146 replies to this topic

[to age or not to age]

 

 

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. 

 

I am interested in further mouse testing with BL.  In your opinion, what might be the interaction between beta lapachone and rapamycin?  Both partially overlap CR in terms of gene activation. I have had pure BL synthesized - several of us are thinking of testing it on ourselves.  

 

Edited by to age or not to age, 21 October 2016 - 06:03 PM.

[tunt01]

Did a group buy of beta lapachone ever occur?

[Valijon]

Not that I'm aware of. I think people were just batting the idea around.

[tunt01]

  Lee, J., Park, A., Lee, S., Lee, S., Kim, J., & Yang, S. et al. (2012). Beta-Lapachone, a Modulator of NAD Metabolism, Prevents Health Declines in Aged Mice. Plos ONE, 7(10), e47122. doi:10.1371/journal.pone.0047122

 

This paper's supplementary data caught my eye:

 

 

 

Beta-Lapachone cohort appears to outperform both Calorie Restriction cohort and Control group.

 

 

 

 

Spine synapse is greater in BL than CR.  Mitochondria size (seen as important indicator of metabolic health) is also pretty decent in BL.

 

 

METHODS:

 

- Control was a normal diet (5053PicoLab Rodent Diet20)

- BL group was the same control diet with 0.066% Beta-Lapachone.  Approximately 70-80 mg/kg/day (425 mg per day for human equivalent dosing of a 70 kg male)

- CR was 70% intake of control group diet.

 

Treatment began at 6 months of age.  Now, the control group seemed to have a shorter than typical lifespan, which the authors acknowledge.  Maybe BL just reversed what was a flawed group for whatever reason (environment/handling/genetics).  Lifespan wasn't the main focus of this paper, which is probably why it was a supplementary note.  But it's interesting data nonetheless.

 

 

 

I've still got a stack of papers to go (on NAD/Sirtuins), but Beta-Lapachone seems like the magic bullet for NAD+/NADH.  But maybe this is just another pseudo-CR mimetic that falls short.  I don't know.

 

I've never organized a group buy, but I would think Beta-Lapachone cuts across the two major segments of users here 1. Nootropics and 2. Longevity enhancers.  These charts are a tiny piece of data, but it seems to me like BL does both -- enhance cognitive function and enhance longevity, as having a direct effect on NQ01 enzymatic activity and NAD/NADH.

 

 

Although this specific mitochondria data didn't seem that compelling:

 

βL preserves mitochondria.

(A) Electron microscopy (×15,000 magnification) of skeletal muscle. Scale bar represents 2 µm. (B) Quantification of inter-myofibrillar mitochondria number per 100 µm2 in the skeletal muscles after 10 months treatment (analysis of seven images per mouse, n = 5 per group) © Quantitative RT-PCR of genes related to mitochondrial function (n = 4 mice/group). Data represent mRNA levels relative to cyclophilin A. Data represent the mean ± SEM. *P<0.05 versus control.

 

 

I don't understand how BL could not significantly move SIRT3, PGC-1a or TFAM, when it materially improves NAD/NADH ratio and increases AMPK activity (as follows):

 

βL activates AMPK signalling pathway.

(A) βL increases NAD+/NADH ratio by acute injection. NAD+/NADH ratio was calculated in the tissue of mice intravenously with vehicle (n = 5) or 5 mg/kg βL (n = 5) (B) Effect of βL on phosphorylation of AMPK for EDL (n = 5 per each group). Values represent mean± SEM.

 

 

Edited by prophets, 01 January 2017 - 11:53 PM.

[Tom Andre F. (ex shinobi)]

Hi Prophets,

 

I did a summary mainly about this study here: http://www.beta-lapa...f-healthy-life/

 

what is impressive is the result on mito structure as you can see.

 

Also, the lifespan increase is much better than the CR group.. thats why I believe its a better option than CR mimetics actually

 

for te SIRT3 activation, its because BL seems to just not target this gene, however NAD+ maintain SIRT3 and this is what mater. You can see this sirt3 maintenance also in the kidney beta-lapachone study

 

(for the record, with aging, we loose activity in sirtuins... so what you want is maintain it at youthfull level)

 

For the group buy, as you will see, I tried to organize it there but it seems hard as not much people was interested but Im still in.. because we dont have much choice bout real compounds that can increase lifespan ABOVE CR

[tunt01]

Thx for your notes, but I am still not settled on this SIRT3/pgc-1a issue.  I will have to think on it.

 

$250/g.  I guess that's why the group buy didn't take off?  We should try again.

 

The Cisplatin trials are using 40 mg/kg.  The Korean paper is using 70-80 mg/kg (2x dose).  What do you think is the right dose?  Any idea on half-life?

 

 

 

 

[Tom Andre F. (ex shinobi)]

the sirtuins / pgc1a / NAD+ axis is not an issue to me, its just that when you have enough NAD, these are maintained at the optimal level, its my opinion. Still some things can directly or not activate sirt1

 

I believe the dosage for beta-lapachone can be much lower than what we could get using the HED formula as its the case with resveratrol for instance. Low dose but long term beta-lapachone would be my ticket personally but even... at this price you see how ard it can be. To age or not to age user has also an offer to make for it, but price will always stay at this level unfortunately or we should be 100+ users..

 

 

[docmaas]

 

 

I am interested in further mouse testing with BL.  In your opinion, what might be the interaction between beta lapachone and rapamycin?  Both partially overlap CR in terms of gene activation. I have had pure BL synthesized - several of us are thinking of testing it on ourselves.  

 

 

 

Since you have had it synthesized what kind of cost and dosage are anticipating.  Do you have intellectual property rights to the process?  I'd really like to see this become available preferably at a reasonable price.

 

Mike 

[to age or not to age]

Mike, dosage is a major question - since late september, I have been taking 20mg - 25mg of beta lapachone per day, periodically taking a few days off. We simply tweeze the red crystals into an empty capsule which has been weighed, reweigh it, and wash it down with water.  I have had no side effects that I can discern.  Unfortunately I didn't do a baseline of biomarkers.

As to anything I have noticed: I would characterize how I feel as "a bit more emotionally in touch, and strikingly sharp intellectually" - between thanksgiving there has been a significant amount of drinking etc, and I haven't once had a hangover"- I don't know what that means. Half of our friends have had colds and the flu, including my wife.  I caught nothing and I am 60ish. As to the price of synthesis, the ingredients cost around 200-225 per gram, without paying the chemists, who have told me that the only way to get down the price significantly is to import the major component from china. They purchased the material we used domestically. So, without importing components (and testing them) a gram will cost between 4 and 5 hundred. Plus each batch has to have an NMR done. They are checking into prices of purchasing the primary component from china.  The turn around time to actually produce it is not long, 7-10 days including drying.  

[Nate-2004]

Mike, dosage is a major question - since late september, I have been taking 20mg - 25mg of beta lapachone per day, periodically taking a few days off. We simply tweeze the red crystals into an empty capsule which has been weighed, reweigh it, and wash it down with water.  I have had no side effects that I can discern.  Unfortunately I didn't do a baseline of biomarkers.

As to anything I have noticed: I would characterize how I feel as "a bit more emotionally in touch, and strikingly sharp intellectually" - between thanksgiving there has been a significant amount of drinking etc, and I haven't once had a hangover"- I don't know what that means. Half of our friends have had colds and the flu, including my wife.  I caught nothing and I am 60ish. As to the price of synthesis, the ingredients cost around 200-225 per gram, without paying the chemists, who have told me that the only way to get down the price significantly is to import the major component from china. They purchased the material we used domestically. So, without importing components (and testing them) a gram will cost between 4 and 5 hundred. Plus each batch has to have an NMR done. They are checking into prices of purchasing the primary component from china.  The turn around time to actually produce it is not long, 7-10 days including drying.  

 

Doesn't sound all that worth it from your results.

[tunt01]

 

As to anything I have noticed: I would characterize how I feel as "a bit more emotionally in touch, and strikingly sharp intellectually" - between thanksgiving there has been a significant amount of drinking etc, and I haven't once had a hangover"- I don't know what that means.

 

 

Seems like it is working as intended.  If you are able to physiologically cope with greater amounts of alcohol then I would think it means the NAD/NADH ratio is being reoriented away from a state of excess calories.  Maybe I'm reading too much into it.  But increased mental focus and ability to recover from empty carbs like alcohol, would seem to be a pretty big positive for me.  We'd probably see greater effects in those with a mitochondrial condition, obviously.

[Tom Andre F. (ex shinobi)]

the dosage seems pretty low actually

 

btw a new study about beta-lapachone and increase in NAD+ :

 

Increased Cellular NAD+ Level through NQO1 Enzymatic Action Has Protective Effects on Bleomycin-Induced Lung Fibrosis in Mice.

Abstract

BACKGROUND:

Idiopathic pulmonary fibrosis is a common interstitial lung disease; it is a chronic, progressive, and fatal lung disease of unknown etiology. Over the last two decades, knowledge about the underlying mechanisms of pulmonary fibrosis has improved markedly and facilitated the identification of potential targets for novel therapies. However, despite the large number of antifibrotic drugs being described in experimental pre-clinical studies, the translation of these findings into clinical practices has not been accomplished yet. NADH:quinone oxidoreductase 1 (NQO1) is a homodimeric enzyme that catalyzes the oxidation of NADH to NAD⁺ by various quinones and thereby elevates the intracellular NAD⁺ levels. In this study, we examined the effect of increase in cellular NAD⁺ levels on bleomycin-induced lung fibrosis in mice.

METHODS:

C57BL/6 mice were treated with intratracheal instillation of bleomycin. The mice were orally administered with β-lapachone from 3 days before exposure to bleomycin to 1-3 weeks after exposure to bleomycin. Bronchoalveolar lavage fluid (BALF) was collected for analyzing the infiltration of immune cells. In vitro, A549 cells were treated with transforming growth factor β1 (TGF-β1) and β-lapachone to analyze the extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT).

RESULTS:

β-Lapachone strongly attenuated bleomycin-induced lung inflammation and fibrosis, characterized by histological staining, infiltrated immune cells in BALF, inflammatory cytokines, fibrotic score, and TGF-β1, α-smooth muscle actin accumulation. In addition, β-lapachone showed a protective role in TGF-β1-induced ECM expression and EMT in A549 cells.

CONCLUSION:

Our results suggest that β-lapachone can protect against bleomycin-induced lung inflammation and fibrosis in mice and TGF-β1-induced EMT in vitro, by elevating the NAD⁺/NADH ratio through NQO1 activation.

 

[to age or not to age]

In my thinking about how to dose beta lapachone it has occurred to me that: given BL has a half life of 11 hours, maybe it should be taken every second or third day.  

but at a 50% higher dosage, say 40mg, but every third day. Back of envelope calculations indicate that on the second day, 10 mg would remain

in the body, and on the third day 2 or 3 mg. Do we know about the duration of the redox cycle Jim Watson speaks about in Vince Giuliano's Aging-Firewalls blog? 

[to age or not to age]

One further note: over the past year+ - several of us were brewing and consuming pau d'arco tea. We used oregon's wild harvest.  Subsequently,

the chemists tested the raw bark used and found no evidence of beta lapachone.  The problem with the bark and the tree is that between the many varieties 

and the question of inner and outer bark, confidence in what you are taking is very low.

Edited by to age or not to age, 04 January 2017 - 05:58 PM.

[motorcitykid]

Is there a beta-lapachone group buy coming around the bend anytime soon?

[tunt01]

I would really like a group buy for beta lapachone.  To me, this seems like a better solution than NR.  Although it is not as well understood.

[Tom Andre F. (ex shinobi)]

Same here, if anyone can organize the group buy ?

 

Age or not to age ?

 

I could promote it there too http://www.beta-lapa....com/group-buy/

 

Im interested by it too

 

Btw, one of the point that should be noticed while on beta lapachone (if you take enough of it) is a complete loss of belly fat and more energy (energy expendure) as noted in the lifespan study in mice

[Nate-2004]

That's a pretty bold claim re: the loss of belly fat. 

 

I'm interested regardless.

[Tom Andre F. (ex shinobi)]

That's a pretty bold claim re: the loss of belly fat. 

 

I'm interested regardless.

 

*based on the mice study

 

you can see their weight was very stable and slim (as calorie restriction but with the stability in more). It remained that way for their entire life, and actually when you REALLY play with metabolism its how it has to be

[docmaas]

 

That's a pretty bold claim re: the loss of belly fat. 

 

I'm interested regardless.

 

*based on the mice study

 

you can see their weight was very stable and slim (as calorie restriction but with the stability in more). It remained that way for their entire life, and actually when you REALLY play with metabolism its how it has to be

 

 

Based on the work of Roy Jones at Newcastle University something that reduces visceral fat could be very useful for those with insulin resistance and/or T2 diabetes.  To date the most effective methods appear to be near starvation dieting or bariatric surgery.   Look up Newcastle diet if you want more info.  

 

Can you give a cite for the mouse study?

 

To be or not to be I'd like to see a group buy as well.  I'm still curious as to whether there are patent issues pending BL synthesis.  

[Tom Andre F. (ex shinobi)]

 

 

That's a pretty bold claim re: the loss of belly fat. 

 

I'm interested regardless.

 

*based on the mice study

 

you can see their weight was very stable and slim (as calorie restriction but with the stability in more). It remained that way for their entire life, and actually when you REALLY play with metabolism its how it has to be

 

 

Based on the work of Roy Jones at Newcastle University something that reduces visceral fat could be very useful for those with insulin resistance and/or T2 diabetes.  To date the most effective methods appear to be near starvation dieting or bariatric surgery.   Look up Newcastle diet if you want more info.  

 

Can you give a cite for the mouse study?

 

To be or not to be I'd like to see a group buy as well.  I'm still curious as to whether there are patent issues pending BL synthesis.  

 

 

I made a summary of this study here: http://www.beta-lapa...f-healthy-life/

 

and the original one where you can found the graph of the weigh / life days is here: http://journals.plos...al.pone.0047122

 

 

[to age or not to age]

We will be able to provide beta lapachone for a group buy. Right now, we are able to synthesize pure beta lapachone crystals (bright red in color), each batch NMR tested,

for research purposes. Both myself and Vince Giuliano (Aging Firewalls) are taking BL. Vince has been experimenting with liposome technology with regard to curcumin and

is looking into doing the same for delivery systems of beta lapachone.  At this point only pure beta lapachone is available.  

 

[Nate-2004]

Do you or Vince Giuliano have any details on your experiences and results with BL?

[to age or not to age]

I have been taking BL for 3 months at a 20mg per day dose.  Vince just started ( the same batch). He does extensive blood baseline work and monitors  some of his biomarkers

on a 24 hour basis. My wife its starting and has recently done baseline blood work, so he and she will be helpful in terms of numbers. I take BL along with NR - which I had already been taking for more than as year.  I have known Lenny Guarante and David Sinclair for 10 years,  Lenny did a publicity tour with me for "To Age..." knows my children and my daughter - she is a molecular biology major - but I'm just not sure NR moves the NAD ratio needle or influences NQ01 - BL seems to. So, in my case any comment is anecdotal.  Having said that, I feel very robust, very on top of it intellectually and emotionally. There has been heavy drinking since Thanksgiving but I'm the only one who hasn't been sick with flu or a hangover.

I also take curcumin, resveratrol and D3 so it's a mishmash with regard to what's doing what at this point.

[tintinet]

I'd be in for a group buy.

[DareDevil]

Hi Tom,

 

I first saw your Group Buy in your dedicated webpage. However, I thought that each participant would have to commit to 10 grams ie $2,500. This is what chilled my enthusiasm. I would however be ready to commit to 1 or 2 grams at that pricing.

 

Also, Nate mentioned that its Bioavailability is 15%. This might increase by bypassing the digestive track, and I would volunteer to be the first to test Beta-Lapachone on my lab rat - first transdermally using DMSO as a carrier as many are adverse to needles, secondly by subQ injection since quite a few researchers are used to injecting Peptides, and thirdly by intranasal spray, a method already successfully used for the nootropic injection of insulin.

 

If this gives positive results, it could open to more cost-effective administration of Beta-Lapachone, with several optional intake methods - cost being the primary stumbling block in generating wider interest in this most promising of anti-aging drugs.

 

If Robert still has a test sample, I will be happy to attempt this and report back in this thread or elsewhere as requested. Otherwise please count me in on the next Group Buy whenever it occurs.

 

Cheers,

 

DareDevil

 

[motorcitykid]

Dido on the group buy for me.

[Tom Andre F. (ex shinobi)]

Hi Tom,

 

I first saw your Group Buy in your dedicated webpage. However, I thought that each participant would have to commit to 10 grams ie $2,500. This is what chilled my enthusiasm. I would however be ready to commit to 1 or 2 grams at that pricing.

 

Also, Nate mentioned that its Bioavailability is 15%. This might increase by bypassing the digestive track, and I would volunteer to be the first to test Beta-Lapachone on my lab rat - first transdermally using DMSO as a carrier as many are adverse to needles, secondly by subQ injection since quite a few researchers are used to injecting Peptides, and thirdly by intranasal spray, a method already successfully used for the nootropic injection of insulin.

 

If this gives positive results, it could open to more cost-effective administration of Beta-Lapachone, with several optional intake methods - cost being the primary stumbling block in generating wider interest in this most promising of anti-aging drugs.

 

If Robert still has a test sample, I will be happy to attempt this and report back in this thread or elsewhere as requested. Otherwise please count me in on the next Group Buy whenever it occurs.

 

Cheers,

 

DareDevil

 

Hey DareDevil,

 

I should actually make a topic about: dosage and bioavailability. We have to check if it respect for instance the 5 rules for the sublingual candidate etc

 

For the group buy, you right, 10g should be ok, maybe i can organize it by email ? I never did it, but.. i have access to the price I gave : 250$ / g if we order 10g

 

To age or not to age can also offer it at lower cost maybe ?

 

[stefan_001]

it may be worthwhile to read this paper and evaluate the comment:

http://www.sciencedi...006291X1632126X

However, at pharmacologic concentrations of β-lap both quinone-based substrates directly oxidized the redox probe, a possible sign of off-target reactivity with cellular thiols.

[DareDevil]

Hi Stefan,

 

That study seems to infer that:

 

Deoxynyboquinone is more effective than Beta-Lapachone at targeting cancer cells.

 

However, is "off-target reactivity with cellular thiols" otherwise a negative?

 

Thanks for explaining your source article to laymen.

DareDevil