146 replies to this topic

[stefan_001]

 

Hi Tom, is there any news from the korean lab members taking ß-L? Do they still take it? Any experienced Side-Effects?

 

Hi Ethic,

 

unfortunately I dont speak to him anymore since a few time now and do not feel confortable to disturb him again as he does not work on beta-lapachone again. Some others of his team does.

 

from what he told me he was willing to use beta lapachone for its long lasting property on a transient and frequent use. But actually to answer your question I prefer to directly quote him here because I dont have more than that answer regarding your concern:

 

"I don't have human data for the synthetic beta laphachone. Some people including me have taken the bL extract, 3 tablets per day, but lead to no side effects as bodily symptoms and normal blood measures. In my case, there is no beneficial effects because I have no health problem. My father in law suffered from cancer in the urinary bladder took it and fully recovered but he also received surgery without anti-cancer therapy in hospital. You know there is no drug for uridary bladder cancer and surgical removal is the only way. In addition, I heard that many people reported dramaticd effects but these results could not be scientifically proved. 

 

I don't study the bL anymore but sometime I will take it if sometime I need it."

 

 

Here they found out that NADH increased following cisplatin damage induced on hearing and that NAD+ level was well increased by beta lapachone treatment: http://www.ncbi.nlm....pubmed/24922076

 

 

Cisplatin (cis-diaminedichloroplatinum-II) is an extensively used chemotherapeutic agent, and one of its most adverse effects is ototoxicity. A number of studies have demonstrated that these effects are related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD⁺) has emerged as a key regulator of cellular energy metabolism and homeostasis. Here, we demonstrate for the first time that, in cisplatin-mediated ototoxicity, the levels and activities of SIRT1 are suppressed by the reduction of intracellular NAD⁺ levels. We provide evidence that the decrease in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) transferase (PARP)-1 activation and microRNA-34a through p53 activation aggravates cisplatin-mediated ototoxicity. Moreover, we show that the induction of cellular NAD⁺ levels using β-lapachone (β-Lap), whose intracellular target is NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD⁺ levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity.

 

This full study confirm the fact that the ratio is what is important once again. You can check their graph at the end of the study (external link picture)

 

I believe beta-lapachone is much more potent to control the NAD+ metabolism than NR because NR will remain only for short term.. and this seems to be validated by the chromadex studies that advice a continual use of NR to feed a pool perforated

 

Hi Tom, I dont understand the ratio discussion. The only thing it tells you is that something has changed in the metabolism compared to an earlier situation. For humans it is known this ratio shifts as we age and that NAD+ declines a lot. But ones you start to thinker with the cell metabolism the ratio doesn't tell too much in my opinion. For example if the thinkering leads to doubling of both NAD+ and NADH I think we would be better off bit and the ratio is unchanged.

 

The big difference with NR is that NR is a path that injects NAD+ from external. Here we are talking about salvage path and possible redistribution. LIke I said earlier I find it interesting and lets see what more study reveals so I will stay in this discussion. Personally however it will not change my view on NR and its usefulness. NR has good track record so far and clear mechanism. 

 

 

Hi Stefan, I think I already gave enough paper reference here about that, it seems clear that the ratio play a huge role on the health and it is actually also proven in vivo in numerous studies as you seen. And as you admited: aging shift this ratio.

 

I dont think NR should be seen as an ennemy for beta-lapachone (or the opposite). The only thing is that the NAD+ pool is perforated and you have to use both. As you know aging is a multi factor disease you we need to think in an holistic approach:

 

Personally my top 3 would be:

 

beta-lapachone (its long-lasting property is critical for the transitent and frequent increase of NAD+/NADH ratio.)

NR ( as a precursor for the NAD+ pool) but this time as low dose since no need for high dose (wich is actually a bad thing on the long run), small dose will be enough if beta-lapachone is used in a transitent way

Pterostilbene (the best SIRT1 activator so far)

 

here you almost control the full aging metabolism. The scientist was also interested by this combination. I would love to see someone able to test that on mice 

 

Hi Tom, well if you think that's enough papers and proof then I stop the discussion. I think there are a lot of holes that may or may not be filled by future research. Also you continue to make statements which I find wrong. You state very easily that NR is "bad in the long term" but you have no such concerns on this product which frankly has never been tested in humans. Sounds like double standards to me.

Edited by stefan_001, 30 May 2016 - 02:01 PM.

[Tom Andre F. (ex shinobi)]

Nahh Stefan, Where did I said that ??

 

I think we miss data for both NR and BL. We need more data of course ! I said we know that NAD+/NADH and NQO1 are already clear to be as important or more than NAD+ alone. And for that yes we have already enough data for me.

 

But still I never seen a single study on NR on mice lifespan in the way it was done for BL. The one for NR is just not that impressive a limit 4% difference in lifespan over control.. While a 17% in lifespan for BL and over the CR group + all the health parameter : glucose, cholesterol, leptin, mitochondria, cognitive test...

 

In this forum we just try to speak about what can help us live longer isnt ? So I want to speak more about NQO1 and the NAD+/NADH ratio instead of just supplement with NAD+ precursor that was already proven to increase it only a couple hours before it return back to normal according to chromadex. So they advice to consume more.. if this is true regarding they turnover health, its not true for our health because still NR is just a niacinamide linked to a glucose in order to enter better into the cells and increase NAD+. So it means we are under the strict same side effect associated with niacinamide: increase in homocysteine level (the worst cardiovascular factor) and SIRT1 silencing all already discussed in the NR page. So Im more for low dose to play safe and make sure we fixe the reason why NAD+ go back to normal so fast to truly handle aging.

 

So im not against NR, but more looking for a combination, and thats why this thread. If you have better compound than better beta-lapachone, do not hesitate, I dont have financial interest into this one.

[Tom Andre F. (ex shinobi)]

I think we also need more paper regarding P53-Pcg-1a axis and NQO1:

 

http://www.cell.com/...(15)00825-6.pdf

 

Telomere dysfunction and DNA damage cause aging and related chronic disorders. Xiong et al. show that PGC-1 a disruption drives telomerase TERT downregulation, telomere malfunction, and DNA damage, thereby developing vascular aging and atherosclerosis. Ectopic expression and induction of PGC-1a by ALA activate TERT and ARE/ ERE signaling and ameliorate aging- related pathology.

Telomere dysfunction and DNA damage cause aging and related chronic disorders. Xiong et al. show that PGC-1 a disruption drives telomerase TERT downregulation, telomere malfunction, and DNA damage, thereby developing vascular aging and atherosclerosis. Ectopic expression and induction of PGC-1a by ALA activate TERT and ARE/ ERE signaling and ameliorate aging- related pathology.

 

This confirm again that PCG-1a promotes telomerase expression (TERT)

 

 

http://www.ncbi.nlm....pubmed/23648480

 

The protein level of PGC-1α, a key metabolic regulator, is controlled by NADH-NQO1.

Abstract

PGC-1α is a key transcription coactivator regulating energy metabolism in a tissue-specific manner. PGC-1α expression is tightly regulated, it is a highly labile protein, and it interacts with various proteins--the known attributes of intrinsically disordered proteins (IDPs). In this study, we characterize PGC-1α as an IDP and demonstrate that it is susceptible to 20S proteasomal degradation by default. We further demonstrate that PGC-1α degradation is inhibited by NQO1, a 20S gatekeeper protein. NQO1 binds and protects PGC-1α from degradation in an NADH-dependent manner. Using different cellular physiological settings, we also demonstrate that NQO1-mediated PGC-1α protection plays an important role in controlling both basal and physiologically induced PGC-1α protein level and activity. Our findings link NQO1, a cellular redox sensor, to the metabolite-sensing network that tunes PGC-1α expression and activity in regulating energy metabolism.

 

 

and TERT inhibit P53 in the loop as confirmed also in the graph of the first link above

 

PGC1a is one step above and after TERT

 

 

 

 

 

 

[Tom Andre F. (ex shinobi)]

im still waiting for a good description of that beta lapachone being present in various herbs but it might take a while it seems *yawns*

 

Maybe its because no one knows ? The only info I have I already gave, the professor in the video and the scientist to who I spoke mentioned a chinese ginseng concentrated extract but I dont know more and never seen any reference of beta lapachone being present in it.. So should be independent test I guess as its done by numerous lab.. But Im also interested to get an herbal extract concentrated into beta-lapachone if one may offer

[to age or not to age]

Hi Tom et al

I have had my eye on Beta Lapachone for more than a year.  After reading The 2012 Korean paper and interviewing Lenny Guarante and David Sinclair on the subject, I decided to have beta lapachone synthesized by two chemists I know.  It really took much longer than I had anticipated; I am not a chemist but

now I know a bit more.  Chemistry is messy.  Several different methods were used to make the molecule.  Sinclair told me how at Sirtris they were making literally hundreds, if not thousands of molecule analogues to resveratrol etc. Daunting.

Anyway, three weeks ago they successfully produced beta lapachone.  I had a proton NMR done on the sample and it is, indeed, pure beta lapachone.

We have begun to produce the first large batch, 10 grams, which will be synthesized and tested by June 15th.  I will be bringing samples up to the Glenn Symposium - David is very interested in the compound, as is Lenny Guarante, and Jim Watson.  One of the big question is dosage; it's one thing to load up sick mice on the stuff, another thing to give it to a healthy animal.  Jim Watson, a surgeon, is considering human tests.

I, myself, want to test it on older mice, in combination with NR, and forms of resveratrol.

I can make available perhaps 5 grams for research purposes.  The price will be 1500 -2000 per gram, a fraction of what it costs at aldrich etc.

I directed the Film "To Age or Not To Age" (2010) and have been filming scientists on an ongoing basis since 2006. I have posted several video clips of my conversations with various scientists.

I have never sold a compound but beta lapachone shows such promise that I want to make it available to speed up the process. Robert

 

[adamh]

adamh, where did you find out in which herbs it is present? its kind of difficult to find this. also, this whole "superfood" fiasco is some kind of a soccer mom term and i dont like it one bit. blueberries make me gain weight, amazingly superpower!

 

I used my secret method, I did a search on it. Not google but duckduckgo.com

 

http://umm.edu/healt.../herb/pau-darco

 

 

 

Scientists have identified two active chemicals in pau d'arco. These chemicals are called naphthoquinones: lapachol and beta-lapachone. In lab tests, these chemicals killed some bacteria, fungi, viruses, and parasites. They also have anti-inflammatory properties, and may be effective against diseases such as osteoarthritis. But no one knows whether they will have the same effects in humans, and the dose required would have severe, toxic side effects.

 

 

Bilberry is said to have some too. I love blueberries and they are not high in clalories.

[normalizing]

blueberries are nothing but sugar

[Tom Andre F. (ex shinobi)]

Hi Tom et al

I have had my eye on Beta Lapachone for more than a year.  After reading The 2012 Korean paper and interviewing Lenny Guarante and David Sinclair on the subject, I decided to have beta lapachone synthesized by two chemists I know.  It really took much longer than I had anticipated; I am not a chemist but

now I know a bit more.  Chemistry is messy.  Several different methods were used to make the molecule.  Sinclair told me how at Sirtris they were making literally hundreds, if not thousands of molecule analogues to resveratrol etc. Daunting.

Anyway, three weeks ago they successfully produced beta lapachone.  I had a proton NMR done on the sample and it is, indeed, pure beta lapachone.

We have begun to produce the first large batch, 10 grams, which will be synthesized and tested by June 15th.  I will be bringing samples up to the Glenn Symposium - David is very interested in the compound, as is Lenny Guarante, and Jim Watson.  One of the big question is dosage; it's one thing to load up sick mice on the stuff, another thing to give it to a healthy animal.  Jim Watson, a surgeon, is considering human tests.

I, myself, want to test it on older mice, in combination with NR, and forms of resveratrol.

I can make available perhaps 5 grams for research purposes.  The price will be 1500 -2000 per gram, a fraction of what it costs at aldrich etc.

I directed the Film "To Age or Not To Age" (2010) and have been filming scientists on an ongoing basis since 2006. I have posted several video clips of my conversations with various scientists.

I have never sold a compound but beta lapachone shows such promise that I want to make it available to speed up the process. Robert

 

Hi Robert,

 

it would be awesome ! I really want to see test for the dosage in vivo, its what we need. Also human data would be perfect.. And for the combination, Its exactly what I would like to test too. However I would use pterostilbene instead of resveratrol, the more data, the more we see pterostilbene is far better. Just saying..

 

Also, it would be nice to make the direct connexion between beta-lapachone and telomerase since we know now the role of NQO1 with PGC-1α

 

Now about the price, 1500$ still too high. Because if for instance we want a low daily dose such as 50mg it means 1,5 gram per month.. Im not sure we can all afford that. Or maybe you planed to use even less such as 10 / 20mg a day ? In mice they used from 40 to 120mg / kg.

 

So first we need data about dosage.

 

Did you contacted the company in korea that supplied the beta-lapachone for the korean study and that merged with the tabaco company ?

Edited by Tom Andre F. (ex shinobi), 30 May 2016 - 10:49 PM.

[to age or not to age]

I think that it has to be deduced whether - like rapamycin - beta lapachone might well be administered on a non continuous basis.

The price Aldrich quotes per gram is 25,000 dollars.  What is striking is that data indicates lapachone both overlaps calorie restriction in terms of affected genes, but may also go beyond it in other health related pathways. Relevant testing needs to be done.

[mrkosh1]

So do we know for sure that Beta Lapachone doesn't downregulate PARP or other NAD+ consuming mechanisms?

 

If Beta Lapachone in no way down regulates anti-aging mechanisms that use NAD+, then this substance seems extremely interesting.

[mrkosh1]

NQ01 can be activated by alpha lipoic acid. I wonder what is a stronger inducer of NQ01: beta lapachone or alpha lipoic acid?

 

 http://www.ncbi.nlm....pubmed/18813798

[mrkosh1]

I just found this. Alpha Lipoic Acid has proven to change the NAD+ ratio in mice and increase SIRT 1.

 

α-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase.

 

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

[normalizing]

NR was mentioned to down regulate NAD+ but people continue to praise it...

[stefan_001]

So do we know for sure that Beta Lapachone doesn't downregulate PARP or other NAD+ consuming mechanisms?

 

If Beta Lapachone in no way down regulates anti-aging mechanisms that use NAD+, then this substance seems extremely interesting.

 

I think there is plenty to find out. This is one the graphs that creates doubts in my mind from the earlier cited papers.You can see that in the cisplatin treated mice BL helps recover SIRT1 and SIRT3. But the impact of BL on healthy mice SIRT levels is more or less zero. So the claim that it acts like the CR mechanism is not supported by that graph at least for the healthy mice.The mice used were only 8 weeks old so perhaps the effect may be different in aging mice that have declining SIRT levels.

 

The graphs also show that the SIRT levels dont recover to the heathy mice level with BL treatment. Why is that? Still not enough NAD+ in the cell? Another rate limiting mechanism? This is one of the reasons I would love to see graphs showing the absolute values of NAD+ instead of the ratio's.

 

But again from this graph, in my opinion, you can only conclude that BL is effective in partially recovering SIRT levels when the body is under cancer treatment attack indicating a neutralizing mechanism for that case.

Attached Files

•  blsirts.JPG   76.16KB   2 downloads

Edited by stefan_001, 31 May 2016 - 05:21 AM.

[stefan_001]

 

In this forum we just try to speak about what can help us live longer isnt ? So I want to speak more about NQO1 and the NAD+/NADH ratio instead of just supplement with NAD+ precursor that was already proven to increase it only a couple hours before it return back to normal according to chromadex. 

 

and where does it say this is not the case for BL? The mice were fed continuously with BL.

[Tom Andre F. (ex shinobi)]

So do we know for sure that Beta Lapachone doesn't downregulate PARP or other NAD+ consuming mechanisms?

 

If Beta Lapachone in no way down regulates anti-aging mechanisms that use NAD+, then this substance seems extremely interesting.

 

PARP is over expressed in aged person.. (if need reference just ask). So what you want is to downregulate it. But importance is the way you do it. Where did you see BL plays against PARP healthy cells please ? Because it seems NQO1 actually regulate it

 

I just found this. Alpha Lipoic Acid has proven to change the NAD+ ratio in mice and increase SIRT 1.

 

α-Lipoic acid regulates lipid metabolism through induction of sirtuin 1 (SIRT1) and activation of AMP-activated protein kinase.

 

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

 

This is logical if ALA played on NQO1, it mediated the NAD+ level and then all the sirtuins. It also control AMPK, ATN, P53 PCGa etc

 

Still since its produced naturally by the body i wouldnt feel confortable to just feed us more ALA. And my feeling is confirmed by some studies: http://www.ncbi.nlm....pubmed/22785389 ALA decrease lifespan in some studies while beta-lapachone increase it over CR

 

 

So do we know for sure that Beta Lapachone doesn't downregulate PARP or other NAD+ consuming mechanisms?

 

If Beta Lapachone in no way down regulates anti-aging mechanisms that use NAD+, then this substance seems extremely interesting.

 

I think there is plenty to find out. This is one the graphs that creates doubts in my mind from the earlier cited papers.You can see that in the cisplatin treated mice BL helps recover SIRT1 and SIRT3. But the impact of BL on healthy mice SIRT levels is more or less zero. So the claim that it acts like the CR mechanism is not supported by that graph at least for the healthy mice.The mice used were only 8 weeks old so perhaps the effect may be different in aging mice that have declining SIRT levels.

 

The graphs also show that the SIRT levels dont recover to the heathy mice level with BL treatment. Why is that? Still not enough NAD+ in the cell? Another rate limiting mechanism? This is one of the reasons I would love to see graphs showing the absolute values of NAD+ instead of the ratio's.

 

But again from this graph, in my opinion, you can only conclude that BL is effective in partially recovering SIRT levels when the body is under cancer treatment attack indicating a neutralizing mechanism for that case.

 

 

Because BL play only on the metabolitic pathway. Healthy mice used as control have already almost full SIRT. Still BL increased slightly compared to control. On mice strong aging or stress unduced treatment only will depleted their sirt. I bet its same for CR, it wouldnt have increased it much here. What we want is healthy level of sirt isnt ? To boost it even more i would combined it with NR and pterostilbene. Again the combination will make the difference. But even for well known direct sirt activator we use vitro study or mice high fat diet

 

As for absolute level of NAD+.. I already gave a link with the graph.. it clearly show an increase in NAD+ + all the calculation explained in all paper even on the one that speak about the ratio.. Please stefan read the reference i send otherwize there is no point to discuss. Thank you

 

And about the long lasting property of NQO1 treatment this is speculation from me and the korean scientist and anti aging firewall I admit

[stefan_001]

Because BL play only on the metabolitic pathway. Healthy mice used as control have already almost full SIRT. Still BL increased slightly compared to control. On mice strong aging or stress unduced treatment only will depleted their sirt. I bet its same for CR, it wouldnt have increased it much here. What we want is healthy level of sirt isnt ? To boost it even more i would combined it with NR and pterostilbene. Again the combination will make the difference. But even for well known direct sirt activator we use vitro study or mice high fat diet

 

 

 

As for absolute level of NAD+.. I already gave a link with the graph.. it clearly show an increase in NAD+ + all the calculation explained in all paper even on the one that speak about the ratio.. Please stefan read the reference i send otherwize there is no point to discuss. Thank you

 

And about the long lasting property of NQO1 treatment this is speculation from me and the korean scientist and anti aging firewall I admit

 

 

Well I cannot find that graph from your links. I thought you wanted a discussion group to dig deeper but it appears you want a "I agree" group. So in that sense I am fine with the "no point to discuss". I am out of this one.

[Tom Andre F. (ex shinobi)]

No Stefan but at least you can avoid to ask several times the same question if its not to read then the answer...  I have to quote myself then I think:

 

Here they found out that NADH increased following cisplatin damage induced on hearing and that NAD+ level was well increased by beta lapachone treatment: http://www.ncbi.nlm....pubmed/24922076

 

Augmentation of NAD(+) by NQO1 attenuates cisplatin-mediated hearing impairment.

 

Cisplatin (cis-diaminedichloroplatinum-II) is an extensively used chemotherapeutic agent, and one of its most adverse effects is ototoxicity. A number of studies have demonstrated that these effects are related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD⁺) has emerged as a key regulator of cellular energy metabolism and homeostasis. Here, we demonstrate for the first time that, in cisplatin-mediated ototoxicity, the levels and activities of SIRT1 are suppressed by the reduction of intracellular NAD⁺ levels. We provide evidence that the decrease in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) transferase (PARP)-1 activation and microRNA-34a through p53 activation aggravates cisplatin-mediated ototoxicity. Moreover, we show that the induction of cellular NAD⁺ levels using β-lapachone (β-Lap), whose intracellular target is NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD⁺ levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity.

 

This full study confirm the fact that the ratio is what is important once again. You can check their graph at the end of the study (external link picture)

 

I believe beta-lapachone is much more potent to control the NAD+ metabolism than NR because NR will remain only for short term.. and this seems to be validated by the chromadex studies that advice a continual use of NR to feed a pool perforated

 

and the graph I mentioned in red:

 

 

 

On the above you can see an impressive 38% increase in NAD+ using 2uM beta-lapachone versus healthy control. Cisplatin damage induce depleted NAD+ and increased NADH. Beta-lapachone even at very low dose rreturn back to normal the NAD+ level even at low dose. I think both from damage point of view and beneficial (CR for instance) you see how the NAD+/NADH play together. CR decrease NADH and increase NAD+ as does beta lapachone while cisplatin damage make the opposite.

 

You can also see PARP was reduced by beta lapachone only to return back to normal after cisplatin injury and didnt change the healthy level of PARP, thats really interesting : http://www.ncbi.nlm....is2014255f3.jpg

 

 

 

 

 

Edited by Tom Andre F. (ex shinobi), 31 May 2016 - 08:11 PM.

[Skyguy2005]

Anyone else wondering whether more tree bark studies might be worth doing, possibly on trees besides Lapacho and Willow? 

 

Both of these are *hot* on the forums atm. There are so many amazing trees out there, who knows whats left to find? I'm just saying. 

Edited by Skyguy2005, 31 May 2016 - 09:10 PM.

[mrkosh1]

Could the high expression of PARP in old people be due to the fact they have more DNA damage that needs to be repaired?

 

Could the negative effects of too much PARP be that it consumes NAD+ and therefore SIRT activity is reduced?

 

I'm thinking that by supplementing enough NR, there could be enough NAD+ for PARP and SIRT processes to continue.

[Tom Andre F. (ex shinobi)]

Could the high expression of PARP in old people be due to the fact they have more DNA damage that needs to be repaired?

 

Could the negative effects of too much PARP be that it consumes NAD+ and therefore SIRT activity is reduced?

 

I'm thinking that by supplementing enough NR, there could be enough NAD+ for PARP and SIRT processes to continue.

 

Yes more DNA damage, more inflammation etc.. But its a loop and NR will not even in theory be enough to calm down the parp. You can also check the study where they fed mice with NR, the lifespan increase was really poor (around 4% only..) but encouraging however. For the reference just check the nicotinamide riboside curated thread please.

 

Its also why Im looking for best combo and this topic is open

[Tom Andre F. (ex shinobi)]

Diabetes. 2016 May 31. pii: db151423.

 

Beta-lapachone prevents diet-induced obesity by increasing energy expenditure and stimulating the browning of white adipose tissue via down-regulation of miR-382 expression.

 

Abstract

There has been great interest in the browning of fat for the treatment of obesity. Although β-lapachone (BLC) has potential therapeutic effects on obesity, the fat browning effect and thermogenic capacity of BLC on obesity have never been demonstrated. Here, we showed that BLC stimulated the browning of white adipose tissue (WAT), increased the expression of brown adipocyte-specific genes (e.g., uncoupling protein 1 [UCP1]), decreased body weight gain, and ameliorated metabolic parameters in high-fat diet-fed mice. Consistently, BLC-treated mice showed significantly higher energy expenditure compared to control mice. In vitro, BLC increased the expression of brown adipocyte-specific genes in stromal vascular fraction-differentiated adipocytes. BLC also controlled the expression of miR-382, which led to the up-regulation of its direct target, Dio2. Up-regulation of miR-382 markedly inhibited the differentiation of adipocytes into beige adipocytes, whereas BLC recovered beige adipocyte differentiation and increased the expression of Dio2 and UCP1. Our findings suggest that the BLC-mediated increase in the browning of WAT and thermogenic capacity of BAT significantly results in increases in energy expenditure. Browning of WAT by BLC was partially controlled via the regulation of miR-382 targeting Dio2 and may lead to the prevention of diet-induced obesity.

 

© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

 

for the record, brown fat is found the most in young girl and we loose it as we age.. Some even proposed it as an explanation for hair loss (balding men miss it in their scalp)

 

http://www.hairgrowt.../brown-fat.html

 

 

 

 

[Tom Andre F. (ex shinobi)]

Hi Everyone,

 

I think I got a good source for pure beta-lapachone. Knowing the dosage on mice and if we take like 4 times less, it would mean around 1g per month per persons.

 

The price would be 250$ per grams without shipping fees. I know its a lot but much less than TA65 crap or the current price for beta lapachone on the market.. I think also no need to use it daily, a transitent use can be ok.

 

So anyone interested in ?

[normalizing]

nah im out of this crap, its ridiculous. good luck wasting money and time on this

[tunt01]

Hi Everyone,

I think I got a good source for pure beta-lapachone. Knowing the dosage on mice and if we take like 4 times less, it would mean around 1g per month per persons.

The price would be 250$ per grams without shipping fees. I know its a lot but much less than TA65 crap or the current price for beta lapachone on the market.. I think also no need to use it daily, a transitent use can be ok.

So anyone interested in ?

I would be interested.

[Tom Andre F. (ex shinobi)]

We have to be at least 10 persons to get it at this price (10g order), so anyone else ?

[Tom Andre F. (ex shinobi)]

stefan and I used to debate about if NAD+/NADH rati owas really a matter. Well I guess this is another study explaining how important is the ratio in aging:

 

Age Related Changes in NAD+ Metabolism Oxidative Stress and Sirt1 Activity in Wistar Rats

 

The cofactor nicotinamide adenine dinucleotide (NAD+) has emerged as a key regulator of metabolism, stress resistance and longevity. Apart from its role as an important redox carrier, NAD+ also serves as the sole substrate for NAD-dependent enzymes, including poly(ADP-ribose) polymerase (PARP), an important DNA nick sensor, and NAD-dependent histone deacetylases, Sirtuins which play an important role in a wide variety of processes, including senescence, apoptosis, differentiation, and aging. We examined the effect of aging on intracellular NAD+ metabolism in the whole heart, lung, liver and kidney of female wistar rats. Our results are the first to show a significant decline in intracellular NAD+ levels and NAD∶NADH ratio in all organs by middle age (i.e.12 months) compared to young (i.e. 3 month old) rats. These changes in [NAD(H)] occurred in parallel with an increase in lipid peroxidation and protein carbonyls (o- and m- tyrosine) formation and decline in total antioxidant capacity in these organs. An age dependent increase in DNA damage (phosphorylated H2AX) was also observed in these same organs. Decreased Sirt1 activity and increased acetylated p53 were observed in organ tissues in parallel with the drop in NAD+ and moderate over-expression of Sirt1 protein. Reduced mitochondrial activity of complex I–IV was also observed in aging animals, impacting both redox status and ATP production. The strong positive correlation observed between DNA damage associated NAD+ depletion and Sirt1 activity suggests that adequate NAD+ concentrations may be an important longevity assurance factor.

 

 

Figure 6 B, : http://journals.plos...l.pone.0019194 you can even see that raw NADH increased while we age. NAD+ (fig A) decreased as the opposite.

 

while NADH increase SIRT1 is turned off as the opposite for NAD+ once again.

 

Having high blood sugar levels results in higher NADH and lower NAD+ : http://diabetes.diab...53/11/2931.full

 

Insulin also decrease the NAD+/NADH ration: http://www.ncbi.nlm....pubmed/11939620

 

Low NAD+ and high NADH also show here to decrease SIRT1: www.ncbi.nlm.nih.gov/pmc/articles/PMC3746174/

 

Calorie restriction induces a decrease in both NADH and nicotinamide concentrations and is associated with increased life span and Sir2 activity (13, 201–203, 286). Despite strong genetic evidence, a subsequent biochemical study questioned whether NADH is in sufficient concentrations in vivo to inhibit sirtuins. This study suggested that the ratio of NAD⁺ to nicotinamide is the primary mechanism of sirtuin regulation (291).

 

So to control our ratio, the only things that modulate it positively is beta-lapachone via NQO1 gene..

[Steve H]

To someone who has studied the PCG-1a pathway (Dephino P53-PCG-1a-Mitochondria Aging Axis 2012/13) it seems fairly obvious that NAD+ is controlled to a greater extent by this mechanism. We know from Dephinos work that less PCG-1a forms a feedback loop with telomere dysfuction and decline of stem cells via this pathway. Less PCG-1a means upregulation of P53 which gradually inhibits stem cells and damages mitochondria, its all explained clearly in Dephinos work. You can see the downstream effects loss of NAD+ has on the PCG-1a pathway here 

 

http://www.ncbi.nlm....pubmed/22588366

 

However BL seems to control PCG-1a upstream via NQ01 and the papers cited plus James P Watson says:   http://www.anti-agin...-interventions/

 

There is strong evidence now that the levels of PGC-1a in cells is regulated primarily by the degradation rate of PGC-1a, and only secondarily by the gene expression of the PGC-1a gene.  There are two degradation pathways for PGC-1a.  The two pathways are the Ubiquitin Proteasome system (UPS) and the ubiquitin-independent proteasome system called 20S PC..

Under conditions of no oxidative stress, the UPS system may regulate PGC-1a levels within the cell.  However when the cell is under cellular stress and the PGC-1a protein is damaged by ROS-induced oxidation, the 20S proteasome controls the degradation rate of PGC-1a. NQO1 is the “gate-keeper” for this 20S PC system that prevents PGC-1a from being degraded during periods of cellular oxidative stress.  Thus with aging, the 20S PC system is more important than the26S proteasome  (i.e. the UPS) and thus the 20S proteasome degrades PGC-1a in the cell, unless NQO1 protects it from degradation.Thus it appears that under conditions of oxidative stress, such as with aging, NQO1 may be a major factor that controls the concentration of PGC-1a in the cell. 

 

 

 

This mechanism and its regulatory system is explained here also:

 

http://www.ncbi.nlm....les/PMC3700121/

 

So if BL induces increased NAD+ and thus increased PCG-1a this has a host of benefits downstream as you can clearly see from Dephinos work. This would also in theory include influencing telomeres due to increased TERT expression as PCG-1a regulates TERT and is probbaly why we see increased lifespan in rats using ALA to modulate PCG-1a (Wayne Alexander 2015).

 

This pathway is fundamentally important and BL seems to be able to influence it far better than NMN and NR and other supplments being tacked onto the back of the Sinclair work which uses direct upregulation of NAD+ as does the work George Church is doing now using CRISPR to target TAMF to upregulate NAD+ directly. If BL can in part induce NAD+ increase (even if far less effective than CRISPR) it should still reduce a range of aging decline accross the system. I personally think that is worth testing and testing now rather than later!

 

 

 

Edited by Steve H, 22 June 2016 - 12:53 PM.

[Tom Andre F. (ex shinobi)]

I couldnt agree more

 

This looks much more safe to avoid nicotinamide metabolite

[Steve H]

I think there is plenty to find out. This is one the graphs that creates doubts in my mind from the earlier cited papers.You can see that in the cisplatin treated mice BL helps recover SIRT1 and SIRT3. But the impact of BL on healthy mice SIRT levels is more or less zero. So the claim that it acts like the CR mechanism is not supported by that graph at least for the healthy mice.The mice used were only 8 weeks old so perhaps the effect may be different in aging mice that have declining SIRT levels.

 

 

This is a reasonable conclusion. Very young mice at 8 weeks are unlikely to benefit from it as they already presumably have optimal levels. We have found this working in Senolytics too, very old mice benefit but very young mice do not because they have not developed the declines associated with aging so there is nothing to treat. I would not be at all surprised to see exactly the same with BL here because again a young mouse does not need repairing. 

 

The graphs also show that the SIRT levels dont recover to the heathy mice level with BL treatment. Why is that? Still not enough NAD+ in the cell? Another rate limiting mechanism? This is one of the reasons I would love to see graphs showing the absolute values of NAD+ instead of the ratio's.

 

 

It may be as simple as not enough induction from the dosage. Bearing in mind the optimal dosage and frequency are yet to be established. So increasing the dose could well increase that NAD+ ratio. This is very easy to investigate and I could design a test group to estalish the dosage rapidly. 

To conclude there is in my view sufficient data to suggest that BL may be able to upregulate the master controller NQ01 and as it is a primary target far upstream worth investigating.