• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo
- - - - -

Cycling mTOR inhibitors & NAD+ precursors?

nad+ nmn mtor rapamycin

  • Please log in to reply
6 replies to this topic

#1 Chris Pollyanna

  • Member
  • 51 posts
  • 179
  • Location:Toronto, Canada

Posted 30 May 2019 - 03:12 AM


Hello all,

 

I have been taking the NAD+ precursor NMN (250mg daily, sublingually) for the past several months and have recently added Rapamycin (5mg weekly). 

 

I was wondering whether it would be a good idea to not take the NAD+ precursor during the peak part of the Rapamycin dose (approx 60hr half-life). I was thinking of three days no NAD precursor following Rapa and then four days taking the precursor (maybe at a higher dose, say 375mg daily). My rational is as follows:

 

1. Rapa & the NAD precursors seem to work in different directions. Rapa is not about cell growth, but repair eg autophagy. The NAD precursors and especially NMN seem to be more about extra energy and growth - I'm thinking in particular of the mouse studies showing capillary growth in muscles and all of the anecdotal evidence of people increasing muscle mass etc (often from this site). 

 

2. The study I have posted below seems to show an antagonism between Rapa and in this case NR, when it comes to stem cells in the gut (see bolded text). This is the only instance that I have found in a search of Pubmed, but since not much research has gone into looking at both of these pathways, I wonder if it is the tip of the iceberg.

 

3. From various sources it appears that homeostasis kicks in with NAD precursors after a certain while (though levels do not return completely back to where they had been). By skipping them for three days a week, could this perhaps be prevented?

 

4. Also save a bit of money on the NMN! (even if I increase the dose by 125mg on the on days it is still only 12 pills instead of 14 weekly)

 

I realise that although they both raise NAD+, NMN & NR are not the same, but until the science is fully elucidated, I am here assuming them to be.

 

I am very curious as to your thoughts on this, especially if you are also combining them.

 

    NAD+ supplementation rejuvenates aged gut adult stem cells      

The tissue decline due to aging is associated with the deterioration of adult stem cell function. Here we show the number and proliferative activity of intestinal stem cells (ISCs) but not Paneth cells decline during aging, as does ISC function assessed ex vivo. Levels of SIRT1 and activity of mTORC1 also decline with aging. The treatment with the NAD(+) precursor nicotinamide riboside (NR) rejuvenates ISCs from aged mice and reverses an impaired ability to repair gut damage. The effect of NR is blocked by the mTORC1 inhibitor rapamycin or the SIRT1 inhibitor EX527. These findings demonstrate that small molecules affecting the NAD/SIRT1/mTORC1 axis may guide a translational path for maintenance of the intestine during aging.

https://onlinelibrar...1111/acel.12935

 

 

 


  • like x 1

#2 VP.

  • Member
  • 452 posts
  • 170

Posted 30 May 2019 - 04:00 PM

That might work. E-mail Dr. Green and he may have an answer. I think you may want to cycle NMN with a senolytic, once every 6 months are so?  D&Q is the best senolytic that's easily available. This article in today's Scientific American explains why. 

 https://www.scientif...nts/?redirect=1

 



sponsored ad

  • Advert
Click HERE to rent this advertising spot for SUPPLEMENTS (in thread) to support LongeCity (this will replace the google ad above).

#3 smithx

  • Guest
  • 1,126 posts
  • 305

Posted 30 May 2019 - 08:47 PM

You may mean this article? https://www.scientif...l-zombie-cells/ it's from 2017 and doesn't say D&Q is the best. The article that you linked is very interesting but is about NAD+.

 

 

That might work. E-mail Dr. Green and he may have an answer. I think you may want to cycle NMN with a senolytic, once every 6 months are so?  D&Q is the best senolytic that's easily available. This article in today's Scientific American explains why. 

 https://www.scientif...nts/?redirect=1

 


Edited by smithx, 30 May 2019 - 08:48 PM.

  • Informative x 1

#4 VP.

  • Member
  • 452 posts
  • 170

Posted 30 May 2019 - 09:54 PM

You may mean this article? https://www.scientif...l-zombie-cells/ it's from 2017 and doesn't say D&Q is the best. The article that you linked is very interesting but is about NAD+.

No, I meant the article I posted. D&Q is the best "easily available" senolytic. Others are better better but you would have to get them synthesized and possibly inject them. Here is why I think you may want to use a senolytic (only intermittently) with NAD+, NMN. 

 

In a Nature Cell Biology study in February scientists reported a newly discovered role for NAD+ metabolism at the intersection of cellular aging and cancer—specifically, in a process called cellular senescence. Senescence occurs when aging, damaged cells stop dividing. The process can help suppress cancer, but it leads cells to produce inflammatory molecules that can also promote cancer growth under certain conditions. In the Nature Cell Biology study, Rugang Zhang of the Wistar Institute, and his colleagues found that in cells entering senescence, rising levels of NAMPT (a major NAD+-producing enzyme in mammals) encourage the release of inflammatory and potentially protumor molecules. Consistent with those findings, mice genetically predisposed toward pancreatic cancer developed more precancerous and cancerous growths when they consumed the NAD+ precursor NMN. Zhang says more research is needed to fully understand the role of NAD+ in cancer, but he adds that “we should be cautious and bear in mind the potential downside of NAD+supplementation as a dietary approach for antiaging.”



#5 VP.

  • Member
  • 452 posts
  • 170

Posted 31 May 2019 - 07:28 PM

Here is a study that just came out that agrees NAD+ should be taken with a Senolytic if at all. 

 

Interacting NAD+ and Cell Senescence pathways complicate anti-aging therapies.

During human aging, decrease of NAD+ levels is associated with potentially reversible dysfunction in the liver, kidney, skeletal and cardiac muscle, endothelial cells and neurons. At the same time, the number of senescent cells, associated with damage or stress that secrete pro-inflammatory factors (SASP, Senescence-Associated Secretory Phenotype), increases with age in many key tissues, including the kidneys, lungs, blood vessels, and brain. Senescent cells are believed to contribute to numerous age-associated pathologies and their elimination by senolytic regimens appears to help in numerous preclinical aging-associated disease models including those for atherosclerosis, idiopathic pulmonary fibrosis, diabetes, and osteoarthritis. A recent report links these processes, such that decreased NAD+ levels associated with aging may attenuate the SASP phenotype potentially reducing its pathological effect. Conversely increasing NAD+ levels by supplementation or genetic manipulation which may benefit tissue homeostasis, also may worsen SASP and encourage tumorigenesis at least in mouse models of cancer. Taken together these findings suggest a fundamental trade-off in treating aging related diseases with drugs or supplements that increase NAD+. Even more interesting is a report that senescent cells can induce CD38 on macrophages and endothelial cells. In turn increased CD38 expression is believed to be the key modulator of lowered NAD+ levels with aging in mammals. So accumulation of senescent cells may itself be a root cause of decreased NAD+, which in turn could promote dysfunction. On the other hand, the lower NAD+ levels may attenuate SASP, decreasing the pathological influence of senescence. The elimination of most senescent cells by senolysis before initiating NAD+ therapies may be beneficial and increase safety, and in the best case scenario even eliminate the need for NAD+ supplementation.

 

https://www.ncbi.nlm...pubmed/31140365


Edited by VP., 31 May 2019 - 07:29 PM.

  • Informative x 1

#6 smithx

  • Guest
  • 1,126 posts
  • 305

Posted 01 June 2019 - 07:13 PM

mTOR inhibitors may make it less likely that cells become senolytic, and may even revive senescent cells to some extent. Since we don't want to stimulate senescent cells to produce more inflammatory compounds, mTOR inhibitors could be beneficial in general in this regard.

 

Senolytics, on the other hand, can eliminate senescent cells, but cells which have been prevented from becoming senescent would be less likely to be eliminated. So there should probably be a fairly long wash-out period between stopping dosing of both mTOR inhibitors and NAD+ supplements prior to senolytic treatment.

 

With regard to D&Q being "best available senolytic" I'm not sure. FOXO4-DRI seems much more selective and possibly much safer, just based on mechanism of action. Dasatinib has a horrible and dangerous side effects profile, Some highlights (https://www.drugs.co...de-effects.html):

 

Hematologic

Very common (10% or more): Hemorrhage (11 to 26%)

Common (1% to 10%): Febrile neutropenia, pancytopenia

 

Gastrointestinal

Very common (10% or more): Diarrhea (18 to 31%), vomiting (11 to 16%), nausea (18 to 24%), abdominal pain (12%)

Common (1% to 10%): Enterocolitis infection, gastrointestinal bleeding, neutropenic colitis, gastritis, mucositis, stomatitis, dyspepsia, abdominal distension, constipation, oral soft tissue disorder

 

Nervous system

Very common (10% or more): Headache (13 to 33%)

Common (1% to 10%): Neuropathy, peripheral neuropathy, dizziness, dysgeusia, somnolence

 

Musculoskeletal

Very common (10% or more): Musculoskeletal pain (11 to 22%)

Common (1% to 10%): Arthralgia, myalgia, muscular weakness, musculoskeletal stiffness, muscle spasm, chills

 

Respiratory

Very common (10% or more): Pleural effusion (11 to 24%), dyspnea (15 to 24%), cough

Common (1% to 10%): Pneumonia (including bacterial, viral, fungal), upper respiratory tract infection, pulmonary edema, pulmonary hypertension, lung infiltration, pneumonitis

 

Cardiovascular

Common (1% to 10%): Congestive heart failure, cardiac dysfunction, pericardial effusion, arrhythmia, tachycardia, palpitations, hypertension, chest pain

 

Ocular

Common (1% to 10%): Visual disturbance, blurred vision, reduction in visual acuity, dry eye

 

Immunologic

Very common (10% or more): Infection (including bacterial, viral, fungal, non-specified) (10 to 14%)

 

 

 

 

 

 

 


Edited by smithx, 01 June 2019 - 07:13 PM.

  • Good Point x 1
  • Informative x 1

sponsored ad

  • Advert
Click HERE to rent this advertising spot for SUPPLEMENTS (in thread) to support LongeCity (this will replace the google ad above).

#7 VP.

  • Member
  • 452 posts
  • 170

Posted 02 June 2019 - 03:42 PM

Dasatinib taken daily at doses from 30-200 mg a day for months or years has some nasty side effects (dosing for CML). One or two doses a year not so much IMHO. Aspirin at 1 gram a day is very bad. Twice a year and you'll be fine.  FOXO4-DRI has no human trials completed or even underway. The risk is much higher until we get some human data and it's also very difficult to source compared to D&Q. 


Edited by VP., 02 June 2019 - 03:48 PM.

  • Good Point x 2





Also tagged with one or more of these keywords: nad+, nmn, mtor, rapamycin

0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users