos. It's the NAD ratio Vis a vis NQO1 that they feel is key.
You cant imagin how much you make me happy to read that ! I study beta-lapachone for a while now and im also sure its a missing link in aging. I speak directly witgh the researcher involved in that beta lapachone life extension study. Nature was also interested by this study but didnt published because their control group lived shorter, probably due to some manipulation stress.
NAD+ pool is important, but NAD+/NADH ratio is another very important thing in aging.
" ' Beta Lapachone is very interesting. Do you have a trusted source for beta lapachone; do you take it?' That is close to a quote. Another aging researcher
I know had also zeroed in on the NAD rationed beta lapachone. Bottom line here is that I think they think beta lapachone could be the missing link."
The missing link? Of what? To what?
It has been ten years and neither Sinclair nor anyone else that I know of have even shown resveratrol has anti-aging effects on people.
Did I read this right, it had its greatest effect when administered at the beginning of the active wake cycle. Which for the rats was at dusk. Can we pin this down to a human 24-hour circadian cycle? I assume this equates to when we wake up?
A couple of hours prior to your most active time, that's how i'd interpret their results, you're welcome
From what I have been told it is hard to keep the NAD levels up for a prolonged period due to feedback loops. It tends to readjust due to
an underlying change in NAMPT with age. I am not a scientist but it seems that the NAD+/NADH ratio is more important than absolute levels of NAD.
The NQ01 gene drives this ratio. Beta Lapachone drives influences NQ01.
As to Sinclair and Guarante's research, I think that in general it works as follows - (and this is true in many research areas including stem cell research);
scientists make discoveries that are on the dart board but not exactly right. Critics and peers write papers that poke holes in this or that advance.
The media grabs hold off the story and the breakthrough is deemed wrong. Then years later, the research comes around again, is refined, and turns out to be true in its essence after all. This is the same thing that is happening in stem cell work, Wagers was not quite right, Conboy is more right, Wagers
will refine her stuff and turn out to have offered some good insight. That's how it works. The story of the initial rebuttal tends to hang around even
after it is out of date. Resveratrol and pterostilbene will likely be found to be quite valuable, particularly in combination with and NAD enhancer.
I believe it is important to tease out combination therapies.
Sorry for the typos. It's the NAD ratio Vis a vis NQO1 that they feel is key.
You cant imagin how much you make me happy to read that ! I study beta-lapachone for a while now and im also sure its a missing link in aging. I speak directly witgh the researcher involved in that beta lapachone life extension study. Nature was also interested by this study but didnt published because their control group lived shorter, probably due to some manipulation stress.
NAD+ pool is important, but NAD+/NADH ratio is another very important thing in aging.
Im very glad to see things move on positively.
Hey Tom! I've read your blog and find it very interesting, but I couldn't find any source for the CR vs. ßL results?
If it's true, someone should definitely try your suggestion:
They showed a 17% increase in mean survival period compared to the control mice (the βL group: 9.1±0.2 months vs the control group: 7.8±0.3 months, p<0.001 by the log rank test), whereas the CR group showed 10% (the CR group: 8.6±0.2 months, p<0.05), suggesting that βL was more effective than CR in increasing survival rate
In my knowledge, its the first time we found a molecule able to provide better result in lifespan in mamals than the CR...
And you can check also the mitochondria protectiv effect.. Its just impressiv and its a vivo study..
But again, here its a NR thread, we should open and discuss it in a more general thread since its offtopic
Edited by Tom Andre F. (ex shinobi), 23 February 2016 - 06:07 PM.
Also tagged with one or more of these keywords: nicotinamide riboside, nicotinamide, nad boosting, charles brenner, david sinclair, leonard guarente, niagen, niacinamide, nicotinamide mononucleotide
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