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J-147 and Fisetin for Treatment Resistant Depression and Aging in General

j-147 j147 fisetin aging depression energy fatigue bipolar antiaging sports

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#1 The Capybara

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Posted 17 May 2019 - 12:53 AM


I don't even know how to begin this thread without it sounding like just more premature hype over a fairly new compound.

 

Since I was 13 years old, I've had treatment-resistant major depression. I've tried every single class of antidepressant currently out there - without exception, various flavors of psychotherapy. and a hefty amount of treatments that sounded plausibly applicable to depression, going as far as having investigational compounds synthesized both domestically and overseas. Very few of these worked at all. Some maybe helped a bit, and two worked noticeably (selegiline and tianeptine), albeit temporarily.

I'm now in my 50s. When did that happen?

 

Enough background - you get the idea.

 

I was reading up on J-147 one day and decided to have some synthesized. It's essentially a synthetic analog of curcumin that is stable upon ingestion, something that is sorely needed since curcumin is amazing in animal studies where it's overwhelmingly administered by injection. Curcumin taken orally doesn't fare too well since it is broken down readily in several biochemical pathways and apparently when entering the duodenum with the subsequent pH change that occurs, little is absorbed intact. It appears that when the molecule was designed there was an unanticipated effect. The molecule seemed to have an affinity for the mitochondria and increased ATP production via ATP synthase. ATP is your primary energy source and precipitously declines in aging.

 

I'd highly recommend going over to PubMed and reading journal abstracts on the topic and then, should the full article not be available for free, making your way over to SciHub to read the full text. if you get nothing else from this post, you should keep those links.

When the compound was delivered, I began to try and figure out the appropriate human dose based on the dosage used in mice. I escalated the dosage of the powder every two days beginning at 10mg taken upon awakening and making my way up to 40mg where I began to wake up without a hint of depression. Truly no depression at all. That's not to say I couldn't push my luck and end up with an acute depression. But this is rare, of much less magnitude, and shorter in duration.

 

Long term use could be considered nootropic, and an increase in memory recall is absolutely there, though not for all things. I'm going to skip over this topic since I don't have solid data on this. You can read up on the animal studies. They too experienced improved memory, and in a very rare occurrence, the animal data seemed to largely apply to what self-experimenters are experiencing.

 

Side effects?

 

Nothing major has so far been observed long term. Short term it seems that a minority of people experience a fairly quick onset of sleepiness and a feeling of being cold near the middle of their day, which is relieved by taking a nap. This seems to be due to taking too high a dose, too soon after initially taking this compound. Backing off on the dose by only 5 or 10mg for only a couple of days seems to get around this issue. There can also be a feeling of too much energy at the start. Not a caffeine or amphetamine type of energy, but more a natural energy. I enjoyed this phase since I was able to think about doing something such as bike riding, and then do it without any hesitancy or having to convince myself to get started. Motivating myself was effortless. This largely dissipated after a few weeks, and while I enjoyed this feeling, other may not, and so I'm listing this as a potential side effect. One bipolar friend did cut his dose to 20mg daily, and is comfortable at that level long term. The other noted side effect in some, was a raise in blood pressure. This tended to occur in those that already had high blood pressure, and appears to just require an anti-hypertensive medication readjustment.

 

I personally experienced some weight loss over the year I've been taking this compound. I lost approximately 15 lbs. For some this may be a good thing, but I'm thin to begin with and had to consciously increase my caloric intake a bit to maintain my weight. This makes sense, in light of the effect this compound seems to have on the mitochondria and likely one's metabolic rate.

 

Personally, I don't considering these potential side effects as being major, or even close to the side effects of standard medications. There was no feeling of some drug altering my perception. No sedation. No blunted moods. I felt alive and would happily greet the day. Best of all, it felt like it was all me.

 

So if you have long standing depression, now, as I did then, you're likely skeptical...and you should be. Most posts made here on Longecity are probably dominated by the placebo effect, or the person is self reporting during the "romance phase" of a new drug treatment in which everything is just right. The full spectrum of side effects hasn't yet kicked in; the medication hasn't yet fizzled out as the body adjusts back to its depressive set point.

 

I don't want to be that guy. Good intentions, but a bit premature in one's observations and conclusions.

 

When I wrote about obtaining the J-147 and figuring out the ideal dosage (just above), that was nearly a year ago. The antidepressant effects have not worn off at all. Not one iota. Additionally, more very diverse benefits keep appearing. The one, perhaps more amazing than the antidepressant effects, was my newly acquired athletic abilities. I was never athletic, and I still don't appear to be anything but a thin guy, but I can now keep up with most 30 year olds for sure and a good percentage of 20 year olds when playing field games. It's crazy, and it's awesome.

 

I wondered if the compound was fundamentally resetting something in my body and so I stopped taking the stuff to see what was due to the compound, and what was due to physical changes that would remain after stopping it. Within about four days, all the effects described so far disappeared. It took four days after starting the J-147 for the positive effects to show up, and the same four days for them to disappear after stopping it. A bit of a bummer, but still pretty amazing.

 

Hopefully you're skeptical enough to be thinking to yourself; "Sounds great, but you're only one data point. Odds are that this won't pan out the same way for me. n=1? Pffft!"

 

There is most certainly that chance. However, similar to the fact that I'm approaching a year on J-147, there's another detail I've held back. So far approximately 20-30 people have been trying this around my area. The response rate is somewhere around 75%. To be clear, people are taking it for many reasons. There are a few in their 80s that are taking it for "normal aging" a lack of energy and not feeling engaged in life; a few with autoimmune disease, and several with major depression, both unipolar and bipolar. Other conditions that seem to respond are some flavors of neuropathy in the legs and feet, as well as lethargy, post treatment, due to chemotherapy for cancer. The bipolar people have all remained on their standard meds while taking the J-147 since they (probably wisely) didn't want to risk a manic phase. Though all of them still never really experienced full relief of their depression through standard treatments. I'm not telling you to take on your own treatment regimen, I'm just passing on the facts as well as my personal observations. All the information in this post should be taken as such. Let me also reemphasize the very limited number of people experimenting with J-147, and the even fewer that I have access to.

 

So how does fisetin play into this?

 

Fisetin is a plant flavonoid (7-hydroxyflavonol) that differs from quercetin by possessing one less hydroxyl group. It is thought to be a senololytic compound on its own. There is even a clinical trial currently looking at one aspect of its potential senolytic activity (see trial description here).

 

I had a kilogram of the powder on hand and took the somewhat large dosages described in the clinical trial orally, with pretty much nothing noticeable to report. Subjectively it was pretty disappointing. However, since I had so much of the stuff around, I poured a little into my hand whenever I thought about it, generally when I awoke and before going to bed. I'd estimate the powder weight to be about 200mg taken twice each day.

 

While I had always been really disappointed by taking plant flavanoids in the past, so much so that I never really gave them any thought no matter what claims were made for them in animal studies, this one was different.

 

Over a period of maybe two weeks, I began to change from a late night person with pretty poor sleep quality, to a person that would get tired each evening at 9:30 like clockwork. I'd wake up from an awesome night of sleep at 6:30 am. Normally I would go to sleep at about 3 am and wake at 11am, with mediocre sleep quality at best. When I began waking at 6:30 in the morning, it was such a drastic change that cognitively I felt uneasy, even if my body felt rested, and I'd try and go back to sleep without success. This early morning waking did back off a bit with continuing use, but not entirely. The amazing sleep has remained.

 

While I think that fisetin most certainly deserves its own thread, I believe that this fisetin report should be integrated into the J-147 report since I can't say that the observations attributed to fisetin aren't due to my having taken both compounds together. Both substances have complex metabolic pathways, but J-147 seems to be a bigger player in the AMPK pathways, while fisetin seems to be more of a PI3-K/Akt/mTOR compound (though there is most certainly overlap). One would think they'd complement each another, but you never know.

 

Last thing, in an effort to offer full disclosure. I do have problems when taking J-147 with either berberine or metformin. Others have not had this issue. Even a day after taking berberine, I simply feel bad when taking J-147. There is nothing I can pinpoint as a cause. Both metformin and berberine significantly act through AMPK, but other compounds that do so have had no interaction. This is a data point of one. It may just be me.

 

I order my J-147 from aas19@aasraw.com. That's not a plug, just a legitimate supplier that I've been using. Think of this as the “Materials and Methods” section. They ship quickly and have much lower pricing than any domestic suppliers. All I can say is that if you're going to try this self-experimentation, do make sure that you have a legitimate source. No point is trying and dismissing the compound after using something suspect. The powder should be tasteless, and it won't dissolve in your mouth.

 

 

 

 


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#2 The Capybara

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Posted 18 May 2019 - 08:06 PM

I do want to add one more significant effect of fisetin that seems unreported in the literature, but is reported by many users described above. At the ballpark dose of 200mg twice a day, it seems to act as a potent antidiuretic, though this term seems a little inaccurate. It doesn't seem to act as a vasopressin analog in which water toxicity is always a concern, but rather it seems to increase the concentration of the urine produced. In middle aged men, this can potentially allow for a better night's sleep. If this is indeed due to better kidney function, it could prove beneficial for everyone.

There are journal reports mentioning fisetin's positive effects on kidney function.

For example see this article, though it's not primarily addressing fisetin and kidney function as its main topic.


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#3 The Capybara

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Posted 19 May 2019 - 02:40 AM

 

Attached File  j147mice.jpg   99.48KB   0 downloads

Bottom: A mouse from a strain bred to age rapidly, treated with the potential Alzheimer’s drug j147, scores better on cognitive tests and presents a younger metabolic profile than untreated mice.

Top: Mouse from the same strain, untreated, shows a more ruffled coat, and more metabolic signs of aging than the treated mouse.

/ Salk Institute

 


Edited by The Capybara, 19 May 2019 - 02:45 AM.

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#4 Daniel Cooper

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Posted 20 May 2019 - 06:30 PM

Have you has any analytical testing of your J-147 done? I'm just very leary of Chinese suppliers without testing their product.

And if you don't mind me asking, what did you pay for it?
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#5 Immutabledestiny

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Posted 21 May 2019 - 12:41 AM

Have you has any analytical testing of your J-147 done? I'm just very leary of Chinese suppliers without testing their product.

And if you don't mind me asking, what did you pay for it?

I’m also interested in answers to the above questions. The site you linked has a lot of grammatical errors in the about us section and in general the description of their credentials on that part of the site sounds a bit gimmicky to say the least.

That said your positive experience with the substance along with all the other individuals that have benefited sounds quite promising. Your review is really comprehensive and I appreciate you adding all of that information. I mean the fact that you’ve suffered from treatment resistant depression since 13 and have tried so many meds for it before finding relief in j147 really says a lot in my opinion. Not to mention the myriad of other positive effects. I read somewhere it interferes with the CREBS cycle and may be implicated in the development of cancer so maybe it’s not totally without any downsides.


There’s some interesting information on this site about it and mechanisms. The author claims you could make a better alternative to it called T-006 out of turmeric and chocolate but I’m skeptical as I have been unable to find any information on it other than his site.

https://mybiohack.co...itochondria-buy

#6 The Capybara

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Posted 21 May 2019 - 07:08 PM

Some interesting points brought up....

 

I too tried to find any sort of factual logic for the "T-006" tumeric and chocolate claims.

I couldn't find anything in the literature, nor even within online discussion groups.

It seems to be totally unfounded and may be some sort of self-promotion. I don't know.

I did try it, and felt no more than if I had just taken some tumeric/curcumin, which for me was nothing.

J-147 is totally different.

 

J-147 does indeed modulate aspects of the Krebs (citric acid) cycle, though I wouldn't call it interference. The increase in ATP production by J-147, via ATP synthase, is most certainly coupled to the Krebs cycle in a beneficial way. Nothing I would suspect of inducing cancer.

 

This supplier's J-147 was third party tested, but back before I began taking it. I have not tested it in the last year.

I'm not trying to push this vendor on anyone, and certainly can't speak about their spelling errors on their site. I can tell you that they are my supplier for the last year, and about a year ago their product tested in the high nineties in percent purity. The same company has been sending me the same subjective quality product ever since, which has been producing the same consistent effects.

 

My cost varied depending on how much I'd buy. Even for small amounts, it was pretty reasonable per dose. You'd just need to contact them for pricing. That's not really the reason for this post.


Edited by The Capybara, 21 May 2019 - 07:28 PM.

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#7 MentholFlavoring

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Posted 29 May 2019 - 04:03 PM

Thank you @The Capybara for this, to say the least, comprehensive review on J-147 and Fisetin! This is highly valuable information for the community. I'm happy that you enclosed information about people trying this substance in your area, as there has been a lack of anecdotal reports. Seeing a response rate of around 75% confirms the effectiveness of this compound.

 

Some science papers note T-006, and here it is. It seems to be an even more potent version of J-147. The chocolate variant is of course nowhere near as potent as the real substance

 

jGVAnn8.png

 

To augment the therapeutic effect of TMP and discover novel multi-functional molecule for the treatment of neurodegenerative disease, in the current work, we designed and synthesized a new TMP derivative, termed T-006 (Fig. 2), in which the methoxyphenyl group of J147 was replaced with TMP. The methoxyphenyl group has no bioactivities, while TMP has diverse pharmacological functions.

 

Source: https://www.research...amethylpyrazine

 


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#8 The Capybara

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Posted 30 May 2019 - 08:54 PM

Thanks Menthol for posting the link to the T-006 article, and for the gracious thumbs up on my post.

I did retrieve the entire article on SciHub. It's sitting behind a large paywall on the publisher's site.

I don't know how the website advocating for T-006 came up with the idea that eating chocolate and curcumin together would yield T-006 in one's body (see: https://mybiohack.co...ochondria-buy).

Although J-147 and T-006 only appear to really differ by the add on molecule used to stabilize the curcumin, cyclohexyl-bisphenol and tetramethylpyrazine respectively, these are not likely trivial differences.

It is thought that the cyclohexyl-bisphenol is somehow the cause of the increased production of ATP, and thus the increased energy and athletic abilities seen in many taking this compound.This increase in ATP may very well play into the antidepressant effects. That's speculation but certainly a possibility. There's no mention of this phenomenon in the T-006 paper.

I'm certainly not married to J-147, though to me it's currently the most effective compound for so many very diverse issues, and if something profoundly more effective shows up at some point, I'll likely jump on that bandwagon. J-147 also has a lot of animal data behind it, and comes from the respected Salk Institute.

Thanks again Menthol for the input!


Edited by The Capybara, 30 May 2019 - 08:57 PM.

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#9 Turnbuckle

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Posted 01 June 2019 - 02:45 PM

Have you tried liposomal cucurmin?

 

After 48 h incubation, nanoliposomal CUR [cucurmin] resulted in death of 70%–80% cells while free CUR needed 10-fold higher doses to reach similar inhibition. Thus, the trial showed that nanoliposomes improved the bioavailability of CUR.

https://www.ncbi.nlm...b34-ijn-12-6027

 

 

 


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#10 The Capybara

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Posted 02 June 2019 - 04:40 AM

I have not tried this.

There is no clinical data on the liposomal curcumin that I could find. No long term animal studies.

Not saying it won't work.

The other important issue is that liposomal curcumin shouldn't up-regulate ATP synthesis as J147 does, since this seems to be attributable to the molecular modification made to stabilize this compound.

The other, much larger issue for me personally, is why would I change something that works?

Look how many people reporting "amazing" compounds on Longecity, only to end up stopping the compound they just touted fairly quickly.

This is far more the rule than the exception.

Look how many papers on amazing advances go nowhere post publication.

Again, this is more the rule than the exception.



#11 Turnbuckle

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Posted 02 June 2019 - 09:31 AM

Despite thousands of in vivo studies demonstrating the therapeutic efficacy of curcumin, even at very low doses, limited systemic bioavailability has hindered its development as a potential therapeutic agent. ...

 

...nanoparticle curcumin has been widely tested in preclinical models for non-cancer diseases including Alzheimer, hepatitis, cerebral ischemia, asthma, and heart failure.42–45 The success of these preclinical studies has built high hopes for many of the currently on-going clinical trials...

 

An in vitro study demonstrated that dimyristoyl phosphatidylcholine (DMPC)-based liposomal formulated curcumin only required one-tenth of the parent curcumin dose to exert equivalent proliferation inhibition in prostate cancer cell lines.46 Similarly, curcumin formulated in dimyristoyl-sn-glycero-3-phosphocholine showed significant suppression of pancreatic tumor growth in a xenograft model.47 In addition, a recent study demonstrated that liposomal curcumin coated with a thin layer of synthesized chitosan derivative released curcumin in a sustained manner, while exerting selective cytotoxicity to melanoma cells.48 Although liposomal curcumin is a promising delivery system to increase bioavailability of curcumin, there is still substantial room to optimize its formulation to enhance bioavailability as well as stability...

 

https://www.ncbi.nlm...les/PMC6424351/

 

 



#12 The Capybara

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Posted 06 June 2019 - 11:14 PM

Since originally posting this report, I've revisited several people taking J-147 and checked in with them.

These are all people that had responded favorably from the start (as described in the original post above).

It seems that some of them, not all, have become more sensitive to the compound over time and have had to reduce their dose.

Typically people would begin to feel some anxiety on their typical dose. It could very well be an increase in their metabolic rate.

You also see this in hyperthyroidism, with a corresponding increase in metabolic rate and sympathetic activity.

Symptoms were alleviated with the beta blocker propranolol in one person (40mg tid), further evidence of increased sympathetic activity.

This issue resolved when the dose was lowered, though the compound seems to remain just as efficacious.

Some lowered their dose to the 20mg range, which is substantial, but maybe not unexpected since it was mentioned in the first post that one person found the compound effective at this dose. This increased sensitivity to J-147 doesn't seem to correlate with age or health, but you'd almost certainly need a lot more people experiencing this effect in order to notice any meaningful correlation.

 



#13 Peatson

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Posted 13 June 2019 - 07:25 PM

Wondering what anyone thinks of these comments about Curcumin? 

 

https://blogs.scienc...waste-your-time


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#14 tunt01

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Posted 16 June 2019 - 02:20 PM

Wondering what anyone thinks of these comments about Curcumin? 

 

https://blogs.scienc...waste-your-time

 

There is a comment below comparing Resveratrol to Curcumin, and that was also my first thought.  Curcumin is a dirty compound acting all over the place and there just isn't enough data to fully understand what is going on, especially when compared to nanoparticles or liposomal delivery methods.

 

All told, the 2018 Goldberg/Shubert paper on J147 is pretty interesting, given that it demonstrates it's acting directly upon ATP synthase and AMPK/mTOR.  The principle of improving fatty acid oxidation reducing acylcarnitines, shutting down ACC, just points to simulating improving the metabolic profile.  It'd be nice to have data in normal mice and not just SAMP8, as a cover for a successful drug candidate. 

 

I'd also love to know is more about the decision for the lab to formulate CAD-031 and why they moved to that over J147.  The 2017 paper they put out on the metabalomics is pretty interesting.


Edited by tunt01, 16 June 2019 - 06:27 PM.

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#15 Peatson

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Posted 17 June 2019 - 08:06 AM

There is a comment below comparing Resveratrol to Curcumin, and that was also my first thought.  Curcumin is a dirty compound acting all over the place and there just isn't enough data to fully understand what is going on, especially when compared to nanoparticles or liposomal delivery methods.

 

All told, the 2018 Goldberg/Shubert paper on J147 is pretty interesting, given that it demonstrates it's acting directly upon ATP synthase and AMPK/mTOR.  The principle of improving fatty acid oxidation reducing acylcarnitines, shutting down ACC, just points to simulating improving the metabolic profile.  It'd be nice to have data in normal mice and not just SAMP8, as a cover for a successful drug candidate. 

 

I'd also love to know is more about the decision for the lab to formulate CAD-031 and why they moved to that over J147.  The 2017 paper they put out on the metabalomics is pretty interesting.

 

Thanks tunt01, are you thinking about purchasing some J147 then? Also, just wondering where you think would be the best place to obtain it. 

 

I know you can get 10mg from - https://www.tocris.c...product-details or as OP states from that email address. However AASRAW appear very fishy and have some negative reviews where many people are calling them a scam. 


Edited by Peatson, 17 June 2019 - 08:11 AM.


#16 The Capybara

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Posted 22 June 2019 - 09:30 PM

Tunt01 wrote "I'd also love to know more about the decision for the lab to formulate CAD-031 and why they moved to that over J147."

 

In answer to that question, I have this:

"CAD31 is a derivative of J147 that has many of the same neuroprotective properties and also stimulates nerve stem cell division"

 

It's the additional observation of neurogenesis in rodents and tissue culture that sets CAD-031 apart from J-147.

I can also find no mention of ATP-synthase interactions with CAD-031, which is in stark contrast to J-147.

Both synthetic compounds seem to hit the same biological pathways as curcumin, including anti-inflammatory pathways, and both are stable when taken orally - unlike curcumin.

 

It appears that they haven't tossed out J-147, but rather added CAD-031 to their list of curcumin analogs. Remember that J-147 is currently in phase 1 clinical trials at the time of this posting, so that one appears to be moving forward.

 

I will have some CAD-147 synthesized and update this thread as I know more.

 

 



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#17 The Capybara

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Posted 23 June 2019 - 09:00 AM

Oops!

That last line just above should read:

I will have some CAD-031 synthesized and update this thread as I know more.

 

 







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