201 replies to this topic

[yz69]

Reversing the methylation patterns does nothing for reversing the accumulated damage. 

 

 

How do you make such conclusion? Do you have any source to support this conclusion?

[Guest]

How do you make such conclusion? Do you have any source to support this conclusion?

 

That's not how science works. You can't prove a negative.

 

But you can prove a positive - i.e. demonstrating, that reversing methylation is reversing your accumulation of damaged mitochondria and breaking up cross-links or lipofuscin (or cardiovascular plaque etc.).

 

 

Those studies, to my knowledge, do not exist (maybe there are some very recent ones).

 

 

To my knowledge there are studies in twins, that show lower mortality over time in association to certain methylation patterns. So there might be an effect on the accumulation of future damage. But to my knowledge there are no studies demonstrating reversal of the damages, that in summary constitute the aging phenotype.

[yz69]

Would improving kidney function (better eGFR) be considered some sort of "reversing damage", according to Fahy's TRIIM paper, the participants saw increased eGFR after trial as well as lowered DNAm age.

[Guest]

I would also suggest to read the Wikipedia article about this topic:

 

https://en.wikipedia...pigenetic_clock

 

....making clear, that it is very much uncertain, what methylation clocks actually mean in terms of interventions for biological age.

 

 

And ask yourself:

 

The human body lacks the enzymes, to break up the lipofuscin, that accumulates in lysosomes. How is reversing methylation patterns going to change that, to make autophagy function again?

 

Plaque are forming in your vascular system, because immune cells can't digest the fatty deposits - forming foam cells instead. How is reversing methylation patterns going to reverse that?

 

Cross-linked proteins/AGE are forming between cells, disturbing normal tissue function. Once established the human body has no effective mechanism to remove them. How is reversing methylation patterns going to change that, if even young people can't do it?

 

etc. 

 

etc.

[yz69]

You are saying some "damages" are hard to reverse. But there are some "damages" can still be reversed, which is not bad, right? At least according to Fayh, Kennedy, they are making some progress.

[TMNMK]

@TMNMK:

 

EVERY Vitamin is useful. The point was, that overdosing on Vitamin A is a problem. The in-vitro studies you are quoting don't change that.

 

Vitamin A is fat-soluble vitamin. It is in circulation much longer than water soluble Vitamins. Rejuvant contains 100% of the RDA for Vitamin A. We have studies in living humans (not mice cells in a dish) demonstrating long term liver damage, if you take about 10 times the RDA of Vitamin A for a prolonged duration. And if you want to have the mice effects you need to take more than the single serving of Rejuvant on their label (the mice consumed up to 30 times the amount, scaled for humans).

 

 

Yes I should have been more clear, I do agree with  your point entirely about that, mine was more from a general sense of one reason that they may be including vit. A in that product generally speaking.

[TMNMK]

 

To my knowledge there are studies in twins, that show lower mortality over time in association to certain methylation patterns. So there might be an effect on the accumulation of future damage. But to my knowledge there are no studies demonstrating reversal of the damages, that in summary constitute the aging phenotype.

 

There are appearing some demonstrations under very specific circumstances that suggest such things may be possible. Will studies such as the following be repeatable and further will they generalize? We won't know for some time yet.

 

These studies remind me of the development of immune checkpoint inhibitors; how quickly that changed the tone of tens of thousands of conversations had between oncologists and their patients. You can see it in their eyes, they smile much more often! A mere 5-10 years ago those conversations were often much darker.

 

https://www.biorxiv....710210.full.pdf

 

 

https://www.biorxiv....426786.full.pdf

 

 

https://www.research...nd_rejuvenation

Edited by TMNMK, 28 February 2021 - 08:38 PM.

[QuestforLife]

And ask yourself:

The human body lacks the enzymes, to break up the lipofuscin, that accumulates in lysosomes. How is reversing methylation patterns going to change that, to make autophagy function again?

Plaque are forming in your vascular system, because immune cells can't digest the fatty deposits - forming foam cells instead. How is reversing methylation patterns going to reverse that?

Cross-linked proteins/AGE are forming between cells, disturbing normal tissue function. Once established the human body has no effective mechanism to remove them. How is reversing methylation patterns going to change that, if even young people can't do it?

etc.

etc.

Thanks but I've already read Aubrey's book.

I remind you that metabolic waste products being the root cause of aging is a theory.

That is not to say we shouldn't investigate such a theory. But let's not dismiss epigenetic changes out of hand.

[TMNMK]

Well as usual people get to talking here and I wind up blowing an entire late Sunday evening. Relevant to some of what was being discussed here, so if you haven't seen it, it is a nice one: https://www.foundmyf...n=steve_horvath

 

Minutes 47+ gets pretty neat!

 

[Guest]

Thanks but I've already read Aubrey's book.

I remind you that metabolic waste products being the root cause of aging is a theory.

That is not to say we shouldn't investigate such a theory. But let's not dismiss epigenetic changes out of hand.

 

You are right, that Aubrey's propositions are a theory - but this does not mean, that they are "theoretical" in a sense, that they are speculative.

 

He is specifically looking at, what specific cellular/tissue changes are causing the aging-associated pathologies and death - and then tracing them back to a number of common root mechanisms. E.g. there is not much to debate about, that aging associated cardiovascular disease (stroke, heart attack, declining blood supply) is caused by ruptured plaque (that is foam cells) and stiffening of arteries (that is cross links).

 

 

Epigenetic changes as measured by methylation clocks (and their reversal) might tie in into some of the damages - e.g. stem cell exhaustion or senescent cells. So there is possibly some room for a role here, I agree. But which methylation changes you need to create, that are reversing those components of the "damage theory of aging" is still an open question and should not be concluded from the broad test that are currently commercially offered.

[QuestforLife]

You are right, that Aubrey's propositions are a theory - but this does not mean, that they are "theoretical" in a sense, that they are speculative.

 

He is specifically looking at, what specific cellular/tissue changes are causing the aging-associated pathologies and death - and then tracing them back to a number of common root mechanisms. E.g. there is not much to debate about, that aging associated cardiovascular disease (stroke, heart attack, declining blood supply) is caused by ruptured plaque (that is foam cells) and stiffening of arteries (that is cross links).

 

 

Epigenetic changes as measured by methylation clocks (and their reversal) might tie in into some of the damages - e.g. stem cell exhaustion or senescent cells. So there is possibly some room for a role here, I agree. But which methylation changes you need to create, that are reversing those components of the "damage theory of aging" is still an open question and should not be concluded from the broad test that are currently commercially offered.

 

I have been a supporter of SENS for many years, with a small direct debit per month contribution. I do think that ultimately we will need to deal with various ingestible metabolic products and that this should be done in tandem with other exciting treatments discussed here and elsewhere. It is not clear to me which treatments will have the greatest benefit, or if as Aubrey claims, nothing will work until everything works.

 

I do think it is a mistake to list various things that change with age and assume they are the cause of aging (whether these are the build up of waste products, or epigenetic changes). We just don't know.

 

SENS was invented 20 years ago. MitoSENS is looking shaky now; WILT never looked promising; extracellular and intracellular aggregates still look a good bet. Nothing about epigenetics was known. It is probably not the place here to discuss this further.

 

I wholeheartedly agree with you on the problems with epigenetic clocks. It seems unlikely that the changes Horvath sees for example, are the cause of aging; if they were we wouldn't find them in so many surviving old people. But some subset of those epigenetic changes probably do play a causal role in some fraction of the deterioration we see with age.  Time and testing will tell.

Edited by QuestforLife, 01 March 2021 - 02:37 PM.

[platypus]

Is AAKG equally good as CaAKG and ohers, and what should be a conservative starting dosage?

[aribadabar]

Is AAKG equally good as CaAKG and ohers, and what should be a conservative starting dosage?

It is close enough. 3g of AAKG fits your requirement.

[Starchild]

New rejuvant user here. 1 tablet/day seems to do the trick for me. I experienced significant improvement in exercise performance. Am encouraged by a forum-member reporting their hair turning darker after ~6 months. Also reports of significant decrease in epigenetic age (outside of company claims). Also encouraging: This compound has anti-cancer effects. IMO, this differentiates it from the likes of NR/NMN, which have some worries regarding encouraging cancer growth.

 

 

Alpha-ketoglutarate (AKG) inhibits proliferation of colon adenocarcinoma cells in normoxic conditions, 2012

 

α-Ketoglutarate attenuates Wnt signaling and drives differentiation in colorectal cancer, 2020

"Using CRC patient-derived organoids and several in vivo CRC tumour models, we show that aKG supplementation suppresses Wnt signaling and promotes cellular differentiation, thereby significantly restricting tumour growth and extending survival. "

 

The multifaceted contribution of α-ketoglutarate to tumor progression: An opportunity to exploit? 2020

"Elevated intracellular levels of αKG impinge on tumor progression.

Increase of αKG levels may represent a possible anti-cancer strategy."

 

α-ketoglutarate dehydrogenase inhibition counteracts breast cancer-associated lung metastasis, 2018

 

[Michael]

First: a new Ca-AKG supplement has become available from a vendor I consider generally reliable that is both cheaper and higher-dose than the Kirkman product that a number of people are using. (I generally consider them reliable because of their fairly long track record and frequent use of quality branded ingredients, such as Niagen back when Chromadex was still offering it as an ingredient to third-party manufacturers and Longvida curcumin; they also make some of the right noises on quality, and are members with a good rating on the BBB. I wish they were clearer about their QC and (preferably) enrolled in an independent quality monitoring system, such as NSF's or USP's GMP certification programs or (lesserly) ConsumerLab), but I do think the above criteria give it some credibility).
 
Second:
 

 

Is AAKG equally good as CaAKG and ohers, and what should be a conservative starting dosage?

 
It is close enough. 3g of AAKG fits your requirement.

 

Aribadabar, you should know that this is incorrect: see my previous post on arginine alpha-ketoglutarate and this followup.

Platypus: please use the search function to look for previous discussions of a topic, to avoid cluttering the Forum with continuous repetitions of the same questions and answers.
 
Also, it seems likely IAC that a much higher dose of calcium alpha-ketoglutarate is required than is contained in 3 g AAKG, even if the arginine wasn't a problem.

Edited by Michael, 23 August 2021 - 07:34 PM.

[aribadabar]

Aribadabar, you should know that this is incorrect: see my previous post on arginine alpha-ketoglutarate . Platypus: please use the search function to look for previous discussions of a topic, to avoid cluttering the Forum with continuous repetitions of the same questions and answers.

 

Also, it seems likely IAC that a much higher dose of calcium alpha-ketoglutarate is required than is contained in 3 g AAKG, even if the arginine wasn't a problem.

 

The question was how much AAKG is needed to achieve ~1g AKG and the answer is about 3g as most AAKG is usually bound 2:1 and given the fact that Arg (174) and AKG (146) have similar molecular weights 3g sounds accurate enough.

Those potential side effects that you mentioned in your previous post are rare, otherwise gym enthusiasts who regularly consume AAKG and in significantly higher amounts would have reported them left, right and center.

 

2g of daily Arg can be easily consumed via regular diet so your caution for such a trivial amount seems overblown.

[APBT]

Alive By Science has a soon to be released LIPO CaAKG product.  I wonder if this may be more bioavailable, thus needing a lower dose, with improved efficacy. 
https://alivebyscien...al-90-x-300-mg/

[Advocatus Diaboli]

Risk assessment for the amino acids taurine, l-glutamine and l-arginine

 

"The OSL risk assessments indicate that based on the available published human clinical trial data, the evidence for the absence of adverse effects is strong for Tau at supplemental intakes up to 3 g/d, Gln at intakes up to 14 g/d and Arg at intakes up to 20 g/d, and these levels are identified as the respective OSLs for normal healthy adults. Although much higher levels of each of these amino acids have been tested without adverse effects and may be safe, the data for intakes above these levels are not sufficient for a confident conclusion of long-term safety, and therefore these values are not selected as the OSLs."

Edited by Advocatus Diaboli, 21 July 2021 - 08:57 PM.

[TMNMK]

First: a new Ca-AKG supplement has become available from a vendor I consider generally reliable that is both cheaper and higher-dose than the Kirkman product that a number of people are using. (I generally consider them reliable because of their fairly long track record and frequent use of quality branded ingredients, such as Niagen back when Chromadex was still offering it as an ingredient to third-party manufacturers and Longvida curcumin; they also make some of the right noises on quality, and are members with a good rating on the BBB. I wish they were clearer about their QC and (preferably) enrolled in an independent quality monitoring system, such as NSF's or USP's GMP certification programs or (lesserly) ConsumerLab), but I do think the above criteria give it some credibility).

 

 

I went ahead and bought some, tasted it, a lot of rice flower in it so I was suspicious because it didn't have the same taste that I'm used to - perhaps very faint. So in the little kitchenette I have here in the hotel room (traveling), opened caps, slurried in water, filtered, flooded with NaOH soln (not measured) which did produce the expected precipitate. So there might be at least some calcium salt of some kind in there.

[smithx]

NB: This was one of the main papers that made me start taking AKG, and it has now bee RETRACTED:

 

https://www.nature.c...#change-history

RETRACTED ARTICLE: Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways

 

 

 

[Michael]

NB: This was one of the main papers that made me start taking AKG, and it has now bee RETRACTED:
 
https://www.nature.c...#change-history
RETRACTED ARTICLE: Alpha-ketoglutarate promotes skeletal muscle hypertrophy and protein synthesis through Akt/mTOR signaling pathways

 
Good find. They say that "concerns were raised that lanes 1 and 2 and lanes 4 and 5 in Figure 3B appear to be duplications of each other. The authors have confirmed that there are problems with the data presented in this Figure and stated that they no longer have the original data files." If this means that the study actually didn't find evidence of mTOR activation by AKG in the first place, it would explain something potentially important. The first report of life-extension by AKG (PMID: 24828042 — in C. elegans, to which one shouldn't really pay attention from a direct translational POV) indicated that the effect was mediated in part by mTOR inhibition. The Kennedy/Lithgow report found (very modest) life extension but "did not detect any decrease in mTORC1 signaling upon three months of CaAKG treatment in different tissues of mice", which was already a bit of a surprise; a report that AKG actually boosted mTOR signaling in mice would have been much harder to reconcile.
 

Risk assessment for the amino acids taurine, l-glutamine and l-arginine
 
"The OSL risk assessments indicate that based on the available published human clinical trial data, the evidence for the absence of adverse effects is strong for Tau at supplemental intakes up to 3 g/d, Gln at intakes up to 14 g/d and Arg at intakes up to 20 g/d, and these levels are identified as the respective OSLs for normal healthy adults. Although much higher levels of each of these amino acids have been tested without adverse effects and may be safe, the data for intakes above these levels are not sufficient for a confident conclusion of long-term safety, and therefore these values are not selected as the OSLs."

 
So first, while one should generally be cautious about ad hominem attacks (and I don't just mean, "Yeah, and yo' mamma"), in this case I think it's reasonable to consider the source. Both the authors are employees of the Council for Responsible Nutrition, a lobbying group for the dietary supplement industry.
 
More importantly: this paper was published in 2008, when only two of the several studies showing dangers of multi-gram doses of arginine or AAKG I highlighted in my earlier post had been published — and the review doesn't cite any of them. Obviously they can't find any evidence of harm if they miss reports of harm and/or the harms are reported after they publish.
 
They're also using an OSL method to look for a threshold of harm, which is far less conservative than a standard NOAEL. But it's the lack of the actual evidence on the subject that makes this review irrelevant.
 

The question was how much AAKG is needed to achieve ~1g AKG and the answer is about 3g as most AAKG is usually bound 2:1 and given the fact that Arg (174) and AKG (146) have similar molecular weights 3g sounds accurate enough.

I will note again that, while that's the dose in Rejuvant, it's far less than is required to scale up from the rodent data, and is also lower than has been used in successful human trials for other indications.
 

Those potential side effects that you mentioned in your previous post are rare, otherwise gym enthusiasts who regularly consume AAKG and in significantly higher amounts would have reported them left, right and center.
 
2g of daily Arg can be easily consumed via regular diet so your caution for such a trivial amount seems overblown.

I agree that you'd expect to see reports of such harm, but it's also true that the reporting system for adverse events with dietary supplements is very poor, and it's harder to pin the question down since people often don't report their supplement use to doctors, supplement users are often taking a lot of things at once, and doctors rarely know much about supplements. Plus, users of AAKG are almost by definition fairly serious recreational or professonal athletes, who are healthier than the general population to begin with.
 
The best data here comes not from the absence of anecdotal reports, but from randomized controlled trials, where such problems are controlled for and where harm has indeed been reported.
 
You can't simply compare supplemental (A)AKG to dietary intakes of arginine: arginine in food is bound to a food matrix that slows its release, and it comes packaged as part of a whole protein, and is thus available for protein synthesis (and at a time when protein synthesis is activated). Taking single amino acids in an isolated salt necessarily has an entirely different pharmacokinetic profile and metabolism.

Edited by Michael, 23 August 2021 - 08:41 PM.

[Advocatus Diaboli]

.

 

Re post #141

 

 

 

So first, while one should generally be cautious about ad hominem attacks (and I don't just mean, "Yeah, and yo' mamma"), in this case I think it's reasonable to consider the source. Both the authors are employees of the Council for Responsible Nutrition, a lobbying group for the dietary supplement industry.

 

 

Rather than the vague innuendo, it probably would be more instructive if you would provide specific, compelling reasons (affiliation isn't a compelling reason) why your non-ad-hominem ad hominem (your poor attempt at apophasis) directly pertains to the study in question. You don't state in what manner your "..in this case I think it's reasonable to consider the source." is intended to reflect, presumably, on either the validity of the study conclusions, or on the integrity of the authors--assuming that it actually was your contention that consideration of the "source" would do so, and do so in what might be considered to be a negative manner.

 

 You have provided no specific information about how the authors' affiliations might suggest that their work isn't to be trusted, if, indeed, it was your intent to seemingly sow such a distrust of their work on an affiliation basis. 

 

I suspect that it is customary for readers of scientific studies to note the affiliations of study authors, and to reflect upon the possibility of various types of bias, data maniplulation, or even fraud that might possibly be present in a study owing to such affiliations. The fact that you have taken the initiative to point out what would seemingly be a normal function performed by study readers ("consider the source"), would tend to suggest, in my opinion, that you, perhaps, have as-yet-undisclosed reasons that you might consider to be pertinent when considering the validity of the study in question. Why otherwise make the effort to point out something which probably would be an obvious consideration routinely performed by readers of scientific studies?

 

[Yosi]

Would it be more beneficial to use a pure AKG supplement such as this (I have no affiliation with that company), instead of CaAKG?

[Michael]

Hi Yosi,
 

Would it be more beneficial to use a pure AKG supplement such as this (I have no affiliation with that company), instead of CaAKG?

 
No, for one scientific reason and one company-specific reason.
 
Science: as I indicated previously, there's no such thing as pure AKG, including this one: it's clearly mislabeled.
 
Second: that inaccurate label is yet another reason (albeit a minor one) why I wouldn't trust the company vending this specific supplement.  I looked into them a few years ago because they were offering something else I was having a hard time finding, and became quite convinced they were untrustworthy. I tracked down their contract manufacturer, ABH Nature's Products, Inc. (doing business as VITA-gen Laboratories LLC), and found a lot of rot. They tried to pass off a "to the best of our knowledge" letter from the NY Chamber of Commerce as a Good Manufacturing Process certification, and had a bunch of fake certifications up on their website:
 
https://web.archive....certifications/
 
Going to the same link today gets a 404 error.
 
An "ABH Pharma," also in NY, which appears to be the same company based on overlapping leadership and key staff, were caught falsely passing themselves off as certified by NSF and QAI:

https://www.nsf.org/...ctions/cea-2017
 https://web.archive....hpharma.com:80/

(See action of July 12, 2017).
 
They got caught by FDA for GMP regulation violations several times:
https://www.fdalabel...tters/ucm375464
https://fdazilla.com...429954-20100820
https://fdazilla.com...429954-20120612

... and see:

https://www.ripoffre...c-md-ja-1335748
 
https://www.ripoffre...arch/abh pharma

Edited by Michael, 04 September 2021 - 03:37 PM.

[Mind]

Hi Yosi,
 

 
No, for one scientific reason and one company-specific reason.
 
Science: as I indicated previously, there's no such thing as pure AKG, including this one: it's clearly mislabeled.
 
Second: that inaccurate label is yet another reason (albeit a minor one) why I wouldn't trust the company vending this specific supplement.  [SNIP!]

 

Thank you very much for this information Michael. We know your time is limited, so we appreciate when you take the time to provide your expertise and experience.

Edited by Michael, 05 September 2021 - 03:44 PM.
Trim quote

[DanCG]

This: Oncotarget. 2017 Jun 13; 8(24): 38184–38192.

 

This: Amino Acids. 2012 Jun;42(6):2491-500. doi: 10.1007/s00726-011-1060-6

They cite Sigma-Aldrich as the source, but they do not give a catalog number. They all describe what they used as “alpha-ketogutarate” and did not mention Ca2+ or any other counter ion.

 

This: is a nematode study. They used Sigma, K1128, which is in powder form and is not a Ca2+ salt or any other salt.

Sigma also cells K75890 and K1750,  and 61234 all of which are non-salt powders. They also sell a sodium salt.  I can’t find Ca-AKG, but it that may just be me. It is hard to believe they don’t sell it.

 

I had found these papers a few months ago as I was researching the very question asked by Yosi. I concluded that the linked product would be ok to use.

 I did not know about the shady history of the source company. Now I will rethink and maybe look for another source.

Anyway, I think it is fair to say that non-salt, non-ester AKG exists and it can produce effects in vivo. 

 

 

Edited by DanCG, 05 September 2021 - 12:44 AM.

[Andey]

It def exists ) CAS 328-50-7

I took a pure AKG, both in capsules and in a powder form (cant disclose the latter, forgot the site where I bought it)

capsules are from here Amazon.com: Seeking Health | Alpha-Ketoglutarate | 350 mg AKG Supplement | Alpha-Ketoglutaric Acid | Precurser to Glutamic Acid | 60 Vegetarian Capsules : Health & Household

Problem is, its super acidic. TBH I think its borderline unsafe to sell it, coz some people dont use much water when swallowing the pills.

 

Edited by Andey, 05 September 2021 - 06:12 AM.

[Yosi]

Hi Yosi,
 

[I would not use this product] for one scientific reason and one company-specific reason.
 
Science: as I indicated previously, there's no such thing as pure AKG, including this one: it's clearly mislabeled.
 
Second: that inaccurate label is yet another reason (albeit a minor one) why I wouldn't trust the company vending this specific supplement.  [SNIP!]

 

Thank you, Michael, for your detailed reply. It is super helpful and very much appreciated!
 

Edited by Michael, 05 September 2021 - 04:03 PM.
Trim quote

[Harkijn]

There were some first adopters to this product. Still using it? I would appreciate to learn about experiences or test results.

FWIW: I take about 2 grams AAKG on gym days. I do not worry about taking arginine because I am well over 60 and need to prioritize the fight against sarcopenia. My  diet is fully vegan so low in methionine.

[Michael]

... This: is a nematode study. They used Sigma, K1128, which is in powder form and is not a Ca2+ salt or any other salt.

Sigma also cells K75890 and K1750,  and 61234 all of which are non-salt powders. They also sell a sodium salt.  I can’t find Ca-AKG, but it that may just be me. It is hard to believe they don’t sell it.

 

I had found these papers a few months ago as I was researching the very question asked by Yosi. I concluded that the linked product would be ok to use.

 I did not know about the shady history of the source company. Now I will rethink and maybe look for another source.

Anyway, I think it is fair to say that non-salt, non-ester AKG exists and it can produce effects in vivo. 

 

This isn't a salt or ester, but it is alpha-ketoglutaric acid — ie, H⁺AKG, or more likely H²⁺AKG (or IAC some such). I'm surprised it exists as a powder, but there are certainly other acids that exist in powders, including some dietary supplements. I see that DW do actually label it as "Alpha-ketoglutaric acid," and not "Alpha-ketoglutarate" or just "AKG," so I withdraw that objection to the labeling. But I still wouldn't buy from this company, for reasons aforesaid.