Microdosing nicotine increases NAD levels and rejuvenates old mice

[Mauritio]

Very interesting topic. A quick search on pubmed with keywords nicotine liver, majority of what I see is it causing liver injury and fatty liver. Just from looking at titles, I,ll do more research later. Thanks

The dosage makes the poison. We're talking about low or very low doses here .

I agree that this is interesting. A 1mg (or less) dose for a 90kg person seems incredible.

Where does one procure nicotine like this? I searched my usual places and just found the gum in 2mg or 4mg sizes which are apparently too big.

I linked the product I use earlier in this thread ,it has 1mg/drop.

 

[cremes]

I linked the product I use earlier in this thread ,it has 1mg/drop.

Aha, so you did.

I will link it here again for anyone who needs it.

Nicotine – Solution (USP) (30mL / 100mL)

Warning: This product is only for use in non-clinical research scenarios.

mitolab.com

 

[Mauritio]

Aha, so you did.

I will link it here again for anyone who needs it.

Nicotine – Solution (USP) (30mL / 100mL)

Warning: This product is only for use in non-clinical research scenarios.

mitolab.com

Yes that is it.

 

[Mauritio]

This is the NAD salvage pathway that is beeing "leveraged" in this study.

NAM (other names are: niacinamide, nicotinamide or vitamin B3) is beeing converted by NAMPT to NMN ( Niacinamide mononucleotide) ,which is then converted to NAD+, by another enzyme called nicotinamide-nucleotide adenylyltransferase (NMNAT).
The rate limiting enzyme for this metabolic pathway seems to be NAMPT, so it makes sense to focus on that one.

 

[PopSocket]

@Mauritio Very interesting finding and following this thread in order to start my experiment when you guys figure out the proper dosage in water.

I have a feeling the optimal dosage for NAD increase will be more than 1mg per day though. Speaking from 10+years vaping habit. Each time I lower the nicotine in the juice to some tiny amounts compared to traditional vape juices - 0,5mg to 1mg per 1ml, which would translate to 10-20mg nicotine for the whole day divided in hundreds of puffs - seems to be quite rejuvenating for some unknown previously to me reason. Now it makes sense.

 

[Mauritio]

@Mauritio Very interesting finding and following this thread in order to start my experiment when you guys figure out the proper dosage in water.

I have a feeling the optimal dosage for NAD increase will be more than 1mg per day though. Speaking from 10+years vaping habit. Each time I lower the nicotine in the juice to some tiny amounts compared to traditional vape juices - 0,5mg to 1mg per 1ml, which would translate to 10-20mg nicotine for the whole day divided in hundreds of puffs - seems to be quite rejuvenating for some unknown previously to me reason. Now it makes sense.

To me the optimal dose overall seems to be lower than 1mg , I'm aiming for 0.5-0.75mg/day.

For overall longevity and NAD-increases I highly doubt it's 20mg. You should also favor in that inhaling is not the same mechanism ingesting it orally since nictoine has such a high first pass metabolism, the concentration after it reaches the liver are really low.

 

[Mauritio]

Great video posted by @David PS in another thread, which shows why it makes more sense to focus on increasing NAMPT, rather than increasing nad precursor supply.
It makes the approach discussed in this thread even more attractive.


View: https://youtu.be/rHqU3upDUig

 

[Tarmander]

This has been a great game changer for me.

Always had trouble with nicotine. Loved it, but only used it when I needed an edge in life due to the side effects.

But swallowing these lozenges gets around those side effects. I don't get the same high, but still get other benefits.

Definitely increases focus and motivation. I think I have lost some weight from my middle and gained some muscle. I sleep better.

There are still some downsides. Sometimes I get headaches, or this "too focused" feeling behind my eyes. Hard to describe, but they kind of ache a bit.

Also I think my EMF sensitivity has increased. I used to be able to drive around in my car all day with my cell phone next to me and I would only start to feel it after 6+ hours. Now I start to feel it in 2 hours or so. So it isn't all positives, but net net it is positive.

I tried dropping the dose down to under 1mg, but the benefits faded. I am on around 2 mg split up into 2-3 doses per day.

 

[David PS]

@Mauritio - Here is another segment from Dr Nichola Conlon presents about how to use a whole system approach to restore our youthful NAD production.
She mentions the importance of CD38 and flavonoids to restore cellular NAD+ production back to youthful levels

View: https://www.youtube.com/watch?v=fEqtGba4MmI


Here is a related thread on the forum:

CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism

CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism Highlights •CD38 levels increase in tissues with age and correlate with NAD decline •NAD and mitochondrial function are preserved in old CD38 knockout mice •CD38 metabolizes NMN in vivo and...

raypeatforum.com

Edit - Here is her paper.

A systems-approach to NAD+ restoration

A decline in NAD+ is a feature of ageing and may play a causal role in the process. NAD+ plays a pivotal role in myriad processes important in cellula…

www.sciencedirect.com

 

[Mauritio]

@Mauritio - Here is another segment from Dr Nichola Conlon presents about how to use a whole system approach to restore our youthful NAD production.
She mentions the importance of CD38 and flavonoids to restore cellular NAD+ production back to youthful levels

View: https://www.youtube.com/watch?v=fEqtGba4MmI


Here is a related thread on the forum:

CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism

CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism Highlights •CD38 levels increase in tissues with age and correlate with NAD decline •NAD and mitochondrial function are preserved in old CD38 knockout mice •CD38 metabolizes NMN in vivo and...

raypeatforum.com

Edit - Here is her paper.

A systems-approach to NAD+ restoration

A decline in NAD+ is a feature of ageing and may play a causal role in the process. NAD+ plays a pivotal role in myriad processes important in cellula…

www.sciencedirect.com

Thanks , I'll definitely look into this.

 

[Mauritio]

@Mauritio - Here is another segment from Dr Nichola Conlon presents about how to use a whole system approach to restore our youthful NAD production.
She mentions the importance of CD38 and flavonoids to restore cellular NAD+ production back to youthful levels

View: https://www.youtube.com/watch?v=fEqtGba4MmI


Here is a related thread on the forum:

CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism

CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism Highlights •CD38 levels increase in tissues with age and correlate with NAD decline •NAD and mitochondrial function are preserved in old CD38 knockout mice •CD38 metabolizes NMN in vivo and...

raypeatforum.com

Edit - Here is her paper.

A systems-approach to NAD+ restoration

A decline in NAD+ is a feature of ageing and may play a causal role in the process. NAD+ plays a pivotal role in myriad processes important in cellula…

www.sciencedirect.com

The video is quite interesting,but it doesn't get to a coherent solution. It's interesting that she says you should find out why NAMPT is decreasing with age and not just throw raw materials at the cell, and then goes on to advertise her product that does exactly that in a slightly different way.

I guess the real question is why does NAMPT decrease ? And "aging" or "that's just how it is" doesn't really satisfy me. I haven't looked into it, but I guess that thyroid has to do with it.

Exercise seems to be a thing that reliably increases NAMPT. Although it doesn't seem to work as well in older individual . Maybe it's more like a protective effect of exercise that doesn't work as well in older people . Just like some old people won't build muscle even when they exercise.

- Exercise increases the release of NAMPT in extracellular vesicles and alters NAD+ activity in recipient cells - PubMed

- Skeletal muscle NAMPT is induced by exercise in humans - PubMed


- Resistance training increases muscle NAD+ and NADH concentrations as well as NAMPT protein levels and global sirtuin activity in middle-aged, overweight, untrained individuals - PubMed

 

[cs3000]

I guess the real question is why does NAMPT decrease ? And "aging" or "that's just how it is" doesn't really satisfy me. I haven't looked into it, but I guess that thyroid has to do with it.

aye would be interesting to find this out

Grape Seed Proanthocyanidin Extract Moderated Retinal Pigment Epithelium Cellular Senescence Through NAMPT/SIRT1/NLRP3 Pathway grape seed procyanidins extract also increases NAMPT and NAD+ , helped restore 12 month & 18 month old mice levels closer to 2 month old controls
(& also increases hippocampal neurogenesis & exercise endurance like the oral nicotine . common mechanism. tho i noticed negative mood effects from lower doses of GSPE personally. and the nicotine is a stronger effect. still might be worth a combo if tolerated)

NAD+ in DNA repair and mitochondrial maintenance
So basics of NAD+ role in aging looks like:
cellular stressors -> DNA damage , ramps up NAD+ usage for DNA repair
if not enough NAMPT enzyme around the NAD+ can't replenish well in response to stress. (as NAMPT converts NAM to NMN needed for NAD+)
-> failure to repair mitochondrial DNA -> mitochondrial dysfunction, defective electron transport chain leaking electrons & forming damaging h2o2, less oxidative phosphorylation for ATP energy, messed up mitochondrial permeability prone to more damage etc -> defective cells and increased rate of cell death

 

[LeeLemonoil]

aye would be interesting to find this out

Grape Seed Proanthocyanidin Extract Moderated Retinal Pigment Epithelium Cellular Senescence Through NAMPT/SIRT1/NLRP3 Pathway grape seed procyanidins extract also increases NAMPT and NAD+ , helped restore 12 month & 18 month old mice levels closer to 2 month old controls
(& also increases hippocampal neurogenesis & exercise endurance like the oral nicotine . common mechanism. tho i noticed negative mood effects from lower doses of GSPE personally. and the nicotine is a stronger effect. still might be worth a combo if tolerated)

NAD+ in DNA repair and mitochondrial maintenance
So basics of NAD+ role in aging looks like:
cellular stressors -> DNA damage , ramps up NAD+ usage for DNA repair
if not enough NAMPT enzyme around the NAD+ can't replenish well in response to stress. (as NAMPT converts NAM to NMN needed for NAD+)
-> failure to repair mitochondrial DNA -> mitochondrial dysfunction, defective electron transport chain leaking electrons & forming damaging h2o2, less oxidative phosphorylation for ATP energy, messed up mitochondrial permeability prone to more damage etc -> defective cells and increased rate of cell death

NAD+ is used by malign and senescent cells too. It is not a panacea and it tends to be become more unavailable once said things accumulate. So it’s not a suitable point to break the aging process

 

[joaquin]

This is pretty interesting and connects some dots I have observed.

Most problems with nicotine I have seen others have, and I have had, all come from quickly absorbing nicotine. Either through vaping or sublingual etc. I love nicotine, but I only use it once and awhile because it will make me angry afterwards.

I tried yesterday just swallowing a bit of a lozenge instead of letting it absorb sublingually. I had a nice even energy boost that lasted much longer then normal.

Maybe slow absorbing nicotine is the way?

I never thought about that before, swallowing a bit of lozenge. I may give that a try. What brand do you use? I have used the cheap Equate brand several years ago but IIRC it has some bad additional ingredients.

 

[Mauritio]

NAD+ is used by malign and senescent cells too. It is not a panacea and it tends to be become more unavailable once said things accumulate. So it’s not a suitable point to break the aging process

But then again thyroid increases nad.nad is the product of the anti-cancer metabolism ...So it feeds the thing that it antagonizes ? Isn't it supposed to correct it?

I have seen that they developed anti-cancer drugs based an NAMPT antagonism and that NAMPT levels might even function as a biomarker for certain cancers , might just be a correlation and have desastrous consequences on the whole metabolism.

 

[LeeLemonoil]

But then again thyroid increases nad.nad is the product of the anti-cancer metabolism ...So it feeds the thing that it antagonizes ? Isn't it supposed to correct it?

I have seen that they developed anti-cancer drugs based an NAMPT antagonism and that NAMPT levels might even function as a biomarker for certain cancers , might just be a correlation and have desastrous consequences on the whole metabolism.

We would have to research deeper where the tipping point is of potentially helping with deranged conditions and where it begins to fuel derangement / malignency.

Will be intricate but a broad idea would be nice

 

[Tarmander]

I never thought about that before, swallowing a bit of lozenge. I may give that a try. What brand do you use? I have used the cheap Equate brand several years ago but IIRC it has some bad additional ingredients.

I think it was these:
Amazon product ASIN B079HXQKW8View: https://www.amazon.com/Nicotine-Mini-Lozenge-Smoking-Count/dp/B079HXQKW8/ref=sr_1_6?crid=20ZUFS3PZGOVL&keywords=nicotine%2Blozenge%2B4mg&qid=1682044285&rdc=1&sprefix=nicotine%2Blozenge%2B4m%2Caps%2C128&sr=8-6&th=1


Not great ingredients but its such a small amount I don't think it matters much

 

[LadyRae]

I think it was these:
Amazon product ASIN B079HXQKW8View: https://www.amazon.com/Nicotine-Mini-Lozenge-Smoking-Count/dp/B079HXQKW8/ref=sr_1_6?crid=20ZUFS3PZGOVL&keywords=nicotine%2Blozenge%2B4mg&qid=1682044285&rdc=1&sprefix=nicotine%2Blozenge%2B4m%2Caps%2C128&sr=8-6&th=1


Not great ingredients but its such a small amount I don't think it matters much

Definitely get MINI lozenges! The larger round ones are like a blob of disgusting fake-sweet chalk slowly dissolving in your mouth...

 

[GTW]

Re nicotine. The aromatase inhibition of nicotine was measure at 26,000 vs other high values, chrysin for example at 1,200.
>Another study reported results in units/100 g wet weight (one unit was defined as the dose required for 50% inhibition) and found tea (C. sinensis), coffee (Coffea L. sp.), cocoa (Theobroma cacao L.), collards (Brassica oleracea L.), and tomato leaves (Lycopersicon esculentum Mill.) to strongly inhibit aromatase using a microsomal assay [113]. Interestingly, this study also reported that cigarette smoke (obtained using methylene chloride and aqueous traps) and tobacco leaves (70% ethanol extract; Nicotiana tabacum L.) also potently inhibited aromatase, as reported in cigarette equivalents [113].

Natural Products as Aromatase Inhibitors

With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating also the potential of natural products as AIs. Natural products ...

www.ncbi.nlm.nih.gov