LONGECITY

To Prophets and Thoughtmaze1 - In the video clip I will post, Lenny Guarente says, among other things, that he takes resveratrol.

As a general comment, over the past 7+ years I have found that a number of scientists take compounds but will not go on the record 

admitting this.  I have been told that certain doctors are taking rapamycin, which has been proven to extend lifespan when given to older

animals.  These scientists feel that the public warnings about rapamycin -  because it decisively down regulates the immune

system (which is good when used in cases of organ transplants) are actually a broad brush.  Thus these doctors cycle it. This is the case for many of

compounds; namely, it's a dialing issue, because major pathways like mtor and the like wear white and black hats.  More to come.  I will

post the clip soon.  Right now I am busy watching the masters tournament.  

 

That's interesting.  Because I specifically recall a video clip of Guarente saying he does not take resveratrol.  I will have to try to find it.  I believe it was Charlie Rose or someone interviewing him.

I'd be curious in specific protocols on NMR.  "I take NMR," obviously leads to several follow-up questions like dose, schedule, other related compounds/interaction risks, etc.

Any input you have would be helpful, but obviously it's all second hand speculation to a degree.  Enjoy the tournament.

My interview with Lenny Guarente was very recent, two months ago.

 

Can you please explain to me why you got involved with the Niagen group buy if you are so confident that NA/Niacin is more or less just as efficient as NR and very inexpensive compared to NR.....I'm confused

 

 

Well, I'd say confident is too strong a word.  But, to answer your question more directly, I primarily participated in the group buy based on the Sinclair study, the postings "to age or not to age" made WRT NR being a strong NAD precursor (as an example see post #331) and that the NA and NR molecules look quite different - hence the possibility they could work via different pathways or render different positive results, or may work synergistically together - stacking as it were.

My bigger question is, what's an effective dose of NR?  If it is equal to NA mg to mg, the results are similar and one can endure the flushing (I agree with Darryl's comment about not using NA before a social engagement), then NA is a veritable bargain.  Even the "experts" don't have all the answers. 

 

Here's a bit of support for my comment, which I've emboldened in red in the quote above.
http://jpet.aspetjou.../324/3/883.full
 

Recently, a recycling pathway independent of nicotinamide and nicotinic acid that forms NAD⁺, was found to be broadly conserved in bacteria, yeast, and mammals (Bieganowski and Brenner, 2004). The pathway leads from the metabolite nicotinamide riboside (NR), the dephosphorylated form of NMN. A highly biologically conserved nicotinamide riboside kinase is able to use NR as a substrate and can convert NR to NMN in cells (Bieganowski and Brenner, 2004). This activity allows NR to enter NAD⁺ metabolism via NMN and then to NAD⁺. Thus, NR is converted to NAD⁺ in only two metabolic steps (Figs. 2 and 3) (Bieganowski and Brenner, 2004). Yeast deficient in de novo or B₃-recycling pathways but retaining an intact nmnat activity survive with NR as their only source of B₃, indicating that yeast can efficiently salvage this nucleoside and synthesize adequate amounts of NAD⁺ via this pathway (Bieganowski and Brenner, 2004). In humans, two isoforms of the kinase (Nrk1 and Nrk2) have been cloned, although little is known about the biochemical properties of these enzymes.

Darryl
What are your thoughts on how the circadian clock fits into the timing of NAD+ precursor supplementation?  And the idea of cycling such compounds as "to age or not to age" touches on in post #359?

How would you implement either of those approaches?

 

I will post a video excerpt in the next few days in which Dr Guarente at MIT says on camera that both NMN and NR increase NAD, either one

does it alone.  'It's an emerging situation'  and  'being a natural product very likely to be safe'

In this whole realm, there are questions, and more questions.  One thing for sure though, these scientists absolutely

believe in the truth eventually winning out, of being determined. I'm speaking here about Guarente and Sinclair.  

 

Guarente has always been mildly upbeat on things like Resveratrol but he would never personally take the stuff himself.  I'd be more curious if they are taking NMR with or with out resveratrol.  And if not, what kind of data are they waiting to see that make them take it?  At what point would they turn to their loved ones (wife, etc.) and say -- you should really take this all natural product.  

 

I seem to remember Sinclair stating on camera, that he takes resveratrol as does his wife and some family members.  It may have been in the documentary "To Age or Not to Age", or possibly a TED talk.

I seem to remember Sinclair stating on camera, that he takes resveratrol as does his wife and some family members.  It may have been in the documentary "To Age or Not to Age", or possibly a TED talk.

 

 

Correct.  And Sinclair (at one point) was actually buying Bill Sardi's stuff Longevinex.  But I distinctly recall Guarente saying he took nothing on camera, just ate a balanced diet and maybe something like a multivitamin or aspirin.  

I am reposting what I thought i had posted.  Both Lenny Guarente and David Sinclair take resveratrol.  I will post this

admission by Guarente.  Sinclair said so on Charlie Rose in November 2006 and received major blowback.  THIS IS

PART OF WHAT YOUR WONDERFUL WEBSITE NEEDS TO OVERCOME 

My interview with Lenny Guarente was very recent, two months ago.

Looking forward to watching the next clip you post. The last one was very interesting!

Are you working towards making a full documentary?

Blood, I have continued to collect footage for 7+ years.  After completing my 2010 documentary "To Age or Not To Age" it became

clear to me that this science is a 'moving target' - the implications are numerous and not yet understood. In fact, the macro

societal and business issues will impact if, when and how these advances develop.  My plan now is to create an ongoing series of

shorter segments, covering both the science and the social framework.    

http://youtu.be/Mpf923bUDyc Here is the youtube link to part 4 of NAD and age reversal.  The clip

runs just under 4 minutes. David talks about Lenny Guarente at a tribute to him held at MIT; then

Lenny comments on consuming compounds that increase NAD and sirtuin activity.

 Here is the youtube link to part 4 of NAD and age reversal.  The clip
runs just under 4 minutes. David talks about Lenny Guarente at a tribute to him held at MIT; then
Lenny comments on consuming compounds that increase NAD and sirtuin activity.
 

http://youtu.be/Mpf923bUDyc Here is the youtube link to part 4 of NAD and age reversal.  The clip

runs just under 4 minutes. David talks about Lenny Guarente at a tribute to him held at MIT; then

Lenny comments on consuming compounds that increase NAD and sirtuin activity.

 

Extremely interesting.  Thank you for submitting this information; it is useful.

I'd still really like to know Guarente's thought process on dosage on both NR and resveratrol.

When was this clip taken?

It must have been recent, because he cites the NR/NMN work and that was only published recently.  Even if they had complete data and it was in review, it must have been during the last year.

Darryl
What are your thoughts on how the circadian clock fits into the timing of NAD+ precursor supplementation?  And the idea of cycling such compounds as "to age or not to age" touches on in post #359?

In mice, CLOCK regulated NAMPT expression regulates NAD⁺ concentrations as well as SIRT1 activity on a circadian cycle;

1st figure from: Ramsey, Kathryn Moynihan, et al. "Circadian clock feedback cycle through NAMPT-mediated NAD⁺ biosynthesis." Science 324.5927 (2009): 651-654.

2nd figure from: Nakahata, Yasukazu, et al. "The NAD⁺-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control." Cell 134.2 (2008): 329-340.

So, in mice, NAD⁺ levels are lowest at dawn, and have a lesser peak corresponding to mid-day and a larger peak corresponding to mid-night. If conserved in humans, that means we might simply amplify existing peaks by taking precursors late-morning and at bedtime. However, mice are primarily nocturnal animals, and NAD⁺ mediated circadian rhythms may play a large role there: their NAD⁺/Sirt1 circadian rhythms may be phase shifted from ours.

Till we learn more about human or other diurnal primate NAD⁺ circadian rhythms, I don't think we can argue about dosing times with much authority. I take my supplements with my 2nd cup of coffee in the morning (~9 AM), and a while before bedtime (~ 9 PM). Hopefully this amplifies natural peaks rather than interferes.

With respect to cycling the NAD⁺ precursors, this might be justified if the rate-limiting enzymes in their NAD⁺ synthesis pathways (NA phosphoribosyltransferase, NR kinase, or NMN adenylyltransferases 1-3) are feedback regulated on long timescales. I've no idea whether this occurs, or whether these have fixed/basal level expression like a lot of "housekeeping" genes. I suspect they're basal, and most rate-limiting in the NAD⁺/sirtuin world occurs through nicotinamide inhibition of NAD⁺ consumers.

Thanks Darryl.  This is turning into a great thread.

Maybe the best time for supplementation is early/mid afternoon for humans.  I remember reading that peak physical activity was usually found to be in mid/late afternoon for humans.

Blood, I have continued to collect footage for 7+ years.  After completing my 2010 documentary "To Age or Not To Age" it became

clear to me that this science is a 'moving target' - the implications are numerous and not yet understood. In fact, the macro

societal and business issues will impact if, when and how these advances develop.  My plan now is to create an ongoing series of

shorter segments, covering both the science and the social framework.    

Apologies, I didn't realise that you have already completed a documentary on this topic.

I encourage everyone to take a look at the web site for "To Age Or Not To Age":

http://info.toageornottoage.com/about/

Lots of interesting material.

Are these screening dates current?

http://info.toageorn...ates-locations/

 

When was this clip taken?

 

It must have been recent, because he cites the NR/NMN work and that was only published recently.  Even if they had complete data and it was in review, it must have been during the last year.

 

http://www.longecity...-13#entry655680

 

Posted 11 April 2014 - 11:24 AM

My interview with Lenny Guarente was very recent, two months ago.

I don't know whether there is any collusion going on here between Vince and Darryl, but yesterday Vince published an epic blog post on this very subject: http://www.anti-agin...cadian-rhythms/

An excellent and comprehensive introduction to the epigenetics of the circadian clock, not limited to NAD of course.

I don't know whether there is any collusion going on here between Vince and Darryl, but yesterday Vince published an epic blog post on this very subject: http://www.anti-agin...cadian-rhythms/

 

An excellent and comprehensive introduction to the epigenetics of the circadian clock, not limited to NAD of course.

Serendipitous indeed, thanks for posting.

Given that one day of a mouse life is approx equal to one month of a human life, I don't see how daily dosing and the circadian clock can be compared in any way.

Given that one day of a mouse life is approx equal to one month of a human life, I don't see how daily dosing and the circadian clock can be compared in any way.

The mouse has a faster metabolism, but wouldn't all creatures' circadian clocks be synchronized to the length of the day / night cycle ?  (timing of light and dark onset, specifically)  With respect to chronobiology, it seems like there should be a lot of similarities between species. 

 

Given that one day of a mouse life is approx equal to one month of a human life, I don't see how daily dosing and the circadian clock can be compared in any way.

 

The mouse has a faster metabolism, but wouldn't all creatures' circadian clocks be synchronized to the length of the day / night cycle ?  (timing of light and dark onset, specifically)  With respect to chronobiology, it seems like there should be a lot of similarities between species. 

 

Mice are pretty much nocturnal.

I just don't think a mouse is a good model for this (imrtance of circadian clock) and that is what all the testing of this compound has been done on. No harm in experimenting with time of day but I don't think there is anything scientific that can be used to confirm this at present.

As an aside, I wonder how mice would go with 30 dark light cycles per day. Would they get all stressed or would it be benefical for them?

A mouse's heart rate is about 650 bpm and so its metabolism is way different than ours, that coupled with the fact that it is nocturnal. I cant see any comparison between a humans circadian clock and a mouses.

Humans may all have a similar circadian clock but a lot of us have different eating habits, so I am not really worried about that side of this, personally, I will just take it as I see fit.

As an aside, I wonder how mice would go with 30 dark light cycles per day. Would they get all stressed or would it be benefical for them?

Something tells me it wouldn't be pretty for the mousies.  It would probably work about as well for them as it would for us.   I developed a really keen appreciation for the importance of appropriate amounts of darkness when I spent a month in an ICU with the lights on 24-7.  I got completely psychotic, but as soon as I was allowed to move to a regular room where I could turn out the lights, the psychosis melted away immediately.  This is common enough to have a name- "ICU Psychosis", not surprisingly.  In the eight years since that event, I wonder if some medical super-genius has figured out that if they turned the light down at night, they might not lose as many patients.  Better wait for the Cochrane review to come out before we take any rash steps...

I'd hope this interesting, educational and spirited thread won't devolve into 'mouse-chat'.  But, since the topic was broached, for those who are interested in our furry little test subjects, mouse facts: http://www.informati...se_facts1.shtml

Something else to consider before we leave mouse world....The mice in the MNM trial were fed MNM for one week and they live on average two years. We live 40 times longer than a mouse, which would make it possible that it would take some time for us to see the full effects of NR or NMN.

I was talking about this the other day on the NR results thread, where people are sort of expecting to see results pretty much straight away.

Personally I think it will be over a period months before it has anything like the desired affect. I think this for one or two reasons..

1) body/cell mass (even with high doses) 

2) much slower metabolism compared to the mouse models were used in the trials.....

We have also got to be careful with taking really large doses as we may not be able to metabolize a great deal of NR all at once, and may possibly lose a lot of it passing through the body...This is all new stuff here and I think smaller doses (max 2 grams) per day over a prolonged period would be the best way to go until we know something different through trial results. Better smaller doses getting metabolised than large doses getting half of it pissed away.

Like I said in that post....Patience is a virtue.

Just my opinion.

I think various dosages from various people is best. Someone taking 7 grams a day may find that it works and someone on 125mg a day may not have any effect no matter how many years they take it. The reverse could also be true. It is quite possible that only over a certain level that the effects are felt, the mice got a lot. I'd rather piss some away than miss the effect that could keep me alive. We are all dying, there is no time for patience )

We have also got to be careful with taking really large doses as we may not be able to metabolize a great deal of NR all at once, and may possibly lose a lot of it passing through the body...This is all new stuff here and I think smaller doses (max 2 grams) per day over a prolonged period would be the best way to go until we know something different through trial results. Better smaller doses getting metabolised than large doses getting half of it pissed away.
Like I said in that post....Patience is a virtue.

Just my opinion. 

I had also thought in terms of months for humans versus a week for mice, but "nbourbaki" seems to have experienced results in a matter of days-to-weeks. It might take no longer than a couple of hours for NR to reach the mitochondria and brighten the cellular fires, but even if that's true, maybe it will take months for NR.s main effects to be felt. But we'll find out.