2255 replies to this topic

[Bryan_S]

The yin and yang of mitochondrial dysfunction

V. Summersby/NPG

 

Mitochondrial dysfunction is a hallmark of organismal ageing, but mild mitochondrial stress during development is also known to have beneficial effects, delaying the ageing process. This positive effect on lifespan has been linked to the activation of the mitochondrial unfolded protein response (UPR^mt), which is a stress response that leads to the transcriptional activa…

http://www.nature.co...rm.2016.71.html

http://www.readcube....038/nrm.2016.71

[Harkijn]

I only read the Research Highlights, but here,too, there is no mention of upregulating the Nad/NADH  by pharmalogical intervention.  Just by supplementing (how?) NR several biomarkers in old animals improved. This  old animal finds this interesting  .

[stefan_001]

I only read the Research Highlights, but here,too, there is no mention of upregulating the Nad/NADH  by pharmalogical intervention.  Just by supplementing (how?) NR several biomarkers in old animals improved. This  old animal finds this interesting  .

 

NR supplementation likely increases the pool of NAD+ via a sidedoor process. In practice that means more reactions can take place that require an oxidizing agent like NAD+ to accept electrons from other molecules. 

Edited by stefan_001, 24 May 2016 - 09:41 AM.

[Tom Andre F. (ex shinobi)]

btw tom andre, beta lapachol seems to be toxic to be used for anything at all! i checked around, i cannot find a single data this stuff is safe even in low doses long term.

hey check out this candy, https://www.ncbi.nlm...pubmed/20112181 too mutagenic for school!

 

wrong... your study is about lapachol which is different in structure than beta-lapachone..

 

beta lapachone is tumor selective and does not damage healthy cells, its just the opposite. last in vivo studies does not found any toxicity and used for several months 120mg/kg without side effect.. The researcher even think the health improvement could be maybe even better with higher dosage. Just real the full paper given previously...

 

Another study found 40mg/kg prevent renal damage in mice following chemotherap, another one used 50mg.. All the links are above. And in a media, beta-lapachone does not damage healthy cells but only target the tumor cells

[normalizing]

tom, both beta lapachone and lapachol are found in the bark of the same tree. so its kind of difficult to use the bark as anything really. they probably used highly purified isolate the type that would cost hundreds for some mgs, so useless and impractical.

[Ethic]

James Watson mentions several NQO1 modulators on Agingsciences blog

 

Dimethyl fumarate

Taxifolin (a flavonol like Quercetin)

Resveratrol (Pterostilbene?)

Sulforaphane

Glucosinolates in Pak Choi

Sulindac

Cisplatin

Beta-Lapachone

 

(I didn't check the sources.)

 

 

Personally I made very good experience with young Pak Choi (Bok Choy), tried it twice before going to bed, about 200g, raw and very well chewed.

 

Each time I woke up very early the next morning, well-rested (uncommon for me). It's known that circadian clock and NAD+ level are closely related.

 

I intended to investigate further before I share (chance of placebo), but it's a fairly rare vegetable over here and I'm too lazy to search...

Edited by Ethic, 24 May 2016 - 12:54 PM.

[normalizing]

about NR, does anyone have any idea how it works with alcohol, prevents toxicity before abuse or repairs damage after abuse, studies or just theory?

 

[Tom Andre F. (ex shinobi)]

tom, both beta lapachone and lapachol are found in the bark of the same tree. so its kind of difficult to use the bark as anything really. they probably used highly purified isolate the type that would cost hundreds for some mgs, so useless and impractical.

 

I spoke with the korean team and they always used beta-lapachone synthetic pure. They fed themselves and their family with a natural supplement containing beta-lapachone inside but from an other herb than the tree. I failed to get more info about it.

[Tom Andre F. (ex shinobi)]

James Watson mentions several NQO1 modulators on Agingsciences blog

 

Dimethyl fumarate

Taxifolin (a flavonol like Quercetin)

Resveratrol (Pterostilbene?)

Sulforaphane

Glucosinolates in Pak Choi

Sulindac

Cisplatin

Beta-Lapachone

 

(I didn't check the sources.)

 

 

Personally I made very good experience with young Pak Choi (Bok Choy), tried it twice before going to bed, about 200g, raw and very well chewed.

 

Each time I woke up very early the next morning, well-rested (uncommon for me). It's known that circadian clock and NAD+ level are closely related.

 

I intended to investigate further before I share (chance of placebo), but it's a fairly rare vegetable over here and I'm too lazy to search...

 

All these can be added to beta-lapachone regarding NQO1 but clearly they state beta-lapachone as the real one for NQO1. Also its what think the korean team that tested a lot of compound and always choose beta-lapachone. And they seems right since i never seen such impressive vivo result such the ones they got

 

[works4you2]

The yin and yang of mitochondrial dysfunction

V. Summersby/NPG

http://www.readcube....038/nrm.2016.71

 

Thanks Bryan_S!

 

Really enjoyed reading these lines:

 

 NR.jpg   64.8KB   2 downloads

[normalizing]

 

tom, both beta lapachone and lapachol are found in the bark of the same tree. so its kind of difficult to use the bark as anything really. they probably used highly purified isolate the type that would cost hundreds for some mgs, so useless and impractical.

 

I spoke with the korean team and they always used beta-lapachone synthetic pure. They fed themselves and their family with a natural supplement containing beta-lapachone inside but from an other herb than the tree. I failed to get more info about it.

 

 

 

i dont care to bother with some lab powders, measure and take as accordingly with high prices on top of that. what im curious now is, what is the other source of this compound other than that tree! if you spoke to them, you sure could have tried to find out i think
 

[Tom Andre F. (ex shinobi)]

The yin and yang of mitochondrial dysfunction

V. Summersby/NPG

 

Mitochondrial dysfunction is a hallmark of organismal ageing, but mild mitochondrial stress during development is also known to have beneficial effects, delaying the ageing process. This positive effect on lifespan has been linked to the activation of the mitochondrial unfolded protein response (UPR^mt), which is a stress response that leads to the transcriptional activa…

http://www.nature.co...rm.2016.71.html

http://www.readcube....038/nrm.2016.71

 

Bryan, what do you think they means by :

 

Muscle stem cell numbers and regenerative capacity were substantially increased following NR treatment, which, as shown by reduced expression of senescence and apoptosis markers, protected cells against intrinsic cell senescence. This inhibition of senescence was associated with improved mitochondrial biogenesis and function (with increased OXPHOS).

 

Does this means it removed the P16 positive cells ??

[midas]

I think beta lapachone deserve its own thread isnt ?

 

 

So why don't you start one. To be honest I'm a little tired of you chocking up this thread with it!

[Ethic]

 

James Watson mentions several NQO1 modulators on Agingsciences blog

 

Dimethyl fumarate

Taxifolin (a flavonol like Quercetin)

Resveratrol (Pterostilbene?)

Sulforaphane

Glucosinolates in Pak Choi

Sulindac

Cisplatin

Beta-Lapachone

 

(I didn't check the sources.)

 

 

Personally I made very good experience with young Pak Choi (Bok Choy), tried it twice before going to bed, about 200g, raw and very well chewed.

 

Each time I woke up very early the next morning, well-rested (uncommon for me). It's known that circadian clock and NAD+ level are closely related.

 

I intended to investigate further before I share (chance of placebo), but it's a fairly rare vegetable over here and I'm too lazy to search...

 

All these can be added to beta-lapachone regarding NQO1 but clearly they state beta-lapachone as the real one for NQO1. Also its what think the korean team that tested a lot of compound and always choose beta-lapachone. And they seems right since i never seen such impressive vivo result such the ones they got

 

 

 

Lapachol is a derivative of Vitamin K (structure-wise), so isn't it possible that beta-lapachone is metabolized to lapachol "by accident"?

The korean team should do a human blood test measuring lapachol after beta-lapachone intake (if there is any).

[Bryan_S]

 

I think beta lapachone deserve its own thread isnt ?

 

 

So why don't you start one. To be honest I'm a little tired of you chocking up this thread with it!

 

 

Beta-lacaphone

 

http://www.longecity...beta-lacaphone/

 

Beta-Lapachone as a NQO1 regulator > NAD+/NADH increase

 

http://www.longecity...dnadh-increase/

 

 

Tom started the second thread today and the first one has been there since 2014.

[Tom Andre F. (ex shinobi)]

 

 

James Watson mentions several NQO1 modulators on Agingsciences blog

 

Dimethyl fumarate

Taxifolin (a flavonol like Quercetin)

Resveratrol (Pterostilbene?)

Sulforaphane

Glucosinolates in Pak Choi

Sulindac

Cisplatin

Beta-Lapachone

 

(I didn't check the sources.)

 

 

Personally I made very good experience with young Pak Choi (Bok Choy), tried it twice before going to bed, about 200g, raw and very well chewed.

 

Each time I woke up very early the next morning, well-rested (uncommon for me). It's known that circadian clock and NAD+ level are closely related.

 

I intended to investigate further before I share (chance of placebo), but it's a fairly rare vegetable over here and I'm too lazy to search...

 

All these can be added to beta-lapachone regarding NQO1 but clearly they state beta-lapachone as the real one for NQO1. Also its what think the korean team that tested a lot of compound and always choose beta-lapachone. And they seems right since i never seen such impressive vivo result such the ones they got

 

 

 

Lapachol is a derivative of Vitamin K (structure-wise), so isn't it possible that beta-lapachone is metabolized to lapachol "by accident"?

The korean team should do a human blood test measuring lapachol after beta-lapachone intake (if there is any).

 

 

I replied you here http://www.longecity...rease/?p=775867

 

[Mitochemist]

I am new here. Very simple question but not sure if this is known: has anyone measured the aqueous solubility of pure NR? 

[normalizing]

 

about NR, does anyone have any idea how it works with alcohol, prevents toxicity before abuse or repairs damage after abuse, studies or just theory?

 

 

[Bryan_S]

 

The yin and yang of mitochondrial dysfunction

V. Summersby/NPG

 

Mitochondrial dysfunction is a hallmark of organismal ageing, but mild mitochondrial stress during development is also known to have beneficial effects, delaying the ageing process. This positive effect on lifespan has been linked to the activation of the mitochondrial unfolded protein response (UPR^mt), which is a stress response that leads to the transcriptional activa…

http://www.nature.co...rm.2016.71.html

http://www.readcube....038/nrm.2016.71

 

Bryan, what do you think they means by :

 

Muscle stem cell numbers and regenerative capacity were substantially increased following NR treatment, which, as shown by reduced expression of senescence and apoptosis markers, protected cells against intrinsic cell senescence. This inhibition of senescence was associated with improved mitochondrial biogenesis and function (with increased OXPHOS).

 

Does this means it removed the P16 positive cells ??

 

 

Kim Baumann's article was a simple recap of some of the latest research we've posted. See "Vitamin stops the aging process of organs Nicotinamide riboside rejuvenates stem cells, allowing better regeneration processes in aged mice" Keeping our stem cell reserves healthy with (NR) helps them repair and remain viable over more cell divisions (more than untreated cells) before reaching senescence. For those not so well versed I'm talking about the Hayflick limit. This phenomenon is the number of times a normal human cell population will divide until cell division stops.

 

You are asking specifically about p16 which is a cyclin-dependent kinase inhibitor and a tumor suppressor. Very possibly but I haven't researched this facet. It is part of cell cycle regulation but you're leaping past a lot of supporting cell metabolism to make this association. I think the understanding of whats happening is much further upstream and if p16 is involved its the result of restored metabolism.

 

We already knew NR treatment was likely to reduce the expression of senescence and apoptosis markers. All we have to do is look to some of the other NAD+ precursors which have also shown similar promise.

Nicotinamide Exerts Antioxidative Effects on Senescent Cells

 

Nicotinamide Overcomes Pluripotency Deficits and Reprogramming Barriers

 

So why might (NR) allow more stem cell divisions . . . and are there any other examples of this?

 

As a matter of fact all we have to do is look to the research Brenner did on yeast. This is all wrapped up in the discovery of (NR). Let's think for a moment where our (NR) comes from? Yeast . . . how is this?

 

As we look at the patents and the supporting research used to produce (NR) we find the (NR) we take is generated from a natural communal cell process that has been modified and exploited for our benefit. The initial research suggested the presence of (NR) in the conditioned growth media. These were followup experiments used to discover why sharing media from a previous yeast cultures increased the replicative life span of new colonies placed on that growth media. Then after a host of yeast strains were developed, blocking the production of or ability to utilize different NAD precursors, eventually strain PAB076 was developed that exports (NR) but cannot re-import it because that pathway was genetically blocked.

 

So why might the export of (NR) in cell communities be advantageous? Well its a "pay it forward" situation that helps fellow communal cells in stress. (that's my takeaway) It makes for a healthy community. In the case of yeast the number of budding cells increased over their replicative lifespan. 

 

So the yeast replicative lifespan (RLS), experiments were produced for understanding the aging of dividing cells, defined as the number of divisions that a yeast mother cell undergoes prior to senescence and now it appears to have been conserved and passed down to us. Starting to sound familiar within the context of senescence?

 

Remember the post about NAD⁺-dependent enzymes at the endoplasmic reticulum.

 

 

This relates directly back to the research mentioned in Kim Baumann's article about the mitochondrial unfolded protein response (UPRmt). Think of the amount of downstream cellular damage depleted NAD+ levels from aging, injury or cellular stress might take place if its availability were limited to this organelle? Think how the mitochondria might be affected if this repair pathway were inhibited.

 

 

Mitochondria Retrograde Signaling and the UPRmt: Where Are We in Mammals? "In addition, boosting the NAD+ level not only activates Sirtuins and, especially, mitochondrial Sirtuin 3 [76], but also induces mitonuclear protein imbalances and activates UPRmt [67]. Importantly, these authors revealed that, in mice and C. elegans, in time-course experiments, treatments with nicotinamide riboside (NR), a NAD+ precursor led to a protective response in a two-step process. First, during the early phase response (one day of treatment), the UPRmt was activated, with the associated increase in ClpP and HSP6 expression. Then, after three days of treatment with NAD+ booster/NR, with the UPRmt markers still overexpressed, an antioxidant response was also triggered, as demonstrated by enhanced activation of the promoter of the gene encoding SOD3 and nuclear localization of the transcription factor daf-16 (FOXO3A orthologue in mammals). Interestingly, it appears that both pathways might be interconnected; the induction of Extracellular superoxide dismutase [Cu/Zn] (SOD3) was dependent on UBL-5, a transcriptional regulator activated during the UPRmt [67]."  and    "Similar results were obtained when mitochondrial protein abundance was increased by either increasing the NAD+ concentration with two precursors of its synthesis (nicotinamide mononucleotide (NMN) "abbreviation correction mine" and nicotinamide riboside (NR)) known to trigger the expression of several nuclear gene encoding mitochondrial proteins in an NAD-dependent protein deacetylase Sirtuin-1 (SIRT1)-dependent manner [83] or by boosting mitochondrial biogenesis by mTOR inhibition with rapamycin [67]."

Also see: Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice "NAD+ Repletion Prompts Mitonuclear Protein Imbalance, Inducing the UPRmt Markers CLPP and HSP10 In Vivo, While Reducing Endoplasmic Reticulum Stress" We can put together an entire picture now how (NR) fits into this mitochondrial unfolded protein response (UPRmt) while at the same time reducing endoplasmic reticulum stress. 

 

Most readers here understand the job of the endoplasmic reticulum but for those who don't, its involved in protein and lipid synthesis and when its not working efficiently the protein's manufactured can be somewhat degraded having downstream health ramifications. So its plausible degraded protein production would hasten senescence and increasing intracellular NAD concentrations would support healthy protein production and increase replicative lifespan.

 

All of this research re-enforces the notion that (NR) might be readily exported into the intracellular medium to assist injured or stressed tissues. Remember the post about In vivo Monitoring of Transcriptional Dynamics After Lower-Limb Muscle Injury Enables Quantitative Classification of Healing

 

It suggested the gene expression of Nicotinamide Riboside Kinase 2 after injury was the result of increased uptake of (NR).

 

So to me the inhibition of senescence in mammalian tissue isn't really a big surprise. I think we needn't look further than the Brenner research and we see the same increase in replicative lifespan but in yeast. I'm sure we could boil things down to different regulating proteins but the larger brush strokes suggest removing the NAD+ deficits gives rise to a healthier cellular environment and additional cell division. Its not a great leap to think Stem cells need increased metabolism to repair damaged tissue and older stem cells who might be closer to senescence might benefit and replicate longer before halting.

 

So I think the research is suggesting this conserved (NR) path we are exploiting has many downstream benefits. It appears to be a built in failsafe to help stressed or injured tissues and so far this premise is holding together. The studies above also infer the (NR) molecule itself might be involved in cellular stress signaling, ramping up metabolic repair mechanisms. It will be interesting to read the coming studies to see if this idea continues to be strengthened. 

Edited by Bryan_S, 25 May 2016 - 06:37 PM.
mitochondrial unfolded protein response (UPRmt) addition

[Bryan_S]

 

 

about NR, does anyone have any idea how it works with alcohol, prevents toxicity before abuse or repairs damage after abuse, studies or just theory?

 

 

 

Do you know how to use the built-in search feature in the upper right hand corner of this page? This has been a topic of discussion on many Longecity threads and there is supporting study material that might answer your questions. This might be why you haven't gotten an answer because its been covered before.

 

I don't think you will find anyone here who will advocate taking (NR) to reduce the damage induced from drinking. The best advice is to not drink. Drinking does deplete NAD levels so it stands to reason keeping levels high should afford some protection to the more susceptible tissues. Nobody is going to hang their hat on that premiss however and suggest it as a course of action.

 

So read the studies and judge for yourself but be prepared because there are pages of reading ahead for you.  

[normalizing]

"Drinking does deplete NAD levels so it stands to reason keeping levels high should afford some protection to the more susceptible tissues" so it should help?

[stefan_001]

Protecting mitochondrial function is linked to improved bone health in aging and resistance to osteoporosis

http://www.timelessl...o-osteoporosis/

 

 

[Bryan_S]

Nuclear DNA damage signalling to mitochondria in ageing

http://www.nature.co...rm.2016.14.html

 

 

"Impaired cellular metabolism can be counteracted by treatment with NAD⁺ precursors"

 

​I don't have permission to the full review but maybe someone here can lend a hand.

[APBT]

Nuclear DNA damage signalling to mitochondria in ageing

http://www.nature.co...rm.2016.14.html

 

 

"Impaired cellular metabolism can be counteracted by treatment with NAD⁺ precursors"

 

​I don't have permission to the full review but maybe someone here can lend a hand.

 

FULL TEXT: 

Attached Files

•  Nuclear DNA damage signalling to mitochondria in ageing.pdf   706.5KB   60 downloads

[Bryan_S]

Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice

http://www.nature.co...icles/srep26933

 

 

Vitamin Nicotinamide Riboside Protects Mice from Diabetes Complications

Published: May 27, 2016.
Released by University of Iowa Health Care

http://www.sciencene...2715470061.html

 

A naturally occurring vitamin, nicotinamide riboside (NR), can lower blood sugar levels, reduce fatty liver, and prevent peripheral nerve damage in mouse models of prediabetes and type 2 diabetes (T2D), according to a new study by researchers at the University of Iowa and the Iowa City VA Health Care System.

 

"NAD+ metabolomics shows that NAD+ itself goes down in prediabetes and T2D, but it is not depressed as strikingly as two other metabolites: NADP+ and NADPH," Brenner explains. "When we supplement with NR, the NAD+ bounces back but the NADP+ and NADPH levels don't fully recover, suggesting that the disease process specifically targets these metabolites, which are required for natural resistance to reactive oxygen species (ROS). These results are consistent with research showing that the development of insulin-insensitivity is related to ROS damage and that NR boosts the body's natural anti-oxidant defenses."

 

This study appears to be a prelude to a human clinical study. I expect we will see an announcement after funding is secured.

Edited by Bryan_S, 29 May 2016 - 05:20 PM.
brenner quote added

[Skyguy2005]

I tried Nicotinamide Riboside recently. To be honest, it wasn't as noticeable compared to Niacin! Kind of dissapointing. I mean it did feel good... just... not as good compared to Niacin (nicotinic acid). 

[mrkosh1]

I think a test needs to be performed with rats and/or humans to see if dual supplementation with alpha lipoic acid and nicotinamide riboside can boost the levels of NAD+ and SIRT expression higher than NR alone.

 

My thinking is that cells from an infant need to be tested to determine their level of NAD+ and SIRT expression. Then we need to determine how close just alpha lipoic acid gets to that, just NR, or a combination.

 

Alpha lipoic acid may not be quite as potent as beta-lapachone but it is already mass produced, very affordable, and generally very safe.

 

If Longecity were to ever sponsor research on a supplement, I think this combination should be tested.

[Bryan_S]

I tried Nicotinamide Riboside recently. To be honest, it wasn't as noticeable compared to Niacin! Kind of dissapointing. I mean it did feel good... just... not as good compared to Niacin (nicotinic acid). 

 

Well Niacin has a kick alright and nicotinamide has had 70-years of research behind its benefits. If you're wanting to share your experience we have a thread called the Nicotinamide Riboside (NR/Niagen) personal experience thread. With NAD boosting keep in mind I would trial it several weeks before moving on. I myself discontinued (NR)'s use after a month and it wasn't till I did that I noticed I'd gotten some benefits I hadn't noticed. The effects are also more pronounced the older you are because you're already at a lower NAD base line.

 

So the research unquestionably says as we get older our NAD levels fall. These studies also tell us we develop an NAD deficiency and its availability effects our NAD dependent enzymes and our aerobic metabolism. As a result many ailments of aging have one central  commonality. So the bottom line is, taking NAD precursors can increase those levels and keep these dependent processes humming along.

 

So I advocate NAD boosting and you can research and pick which NAD precursor you feel will do you the most good. This thread covers most of the precursors but overwhelmingly today most of the research today focuses on one.

 

http://www.ncbi.nlm....pubmed/24506863

http://jcb.rupress.o.../199/2/205.full

http://journals.plos...al.pone.0019194

http://www.pnas.org/...9/2876.full.pdf

 

 

I think a test needs to be performed with rats and/or humans to see if dual supplementation with alpha lipoic acid and nicotinamide riboside can boost the levels of NAD+ and SIRT expression higher than NR alone.

 

My thinking is that cells from an infant need to be tested to determine their level of NAD+ and SIRT expression. Then we need to determine how close just alpha lipoic acid gets to that, just NR, or a combination.

 

Alpha lipoic acid may not be quite as potent as beta-lapachone but it is already mass produced, very affordable, and generally very safe.

 

If Longecity were to ever sponsor research on a supplement, I think this combination should be tested.

 

 

I hadn't looked into alpha lipoid acid as an adjunct to NAD boosting. As I look for studies the research into this is slim. I did find some studies that were interesting Increasing bioavailability of ®-alpha-lipoic acid to boost antioxidant activity in the treatment of neuropathic pain. and Alpha-lipoic acid supplementation and diabetes. So I don't think that was what you were looking for but it a start to build on.

[mrkosh1]

From what I have read, Nicotinamide Riboside does not bring about a rapid reversal of the aging process. In one paper on mice NR reversed the aging of muscle tissue in mice after only a couple weeks. But the whole organism didn't revert back to a much younger state. I'm thinking that if we want to reverse the aging process back significantly, we need to boost NAD+ to the levels found in a newborn infant or even a fetus. Restoring them to a healthy adult is not good enough. To accomplish this, a number of NAD+ boosting supplements will probably need to be used synergistically to further enhance the effect.

 

Alpha Lipoic Acid appears to be a fairly safe supplement that could be used to further boost NAD+, activate sirtulins, and even induce telomerase.

 

If NAD+ decline is central to aging, we need to figure out exactly how effective a combination of boosters can be.

 

I strongly hope that companies and institutions studying NR will perform tests utilizing a combination of NR and ALA.

 

http://onlinelibrary...05E54118.f02t04

 

Lipoic Acid Improves Mitochondrial Function in Nonalcoholic Steatosis Through the Stimulation of Sirtuin 1 and Sirtuin 3

Nonalcoholic steatosis is an important hepatic complication of obesity linked to mitochondrial dysfunction and oxidative stress. Lipoic acid (LA) has been reported to have beneficial effects on mitochondrial function and to attenuate oxidative stress. The sirtuin (SIRT) family has been demonstrated to play an important role in the regulation of mitochondrial function and in the activation of antioxidant defenses. In this study, we analyzed the potential protective effect of LA supplementation, via the modulation of mitochondrial defenses through the SIRT pathway, against oxidative stress associated with high-fat feeding. Wistar rats were fed a standard diet (control group ©, n = 10), a high-fat diet (obese group (OB), n = 10) and a high-fat diet supplemented with LA (OLIP, n = 10). A group pair-fed to the latter group (pair-fed OLIP group (PFO), n = 6) was also included. LA prevented hepatic triglyceride (TG) accumulation (−68.2%) and liver oxidative damage (P < 0.01) through the inhibition of hydroperoxide (H₂O₂) production (P < 0.001) and the stimulation of mitochondrial antioxidant defenses. LA treatment upregulated manganese superoxide dismutase (SOD2) (60.6%) and glutathione peroxidase (GPx) (100.2%) activities, and increased the reduced glutathione (GSH): oxidized glutathione (GSSG) ratio and UCP2 mRNA levels (P < 0.001–P < 0.01). Moreover, this molecule reduced oxidative damage in mitochondrial DNA (mtDNA) and increased mitochondrial copy number (P < 0.001– P < 0.01). LA treatment decreased the acetylation levels of Forkhead transcription factor 3a (Foxo3a) and PGC1β (P < 0.001–P < 0.01) through the stimulation of SIRT3 and SIRT1 (P < 0.001). In summary, our results demonstrate that the beneficial effects of LA supplementation on hepatic steatosis could be mediated by its ability to restore the oxidative balance by increasing antioxidant defenses through the deacetylation of Foxo3a and PGC1β by SIRT1 and SIRT3.

 

--- 

 

I just noticed something very interesting. According to the above paper, Alpha Lipoic Acid increased the amount of SIRT1 protein by six fold. However, from the papers I have read about NR, the addition of NAD+ only increases the activity of the SIRT1 protein but not the quantity.

 

Could the combination of ALA and NR lead to both more SIRT1 protein AND increase the activity?

 

I'm thinking NR and ALA may be highly syngergistic.

 

 

 

Edited by mrkosh1, 01 June 2016 - 07:53 PM.

[mrkosh1]

Here is the link to a paper which specifically shows that Alpha Lipoic Acid can boost the levels of NAD+ and change the ratio.

 

http://www.ncbi.nlm....pubmed/22456698

RESULTS:

ALA increased the NAD(+)/NADH ratio to enhance SIRT1 activity and production in C(2)C(12) myotubes. ALA subsequently increased AMPK and ACC phosphorylation, leading to increased palmitate β-oxidation and decreased intracellular triacylglycerol accumulation in C(2)C(12) myotubes. In cells treated with nicotinamide or transfected with SIRT1 siRNA, ALA-mediated AMPK/ACC phosphorylation, intracellular triacylglycerol accumulation and palmitate β-oxidation were reduced, suggesting that SIRT1 is an upstream regulator of AMPK. ALA increased ATGL and suppressed FAS protein production in C(2)C(12) myotubes. Oral administration of ALA in diabetic mice fed on a high-fat diet and db/db mice dramatically reduced the body weight and visceral fat content.