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Dr. Sinclair about the epigenome, NAD, NR, NMN

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#61 Nate-2004

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Posted 10 September 2018 - 12:57 PM

Can we get back to the topic of the video in the OP? 

 

Now that I got my methylation clock info back from DNAge and it says I'm a year older than I am, I've not only got some concerns but I'd like to know how this relates. 

 

Hopefully I can re-explain this accurately as I understood it. Sinclaire explains how over time, we undergo epigenetic changes and lose the original "grooves" for stem cell differentiation. Nerve cells become less of a nerve cell for example, which is part of the dysfunction and one of the primary hallmarks of aging. So two questions come to mind here.

 

1. How does improving NAD+ levels help with this problem?

2. How do we know that restoring these levels with precursors doesn't result in further dysregulation of the salvage cycle due to an excess of NAM and a lack of NAMPT?



#62 Oakman

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Posted 10 September 2018 - 07:56 PM

Can we get back to the topic of the video in the OP? 

 

Now that I got my methylation clock info back from DNAge and it says I'm a year older than I am, I've not only got some concerns but I'd like to know how this relates. 

 

Hopefully I can re-explain this accurately as I understood it. Sinclaire explains how over time, we undergo epigenetic changes and lose the original "grooves" for stem cell differentiation. Nerve cells become less of a nerve cell for example, which is part of the dysfunction and one of the primary hallmarks of aging. So two questions come to mind here.

 

1. How does improving NAD+ levels help with this problem?

2. How do we know that restoring these levels with precursors doesn't result in further dysregulation of the salvage cycle due to an excess of NAM and a lack of NAMPT?

 

I don't see why you have a problem with DNAge 1 yr older Nate.  Haven't you seen the other way off DNAges showing up? These tests give educated guesses at best for your changes over time with multiple testing needed. It's a metric, not an absolute. 

 

Step back and look at the larger picture Nate that the video highlights. We're dealing with one big biochemical factory with many related reactions rate limiting others and using multiple feedback loops. Sinclair's answer (in the video) is mass doses of R, NMN, and Metformin. I hope it works out for him and his father.

 

Impressive - but improving the efficiency of how much and how long NR/NMN/R and associated molecules can be inserted and kept in the blood and tissues, is equally fruitful. My main N=1 right now after seeing this is Sinclair's R/NMN (can't get/want the metformin), then maximize it. I'm fortunate in that I have unlimited NMN for a time and can try whatever. Right now I feel great, better than ever. So the thought of making it better, is like making a good high, just that much higher. Or it's all placebo ... kidding.

 

We know aberrant methylation in aging is tied in part to NAD+ deficits, NAD+ levels are tied to many things, but H2S production and NRFx expression are important enough. And stem cell repair and rejuvenation is dependent on that and more. 

 

An analogy might be gasoline, which is very volatile by itself, actually is a bit to explosive. So we add anti-knock compounds that slow the process, increase the useful performance, and keep the engine from blowing up! That's where I see, for example, H2S and NRFx that we've talking about here. We want to manage the process for our benefit.

 

I googled something like your question and found good info worth reading.

 

1. When stem cells grow old: phenotypes and mechanisms of stem cell aging

 

All multicellular organisms undergo a decline in tissue and organ function as they age. An attractive theory is that a loss in stem cell number and/or activity over time causes this decline. In accordance with this theory, aging phenotypes have been described for stem cells of multiple tissues, including those of the hematopoietic system, intestine, muscle, brain, skin and germline. Here, we discuss recent advances in our understanding of why adult stem cells age and how this aging impacts diseases and lifespan. With this increased understanding, it is feasible to design and test interventions that delay stem cell aging and improve both health and lifespan.

 

2. A need for NAD+ in muscle development, homeostasis, and aging

 

The purpose of this review is to highlight recent studies investigating NAD+ function in muscle development, homeostasis, disease, and regeneration. Emerging research areas include elucidating roles for NAD+ in muscle lysosome function and calcium mobilization, mechanisms controlling fluctuations in NAD+ levels during muscle development and regeneration, and interactions between targets of NAD+ signaling (especially mitochondria and the extracellular matrix). This knowledge should facilitate identification of more precise pharmacological and activity-based interventions to raise NAD+ levels in skeletal muscle, thereby promoting human health and function in normal and disease states.

 

3. NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells

 

Here we show that nicotinamide riboside kinase 1 (NRK1) is necessary and rate-limiting for the use of exogenous NR and NMN for NAD+ synthesis. Using genetic gain- and loss-of-function models, we further demonstrate that the role of NRK1 in driving NAD+ synthesis from other NAD+ precursors, such as nicotinamide or nicotinic acid, is dispensable.

 

4. Hydrogen Sulfide Maintains Mesenchymal Stem Cell Function and Bone Homeostasis via Regulation of Ca2+ Channel Sulfhydration

 

Here, we demonstrate that bone marrow mesenchymal stem cells (BMMSCs) produce H2S to regulate their self-renewal and osteogenic differentiation, and H2S deficiency results in defects in BMMSC differentiation. H2S deficiency causes aberrant intracellular Ca2+ influx, due to reduced sulfhydration of cysteine residues on multiple Ca2+ TRP channels.


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#63 Nate-2004

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Posted 11 September 2018 - 01:02 PM

I don't see why you have a problem with DNAge 1 yr older Nate.  Haven't you seen the other way off DNAges showing up? These tests give educated guesses at best for your changes over time with multiple testing needed. It's a metric, not an absolute. 

 

I have a problem with it because I was hoping that all my lifestyle changes and intervention over the past three years would have had some dramatic effect on reversing my biological age. That said I don't know what the before picture looked like so I have no reference as to whether it did or didn't. Perhaps it would have said I was 5 years older a few years ago. The site claims that lifestyle changes have an influence on methylation and that it's reversible. Not sure if that's true but I would think that sounds possible.

 

As for your second question, no I haven't seen the other way off DNAges showing up....



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#64 Phoebus

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Posted 11 September 2018 - 02:03 PM

I have a problem with it because I was hoping that all my lifestyle changes and intervention over the past three years would have had some dramatic effect on reversing my biological age. That said I don't know what the before picture looked like so I have no reference as to whether it did or didn't. Perhaps it would have said I was 5 years older a few years ago. The site claims that lifestyle changes have an influence on methylation and that it's reversible. Not sure if that's true but I would think that sounds possible.

 

As for your second question, no I haven't seen the other way off DNAges showing up....

 

previous to your intervetions you could have been 10 years older than your physical age. who knows? 



#65 Oakman

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Posted 11 September 2018 - 02:38 PM

I have a problem with it because I was hoping that all my lifestyle changes and intervention over the past three years would have had some dramatic effect on reversing my biological age. That said I don't know what the before picture looked like so I have no reference as to whether it did or didn't. Perhaps it would have said I was 5 years older a few years ago. The site claims that lifestyle changes have an influence on methylation and that it's reversible. Not sure if that's true but I would think that sounds possible.

 

As for your second question, no I haven't seen the other way off DNAges showing up....

 

I am in 100% agreement with your "hopes". Sent mine in last week and hoping to be "only" as old as you are now :) We will see (in 8-10 weeks)!



#66 PAMPAGUY

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Posted 12 September 2018 - 11:02 AM

Sinclair's latest interview, very long and comprehensive, but very little new.

 

https://www.themonth...ir-cure-old-age



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#67 PAMPAGUY

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Posted 29 September 2018 - 03:26 PM

New NAD+ trial using NMN.

 

https://www.fightagi...lifespan-study/



#68 Kevnzworld

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Posted 29 September 2018 - 04:47 PM

Nate
If it makes you feel any better my results showed that my methylation clock matched my age. I’ve been supplementing for 14 years ( I’m 62 ). I’ve been on Metformin for 6, I’m not diabetic I’ve taken NR for 3-4 years, since development. I’ve also been on bio identical hormone therapy ( testosterone and dhea ) for 12 years.
I exercise regularly, fit and I’m in good health. I don’t eat red meat, I’ve never smoked
My only recreational vice is high end red wine, 2-3 glasses a few days a week.
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#69 PAMPAGUY

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Posted 29 September 2018 - 05:44 PM

Kevnzworld,
Doing a very good job. Your at the age to start looking at rapa to complete the trifecta of slowing ageing. Rapa+Metformin+NAD precussor.

Good Luck

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#70 Vastmandana

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Posted 23 February 2019 - 08:39 PM

I'm not going to take the time to edit the description, but Peter Attia had a pretty technical as well as a fun filled wide ranging interview with Sinclair a couple months ago on slowing aging, sirtuins, & epigenetics... a great discussion with two very smart fellas. While I've followed all that David has said, I learned a LOT of history and hidden gems...

Now for the unedited:

Podcast/Article:
David Sinclair, Ph.D.: Slowing aging – sirtuins, NAD, and the epigenetics of aging

URL:
http://traffic.libsy...?dest-id=713489

Description:

In this episode, David A. Sinclair, Ph.D., a Professor in the Department of Genetics at Harvard Medical School and co-Director of the Paul F. Glenn Center for the Biological Mechanisms of Aging, provides insight into why we age and how to slow its effects based on his remarkable work on the role of sirtuins and NAD in health and diseases. He also presents the case that stabilizing the epigenetic landscape may be the linchpin in counteracting aging and disease.
We discuss:
  • How and why David moved from Australia to Leonard Guarente’s lab at MIT [7:30];
  • Sirtuins and aging [[url=""x-apple-data-detectors://2"]15:00[/url]];
  • A series of experiments elucidating the mechanisms of sirtuins [20:45];
  • How are sirtuins activated? [25:30];
  • NAD and sirtuin activation [31:00];
  • Nicotinamide, sirtuin inhibition, andPNC1 [39:00];
  • Resveratrol [43:00];
  • The NIH/ITP studies on resveratrol [55:45];
  • Does David take any compounds for longevity? [1:00:15];
  • NAD precursors (NR, NMN) and pterostilbene [1:02:45];
  • Female fertility and NAD precursors [1:14:45];
  • A unifying theory of aging [1:20:30];
  • Waddington’s epigenetic landscape [[url=""x-apple-data-detectors://8"]1:23:00[/url]];
  • If David had unlimited resources, what is the experiment he would do? [1:28:25];
  • Testing combinations to extend lifespan [1:31:30];
  • What made David aware of his mortality at such a young age? [01:33:45];
  • What is David’s book going to cover? [01:37:15]; and
  • More.

Learn more at [url=""a%20href="http://www.peterattiamd.com/"]www.PeterAttiaMD.com[/url]

Connect with Peter on [url=""applewebdata://ED13720F-9E71-466F-A057-E4C14E231287/Facebook.com/PeterAttiaMD"] Facebook[/url] | [url=""applewebdata://ED13720F-9E71-466F-A057-E4C14E231287/Twitter.com/PeterAttiaMD"] Twitter[/url] | [url=""applewebdata://ED13720F-9E71-466F-A057-E4C14E231287/Instagram.com/PeterAttiaMD"] Instagram[/url].


This content comes from:
The Peter Attia Drive

URL:
http://peterattiadrive.libsyn.com/rss

Edited by Vastmandana, 23 February 2019 - 08:46 PM.


#71 bosharpe

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Posted 24 February 2019 - 09:56 AM

Anyone know of where to get hold of NMN powder in the UK?



#72 PAMPAGUY

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Posted 24 February 2019 - 10:00 AM

I'm not going to take the time to edit the description, but Peter Attia had a pretty technical as well as a fun filled wide ranging interview with Sinclair a couple months ago on slowing aging, sirtuins, & epigenetics... a great discussion with two very smart fellas. While I've followed all that David has said, I learned a LOT of history and hidden gems...

Now for the unedited:

Podcast/Article:
David Sinclair, Ph.D.: Slowing aging – sirtuins, NAD, and the epigenetics of aging

URL:
http://traffic.libsy...?dest-id=713489

Description:

In this episode, David A. Sinclair, Ph.D., a Professor in the Department of Genetics at Harvard Medical School and co-Director of the Paul F. Glenn Center for the Biological Mechanisms of Aging, provides insight into why we age and how to slow its effects based on his remarkable work on the role of sirtuins and NAD in health and diseases. He also presents the case that stabilizing the epigenetic landscape may be the linchpin in counteracting aging and disease.
We discuss:

  • How and why David moved from Australia to Leonard Guarente’s lab at MIT [7:30];
  • Sirtuins and aging [[url=""x-apple-data-detectors://2"]15:00[/url]];
  • A series of experiments elucidating the mechanisms of sirtuins [20:45];
  • How are sirtuins activated? [25:30];
  • NAD and sirtuin activation [31:00];
  • Nicotinamide, sirtuin inhibition, andPNC1 [39:00];
  • Resveratrol [43:00];
  • The NIH/ITP studies on resveratrol [55:45];
  • Does David take any compounds for longevity? [1:00:15];
  • NAD precursors (NR, NMN) and pterostilbene [1:02:45];
  • Female fertility and NAD precursors [1:14:45];
  • A unifying theory of aging [1:20:30];
  • Waddington’s epigenetic landscape [[url=""x-apple-data-detectors://8"]1:23:00[/url]];
  • If David had unlimited resources, what is the experiment he would do? [1:28:25];
  • Testing combinations to extend lifespan [1:31:30];
  • What made David aware of his mortality at such a young age? [01:33:45];
  • What is David’s book going to cover? [01:37:15]; and
  • More.

Learn more at [url=""a%20href="http://www.peterattiamd.com/"]www.PeterAttiaMD.com[/url]
Connect with Peter on [url=""applewebdata://ED13720F-9E71-466F-A057-E4C14E231287/Facebook.com/PeterAttiaMD"] Facebook[/url] | [url=""applewebdata://ED13720F-9E71-466F-A057-E4C14E231287/Twitter.com/PeterAttiaMD"] Twitter[/url] | [url=""applewebdata://ED13720F-9E71-466F-A057-E4C14E231287/Instagram.com/PeterAttiaMD"] Instagram[/url].

This content comes from:
The Peter Attia Drive

URL:
http://peterattiadrive.libsyn.com/rss

 



#73 PAMPAGUY

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Posted 24 February 2019 - 10:25 AM

I also had read this interview 2 months back.  Very informative, but if you would also read what Dr. Attia had to say about oral delivery of NAD, NMN, NR he would recommend either IV or sublingual.  Oral never gets into the cells.  He also quotes a trial that he had not read when he interviewed Dr. Sinclair, where they traced NAD, NMN, and NR through the body and it did not get into cells.  You must bypass the liver to get into the cells.  This video came out after the Sinclair interview.   Please skip to 1:57 on video to hear what he has to say about it.  https://peterattiamd.com/ama03/ Cells cannot take up NAD, must manufacture there own, so precursors are the way to go, but not orally.  "Anyone using oral delivery for NAD precussors, is doing nothing but making the manufactures and distributors wealthy."

 

In a newer followup on the Kevin Rose Show, Dr. Attia talks about taking Rapamycin, but at the end of the podcast he talks about NAD supplementation, specifically about NAD precussors delivered IV or subliminally to skip the liver..https://podcastnotes.../01/17/attia-5/

 

Human longevity is moving very fast these days, and it is difficult to keep up.



#74 Phoebus

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Posted 24 February 2019 - 03:28 PM

I also had read this interview 2 months back.  Very informative, but if you would also read what Dr. Attia had to say about oral delivery of NAD, NMN, NR he would recommend either IV or sublingual.  Oral never gets into the cells.  

 

 

Gonna have to mostly agree here. After trying different ways of taking NMN, sublingual is the only one that I really felt was giving me true benefits. 

 

Having said that there are folks who seem to get dramatic results with just gulping down pills, so who knows? 



#75 Vastmandana

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Posted 25 February 2019 - 04:52 AM

I've been using it sublingually for years... It has definitely improved my eyesight, which I've discussed/detailed several times. At 68, just one of several arrows in my quiver aimed at quality of life...

Attia is the first to acknowledge he is no expert in this area but his interviews are always deep and informative...

We are peering into the darkness at this point... And a number of exciting pathways are being explored... Glad to be vigorous enough to be participating in the journeys

Edited by Vastmandana, 25 February 2019 - 05:03 AM.


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#76 Vastmandana

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Posted 25 February 2019 - 05:00 AM

Double post

Edited by Vastmandana, 25 February 2019 - 05:04 AM.






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