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David Sinclair strikes again

aging aging theories david sinclair mitochondria nad sinclair niagen nmn nicotinamide riboside

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#1 PWAIN

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Posted 19 December 2013 - 08:42 PM


New wonder drug...
http://m.theage.com....1220-2zohf.html

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#2 johnross47

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Posted 19 December 2013 - 08:44 PM


Dec. 19, 2013 — Researchers have discovered a cause of aging in mammals that may be reversible.


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The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.
"The aging process we discovered is like a married couple -- when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down," said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. "And just like with a couple, restoring communication solved the problem."
This study was a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.
The findings are published Dec. 19 in Cell.
Communication breakdown
Mitochondria are often referred to as the cell's "powerhouse," generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional over time, many age-related conditions such as Alzheimer's disease and diabetes gradually set in.
Researchers have generally been skeptical of the idea that aging can be reversed, due mainly to the prevailing theory that age-related ills are the result of mutations in mitochondrial DNA -- and mutations cannot be reversed.
Sinclair and his group have been studying the fundamental science of aging -- which is broadly defined as the gradual decline in function with time -- for many years, primarily focusing on a group of genes called sirtuins. Previous studies from his lab showed that one of these genes, SIRT1, was activated by the compound resveratrol, which is found in grapes, red wine and certain nuts.
Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which this SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell's nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.
"This was at odds with what the literature suggested," said Gomes.
As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell's nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1's role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.
For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell's ability to make energy, and signs of aging and disease become apparent.
"This particular component of the aging process had never before been described," said Gomes.
While the breakdown of this process causes a rapid decline in mitochondrial function, other signs of aging take longer to occur. Gomes found that by administering an endogenous compound that cells transform into NAD, she could repair the broken network and rapidly restore communication and mitochondrial function. If the compound was given early enough -- prior to excessive mutation accumulation -- within days, some aspects of the aging process could be reversed.
Cancer connection
Examining muscle from two-year-old mice that had been given the NAD-producing compound for just one week, the researchers looked for indicators of insulin resistance, inflammation and muscle wasting. In all three instances, tissue from the mice resembled that of six-month-old mice. In human years, this would be like a 60-year-old converting to a 20-year-old in these specific areas.
One particularly important aspect of this finding involves HIF-1. More than just an intrusive molecule that foils communication, HIF-1 normally switches on when the body is deprived of oxygen. Otherwise, it remains silent. Cancer, however, is known to activate and hijack HIF-1. Researchers have been investigating the precise role HIF-1 plays in cancer growth.
"It's certainly significant to find that a molecule that switches on in many cancers also switches on during aging," said Gomes. "We're starting to see now that the physiology of cancer is in certain ways similar to the physiology of aging. Perhaps this can explain why the greatest risk of cancer is age. "
"There's clearly much more work to be done here, but if these results stand, then many aspects of aging may be reversible if caught early," said Sinclair.
The researchers are now looking at the longer-term outcomes of the NAD-producing compound in mice and how it affects the mouse as a whole. They are also exploring whether the compound can be used to safely treat rare mitochondrial diseases or more common diseases such as Type 1 and Type 2 diabetes. Longer term, Sinclair plans to test if the compound will give mice a healthier, longer life.

http://www.scienceda...31219130738.htm
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#3 nhenderson

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Posted 19 December 2013 - 08:50 PM

This is out of David Sinclair's lab at Harvard. it is said to be a novel theory of aging. It seems to me there was some mention of this earlier, but I could be wrong.

http://hms.harvard.e...-aging-12-19-13

The quote below is from the press release from Harvard:

Researchers have discovered a cause of aging in mammals that may be reversible.
The essence of this finding is a series of molecular events that enable communication inside cells between the nucleus and mitochondria. As communication breaks down, aging accelerates. By administering a molecule naturally produced by the human body, scientists restored the communication network in older mice. Subsequent tissue samples showed key biological hallmarks that were comparable to those of much younger animals.

“The aging process we discovered is like a married couple—when they are young, they communicate well, but over time, living in close quarters for many years, communication breaks down,” said Harvard Medical School Professor of Genetics David Sinclair, senior author on the study. “And just like with a couple, restoring communication solved the problem.”
This study was a joint project between Harvard Medical School, the National Institute on Aging, and the University of New South Wales, Sydney, Australia, where Sinclair also holds a position.
The findings are published Dec. 19 in Cell.

Communication breakdown

Mitochondria are often referred to as the cell's "powerhouse," generating chemical energy to carry out essential biological functions. These self-contained organelles, which live inside our cells and house their own small genomes, have long been identified as key biological players in aging. As they become increasingly dysfunctional overtime, many age-related conditions such as Alzheimer’s disease and diabetes gradually set in....


...Ana Gomes, a postdoctoral scientist in the Sinclair lab, had been studying mice in which this SIRT1 gene had been removed. While they accurately predicted that these mice would show signs of aging, including mitochondrial dysfunction, the researchers were surprised to find that most mitochondrial proteins coming from the cell’s nucleus were at normal levels; only those encoded by the mitochondrial genome were reduced.
“This was at odds with what the literature suggested,” said Gomes.

As Gomes and her colleagues investigated potential causes for this, they discovered an intricate cascade of events that begins with a chemical called NAD and concludes with a key molecule that shuttles information and coordinates activities between the cell’s nuclear genome and the mitochondrial genome. Cells stay healthy as long as coordination between the genomes remains fluid. SIRT1’s role is intermediary, akin to a security guard; it assures that a meddlesome molecule called HIF-1 does not interfere with communication.
For reasons still unclear, as we age, levels of the initial chemical NAD decline. Without sufficient NAD, SIRT1 loses its ability to keep tabs on HIF-1. Levels of HIF-1 escalate and begin wreaking havoc on the otherwise smooth cross-genome communication. Over time, the research team found, this loss of communication reduces the cell's ability to make energy, and signs of aging and disease become apparent.
“This particular component of the aging process had never before been described,” said Gomes.


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#4 johnross47

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Posted 19 December 2013 - 09:03 PM

A New -- And Reversible -- Cause of Aging: A Naturally Produced Compound Rewinds Aspects of Age-Related Demise in Mice


this has already been posted

#5 Elus

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Posted 19 December 2013 - 09:06 PM

Interested to know why NAD levels decline. Usually these things get exponentially worse with age, so NAD treatment may have diminishing returns as one gets older. The reason being, if the mechanisms which cause NAD deterioration over time are amplified with age, then supplementing NAD will be progressively less effective.

Just a thought, though I hope I am wrong.

Edited by Elus, 19 December 2013 - 09:07 PM.


#6 PWAIN

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Posted 19 December 2013 - 09:51 PM

Does anyone know what this compound is? Is there a way to find out?

#7 Hebbeh

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Posted 19 December 2013 - 09:58 PM

http://www.sigmaaldr...ng=en&region=US

#8 Darryl

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Posted 19 December 2013 - 10:03 PM

As far as I can tell, its beta-Nicotinamide mononucleotide. Dr. Sinclair is by no means on the ground floor.

Edited by Darryl, 19 December 2013 - 10:18 PM.


#9 Mind

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Posted 19 December 2013 - 10:15 PM

"...in mice". Yawn (for now).
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#10 Hebbeh

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Posted 19 December 2013 - 10:21 PM

Perhaps justification for...

http://nicotinamideriboside.org/

https://chromadex.co...nts/NIAGEN.html

http://www.resveratr...aging-pill/566/

Edited by Hebbeh, 19 December 2013 - 10:24 PM.


#11 Hebbeh

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Posted 19 December 2013 - 10:36 PM

Redemption for benaGene?

http://www.longecity...-with-benagene/
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#12 hav

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Posted 19 December 2013 - 11:15 PM

Here's another article on the study indicating they used a mouse dosage of 500 mg/kg.

http://www.news.com....d-1226786877989

Howard

#13 timar

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Posted 19 December 2013 - 11:28 PM

As far as I can tell, its beta-Nicotinamide mononucleotide. Dr. Sinclair is by no means on the ground floor.


Not at all. It seems almost like a remake of this 2011 study by Yoshino et al (with aging substituted for diabetes).

The recent study by Schmeisser et al. also fits right into the scheme.

Edited by timar, 19 December 2013 - 11:34 PM.

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#14 timar

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Posted 19 December 2013 - 11:57 PM

If you don't want to wait for human trials you can get NMN from Sigma-Aldrich. It's only $1700 a gram. :happy:

#15 PWAIN

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Posted 19 December 2013 - 11:59 PM

Here's another article on the study indicating they used a mouse dosage of 500 mg/kg.

http://www.news.com....d-1226786877989

Howard


This article refers to it as NMN which sounds more like beta-Nicotinamide MonoNucleotide than Nicotinamide Riboside. Also they say they injected it, anyone know if beta-Nicotinamide MonoNucleotide is normally injected and if 500mg/kg would be considered safe?

#16 Hebbeh

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Posted 20 December 2013 - 12:07 AM

This article refers to it as NMN which sounds more like beta-Nicotinamide MonoNucleotide than Nicotinamide Riboside. Also they say they injected it, anyone know if beta-Nicotinamide MonoNucleotide is normally injected and if 500mg/kg would be considered safe?


Both are intermediaries for NAD. It is the end result of increasing NAD that performs the supposed magic.

#17 PWAIN

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Posted 20 December 2013 - 12:13 AM

This article refers to it as NMN which sounds more like beta-Nicotinamide MonoNucleotide than Nicotinamide Riboside. Also they say they injected it, anyone know if beta-Nicotinamide MonoNucleotide is normally injected and if 500mg/kg would be considered safe?


Both are intermediaries for NAD. It is the end result of increasing NAD that performs the supposed magic.


I realise this, however, I think the implication here is that one is orders of magnitude more effective that all others. If I pop a lot of Niacin, I probably won't get the same effect or at least not to the same level. The articles seem to imply that the NAD production is way up, like the floodgates have been opened. Not sure that Riboside does this. Also wonder if these chemicals have been around for a while, how come no one noticed this before? Is it the dose?
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#18 timar

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Posted 20 December 2013 - 12:18 AM

Also wonder if these chemicals have been around for a while, how come no one noticed this before? Is it the dose?


See Darryl's and my posts...

#19 Hebbeh

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Posted 20 December 2013 - 12:20 AM

This article refers to it as NMN which sounds more like beta-Nicotinamide MonoNucleotide than Nicotinamide Riboside. Also they say they injected it, anyone know if beta-Nicotinamide MonoNucleotide is normally injected and if 500mg/kg would be considered safe?


Both are intermediaries for NAD. It is the end result of increasing NAD that performs the supposed magic.


I realise this, however, I think the implication here is that one is orders of magnitude more effective that all others. If I pop a lot of Niacin, I probably won't get the same effect or at least not to the same level. The articles seem to imply that the NAD production is way up, like the floodgates have been opened. Not sure that Riboside does this. Also wonder if these chemicals have been around for a while, how come no one noticed this before? Is it the dose?


Correct, niacin is not the rate limiting factor and therefor will not increase NAD on it's own. Other precursors and intermediaries have been discussed in the past such as benaGene (Oxaloacetic Acid) http://www.longecity...-with-benagene/

Also check out the links in post 10 which discuss the same pathway involved in NAD.

#20 Hebbeh

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Posted 20 December 2013 - 12:26 AM

Vince had a discussion sometime back...

http://www.anti-agin...od-or-bad-idea/
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#21 joelcairo

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Posted 20 December 2013 - 12:28 AM

I'll be honest and say that I don't understand the science on this one and perhaps never will. Let me just ask...

Flavonoid Apigenin [also Quercetin] Is an Inhibitor of the NAD+ase CD38
http://diabetes.diab.../62/4/1084.long

Relevant?

AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
http://www.nature.co...ature07813.html

I know of several ways to improve AMPK activation. Relevant?

#22 PWAIN

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Posted 20 December 2013 - 12:30 AM

 

If I pop a lot of Niacin, I probably won't get the same effect or at least not to the same level. The articles seem to imply that the NAD production is way up, like the floodgates have been opened. Not sure that Riboside does this. Also wonder if these chemicals have been around for a while, how come no one noticed this before? Is it the dose?


Correct, niacin is not the rate limiting factor and therefor will not increase NAD on it's own. Other precursors and intermediaries have been discussed in the past such as benaGene (Oxaloacetic Acid) http://www.longecity...-with-benagene/

Also check out the links in post 10 which discuss the same pathway involved in NAD.

I have looked at all the links on this thread. BenaGene had some good press but I didn't see any indication of results even close to those claimed by Sinclair. No 60yo changed their physiology to match that of a 20yo or anywhere near as far as I am aware. My understanding is that whatever Sinclair is doing, it is increasing NAD by significantly more than anything else to date. But then the problem is that this is not a new chemical so why was it not noticed before? Are you saying that Sinclair has some other compounds involved in this? I thought that the NMN was doing all the work in increasing NAD to high levels.


Edited by Michael, 30 July 2017 - 09:04 PM.
trim quote


#23 Hebbeh

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Posted 20 December 2013 - 12:35 AM

I have looked at all the links on this thread. BenaGene had some good press but I didn't see any indication of results even close to those claimed by Sinclair. No 60yo changed their physiology to match that of a 20yo or anywhere near as far as I am aware. My understanding is that whatever Sinclair is doing, it is increasing NAD by significantly more than anything else to date. But then the problem is that this is not a new chemical so why was it not noticed before? Are you saying that Sinclair has some other compounds involved in this? I thought that the NMN was doing all the work in increasing NAD to high levels.


Well, as Mind mentioned, it was in mice, not humans. But this anti-aging angle through the NAD pathway has been on the radar for some time through various stages of the pathway via various intermediaries.

#24 timar

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Posted 20 December 2013 - 12:41 AM

Flavonoid Apigenin [also Quercetin] Is an Inhibitor of the NAD+ase CD38
http://diabetes.diab.../62/4/1084.long

Relevant?


Probably. It may be the mechanistic explanation for some of those flavonoids' health effects.

AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
http://www.nature.co...ature07813.html

I know of several ways to improve AMPK activation. Relevant?


Again, probably. It is the boost in NAD+ you want to see, by whatever means.

Required reading regarding NAD+ metabolism.

Edited by timar, 20 December 2013 - 12:44 AM.


#25 Hebbeh

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Posted 20 December 2013 - 12:42 AM

AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity
http://www.nature.co...ature07813.html

I know of several ways to improve AMPK activation. Relevant?


That's my understanding. I believe there are some threads in the past discussing this and incorporating resveratrol in the stack for it's AMPK activation (which is supposedly how res may activate SIRT1....AMPK).

#26 Adamzski

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Posted 20 December 2013 - 01:56 AM

Perhaps justification for...

http://nicotinamideriboside.org/

https://chromadex.co...nts/NIAGEN.html

http://www.resveratr...aging-pill/566/


Is this the same type of thing?
http://www.amazon.co...howViewpoints=1

There is a wide range of benefits reported by the reviewers.

and a skin cream with a lot of posative reviews

http://www.amazon.co...howViewpoints=1

I dunno for some reason Amazon reviews always sound fake to me? maybe it is because I have read many that were obviously fake.

I am just taking Vit C topically and internally at the moment and was looking for something new to add.

#27 Ukko

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Posted 20 December 2013 - 02:12 AM

I actually am convinced that NAD and NADH play a massive role in health and aging. Certainly, they play a key role in the Krebs cycle, in the synthesis of major neurotransmitters and in BH4 synthesis. But I suspect supplementing with methylfolate is a cheaper and more efficient way of boosting that.

#28 Hebbeh

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Posted 20 December 2013 - 02:26 AM

Perhaps justification for...

http://nicotinamideriboside.org/

https://chromadex.co...nts/NIAGEN.html

http://www.resveratr...aging-pill/566/


Is this the same type of thing?
http://www.amazon.co...howViewpoints=1


That is just plain niacinamide or vitamin B-3.
Niiacin and/or niacinamide are involved in the NAD pathway but are not the rate limiting substrates and as such, dosing B-3 will not increase NAD levels (providing you are not B-3 deficient which would be unlikely). The general pathways are........

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#29 Hebbeh

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Posted 20 December 2013 - 02:42 AM

I have looked at all the links on this thread. BenaGene had some good press but I didn't see any indication of results even close to those claimed by Sinclair. No 60yo changed their physiology to match that of a 20yo or anywhere near as far as I am aware. My understanding is that whatever Sinclair is doing, it is increasing NAD by significantly more than anything else to date. But then the problem is that this is not a new chemical so why was it not noticed before? Are you saying that Sinclair has some other compounds involved in this? I thought that the NMN was doing all the work in increasing NAD to high levels.


Probably one of the reasons Sinclair got the results he did with NMN that haven't apparently been duplicated with other substrates in the pathway such as Oxaloacetic Acid (benaGene) or Nicotinamide Riboside (Niagen) is more than likely because he was injecting massive quantities of NMN and thereby reaching in vivo concentrations that have been prior unachievable with oral doses of the other substrates (as oral dosing is all I've seen tested). I'm guessing the trick is achieving cell saturation of the substrates which more than likely isn't possible with oral dosing.


Edited by Michael, 30 July 2017 - 09:06 PM.
trim quotes


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#30 Ukko

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Posted 20 December 2013 - 02:43 AM

Here is a related article. Sounds like excess choline and B3 are actually bad news for NAD(H). While methylation is good.

http://www.ncbi.nlm....les/PMC3318212/

"Depletion of available methyl groups, whether from a poor diet or one with excessive nicotinamide, may be a common cause of epigenetic phenomena given the marked influence methylation has on gene expression in pluripotent and differentiated cells that maintain cellular identity [265]. The methylome is an important mediator of information and modifies gene transcription and translation including riboswitches affecting RNA metabolism and in toxicology pathways in concert with NAD and ATP and all appears to be involved in a number of diseases seen within the pellagra phenotype such as cancer and motor neurone disease [267272]. A major role for the methylome is well accepted for many cancers and their related epimutations sometimes working in concert with DNA sequence mutations in tumour suppressor and DNA repair genes and may well be modifiable by diet [273277]. There may be several mechanisms whereby such metabolic programming can be inherited and affect offspring [278]."

Logical really. Up to 75% of us have methylation issues with MTHFR. And those folks will suffer rather than benefit from things like nicotinamide. Unless one equally boosts methylation to a similar unnatural degree.

See this too:

http://biograph.be/c...016412/C0027289

Edited by Ukko, 20 December 2013 - 02:54 AM.






Also tagged with one or more of these keywords: aging, aging theories, david sinclair, mitochondria, nad, sinclair, niagen, nmn, nicotinamide riboside

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