The Plasma NAD+ Metabolome Is Dysregulated In ‘‘Normal’’ Aging

[Mito]

“To our knowledge, this is the first study to show that NAD+ levels steeply declines with age in human plasma. On the contrary to previous reports, this study provides strong evidence for the availability of the extracellular NAD+ and its related metabolites in plasma. This is important since NAD+ is vital to numerous cellular processes including oxidative phosphorylation and energy production, immune function (through CD38 activity), DNA repair (through PARP activity), nuclear signaling and protein function (through sirtuin activity), and telomere maintenance (through Tankyrase1 activity). Critical depletion of NAD+ results in cell death through reduced ATP production and activation of apoptosis.62Reliable measurements of plasma NAD+ metabolites should greatly aid in the effective upregulation of intracellular NAD+ using NAD+ and related precursors for the purpose of maintaining critical cellular processes and thereby ameliorating some age-related cellular degeneration and resulting pathologies.”

https://www.liebertpub.com/doi/10.1089/rej.2018.2077

 

[LeeLemonoil]

Highly important implications from that paper.

I doubt that in aging that the precursors of NAD+ like niaciamide or ribose are scarce.
Looks like methylene blue is an obvious candidate for treatment, it shifts the balance towards NAD+ and is effective in premature aging condition progeria

 

[LeeLemonoil]

Meat Intake and the Dose of Vitamin B3 – Nicotinamide: Cause of the Causes of Disease Transitions, Health Divides, and Health Futures?
Lisa J Hill1 and Adrian C Williams2
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
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Abstract
Meat and vitamin B3 – nicotinamide – intake was high during hunter-gatherer times. Intake then fell and variances increased during and after the Neolithic agricultural revolution. Health, height, and IQ deteriorated. Low dietary doses are buffered by ‘welcoming’ gut symbionts and tuberculosis that can supply nicotinamide, but this co-evolved homeostatic metagenomic strategy risks dysbioses and impaired resistance to pathogens. Vitamin B3 deficiency may now be common among the poor billions on a low-meat diet. Disease transitions to non-communicable inflammatory disorders (but longer lives) may be driven by positive ‘meat transitions’. High doses of nicotinamide lead to reduced regulatory T cells and immune intolerance. Loss of no longer needed symbiotic ‘old friends’ compounds immunological over-reactivity to cause allergic and auto-immune diseases. Inhibition of nicotinamide adenine dinucleotide consumers and loss of methyl groups or production of toxins may cause cancers, metabolic toxicity, or neurodegeneration. An optimal dosage of vitamin B3 could lead to better health, but such a preventive approach needs more equitable meat distribution. Some people may require personalised doses depending on genetic make-up or, temporarily, when under stress.


Tricky stuff, Niacinamide.

Regarding NAD+ in aging. There is the enzyme CD38 that is much more active in age which is catabolic to NAD+. Unfortunately, it is upregulated by Vitamin A but inhibited for example by Apigenin.

https://www.sciencedirect.com/science/article/pii/S1550413116302248

 

[DennisX]

Meat Intake and the Dose of Vitamin B3 – Nicotinamide: Cause of the Causes of Disease Transitions, Health Divides, and Health Futures?
Lisa J Hill1 and Adrian C Williams2
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
Go to:
Abstract
Meat and vitamin B3 – nicotinamide – intake was high during hunter-gatherer times. Intake then fell and variances increased during and after the Neolithic agricultural revolution. Health, height, and IQ deteriorated. Low dietary doses are buffered by ‘welcoming’ gut symbionts and tuberculosis that can supply nicotinamide, but this co-evolved homeostatic metagenomic strategy risks dysbioses and impaired resistance to pathogens. Vitamin B3 deficiency may now be common among the poor billions on a low-meat diet. Disease transitions to non-communicable inflammatory disorders (but longer lives) may be driven by positive ‘meat transitions’. High doses of nicotinamide lead to reduced regulatory T cells and immune intolerance. Loss of no longer needed symbiotic ‘old friends’ compounds immunological over-reactivity to cause allergic and auto-immune diseases. Inhibition of nicotinamide adenine dinucleotide consumers and loss of methyl groups or production of toxins may cause cancers, metabolic toxicity, or neurodegeneration. An optimal dosage of vitamin B3 could lead to better health, but such a preventive approach needs more equitable meat distribution. Some people may require personalised doses depending on genetic make-up or, temporarily, when under stress.


Tricky stuff, Niacinamide.

Regarding NAD+ in aging. There is the enzyme CD38 that is much more active in age which is catabolic to NAD+. Unfortunately, it is upregulated by Vitamin A but inhibited for example by Apigenin.

https://www.sciencedirect.com/science/article/pii/S1550413116302248

Thanks for the cd38 reference. If you Google cd38inhibitors quercetin is also a cd38 inhibitor

 

[bdawg]

Meat Intake and the Dose of Vitamin B3 – Nicotinamide: Cause of the Causes of Disease Transitions, Health Divides, and Health Futures?
Lisa J Hill1 and Adrian C Williams2
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
Go to:
Abstract
Meat and vitamin B3 – nicotinamide – intake was high during hunter-gatherer times. Intake then fell and variances increased during and after the Neolithic agricultural revolution. Health, height, and IQ deteriorated. Low dietary doses are buffered by ‘welcoming’ gut symbionts and tuberculosis that can supply nicotinamide, but this co-evolved homeostatic metagenomic strategy risks dysbioses and impaired resistance to pathogens. Vitamin B3 deficiency may now be common among the poor billions on a low-meat diet. Disease transitions to non-communicable inflammatory disorders (but longer lives) may be driven by positive ‘meat transitions’. High doses of nicotinamide lead to reduced regulatory T cells and immune intolerance. Loss of no longer needed symbiotic ‘old friends’ compounds immunological over-reactivity to cause allergic and auto-immune diseases. Inhibition of nicotinamide adenine dinucleotide consumers and loss of methyl groups or production of toxins may cause cancers, metabolic toxicity, or neurodegeneration. An optimal dosage of vitamin B3 could lead to better health, but such a preventive approach needs more equitable meat distribution. Some people may require personalised doses depending on genetic make-up or, temporarily, when under stress.


Tricky stuff, Niacinamide.

Regarding NAD+ in aging. There is the enzyme CD38 that is much more active in age which is catabolic to NAD+. Unfortunately, it is upregulated by Vitamin A but inhibited for example by Apigenin.

https://www.sciencedirect.com/science/article/pii/S1550413116302248

Good pickup on CD38

 

[Ella]

Meat Intake and the Dose of Vitamin B3 – Nicotinamide: Cause of the Causes of Disease Transitions, Health Divides, and Health Futures?
Lisa J Hill1 and Adrian C Williams2
Author information Article notes Copyright and License information Disclaimer
This article has been cited by other articles in PMC.
Go to:
Abstract
Meat and vitamin B3 – nicotinamide – intake was high during hunter-gatherer times. Intake then fell and variances increased during and after the Neolithic agricultural revolution. Health, height, and IQ deteriorated. Low dietary doses are buffered by ‘welcoming’ gut symbionts and tuberculosis that can supply nicotinamide, but this co-evolved homeostatic metagenomic strategy risks dysbioses and impaired resistance to pathogens. Vitamin B3 deficiency may now be common among the poor billions on a low-meat diet. Disease transitions to non-communicable inflammatory disorders (but longer lives) may be driven by positive ‘meat transitions’. High doses of nicotinamide lead to reduced regulatory T cells and immune intolerance. Loss of no longer needed symbiotic ‘old friends’ compounds immunological over-reactivity to cause allergic and auto-immune diseases. Inhibition of nicotinamide adenine dinucleotide consumers and loss of methyl groups or production of toxins may cause cancers, metabolic toxicity, or neurodegeneration. An optimal dosage of vitamin B3 could lead to better health, but such a preventive approach needs more equitable meat distribution. Some people may require personalised doses depending on genetic make-up or, temporarily, when under stress.


Tricky stuff, Niacinamide.

Regarding NAD+ in aging. There is the enzyme CD38 that is much more active in age which is catabolic to NAD+. Unfortunately, it is upregulated by Vitamin A but inhibited for example by Apigenin.

https://www.sciencedirect.com/science/article/pii/S1550413116302248

@LeeLemonoil thanks for posting. Love the direction this research is heading. This is an excellent paper mirroring my thoughts - double edge sword whether we are talking about vitamin A or B-vitamins. Too little attention is placed on how the microbiome is transformed during starvation and over-nourished states. Context is important.

We will argue that nobody ever systematically checked that pellagra was eliminated globally (dietary supplementation mainly happened in rich countries). Pellagra may be common and misdiagnosed masquerading as ‘environmental enteropathy’, poor cognition, eczema, or general ill health and a lack of well-being or poor homeostasis when under environmental stress with shortened lives.38,39

Controversially, we suggest that many people in rich countries may be on too high a dose. A hyper-vitaminosis B3 state may be common and, like pellagra, have a wide phenotype that includes the metabolic syndrome, several cancers, and some degenerative or neuro-behavioural disorders.40

Its finding that elusive goldilocks dose of "just right" and "just time" which is challenging - one size does not fit all.

Tannic acid is an CD38 inhibitor, I am big tea drinker and have feared the TA in it. I crash if I have too much which I have attributed to the fluoride. Since TA along with quercertin reduces LPS upregulation of CD38, i'll keep enjoying my tea in reduced quantities and increase chamomile.

 

[LeeLemonoil]

Thanks all for participating in this thread.

The publication Mito posted is really groundbreaking but explains a lot. If it were so easy to maintain a favorable NAD+/NADH-ratio in important tissues and organelles, then we would not have seen so many civilatory diseases associated with B3-availability in industrial food availability.

If anybody has ideas to adress the issue of NAD+ decline in aging despite b3 supplementation pls join the discussion.

Cd38-inhibition was my first intuition along with MB, but I have not yet searched for validation

 

[LeeLemonoil]

New Insight Into the Balance Between the Tumor-suppressive and Tumor-promoting Effects of Cellular Senescence


So the study I posted circulates heavily in scientific circles. No wonder given that NAD+ was touted (in RP-Forum also) as a universal anti-age/pro-health parameter to influence.

It is way more complex and "blindly" increasing NAD+/NADH-ratio without being able to ensure where this ration is modulated is even possibly to be a potent cancer risk, see the article above.

Thoughts to summarize the implications of the new publication and the discussion:

NAD+ - increase has different physiological effects in older than in young people. Simply keeping NAD+ high does not prevent aging or the phneomena of age.

It might be crucial to flank NAD+-increasing measures with ant-inflammatory measure wuth regards to possible pro-cancerogenic effects of NAD+

Cyclic increase of NAD+ seems more favourable (fasting/calorie restriction! - Very unpeaty)

Senescent cells turn maligne more quickly with more energy. Prevention of senescence or senolytic measures seem prudent to prevent the hazardous aspects of high NAD+ in aging. This is where Peat seems to be in accordance with this new findings but in general it seems that his views of Niacinamide as NAD+-precursor and keeping NAD+/NADH-ration highly in favour of the former is outdated.

 

[LeeLemonoil]

PHILADELPHIA — (Feb. 18, 2019) — Researchers at The Wistar Institute have described a novel role of nicotinamide adenine dinucleotide (NAD+) metabolism in the ability of senescent cells to release tumor-promoting molecules. This study, published online in Nature Cell Biology, also cautions that NAD+-augmenting supplements, currently in development for their anti-aging effects as nutroceuticals, should be administered with precision given their potential pro-tumorigenic side effects.

Cellular senescence is a process in which cells irreversibly stop dividing and represents a potent tumor suppressive mechanism. At the same time, senescent cells also produce a variety of inflammatory soluble molecules that can promote tumor growth, known by the name of senescence-associated secretory phenotype (SASP).

The laboratory of Rugang Zhang, Ph.D., deputy director of The Wistar Institute Cancer Center, professor and co-program leader of the Gene Expression and Regulation Program, investigated the role of a family of proteins called HMGAs in cellular senescence and the SASP.

HMGAs are DNA-binding proteins that regulate gene expression. They are frequently overexpressed and associated with poor prognosis in many cancer types, yet they are known to promote senescence. This new research aims to clarify these mechanisms to unveil the dual role of the HMGA family of proteins in cancer.

Zhang and colleagues discovered that in cells undergoing senescence HMGAs increase the levels of NAMPT, a key enzyme in the production of nicotinamide adenine dinucleotide (NAD+), a cellular factor critical for metabolism and enzyme function. Importantly, increased NAD+ levels enhanced the SASP.

“Our data show that NAD+ levels influence the secretory activity of senescent cells in a way that may promote tumor progression,” said Zhang. “It is well documented that cellular NAD+ concentrations decrease during aging and the use of NAD+ supplementation is being studied as a new preventive opportunity for aging and age-associated disorders. Our results may have far-reaching implications on this field of investigation.”

In fact, by manipulating the expression of HMGA1 and NAMPT, the researchers observed that increased NAD+ metabolism promotes cancer cell proliferation and progression in vivo in mouse models of pancreatic and ovarian cancers.

These data point to a model whereby increased NAD+ metabolism resulting from higher HMGA1 and NAMPT expression promotes a higher SASP and enhances the inflammatory environment around the tumor, which in turn has a stimulatory effect on cancer growth.

“We found that HMGA1 provides a link between the two opposite sides of the coin in the process of senescence — growth arrest and the tumor promoting, proinflammatory secretory phenotype,” said Zhang.

“Our data raise the possibility that targeting NAMPT may be an effective approach to suppress a proinflammatory, tumor promoting microenvironment in tumors that overexpress HMGA1 when treated with senescence-triggering cancer therapeutics such as chemotherapy and radiotherapy,” said Timothy Nacarelli, Ph.D., first author of the study and a postdoctoral researcher in the Zhang Lab. “NAMPT inhibitors are currently in clinical trials and thus readily available for these new applications.”

 

[tankasnowgod]

Thanks all for participating in this thread.

The publication Mito posted is really groundbreaking but explains a lot. If it were so easy to maintain a favorable NAD+/NADH-ratio in important tissues and organelles, then we would not have seen so many civilatory diseases associated with B3-availability in industrial food availability.

Well, maybe it is that easy. Industrial food isn't a good measure at all, since it doesn't simply supply B3. It also supplies a significant amount of raw iron, a known reducing agent. Iron fortification causes an increased formation of NADH. If you are talking about bread and most multivitaimins that contain some form of added B3, they also contain added iron. As the very least, it's a massive confounder, and the B3/Iron combo might even be suspected to shift the ratio toward NADH. Industrial fortified food is far different than eating a diet without added iron and supplementing Niacinamide.

 

[LeeLemonoil]

That doesn’t change that high NAD+ in certain physiological situations, especially old age and I assume bad health, can foster cancer and precursors simply don’t elevate NAD+ where it is needed most. These are the takeaways of the recent research of one takes them to be true

 

[tankasnowgod]

That doesn’t change that high NAD+ in certain physiological situations, especially old age and I assume bad health, can foster cancer and precursors simply don’t elevate NAD+ where it is needed most. These are the takeaways of the recent research of one takes them to be true

I didn't see any evidence of this in any of the studies listed. At best, this is a theory.

 

[Mauritio]

New Insight Into the Balance Between the Tumor-suppressive and Tumor-promoting Effects of Cellular Senescence


So the study I posted circulates heavily in scientific circles. No wonder given that NAD+ was touted (in RP-Forum also) as a universal anti-age/pro-health parameter to influence.

It is way more complex and "blindly" increasing NAD+/NADH-ratio without being able to ensure where this ration is modulated is even possibly to be a potent cancer risk, see the article above.

Thoughts to summarize the implications of the new publication and the discussion:

NAD+ - increase has different physiological effects in older than in young people. Simply keeping NAD+ high does not prevent aging or the phneomena of age.

It might be crucial to flank NAD+-increasing measures with ant-inflammatory measure wuth regards to possible pro-cancerogenic effects of NAD+

Cyclic increase of NAD+ seems more favourable (fasting/calorie restriction! - Very unpeaty)

Senescent cells turn maligne more quickly with more energy. Prevention of senescence or senolytic measures seem prudent to prevent the hazardous aspects of high NAD+ in aging. This is where Peat seems to be in accordance with this new findings but in general it seems that his views of Niacinamide as NAD+-precursor and keeping NAD+/NADH-ration highly in favour of the former is outdated.

So you're saying by first taking senolytics or removing senescent cells through some mechanism and then raising NAD+ ,we get the benefits of less senescent cells (less inflammtion) and simultaneously not getting an increased cancer risk?

Also it would interest me why you think niacinamide as an nad+ precursor is outdated ,what do you think of NMN then ?

 

[LeeLemonoil]

Yes, but senolytics that achieve that are just a wet fantasy of the immortalists. Also, senescence has a homeostatic role in some conditions.

Other NAD+ precursors are as problematic as niacinamide. I meant the theory behind blindly taking NAD+ precursors and deeming it universally beneficial is outdated - as in falsified

 

[Mauritio]

Yes, but senolytics that achieve that are just a wet fantasy of the immortalists. Also, senescence has a homeostatic role in some conditions.

Other NAD+ precursors are as problematic as niacinamide. I meant the theory behind blindly taking NAD+ precursors and deeming it universally beneficial is outdated - as in falsified

But let's suppose for a minute there would be such a senolytic that gets rid of almost all senescent cells. Wouldn't there always be enough senesence going on to get the benefits from it or would you say you its limitations reached up to a point where it causes more harm than benefits?

I think it's almost not possible to get rid of all senescent cells as there's circa 1 DNA damage per second ,per cell !

 

[LeeLemonoil]

Yes, keeping senescence at a „healthy“ level and removing senescent cells that don’t fulfill any beneficial function would certainly make supplementing NAD+ precursors seem safer and endlessly beneficial.

But we have a literal „death switch“ working in us. Apoptosis and senescence work intricately together but also opposing each other making either fictive ultra-senolysis pro cancerous or ultra-apoptosis massively pro aging and thus deadly

 

[LeeLemonoil]

Deleted, double post.

 

[Mauritio]

Yes, keeping senescence at a „healthy“ level and removing senescent cells that don’t fulfill any beneficial function would certainly make supplementing NAD+ precursors seem safer and endlessly beneficial.

But we have a literal „death switch“ working in us. Apoptosis and senescence work intricately together but also opposing each other making either fictive ultra-senolysis pro cancerous or ultra-apoptosis massively pro aging and thus deadly

The question is :what Is a healthy level and how can it be achieved and maintained?
Not easy and probably highly individual.
Anyway thanks for your insights . Cellular senesence, telomere shortening ,... stuff like that is not nearly enough talked about on the forum or even by peat himself!

 

[LucyL]

That doesn’t change that high NAD+ in certain physiological situations, especially old age and I assume bad health, can foster cancer and precursors simply don’t elevate NAD+ where it is needed most. These are the takeaways of the recent research of one takes them to be true

So, metformin alongside the niacinamide/aspirin?

 

[Pompadour]

@LeeLemonoil , have you dig this topic more? Can it be, that niacinamide is indeed dangerous?
I have read some of the studies and they are concerning . But i am bad in reading studies and not sure what to think about it .