Calcium Alpha-Ketoglutarate Supplementation Reduces Epigenetic Age in Humans

The company Ponce De Leon Health claims that a recent pilot study of calcium alpha-ketoglutarate supplementation results in an average reduction of 8.5 years of epigenetic age via the DNA methylation test offered by TrueMe Labs. This being the supplement industry, expect to have to wade through a lot of dubious and excessive marketing to find any solid information about what actually happened here. The best pace to start is with the 2019 paper on the effects of calcium alpha-ketoglutarate in mice, which is a reputable study authored by reputable researchers. Delivered late in life, this intervention reduced frailty to a meaningful degree, but with only a modest effect on life span. It did not reduce senescent cell burden, but did reduce inflammatory signaling - and chronic inflammation is an important aspect of degenerative aging.

The important point to consider here is that the TrueMe Labs assay is not a relabeling of any of the more established epigenetic clocks, those with significant research associated with their behavior. It is is its own beast, an independently developed test. It uses only 13 DNA methylation sites, and so it is very possible that it is much more sensitive to some interventions than others, in comparison to, say, the original Horvath clock, depending on which mechanisms influence those sites. Thus one cannot take any of the established research into the better studied clocks and use it to inform expectations as to how the TrueMe Labs assay will behave. 8.5 years might sound like a large effect size, but it is impossible to say whether or not that is the case.

That is the challenge with all epigenetic clocks, frankly. None are yet strongly connected to underlying mechanisms of aging; it is hard to say what any specific change or outcome actually represents in terms of metabolic processes. The assays will produce a number, but that number cannot be compared between clocks, and it cannot be compared between interventions. It cannot even be used to say how good any specific intervention might be, without a great deal of further calibration for that specific intervention. Not that one would learn that by reading the Ponce De Leon Health marketing materials. A cynic might suggest that they shopped for the clock that would produce the most sizable outcome for their intervention. Whether or not that is the case here, I'm sure that this strategy will become prevalent.

Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice

Metabolism and aging are tightly connected and specific perturbations of nutrient-sensing pathways can enhance longevity in laboratory animals. Here we show that alpha-ketoglutarate (delivered in the form of a Calcium salt, CaAKG), a key metabolite in tricarboxylic (TCA) cycle that is reported to extend lifespan in worms, can significantly extend lifespan and healthspan in mice. AKG is involved in various fundamental processes including collagen synthesis and epigenetic changes.

Due to its broad roles in multiple biological processes, AKG has been a subject of interest for researchers in various fields. AKG also influences several age-related processes, including stem cell proliferation and osteoporosis. To determine its role in mammalian aging, we administered CaAKG in 18 months old mice and determined its effect on the onset of frailty and survival, discovering that the metabolite promotes longer, healthier life associated with a decrease in levels of inflammatory factors. Interestingly the reduction in frailty was more dramatic than the increase in lifespan, leading us to propose that CaAKG compresses morbidity.

Pilot Study Results Suggest Epigenetic Age Reversal

Ponce de Leon Health initially worked with Dr. Brian Kennedy, who was, at the time, based at the Buck Institute for Research on Aging, searching for compounds that were generally recognized as safe (GRAS) but that had the potential to influence aging in mammals. The company screened over 300 GRAS compounds and identified compounds that could modulate a number of pathways that are linked to aging. Dr. Kennedy subsequently joined Ponce de Leon Health as its Chief Scientific Officer, and the company has been busy testing and preparing to translate these findings to people. Its strategy has been to test its products on mammalian models that closely emulate human aging in order to give the best chance of translating beneficial results to us.

For consumer testing the company gave participants Rejuvant and measured their epigenetic ages using DNA methylation testing. This supplement contains a proprietary form of calcium alpha-ketoglutarate, which the FDA considers to be GRAS. The company believes that Rejuvant works by slowing down the rate of age-related DNA methylation and reducing the inflammation caused by senescent cells, two proposed reasons why we age.

Comments

Coincidentally, I stumbled on their site a couple of days ago, I wondered why they were so under the radar. Now I see that's changing.

Posted by: Allen at July 6th, 2020 4:18 PM

"A cynic might suggest that they shopped for the clock that would produce the most sizable outcome for their intervention. Whether or not that is the case here, I'm sure that this strategy will become prevalent."
Spot on.
Let alone the fact that 8.5 years of rejuvenation should be visible to the naked eye. Since phenotype reflects the going ons in a myriad of systems, zero change in the way someone looks - be it wrinkles or muscle mass - is likely to mean negligible effect on lifespan.

Posted by: Barbara T. at July 6th, 2020 6:27 PM

Looks like Brian Kennedy has sold out and joined the supplements industry.

Posted by: jimofoz at July 7th, 2020 4:00 AM

I were sceptical when I read that Calcium Alpha-Ketoglutarate were used in the body builder industry which are known for using compounds that accelerates aging like proteins with high methionine amount and Human Growth Hormone (HGH), which can cause cancer.

Posted by: thomas.a at July 7th, 2020 5:32 AM

Assuming some modest benefit with Rejuvant, wondering what the effect would be If combined with nicotinamide riboside.

Posted by: yanik at July 7th, 2020 5:16 PM

Hi there! Just a 2 cents.

Alpha-Ketoglutarate is good supplement, that is like/mimics..the other CR mimicsm and thus is basically a CR mimic. It works in the same method as CR, fasting and ketogenic diet, it is an antioxidant and also a substrate in the OXPHOS (oxidative phosphorylation) cycle of mitochondria to produce ATP. But not much more than that, it is not cure. It will modestly slow aging by improving autophagy burden (less), so autophagy acn do a better job of mopping the giant senescent mitos, oxidized DNA and other residues. Also, it probably affects metabolism just like CR does. CR is capable of giving 5-15 years of healthspan in human (roughly), while in mouse it is up 30-50% lifespan extension; thus, in humans it's about 10-15% or less. Not much more, 20% is probably pushing it. I highly doubt CR in humans can give 40-50 years extra.
10 years sounds about right. And about you get with Alpha-Ketoglutarate, but less so; CR is Always stronger than Any of these supplements; it has been compared to Everything under the sun; and time/time again, it still stronger in 'total (systemic) effect'; because it hits So many points (DNA damage, autophagy, oxidation, glucose levels, metabolism slowing, etc.. etc...so it is Wide...) some of the supplements don't have as much 'far-reaching/wide' effect inbody. It's tested and does have an effect. Alpha-Ketoglutarate turns on the switch for ketotic pathway (just like body ketones and ingesting ketones (from raspberries for example/raspeberry ketones), they make you lose weight and control blood glucose; none of that is really profoudn slowed aging, but yes it ends up as so becaus you gain a bit of healthspan (in the long run). Probably, the epigenetic clock is also delayed/lowers a bit after A-KG. Same as CR, it reduced most clocks and why animals live longer; but for humans it's not enough; with age, the ROS signal overcomes that and supplants any tactic. In the end, your telomeres still drop and there is net negative loss; and then, around late age, there are moer more pulses ROS, too much.
Around 8th decade mega ROS pulse, It rises up in Logarhitmic ROS elevation (DCF signal).
Many studies don'T study what happens 'later' in 8-9-10th decade and it'S why we can't solve the problem of aging; thankfull some studies studied elders..but if we can't slow/reverse their age, then no we acn't stop aging. Epiclock crucial, but now I am believer - full pin - telomeres are the biggest crucial element (not Mitos, and they sure matter for are ROS source), but telomeres/chromsomes (DNA) that is, are the ultimate decider of longevity (Maximal not just healthspan). DNA loss means heayflick one day and cell senesce. But in Every cell of your body, and then one essential organ or several, 'too old to function' just fail(s), that's teh end.

Just a 2 cents.

PS: It's why it'S crucial that our telomeres stay in top size/top shape; short size/bad shape = end.
If a clam has Telomere Elongation during 150 years (yes it Rises with its age/due to processive telomerase)...and lives up to 500; and a California Tree lives 5000 years and has cyclick telomerase bouts Too...and we have Continuous telomere erosion and we live 122 max...then it's clear what'S going on. And the kicker/it's interesting because that clam living 200+ well..in its last 10 years of lifespan 190-200 decade...Massive ROS increase and telomere go alll the way down..in space of 10 years (while the animal maintained high ones over 150+ plus years). This means rate of telomere erosion/chromosomal nDNA erosion-loss = maximal longevity.

Posted by: CANanonymity at July 8th, 2020 2:18 AM

PPS: combining A-KG + NAD supplements is better but it is a bit redundant, for like CR, CR increases NAD simply by less metabolic crap going on/oxidation...so more NAD left/produced...there will be a slight boosting/even maybe a synergy...but it's even possible A-KG already increases NAD (just like CR), thus redundance...but you want More of it...so take both. But don't think this will necessarily Double the effect or something; NAD will increase the replicative bouts/replicative capacity of the cell (it will be replicative senescent farther/Hayflick later); just like taking B3/Niacin/Niacinamide/nicotinic acid, all of them increase NAD levels and give approx. 30-40% increase in replicative lifespan; which very strong effect; it would Technically mean 20-40 years human lifespan extension (for, general replicative capacity is 60-90 bouts; with NAD or B3...it increases to 115-125; so a pretty huge increase; that's because NAD will reduce substantially ROS at mitochondria (through the Redox/Gsh:Gssg (antioxidant system in mito/cytosol and ECM; especially, the SOD ones (like Extra-Cellular SOD has dramatic effect on cell ROS; it catches all the ROS that goes out in the EC; apparently it is even worse that mitochondrial ROS; because ECM ROS causes macro-molecular damage; and why ablation of ECM SOD/SOD3 can cause senescence rapidly; mtSOD (SOD2) too); which all these redox antioxidation system are dependent on NAD avail./redox) and this will end up, down the line - as telomere erosion Rate reduction (if increasing NAD). But don't go thinking NAD is cure...it's not. Telomere/telomeric DNA still skrink and you still lose epigenomic DNA too.NAD/B3 give about 30% exntesion of healthspan in human cells (it should techincally translate as 30 years extra rough...because 60-90 PDs is what they do normally, and is the life of a human (60-90 years). But none of this will work if starting late..it was demonstrated in human fibrobast cell; you only get to 120 bouts if you Start Young...not old. That is why I repeat, therapies To Work must be started earliest; obviously they must work in old people but studies don't point to that; they point to 'it's too late' (had to start in young age/low bouts, not high bouts/late in old age). The accumulation of damage/crap with age is why the effect don't work in old cells; but generally in only young ones (until we can Reverse every aspect of the 'clock/signature' and everything else in old cells...like they do with iPSCs reprogramming (yamanaka) doN't count on it - in very old cells to magically stop aging/reverse).

The only way - I think - that we could reverse this process in the Very Old cells/people...is making sure we get back the signature and reverse our telomere erosion; back to correct size and the 'rest' (junk, lipofuscin, glucosepane, progerin, drusen, A2E, furosine, CML, AGEs, ALEs, transthyretin, amyloid, tau...) will figure that one; I'm 100% sure it is not 'terminal' and can be worked around. The body has the capacity to work around these limitations; if an animal live 500-5000 years; it means that the Threshold can be Pretty Low (although Quality of Lifespan may suffer...and Iwould understand why people would Not want to be Reverted if they are too old; they would say :''What's the point of gooing back to 50 years old if I still move like a 80-90 year old (because of residue burden not all removed after therapy); I rather end it..now, at my 90 years old''. That will depend with people, I believe there will be people who want nothing of it; because quality of life will supplant longevity in 99% people; if the benefits in longevity (at old age) are accompanied by not enough improvement in health; then they won't want it/bother. Guaranteed it'S what's going to happen. I heard so many people say that (prefer to die than live crippled/decripit 'forever'); thus, we have to absolutely improve health; I think the effect will substantial enough that if they get at least 20 years reversal of Health..then they will be sold..because they Were Function 20 years before and quality of life - was ok/manageable...if wedon't obtain that; it'S going to be hard. We want to believe that the health would be 1:1 wit age reversal; so age reversal = health reversal; health Should improve but we don't know the effect of all the 'accumulated junk' of someone 100 years old; that is Reversed to a younger age; For sure, lots of that junk will be Diluted/Excreted/Destroyed by the autophagy systems; thus, we think they are Permanently as junk..it may not be so; with age they Become permanent...but if you reverse aging you Remover permanence of junk; and allow now to have body be capable of removing them. Just a 2 cents.

Posted by: CANanonymity at July 8th, 2020 2:56 AM

"but did reduce inflammatory signaling - and chronic inflammation is an important aspect of degenerative aging"

So, is this not a biomarker in-and-of-itself--the "reduction of inflammatory signaling"? Why can't we ignore the issue with what clock to use and different proponents of such, and instead look at what the intervention actually accomplished, versus the measuring device we are inventing to extrapolate what it did?

Eugene

Posted by: Eugene at July 8th, 2020 9:20 AM

PPPS: Hi Eugene! Just a 2 cents. That's a very good question.

The reason is because, in the past, many studies showed that 'not all seems what it seems'...it is not always 1:1...tit-for-tat. It is not Because you reduce this or that element/damage whatever..that you - Necessarily - see reverseal of aging; it is Much More Confounded/Grey shades...thus, ambiguity is the Biggest thing in anti-aging research. It's why we continuously search for More 'measuring' 'measures'...when, as you said, we should just look at the results of study, like if there was reduction of inflammation or something; should this not be more 'than enough' to see that Indeed there is something going on and we see reversal/slowing of aging.

Measuring/Quantifying-Quantitizing/Qualifying-Qualitizing/Marking....with age markers is Very imoprtant to avoid erring/duping self....if there is one thing I learned of looking at 50K researches it's that many contradict themselves, there is ambiguity still and not one day goes by that another study will refute or acquiece to what another one said (they don't necessarily go out of their way to 'disprove' the others - no, simply they show that Another Result can be obtained - One, that does not corroborate the Other's study results; i.e. The Contrary; that is because many studies do the 'comparative study'/'in résumé'' which is to look at Everything there is currently in the litterature and then make a 'résumé' of it all; weighting the pro/cons....pitting the studies that refute each other to come up to some conclusion/consensus. The 'In Résumé' huge studies have upward of 500-1000 credits/sources/Studies! That goes to show they go far and wide to 'scan' all there is the literatture/body right and 'sum it' into one tidy 'big résumé study'.

Aging is deceiving, smokes&mirrors and full of shades grey/doubts/contradictions/ambiguity..it is why measuring is crucial to remove doubt and ambiguity (aging is Full of Double-Standards, Double Dipping/Catch22/Double-Edged Sword, that is because it is a Balance, and a balance is always finding the right spot; it's like the yin-yan sign...when you think it's white it'S actually black or more so (deceiving), it's grey), if it had been that easy like 1+1 = 2...aging would have been solved/cured long ago. In aging, 1+1 = 11...that's how deceiptful/deceiving. I don't think I can remembe rthe number of times I changed my outlook/point of view of aging....because I was wrong and I learned 'some New True-True... Truth'...

Posted by: CANanonymity at July 8th, 2020 11:30 AM

I just started my second three months on Rejuvant (Ca alpha ketoglutarate) and was pleased to see more detail on the Trume clock (13 DNA methylation sites) that was done on my saliva sample three months back. I was surprised to see a bio age of about 65 when my chrono. age was over 75. I wish I could report some miraculous improvement in the last three months but even if I had experienced one I could not have attributed it too the Rejuvant alone since I make small adjustments almost daily. I was surprised since I thought the first test would be closer to my chronological age and the second test lower. If my second test is eight years younger, my biological age will be 57, which is getting close to my sons age and two bad knees and more than 10% grey hair does not make me feel like mid 50s but my clinical numbers are pretty good (in spite of over 40 years of AFib) so maybe I am relatively healthy on the inside?

Posted by: Dennis Fink at July 12th, 2020 7:49 AM

I welcome results like this. if there is anything we can use today the all the better. people don't realise that once actual therapies come to market they will only be available for specific conditions, when it come to off label use you would haveto find a doctor willing to do that which is near impossible

Posted by: scott emptage at July 24th, 2020 4:37 AM

I'm a little concerned that this is a therapy for renal failure to lower phosphorous and raise calcium.....I run a high normal calcium and have on occasion had palpitations and atrial ectopy, so I'm hesitant to take something that may raise my calcium more. Maybe I'll try NAD. Any thoughts? I'm 67, normal bone density, have been weight training since my 20's, in great shape...work out an hour every day.

Posted by: Patricia at September 1st, 2020 9:42 PM

The comment by Barbara about the article's "cynic" line sums it up. A prune after years of taking this miracle pill still looks like a prune.

Fact: The Rejuvant site of marketing hype is selling a form of calcium for $160/bottle/month (or slightly cheaper, if you are a sucker for "auto-ship"), complete with auto-opt-in, forced-arbitration TOS.

Question: If you were an incorruptible doctor with decades dedicated to research, would you milk the desperate?

Doctors and institutions with solid reputations stay clear of the hype and rapacious pricing of get-rich-quick quacks and moral-fiber-free doctors.

Posted by: Bon T. at September 6th, 2020 2:57 PM

it has obvious advantages over AAKG (Arginine-AlphaKetoGlutarate) for long term usage, and more AKG per gram when combined with calcium instead of arginine... But the price... almost the same as TA-65... AAKG is 10-20 times cheaper. I'll wait for cheaper alternative.

Posted by: SilverSeeker at September 6th, 2020 3:45 PM

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