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Brenner strikes at Sinclair again

nad+ sirtuins lifespan

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#1 Iporuru

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Posted 25 January 2020 - 05:18 PM


Another series of Brenner's tweets, which I coalesced into one text.

 

(If you disagree with BRENNER, please don't downvote ME - I'm just relaying the information ;))

 

One of the problems in biomedicine is that attractive models are sticky, meaning that ppl still refer to them even though the underlying premises have been discredited. In science lingo attractive models = "truthiness." Sound right but they are wrong. Here's an example.

 

Ppl are highly influenced by the idea that sirtuins are central regulators of longevity. Many problems with this concept. 1st, SIR2 is only required for 1 (not both) models of yeast longevity. 2nd, there is NO FITNESS ADVANTAGE to yeast mother cells with long lifespans.

 

This means that it is not plausible that SIR2 was conserved as a longevity gene. 3rd, the mechanism by which SIR2 extends lifespan in yeast is not conserved in other organisms. 4th, SIR2 overexpression in worms, flies & mice doesn't make animals live longer.

 

Sensible ppl long ago decided that SIRTs are interesting but are NOT THE CENTRAL REGULATORS OF LIFESPAN. Others, some of whom are very gifted story tellers, turned the SIRT story into a nonfalsifiable hypothesis that all SIRTs do all good things all the time.

 

But this isn't true--SIRTs do some + things for some cells some of the time & at other times are dispensable or destructive. In cancer, they can be oncogenes or TSGs. SIRT3-5 do some interesting things in mitochondria but aren't nearly as critical as other mito proteins.

 

SIRTs are not the most important proteins in DNA repair, not the most important proteins in longevity, not the most important proteins in epigenetics, not the most important proteins in mito function, & not the most important mediators of boosting or restoring NAD.

 

Everyone who studies metabolism knows that 4 NAD coenzymes are central to biological electron flow. You can't get more than 3-4 steps away from any metabolic step without needing NAD or NADP-dependent redox.

 

However, simplistic ppl decided that the primary function of NAD must be to drive SIRT function. This is simply not the case. The redox biology of NAD+, NADH, NADP+ and NADPH are much more essential than the sum of all SIRT functions in any tissue you can name.

 

Even among the non-redox enzymes that use NAD+, the SIRTs are arguably the least regulated. PARP gets activated ~100x by DNA damage. cADPR synthetases go from OFF to ON based on signals received. There is no comparable regulation for SIRTs & I say that as the person who...

 

was 1st to identify an authentic sirtuin activating compound (NR) & demonstrate extended longevity #inyeast. We didn't claim that because we could extend yeast lifespan that we could extend human lifespan bc the data weren't there. When SIRT stories crashed & burned, ...

 

we were happy that our horses were not hitched to that wagon. The concept that @GSK bought w respect to resveratrol & other so-called STACs was a house of cards. Resveratrol not a STAC & underlying SIRT lore based on overinterpreted, overhyped & nonreproducible experiments.

 

This brings me to today, where ppl are rediscovering NAD biology, which is great. It's so weird though to see NAD-boosting strategies linked to SIRT biology given the 100s of mission critical NAD-dependent processes in every tissue.

 

It is clear that metabolism, resiliency & repair decline in aging. We've shown that the NAD metabolome is under attack in many conditions of metabolic stress--this leads to heart failure, neurodegeneration, hearing loss, nonoptimal postpartum & I am sure a decline in lifespan.

 

I prefer to refer to the role of NR in restoring resiliency & repair capacity as opposed to extending lifespan bc I can readily quantify these things in animals & ppl. I am comfortable with the concept of #agebetter & if we can obtain credible longevity data, I'm all for that.

 

We know that both NMN & NR depend on the NR kinase pathway to restore the NAD metabolome & that this pathway is upregulated when cells are under metabolic stress. NAD boosting strategies restore resiliency through multiple NAD dependent pathways.

 

While I am grateful to gifted story tellers for reaching ppl with their NMN "rejuvenation" stories, I'm uncomfortable bc the same ppl have been wrong so many times. We've never cost anyone billions in research costs for an attractive-simplistic-incorrect model & never will.

 

Our work on NAD led to a licensed molecule that has been safety tested, GRAS & NDI notified & is the subject of ~30 clinical trials. We publish our data, positive or negative. We don't overpromise. So, while I'm a less gifted story teller than some, I will never push BS...

 

such as the concept that we don't have to age. Life is possible because of energy inputs driving homeostatic forces that oppose entropy but, in the end, entropy wins. By studying repair & resiliency we can improve human health & potentially add to the evidence-basis for NR.

 

But if someone is pushing a model based on experiments that can't be reproduced in other labs, run the other way. The model may be attractive but is, in the end, a fantasy.

 


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#2 Kentavr

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Posted 27 January 2020 - 12:58 PM

I don’t even want to comment on this.

Changing just 2 genes in a worm increased his life by 500%, and he talks about entropy in relation to life ...

In this case, the embryos would have to disintegrate with heat!

When will this nonsense end?
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#3 Blu

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Posted 27 January 2020 - 01:15 PM

 

2nd, there is NO FITNESS ADVANTAGE to yeast mother cells with long lifespans.

 

This means that it is not plausible that SIR2 was conserved as a longevity gene.

 

Well, fitness is by no mean the only driver for success and conservation of a gene.

Evolutionism has had some development from the XIX century.


Edited by Blu, 27 January 2020 - 01:16 PM.


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#4 Oakman

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Posted 27 January 2020 - 02:45 PM

Most of this are his thoughts based on research, much of which is inconclusive or somewhat controversial. I would question a few things, but no one knows all the answers, nor has all the needed research been done yet. The guy has been instrumental in much of what we discuss every day, so his ideas should be taken and evaluated fairly.

 

Further at least he's talking about all this, which is helpful to everyone.


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#5 Kentavr

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Posted 27 January 2020 - 03:11 PM

Most of this are his thoughts based on research, much of which is inconclusive or somewhat controversial. I would question a few things, but no one knows all the answers, nor has all the needed research been done yet. The guy has been instrumental in much of what we discuss every day, so his ideas should be taken and evaluated fairly.

Further at least he's talking about all this, which is helpful to everyone.


Of course. However, life resists entropy, and this is its key difference from inanimate matter.

Otherwise, the organization of life would be impossible.

#6 Harkijn

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Posted 27 January 2020 - 04:34 PM

One thing is sure: he believes in 'aging better' and that taking NR can play a  role in this. No weird promises here. After taking NR for about 5 years I believe NR has just that role, among other factors. Perhaps the entropy thing can be solved by senolytics or telomerase etc. but not by a NAD precursor.

I can subscribe to his remarks about Sirtuins: I have heard dr. Sinclair say things that do not do justice to their 'dark side".

 

I deplore dr. Brenner  throws this on Twitter but there's modern times for you...


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#7 Kentavr

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Posted 27 January 2020 - 05:39 PM

One thing is sure: he believes in 'aging better' and that taking NR can play a role in this. No weird promises here. After taking NR for about 5 years I believe NR has just that role, among other factors. Perhaps the entropy thing can be solved by senolytics or telomerase etc. but not by a NAD precursor.
I can subscribe to his remarks about Sirtuins: I have heard dr. Sinclair say things that do not do justice to their 'dark side".

I deplore dr. Brenner throws this on Twitter but there's modern times for you...


He now does not scold NMN)

NMN is not a panacea. However, this is one of the best supplements that shows excellent results.

NMN reduces or reverses the development of many diseases that are practically not treated (arthritis, sarcopenia).
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#8 Castiel

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Posted 13 February 2020 - 05:31 PM

Well, fitness is by no mean the only driver for success and conservation of a gene.

Evolutionism has had some development from the XIX century.

 

Calorie restriction is said requires gradual introduction in adulthood to work.   A famine might not be so gradual in its effects.  Also it works up to 60~% restriction in some animals, a degree to which the animal would not find the required micronutrient dense food during a famine.  And calorie restriction requires adequate micronutrients to work.

 

Some has said it works through a quirk of metabolism.    

 

Sirtuins have been implicated in part of the mechanisms of calorie restriction.

 

Also some sirtuins(sirt4) have been implicated in telomere lengthening, which would also link them to the telomere theory of aging.



#9 Phoebus

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Posted 15 February 2020 - 12:59 AM

He now does not scold NMN)

NMN is not a panacea. However, this is one of the best supplements that shows excellent results.

NMN reduces or reverses the development of many diseases that are practically not treated (arthritis, sarcopenia).

 

 

But what research on your basing that on? Just anecdotes? 

 

It did nothing at all for my arthritis, may have even made it worse. 


Calorie restriction is said requires gradual introduction in adulthood to work.   A famine might not be so gradual in its effects.  Also it works up to 60~% restriction in some animals, a degree to which the animal would not find the required micronutrient dense food during a famine.  And calorie restriction requires adequate micronutrients to work.

 

Some has said it works through a quirk of metabolism.    

 

Sirtuins have been implicated in part of the mechanisms of calorie restriction.

 

Also some sirtuins(sirt4) have been implicated in telomere lengthening, which would also link them to the telomere theory of aging.

 

 

Right - theories, theories and more theories. 

 

That's Brenner's point, you can't make solid statement when all you have is unproven theories. 


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#10 Castiel

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Posted 17 February 2020 - 07:27 PM

 

Right - theories, theories and more theories. 

 

That's Brenner's point, you can't make solid statement when all you have is unproven theories. 

 

Resveratrol has actually rejuvenated human cells including restoring their telomere length and appearance under a microscope as well as behavior.

 

 

 

"When I saw some of the cells in the culture dish rejuvenating I couldn't believe it. These old cells were looking like young cells. It was like magic," she said. "I repeated the experiments several times and in each case the cells rejuvenated. I am very excited by the implications and potential for this research."https://www.scienced...71107113145.htm

 

We now know from experiments on mice that older mice have less telomerase activity than younger mice when exposed to certain doses of resveratrol.   We also know that telomerase activity appears to occur through sirtuin 4 in an NAD dependent manner.  And we see that age related decrease in NAD could jeopardize resveratrol benefits in longer lived animals.

 

In shorter lived creatures resveratrol can almost double lifespan, we also know it can basically abolish the detrimental effects on lifespn of obesity in rodents.   As well as lengthen the lifespan of mice with several types of mitochondrial genetic disfunction.

 

What happens when NAD is kept at adequate levels throughout the life of the animal, even into old age and they are supplemented with resveratrol?  It is unknown, but it seems like the results would likely be beneficial.


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#11 Harkijn

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Posted 18 February 2020 - 07:24 AM

@Castiel: I think we all agree with you. However I think Phoebus'point is that we need a robust human safety study of NMN to begin with. After all these years this has not materialized yet afaik. Except a study that drew conclusions after a onetime dose.


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#12 QuestforLife

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Posted 19 February 2020 - 01:22 PM

Resveratrol has actually rejuvenated human cells including restoring their telomere length and appearance under a microscope as well as behavior.

 

 

 

We now know from experiments on mice that older mice have less telomerase activity than younger mice when exposed to certain doses of resveratrol.   We also know that telomerase activity appears to occur through sirtuin 4 in an NAD dependent manner.  And we see that age related decrease in NAD could jeopardize resveratrol benefits in longer lived animals.

 

In shorter lived creatures resveratrol can almost double lifespan, we also know it can basically abolish the detrimental effects on lifespn of obesity in rodents.   As well as lengthen the lifespan of mice with several types of mitochondrial genetic disfunction.

 

What happens when NAD is kept at adequate levels throughout the life of the animal, even into old age and they are supplemented with resveratrol?  It is unknown, but it seems like the results would likely be beneficial.

 

I agree with Bremmer's comments with respect to the Sirtuins. They're clearly very important for yeast, not so much for mammals. 

 

I'm not going to get involved in the NMN vs. NR bun fight. Bremmer clearly has a dog in that fight, and I'm not impressed with the pricing of NR (or NMN for that matter).

 

Either way I regard NAD+ boosting as mitochondrial repair. It will help one remain healthy with aging, but will not stop aging, To a scientist from the mitochondrial point of view (Bremmer) it would appear that entropy can be held off, but never beaten.

 

But to a researcher in telomerase and stem cells (actually replacing the degraded cells with new, rejuvenated ones) entropy can be reversed no problem (this is what happens in reproduction, it is just a (not so small) matter of engineering to make it work in a person). David Sinclair knows this and that is why he has pivoted from NMN to OSK-reprogramming.   

 

I did a tonne of research into the SIRT4-telomerase connection early on in my 'Alternative methods to length telomeres' thread. It was all dependent on ONE unreplicated 2015 paper (https://pubmed.ncbi....h-muscle-cells/).  I could never find any other leads into why a mitochondrial sirtuin would have such an effect other than in yeast (David Sinclair's world). 

 

The ability of resveratrol and resvertrol analogues to re-elongate telomeres (https://pubmed.ncbi....lar-senescence/) was definitely proven to have nothing to do with the sirtuins (though it might have had something to do with NAD+). It is still mysterious other than being something to do with splicing factors. I suspect it was due to some kind of mitigation of the effect of SASP(even though the lead author denied this and got angry when I pointed out to him that only the ki67 positive cells in culture were rejuvenated, showing senescence was not reversed). The effect of resveratrol on telomeres HAS been replicated in other papers however, so watch this space. 


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#13 MikeDC

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Posted 19 February 2020 - 02:37 PM

There are lots of evidence that Sirtuins (consequently NAD+) regulate telomere homeostasis. I believe Brenner will be proven wrong and Sirtuins have a very big influence in human longevity. Sirt1 also regulate immune homeostasis. Old people are dying from COVID-19 because immune cells are hyper activated due to insufficient Sirt1 (NAD+).

https://www.tandfonl...56.2019.1632613

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#14 p75213

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Posted 20 February 2020 - 06:49 PM

According to David Sinclair, oleic acid is a more potent activator of sirtuins than resveratrol The mediterranean diet is touted as being one of the healthiest in the world. Olive oil plays a prominent roll in this diet and has one of the highest concentrations of oleic acid.

Edited by p75213, 20 February 2020 - 07:06 PM.






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