26 replies to this topic

[onz]

A man who needs no introduction on these forums, David Sinclair, will be joining us on the next longecity podcast!

 

He has just released his new book "LifeSpan: Why we age - and why we don't have to" and has been spending the last few months doing interviews and podcasts.

 

This is a great opportunity for our community to ask the many questions that we discuss on the forums regarding NAD+ and David's research.

 

Here's a summary of his profile from his website, you can also find more information on his wikipedia page.

 

"David Sinclair is a professor in the Department of Genetics and co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School, where he and his colleagues study sirtuins—protein-modifying enzymes that respond to changing NAD+ levels and to caloric restriction—as well as chromatin, energy metabolism, mitochondria, learning and memory, neurodegeneration, cancer, and cellular reprogramming.

 

Sinclair has suggested that aging is a disease—and that we may soon have the tools to put it into remission—and he has called for greater international attention to the social, economic and political risks and benefits of a world in which billions of people can live much longer and much healthier lives.

 

Sinclair is the co-founder of several biotechnology companies (Life Biosciences, Sirtris, Genocea, Cohbar, MetroBiotech, ArcBio, Liberty Biosecurity) and is on the boards of several others. (A full list of disclosures is available here.)

 

He is also co-founder and co-chief editor of the journal Aging. He is an inventor on 35 patents and has received more than 35 awards and honors. In 2014, he was on Time Magazine’s list of the “100 Most Influential People in the World,” and listed as Time's Top 50 in healthcare in 2018."

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Edited by onz, 12 November 2019 - 08:23 AM.

[albedo]

questions:

1. which of the 3 main programs (small molecules, senolytics and reprogramming) will likely get translated first and show effectiveness

2. which geography will be able to better attract funds, ease regulation and turn to be successful for translation of research

3. what key advise he would give to young scientists considering working on aging

[Oakman]

1) What is your opinion of attempting to raise NAD+ levels using supplement cocktails such as Nuchido's and Alive by Nature's that do not use precursors like NR or NMN or NAD+ itself?

2) Are you satisfied with the results you get (not your father) from your daily supplement cocktail (NMN, R, Metformin and ?) and how do you gauge any change or improvement (blood test, anecdotal, other testing, etc.)

3) You once mentioned there was an additional secret sauce to add to precursors that you were developing. Any news on that front?

4) Is it rational to believe there are silver bullets to be discovered (pills, shots, etc.) to keep any population 'young' (younger) and erase symptoms of aging, when most refuse to do any significant physical exercise or correct nutritional deficiencies themselves to try to maintain their bodies in the first place?

[Smith]

Given that a April 2018 study published in Cell Metabolism found that oral NR and NMN are almost entirely converted to NAM in the liver and the study author's conclusion that, "Nearly complete first-pass metabolism of oral NR and NMN [likely results] in these compounds having systemic effects similar to or indistinguishable from oral NAM.", do you still believe there is an advantage to oral supplementation of NMN/NR over NAM?

 

Thank You!

 

Edited by Smith, 12 November 2019 - 08:33 PM.

[able]

Given that a April 2018 study published in Cell Metabolism found that oral NR and NMN are almost entirely converted to NAM in the liver and the study author's conclusion that, "Nearly complete first-pass metabolism of oral NR and NMN [likely results] in these compounds having systemic effects similar to or indistinguishable from oral NAM.", do you still believe there is an advantage to oral supplementation of NMN/NR over NAM?

 

Thank You!

 

Rhonda Patrick asked about this in the just released podcast.  His explanation was the small dose used in the Rabinowitz study.  They are not sure, but he thinks a larger dose is required to overwhelm the ability of liver to metabolize all the NR or NMN.

 

 

https://www.foundmyf.../david-sinclair

[Smith]

Rhonda Patrick asked about this in the just released podcast.  His explanation was the small dose used in the Rabinowitz study.  They are not sure, but he thinks a larger dose is required to overwhelm the ability of liver to metabolize all the NR or NMN.

 

 

https://www.foundmyf.../david-sinclair

 

Thanks for the podcast! Very interesting.  They estimated an equivalent dose of NR in a 180lb man to overwhelm the ability of the liver to metabolize the NR to be around 2 grams per day!!

[TMNMK]

1. In "Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging" is it possible also that sodium thiosulphate may substitute for NaHS and has that been considered?

2. What are your thoughts on the activation of the ten–eleven family proteins in order to demethylate CpG domains as mentioned in "Dietary alpha‐ketoglutarate promotes beige adipogenesis and prevents obesity in middle‐aged mice" Tian et al 2019 and do you know of other small molecules that mediate TET expression?

3. Where might I procure some of your very, very special adenovirus? (that's a joke btw)

Edited by TMNMK, 14 November 2019 - 12:41 AM.

[TMNMK]

oh more importantly than those questions, actually I would be very interested to hear Dr. Sinclair's thoughts on what I thought was a pretty brilliant line of thinking by other members here: In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming (using extracellular vesicles for partial reprogramming - whether that would be something to consider in his research and why or why not).

Edited by TMNMK, 14 November 2019 - 03:56 AM.

[Andey]

1. You probably already tested yourself via the methylation clock, are you comfortable with sharing the result?

2. Do you think(or could speculate on) that the optimal regimen for NAD+ boosters should involve continuous supplementation or do we potentially need some off cycling time to prevent body of seeking new homeostasis point.

3. Do you know of any natural (or synthetic) compound that demethylates DNA and thus could be of interest? (the rationale could be that while if it would be not selective and dont know what should be turn on but younger cells have DNA less methylated as whole so net result of this intervention could be a change to a more younger phenotype)

Edited by Andey, 14 November 2019 - 08:37 AM.

[Steven22]

Thank you for getting David Sinclair on the podcast and for giving us the opportunity to ask questions.

1) Given the effects of aging starting early would there be any benefits to taking NMN beginning in your mid-20s and if so, which dosage would you recommend that one starts with? If not, at which age would you start supplementing with NMN? Would the risks be worth the rewards if one starts so early? Does one run in the risks of disrupting bodily processes and suppressing the natural NAD+ levels with supplementation (at such an early age)?

2) What are your thoughts on cycling NMN as well as other NAD+ precursors every other day, instead of taking them every day as to avoid the impact of homeostasis and to avoid building up tolerance? In your experience, have you seen buildup of any kind of tolerance to NAD boosters?

3) Is there a dosage of NMN that one atleast needs to take in order to have any positive effects at all? If one is on a tight budget, would Niacinamide or Niacin also be an alternative?
 

Edited by Steven22, 16 November 2019 - 06:01 PM.

[DonManley]

1. Given that NMN supplementation can be prohibitively expensive due to the cost of synthesis of NMN and its relatively large dosage, what do you expect will be the impact of novel NDA boosters like MIB-626 on both effectiveness and affordability of NDA boosting? What is the approximate daily dosage of MIB-626 for humans? Will the required dosage be as big as for NMN or novel NAD boosters are more efficient and require a significantly smaller dosage? Is synthesis of novel NDA boosters like MIB-626 significantly easier or cheaper than NMN synthesis (which you mentioned being complicated and expensive due to phosphate chemistry)?

 

2. When will the MIB-626 phase 1 clinical finish?

 

3. How likely do you think that we'll find a novel NDA booster in near future that works (or that MIB-626 will be a success)? Is this a difficult pathway to target with many unknowns or do you think the path towards designing novel NDA boosters is relatively straightforward and it should happen in near future?

 

4. While more affordable novel NDA boosters are being developed, what is currently the most cost-effective way to boost NDA? Perhaps, there is a way to get 2/3 of the benefit with 1/3 of the cost if one is willing to use less efficient but cheaper molecules or methods?

Edited by DonManley, 17 November 2019 - 01:28 AM.

[Mind]

Rhonda Patrick asked about this in the just released podcast.  His explanation was the small dose used in the Rabinowitz study.  They are not sure, but he thinks a larger dose is required to overwhelm the ability of liver to metabolize all the NR or NMN.

 

 

https://www.foundmyf.../david-sinclair

 

As a follow up to this question, I am wondering if "overwhelming the liver's ability to metabolize" a specific substance is a good idea....ie, drink too much alcohol and you end up damaging your liver. I know alcohol and NR are worlds apart, but I am wondering about over-taxing the liver.

[Mind]

1. In "Impairment of an Endothelial NAD+-H2S Signaling Network Is a Reversible Cause of Vascular Aging" is it possible also that sodium thiosulphate may substitute for NaHS and has that been considered?

2. What are your thoughts on the activation of the ten–eleven family proteins in order to demethylate CpG domains as mentioned in "Dietary alpha‐ketoglutarate promotes beige adipogenesis and prevents obesity in middle‐aged mice" Tian et al 2019 and do you know of other small molecules that mediate TET expression?

3. Where might I procure some of your very, very special adenovirus? (that's a joke btw)

 

I would like to ask Sinclair about #2 but I don't see his name on the paper. Has Sinclair talked about this in the past?

[Iporuru]

I would like to ask Sinclair about #2 but I don't see his name on the paper. Has Sinclair talked about this in the past?

 

Sinclair mentioned AKG in a tweet
 

[TMNMK]

Wow, I never saw that tweet! I'm absolutely thrilled as that at least validates my recent excitement about AKG:  Alpha Ketoglutarate thread (and I'll say it again "People, YO!")

 

Not to digress, but I've been drinking it (the free acid dissolved in water) and applying it in a PLO to my hair (Stimulation of Hair Growth) for the last 1.5 months or so, haven't died yet and feel pretty good but nothing really substantial to report on. I asked #2 because in the book he discusses demethylation and TET and it appears that AKG mediates although I don't think he mentioned that in the book.

Edited by TMNMK, 18 November 2019 - 05:53 PM.

[Iporuru]

Wow, I never saw that tweet! I'm absolutely thrilled as that at least validates my recent excitement about AKG:  Alpha Ketoglutarate thread (and I'll say it again "People, YO!")

 

Not to digress, but I've been drinking it (the free acid dissolved in water) and applying it in a PLO to my hair (Stimulation of Hair Growth) for the last 1.5 months or so, haven't died yet and feel pretty good but nothing really substantial to report on. I asked #2 because in the book he discusses demethylation and TET and it appears that AKG mediates although I don't think he mentioned that in the book.

 

TMNMK, have you seen the thread I started yesterday on demethylating agents (including AKG)? https://www.longecit...ylating-agents/
 

[TMNMK]

No I didn't, wow that's great, thank you for sharing! 

[Iporuru]

I second TMNMK's and Andey's questions about small molecules upregulating TETs and DNA demethylation. In this thread I proposed a regimen for reversing epigenetic age by demethylating agents - do you think you could ask D. Sinclair what he thinks of this idea?

[Mind]

The interview is completed. I was able to ask most of the questions. He didn't want to go into much detail about various supplements because of the competitive nature of the supplement market and the propensity of supplement makers to use his quotes - out of context and/or without permission - to hawk their products. He really wanted to focus more on the science and research behind NAD, Sirtuins, and DNA methylation.

 

Sadly, the second half of the interview had some audio trouble. Bad luck seems to strike every time I have a top name interview. So a few of the answers are a little choppy. I apologize. There is still a lot of good information.

 

It should be available in a few days.

[Mind]

questions:

1. which of the 3 main programs (small molecules, senolytics and reprogramming) will likely get translated first and show effectiveness

2. which geography will be able to better attract funds, ease regulation and turn to be successful for translation of research

3. what key advise he would give to young scientists considering working on aging

 

#1 was one of the answers from Sinclair that got a little garbled with the Skype trouble. Suffice it to say he was fairly agnostic toward which branch of rejuvenation research would progress the fastest, but it he seemed to think senolytics and epigenetic reprogramming have the highest chance of a "breakout" soon.

oh more importantly than those questions, actually I would be very interested to hear Dr. Sinclair's thoughts on what I thought was a pretty brilliant line of thinking by other members here: In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming (using extracellular vesicles for partial reprogramming - whether that would be something to consider in his research and why or why not).

 

This was a question I didn't have enough time to ask.

[ambivalent]

Perhaps in future you could arrange the interviewee to record the audio their end too and sync with your recording later if there are glitches.

[ambivalent]

One other request, I wonder if it might be possible to make some of these interviews more known across the forums partiularly when there is a big name interviewed. So, say, append it as temporary sticky on all forums, direct it to this thread - then remove said stickies once the interview has passed. I'm sure I'm not the only one who saw this too late!

[Mind]

One other request, I wonder if it might be possible to make some of these interviews more known across the forums partiularly when there is a big name interviewed. So, say, append it as temporary sticky on all forums, direct it to this thread - then remove said stickies once the interview has passed. I'm sure I'm not the only one who saw this too late!

 

Thanks for the idea. It is a good one.

[Mind]

The podcast is now live on the podcast page.

[DonManley]

The podcast is now live on the podcast page.

 

Great episode! Thanks a lot for making it happen and for asking our questions!

 

It seems that our community got used to conflating "drugs" and "supplements" together, where almost any molecule, no matter how strong or risky it potentially can be we call a "supplement". In addition, we also often discuss something in theory which we are not necessarily planning to do in practice.

 

David seems to treat all his public appearances with extreme care and almost as if he's has an inner lawyer on this shoulder whispering to him to choose every word carefully, as if he's on the record giving a testimony that can be used against him. It was interesting to see how spooky it can be to be a very publicly known scientist who can't just throw wild ideas and speculations into the air, because they can used against him. You navigated that very well and in 20 minutes you managed to cover an impressive amount of territory, and a lot of unique one at that.

 

And I'm gonna thank you again at this point, because you deserve it 

[TMNMK]

Yes, thank you so much Mind! Great podcast, and despite the clipping toward the end I think you must have edited it well because it wasn't terribly hard to fill in what he was saying there. Thanks again and great work!

[ambivalent]

Excellent interview, however, I must say I find Dave Sinclair's position somewhat equivocal on supplement recommendation. He has been quite willing to pass out anecdotes on his father's new lease of life under NMN, as well as sister's menopausal reversal while taking the same molecule. These anecdotes are clearly forms of tacit advice and (obviously) not validated through scientific trials - he certainly has, in effect, been an  NMN advocate, yet wants to row back when pressed on supplement recommendation citing scientific neutrality and maintaining credibility amongst peers. I certainly have no problem with anecdotes or best guesses, that's the game we are (somewhat) forced to be in on this site, it feels as though he both wants the non-committal-without-hard-facts-serious-scientist-status as well as the role of celebrity-anecdotal-bone-thrower. It felt too as though supplement research was menial work, whereas a full time occupation of knitting together the streams of work published would be quite a fruitful activity as many, especially Turnbuckle have demonstrated and could serve well to direct research.  

Edited by ambivalent, 22 November 2019 - 04:54 PM.