NAD Anti-aging Trials In Mice

Peata

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Interesting, thanks.

NADH is available sublingually but on the expensive side.

Niacinamide is supposed to form this in the body, isn't it?
 

haidut

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Niacinamide raises NAD and consequently the NAD/NADH ratio, which is one of the primary ways to measure if the body is in oxidized or reduced state. The higher the NAD/NADH ratio, the more oxidized (oxygenated) your body is, which I think is what Ray Peat says the goal is. High NADH indicates reduced state and is usually found in stress-related conditions like mental "disease" and alcoholism. I would not take supplemental NADH, you want NAD and for that niacinamide is best. The other substances that raise NAD are niacin, nicotinamide riboside (sold as NiaGen), and NMN described in the Telegraph article. One thing to keep in mind is that in addition to NMN and NiaGen being expensive and possibly patented substances, the studies with them claim that both substances activate the sirtuin genes like SIRT-1, SIRT-2, etc. Ray says this probably promotes tumor growth, and niacinamide is a known sirtuin inhibitor, so another reason for taking plain old niacinamide.
Even on the basis of raising NAD alone, niacinamide still wins and in equal doses with NiaGen and NMN raises NAD by about 30%-40% more.
So, I think this is another point for Ray.
 

pone

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haidut said:
Niacinamide raises NAD and consequently the NAD/NADH ratio, which is one of the primary ways to measure if the body is in oxidized or reduced state. The higher the NAD/NADH ratio, the more oxidized (oxygenated) your body is, which I think is what Ray Peat says the goal is. High NADH indicates reduced state and is usually found in stress-related conditions like mental "disease" and alcoholism. I would not take supplemental NADH, you want NAD and for that niacinamide is best. The other substances that raise NAD are niacin, nicotinamide riboside (sold as NiaGen), and NMN described in the Telegraph article. One thing to keep in mind is that in addition to NMN and NiaGen being expensive and possibly patented substances, the studies with them claim that both substances activate the sirtuin genes like SIRT-1, SIRT-2, etc. Ray says this probably promotes tumor growth, and niacinamide is a known sirtuin inhibitor, so another reason for taking plain old niacinamide.
Even on the basis of raising NAD alone, niacinamide still wins and in equal doses with NiaGen and NMN raises NAD by about 30%-40% more.
So, I think this is another point for Ray.

I sent you a PM on this, but if Niacinimide in fact generates more NAD+ than NMN and Niagen, why do you think James Watson failed to discuss that alternative in Point 1 in this article:

http://www.anti-agingfirewalls.com/2014 ... g-in-2013/

There must be some other limitation with Niacinimide? Watson always over-obsesses about risks of supplements, so if there were an NAD+ generator that was both more effective *and* safer, he is exactly the guy I would expect to discuss that.
 

pone

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haidut said:
One thing to keep in mind is that in addition to NMN and NiaGen being expensive and possibly patented substances, the studies with them claim that both substances activate the sirtuin genes like SIRT-1, SIRT-2, etc. Ray says this probably promotes tumor growth, and niacinamide is a known sirtuin inhibitor, so another reason for taking plain old niacinamide.

Do you have any references to studies about SIRT-1 activation causing cancer?

I thought that SIRT-1 is NAD+ dependent? See reference:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527007/

If yes, then how would niacinamide avoid activation of SIRT-1 since it is creating more NAD+ from NADH? Is there a reference for that?

There are so many articles now with resveratrol, claiming that it also activates SIRT-1, and that there are all kinds of health benefits from activating SIRT-1 and - in some species - extended lifespan as well.
 

haidut

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pone said:
haidut said:
One thing to keep in mind is that in addition to NMN and NiaGen being expensive and possibly patented substances, the studies with them claim that both substances activate the sirtuin genes like SIRT-1, SIRT-2, etc. Ray says this probably promotes tumor growth, and niacinamide is a known sirtuin inhibitor, so another reason for taking plain old niacinamide.

Do you have any references to studies about SIRT-1 activation causing cancer?

I thought that SIRT-1 is NAD+ dependent? See reference:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527007/

If yes, then how would niacinamide avoid activation of SIRT-1 since it is creating more NAD+ from NADH? Is there a reference for that?

There are so many articles now with resveratrol, claiming that it also activates SIRT-1, and that there are all kinds of health benefits from activating SIRT-1 and - in some species - extended lifespan as well.

I don't have sources right now, but Ray talked about it here:

viewtopic.php?f=19&t=1316

I also posted something of interest in these related posts:
viewtopic.php?f=10&t=3847&p=45971&hilit=SIRT#p45971
viewtopic.php?f=10&t=2503&hilit=SIRT

I hope that helps.
 

pone

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haidut said:
Niacinamide raises NAD and consequently the NAD/NADH ratio, which is one of the primary ways to measure if the body is in oxidized or reduced state. The higher the NAD/NADH ratio, the more oxidized (oxygenated) your body is, which I think is what Ray Peat says the goal is. High NADH indicates reduced state and is usually found in stress-related conditions like mental "disease" and alcoholism. I would not take supplemental NADH, you want NAD and for that niacinamide is best. The other substances that raise NAD are niacin, nicotinamide riboside (sold as NiaGen), and NMN described in the Telegraph article. One thing to keep in mind is that in addition to NMN and NiaGen being expensive and possibly patented substances, the studies with them claim that both substances activate the sirtuin genes like SIRT-1, SIRT-2, etc. Ray says this probably promotes tumor growth, and niacinamide is a known sirtuin inhibitor, so another reason for taking plain old niacinamide.
Even on the basis of raising NAD alone, niacinamide still wins and in equal doses with NiaGen and NMN raises NAD by about 30%-40% more.
So, I think this is another point for Ray.

The entire reason that everyone got excited about the original Sinclair mouse studies with NiaGen / nicotinamide riboside is because it both dramatically raised NAD+ levels while also activating the SIRT genes. Raising NAD+ without activating SIRT is nothing to get excited about.

Nicotinamide (aka niacinamide) is the form of niacin sometimes used as a supplement because it does not cause flushing, but it also does not reduce cholesterol, most likely because it is an inhibitor of sirtuin activity.
Niacinamide, at the high doses required to impact dyslipidemia, inhibits sirtuin enzymes. See for example:
http://www.ncbi.nlm.nih.gov/pubmed/19897059

What you said about SIRT increasing risk of cancer is highly controversial. Some would argue SIRT prevents cancer. SIRT acts as a tumor suppressor by initiating the BAX pathway when appropriate. SIRT prevents p53’s anti-cancer action at the nucleus, but promotes p53’s apoptotic effect via the BAX pathway. See for example:
http://www.ncbi.nlm.nih.gov/pubmed/18710944

There is a very good discussion of the SIRT / cancer issues in this article:
http://www.lmreview.com/articles/view/r ... an-part-ii

I think how this will end up playing out is that the overall cancer risks - up or down - from SIRT will either not be statistically significant or will be a few percentage points either way. Missing all of the life extension benefits of activating SIRT to avoid the possible cancer concern won't make much sense in the bigger picture.
 
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Yes, everything to do with SIRT requires euphemisms for "scam".
 

pone

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Such_Saturation said:
Yes, everything to do with SIRT requires euphemisms for "scam".

Well, SIRT is the "leading edge", and as they say the leading edge is the bleeding edge....

No one knows how it will all work out, but it's pretty clear that they are on the edge of some huge discoveries that will affect lifespan in dramatic ways. They may not understand why these things happen for 50 years, but I suspect within 10 years they will find that taking certain substances does significantly extend human lifespan.

The one study from 2012 that I still cannot wrap my mind around is where they gave carbon 60 (C60) emulsified in olive oil to rats, and the lifespans of the rats doubled. That's the kind of discovery that will take decades to understand (if the result duplicates in other studies) but will be easy and cheap to implement for a human. You will be able to get benefit from these discoveries before they fully understand the mechanisms.
 

fyo

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I suspect within 10 years they will find that taking certain substances does significantly extend human lifespan.[/quote]

"'Substances that significantly extend human lifespan"
These are already known, though. Just not widely known or appreciated.

Likewise, there are sub stances which significantly shorten human lifespan. These are also already known in an extremely meaningful way, yet still not widely understood.

You could apply the above to mere foods, e.g. PUFAs causing heart disease, or you could extend it to simple substances like aspirin. "Magic pills" already exist in the sense that a good diet is highly regenerative.

Its not really science that is lacking these days, but rather general understanding (or perhaps care) among people.

The one study from 2012 that I still cannot wrap my mind around is where they gave carbon 60 (C60) emulsified in olive oil to rats, and the lifespans of the rats doubled. That's the kind of discovery that will take decades to understand (if the result duplicates in other studies) but will be easy and cheap to implement for a human. You will be able to get benefit from these discoveries before they fully understand the mechanisms.
The carbon is antisceptic, among other things. Similar results are achieved with charcoal/activated charcoal (i.e. carbon) or by raising mice in a germ-free environment (i.e. 2x lifespan improvement). Peat's written about both. You could make charcoal in your backyard.
 

Velve921

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I may have missed this somewhere in the forum, but on Danny Roddy's podcast there was mention of getting the NAD/NADH ratio tested. Is that the formal name of the test? I currently talked to my doctor's office and they have not heard of this test and its not on the Quest labs list of tests. They do have lactate dehydrogenase; would this be considered just as good or close? Any and all thoughts would be great.

My apologies if this has already been answered.
 

haidut

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I may have missed this somewhere in the forum, but on Danny Roddy's podcast there was mention of getting the NAD/NADH ratio tested. Is that the formal name of the test? I currently talked to my doctor's office and they have not heard of this test and its not on the Quest labs list of tests. They do have lactate dehydrogenase; would this be considered just as good or close? Any and all thoughts would be great.

My apologies if this has already been answered.

Unfortunately, it looks like very few labs offer this test and the main ones like Quest/Labcorp do not offer it yet. LDH is a good surrogate, combined with the common bicarbonate test. If LDH is high and bicarbonate low, you are overproducing lactate and are probably low in NAD.
 

David Chung

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If you think about the types of stimuli that activate SIRT1, it seems rather clear that SIRT1 serves to translate stress (e.g., hunger, heat, cold, etc.) into body's adaptive response. Since chronic stress leads to bad things, it seems likely that chronic activation of sirt1 should lead to problems.

However, we know that mortality rate increases among those who are "stress-free" (this is one reason that I wonder if Ray's concept of making all cellular energy utilization as optimal as possible is what is best for the human body - as this would minimize stress at cellular level). For example, lowering cortisol is desirable, but its complete suppression can shunt the feedback loop necessary for adaptation. Following this reasoning, some SIRT1 activation is probably necessary.

It is interesting that mitochondrial biogenesis also appears to involve stress (and therefore SIRT1). So, how does stress lead to mitochondrial biogenesis? Apparently, SIRT1 activation leads to the expression of PGC-1alpha protein. For this translation to occur efficiently, however, it appears we need high NAD level. That is, high NAD/NADH ratio is not only desirable for efficient energy utilization, but also for optimal adaptive response to stress.
 
Last edited:

haidut

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If you think about the types of stimuli that activate SIRT1, it seems rather clear that SIRT1 serves to translate stress (e.g., hunger, heat, cold, etc.) into body's adaptive response. Since chronic stress leads to bad things, it seems likely that chronic activation of sirt1 should lead to problems.

However, we know that mortality rate increases among those who are "stress-free" (this is one reason that I wonder if Ray's concept of making all cellular energy utilization as optimal as possible is what is best for the human body - as this would minimize stress at cellular level). For example, lowering cortisol is desirable, but its complete suppression can shunt the feedback loop necessary for adaptation. Following this reasoning, some SIRT1 activation is probably necessary.

It is interesting that mitochondrial biogenesis also appears to involve stress (and therefore SIRT1). So, how does stress lead to mitochondrial biogenesis? Apparently, SIRT1 activation leads to the expression of PGC-1alpha protein. For this translation to occur efficiently, however, it appears we need high NAD level. That is, high NAD/NADH ratio is not only desirable for efficient energy utilization, but also for optimal adaptive response to stress.

So, niacinamide would be perfect in this case because it both suppresses SIRT1 and also increases NAD levels (which stimulates mitochondrial biogenesis).
I think the effects of stress you mention on mitochondria are similar to the effects of acute stress on steroidogenesis - acute stress stimulates the production of cortisol BUT also of pregnenolone, DHEA, and DHT. However, when present chronically, the adrenals atrophy and only the layer responsible for cortisol production remains intact, thus shifting the steroid balance heavily in favor of cortisol production and reducing/halting mitochondrial biogenesis.
This is sort of confirmed by studies on endurance athletes - i.e. running moderate distances 1-2 times week leads to upregulation of PGC1-a and increased mitochondrial biogenesis, combined with higher tissue levels of DHEA and DHT. However, doing that for a few years or increasing the intensity, duration of frequency of the running stress leads to hypogonadism and hypercortisolemia, combined with decline in mitochondrial number/density to even lower levels than before starting.
 

Peata

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From the article: Turner said a “magic pill” that reverses ageing is several years away, partially due to the cost of the compound, which would be about $50,000 a day for a human.

But trials are expected to commence as soon as next year, with researchers confident that side-effects will be minimal due to the fact the compound is naturally occurring.
 
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