First Place in a Race With No Starting Gun
In early July the longevity internet found a new champion. A paper in Aging Cell had looked at 84 different supplements in a cohort of more than four thousand people and asked which ones were associated with a younger biological age.1 One product came out on top: a delayed-release calcium salt of alpha-ketoglutarate, sold as Rejuvant, associated with a biological age about 1.8 years lower than non-users.
The trade press headline wrote itself. Rejuvant outperforms 83 supplements. Beats NMN. Beats nicotinamide riboside. Beats plain AKG. Within a week it was a screenshot, and the screenshot was the argument.
I want to be careful with this one, because alpha-ketoglutarate is not a joke molecule and I am not going to treat it like one. It is a real metabolite that sits at a real junction of your metabolism. It extended lifespan in worms in a Nature paper.2 It extended lifespan in flies. In 2020 it extended lifespan in mice, in Cell Metabolism, by a margin that would be enormous if it held.3 That is a more respectable pedigree than most of what I review here.
But between that 2020 mouse paper and this month's leaderboard, something happened that almost none of the coverage mentioned. The National Institute on Aging runs a program specifically designed to find out whether results like the 2020 one survive contact with a harder experiment. It has now tested alpha-ketoglutarate twice. Both times, nothing.4,5
And then — because this is never simple, and because I would rather be accurate than clean — there is a number buried in the supplementary tables of that second replication that complicates the debunking too. This issue is about all three of those things at once.
The strongest evidence against AKG has a hole in it. The strongest evidence for it has no control group. That is the whole issue in two sentences.1,4,5
A Molecule You Already Make, in Very Large Amounts
Alpha-ketoglutarate — also called 2-oxoglutarate, and I will use AKG from here — is an intermediate in the citric acid cycle, the central engine that pulls energy out of food in every cell you own. You are producing it continuously right now. It is not exotic and it is not foreign.
It also does a second job, and this is the part that makes the longevity story genuinely interesting rather than merely plausible-sounding. AKG is the obligate co-substrate for an entire enzyme family: the iron-dependent 2-oxoglutarate dioxygenases.6 There are dozens of them. They include prolyl hydroxylases, which is why AKG shows up in collagen synthesis. They include the enzymes that sense oxygen. And they include the TET enzymes and the JmjC histone demethylases — the machinery that removes methyl groups from DNA and from histones.
Hold onto that. We will need it later, and it is the single most under-discussed fact in this entire field.
Plasma AKG falls with age in mice — by some estimates substantially. The intuitive story writes itself: a cofactor declines, the enzymes that depend on it work less well, epigenetic regulation drifts, aging happens. Put the cofactor back and you push the system toward its younger state. It is elegant, it is mechanistically coherent, and I understand completely why serious scientists found it worth pursuing.
Elegance is not evidence. But it is a reason to look hard at the evidence rather than dismissing the molecule out of hand, and that is what the rest of this is.
Sixteen Percent, in Females, in One Strain
The paper that launched the industry appeared in Cell Metabolism in September 2020, out of the Buck Institute for Research on Aging.3 It is a good paper and it deserves to be described accurately, including the parts that are impressive.
Design. Calcium AKG added to the diet of C57BL/6 mice starting at 18 months of age — late life, deliberately, to model a realistic human intervention rather than a lifelong one.3
Results. In females, median lifespan rose 16.6% and 90th-percentile lifespan 19.7%, both statistically significant. In males the numbers were positive but not significant: 9.6% and 12.8%. Frailty measures improved far more than lifespan did, which led the authors to the more interesting claim — that AKG compresses morbidity rather than merely stretching survival. Systemic inflammatory cytokines fell; the authors proposed induction of interleukin-10 as the mechanism.
Limitation: A single inbred strain, at a single institution, with roughly 45 mice per cohort. The headline effect was in one sex. None of that is misconduct — it is a normal-sized mouse lifespan study. It is simply not, on its own, a settled fact.
The morbidity-compression finding is the part I would most want to be true. Living longer while frail is not a goal anyone has. A drug that shortens the bad years is worth more than one that adds indifferent ones. If AKG did that, it would matter.
So the field did the correct thing. It sent the compound to the referees.
Tested Twice by the Program Built to Break Things
The Interventions Testing Program is the closest thing geroscience has to an umpire. It is funded by the National Institute on Aging and it runs every candidate compound in parallel at three independent sites — the Jackson Laboratory, the University of Michigan, and UT Health San Antonio — using identical protocols and centrally manufactured food shipped to all three at once.4
Crucially, it does not use inbred mice. It uses UM-HET3, a four-way cross in which every animal is genetically unique. That design exists precisely to answer the question "did this work, or did it work in that one strain." A result that survives the ITP is about as close to real as mouse biology gets.
AKG has been through it twice.
Design. AKG at 20,000 ppm in the diet, started at 540 days — matching the 2020 study's late-life start as closely as possible.5
Results. Male median lifespan 851 days versus 826 in controls, a 3.0% difference, p=0.58. Female median 914 versus 906, a 0.9% difference, p=0.59. Neither sex significant by log-rank.
Limitation: The authors are careful in print: "It is possible that the differences in outcome reflect the genetic background of the tested animals or environmental differences between the ITP colonies and those used for the previously published study."5 They also note their treated groups — 153 males and 132 females against a double-sized control group — were not underpowered relative to the original study's 45 mice per cohort.
The obvious rebuttal to a failed late-life replication is that 18 months was too late. Maybe the window had closed. So the ITP ran it again, from an earlier start.
Design. Same nominal dose, intervention beginning at 7 months instead of 18. Three sites, 153 males and 132 females on AKG against 300 male and 272 female concurrent controls.4
Results. Male median 841 days versus 813, a 3.44% difference, p=0.429. Female median 889 versus 903, minus 1.61%, p=0.228. The Wang-Allison test, a surrogate for effects on maximum lifespan, returned p=1.000 in males. No effect on body weight in either sex.
Limitation: See the next section. There is a real problem with this experiment, and it is not one the authors dwell on in the main text.
The authors' own summary is unambiguous: "We had tested alpha-ketoglutarate (AKG) in a previous study in which the drug was initiated at 18 months... and found that AKG had no significant effect in either sex using UM-HET3 mice. We reasoned that perhaps this time point had been too late... and we therefore repeated the study, using the same dose, but this time starting the intervention at 7 months. Again, we did not observe any effect of AKG in either males or females."4
Now the complication, and I think it is the most useful thing in this issue.
Buried in Supplementary Table S3 of that 2026 paper is the food assay. The target dose was 20,000 parts per million. The diet the mice actually ate assayed at 3,262 parts per million — 16.3 percent of target — with a coefficient of variation of 40.9 percent, the worst of any compound in the cohort. Both the pilot diet and the lifespan diet came in around one-sixth of intention. Supplementary Table S5, which reports plasma concentrations of every tested compound, lists dashes for AKG in both sexes: they could not measure it in blood at all.
The sentence says "using the same dose." The supplementary table says the food contained one sixth of it. Both are in the same paper.
On reading past the abstractI want to be precise about what this does and does not mean. It does not resurrect AKG. The first ITP test, at a late start, was a separate cohort with its own diet, and it also found nothing. Two independent null results are not erased by a dosing problem in one of them. And the ITP's own closing note applies with full force: the original effects being chased here "were at or near the lower level of what is expected to be able to discover at 80% power," and "chance effects can be expected in any series of studies for truly ineffective agents."4
But it does mean that anyone — including me — who wants to say "the gold standard tested AKG at the same dose and it failed" has to add a footnote. In the C2022 cohort, the dose in the bowl was not the dose on the protocol. That is a limitation of the debunking, and you deserve to know it exists.
Forty-Two People, No Control Group
Everything above is mice. What about us?
The commercial story rests on two analyses, and neither is a trial.
The first, from 2021, is the source of the "eight years younger" claim you have probably seen.7 Forty-two people who had bought Rejuvant took a saliva-based DNA methylation test before starting, took it again after an average of seven months, and were found to have dropped an average of roughly eight years of biological age. Forty of the forty-two improved.
Design. Retrospective analysis of methylation-clock results in customers taking Rejuvant for an average of seven months.7
Results. Average biological age reduction of approximately 8 years; 40 of 42 participants improved.
Limitation: The authors state it themselves — no control arm, small cohort, a single aging clock, and no other aging-relevant data collected. Everyone in it had already chosen to buy the product and chosen to test themselves. There is no way to separate the supplement from the person who buys supplements.
The second is this summer's paper, and it is a better study — genuinely larger, better adjusted, and considerably more honest than its press coverage.1
Design. Data from more than 4,200 people who bought at least one commercial saliva methylation test between 2020 and 2025 and filled in lifestyle and supplement questionnaires. Seventy-one percent used supplements. Eighty-four supplement classes were tested against "Age Residual" — how much older or younger the clock reads than the calendar.1
Results. Delayed-release calcium AKG, among 143 users, was associated with an Age Residual about 1.8 years lower, surviving adjustment for age, sex, smoking, health status and further covariates. It was the standout of the 84.
Limitation: The longitudinal analysis — the one that follows the same people over time, and the only one that comes close to a causal question — found no significant improvement, on 26 participants. The authors flag healthy-user bias in their own text and note that most of the 84 supplements showed nothing at all.
Three things about that paper deserve saying out loud.
First, the design cannot answer the question being asked of it. This is a cross-section of people who bought an epigenetic age test. The ones taking a $55-a-month longevity supplement are not a random draw from the ones who are not. They are, on average, wealthier, more health-engaged, more likely to be doing eleven other things right. Adjusting for exercise and smoking and alcohol trims that problem; it does not remove it. The authors know this and say so.
Second, the within-person analysis was null. When you follow the same body over time — which controls for that person's entire unmeasured life — the effect did not appear. The paper attributes this to a sample of only 26, which is fair. It is also exactly what you would see if the cross-sectional signal were confounding.
Third — and this is a correction to an argument I have seen made against this paper, including by people I respect — the clock's stated mean absolute error of 5.4 years does not by itself invalidate a 1.8-year group difference. That error is per-person noise, and per-person noise averages down across 143 people. You can absolutely detect a group mean smaller than your individual measurement error. The problem with this study is not the ruler. The problem is who chose to stand in front of it.
You Fed the Enzyme That Writes the Test
Now go back to the biology section, because here is where it stops being an aside.
An epigenetic clock is not a measurement of aging. It is a measurement of methylation at a defined set of CpG sites, converted into a number of years by a model trained to predict chronological age. The methyl groups at those sites are put on by DNA methyltransferases and taken off by TET enzymes.
TET enzymes are 2-oxoglutarate dioxygenases. Their obligate co-substrate is alpha-ketoglutarate.6
AKG is the co-substrate for the enzymes that erase DNA methylation. A supplement that moves a methylation clock might be slowing your aging — or it might be feeding the machinery the clock is built out of.
The problem nobody in the coverage raisedI want to be scrupulous here, because this is a hypothesis and I am not going to dress it up as a finding. Nobody has demonstrated that oral AKG shifts TET activity enough to move a methylation clock independently of any effect on aging. Cellular AKG is under tight metabolic control and it is not obvious that a gram a day moves it meaningfully. The mechanism could equally run the other way: if epigenetic drift is partly a consequence of failing demethylation, then restoring the cofactor is exactly how a real intervention would work, and the clock would be reading a genuine improvement.
That is precisely the point. Those two possibilities — a real rejuvenation, and a supplement that greases the assay — produce the same reading on the same test, and the epigenetic clock literature has been warning about this class of problem for years.8 No study anywhere has tried to separate them for AKG. Until one does, "AKG lowered my biological age" is a claim about a laboratory value whose relationship to how long or how well you will live remains unestablished.
And we have a control experiment for that relationship, sort of. In mice, we have both the clock-adjacent enthusiasm and an actual survival endpoint. The survival endpoint has now come back empty twice.
Six Grams, Six Months, and a Bone Marker That Moved
Here is the thing that surprised me most in preparing this issue. AKG does have a proper randomized controlled trial in humans. It is nearly twenty years old, nobody in the longevity conversation cites it, and it is quietly the most informative human study in the file.
Design. Seventy-six postmenopausal women with osteopenia, randomized double-blind for six months to 6 g of AKG calcium salt plus 1.68 g calcium daily, or the same calcium alone.9
Results. The bone resorption marker CTX fell by a maximum of 37% at 24 weeks (p=0.006), with significant between-group separation at 12 and 24 weeks. A clean, real, placebo-controlled biochemical effect.
Limitation: Lumbar bone mineral density — the endpoint that actually corresponds to not breaking a hip — rose 1.6% from baseline, but the difference between groups was 0.9% and not statistically significant. The surrogate moved. The outcome did not.
Read that twice, because it is the same shape as everything else in this issue. Give people AKG, and a biochemical marker moves convincingly. Look at the thing the marker is supposed to stand for, and it does not.
Note also the dose: six grams a day, against the one gram in a Rejuvant tablet. Whatever that trial demonstrated, it demonstrated at six times the commercial exposure.
The study that will actually settle the longevity question is already finished enrolling. ABLE — Alpha-ketoglutarate supplementation and BiologicaL agE — is a double-blind, placebo-controlled randomized trial in Singapore: 120 adults aged 40 to 60 whose methylation age already exceeds their chronological age, given 1 g of sustained-release calcium AKG or placebo for six months with three months of follow-up.10 The primary endpoint is change in DNA methylation age. Secondary endpoints include inflammatory and metabolic blood markers, grip strength, leg extension strength, arterial stiffness, skin autofluorescence and aerobic capacity — in other words, things you can feel, not only things a clock reports.
It recruited 120 participants out of 467 who expressed interest.11 As of this writing, in late August 2026, its results have not been published. A second trial of calcium AKG in human aging is also registered.12
So the sequence of events this summer was: a randomized trial designed specifically to test whether AKG lowers biological age sat unpublished, while a cross-sectional survey of people who had already bought AKG got written up as a victory over 83 competitors. That is not fraud. It is just the wrong study getting the attention.
Four Things Worth Knowing Before You Buy
The same scientist is on almost every paper
Brian Kennedy was an author on the 2020 mouse study, on the 2021 uncontrolled Rejuvant analysis, and on this summer's Aging Cell survey — and he is Chief Science Officer of Ponce de Leon Health, which makes Rejuvant. That is disclosed, not hidden. In fairness, he is also a co-author on the 2026 ITP paper that failed to replicate his own finding, which is more than most people in his position would put their name to. But when nearly all the positive human evidence for a product routes through one scientist affiliated with the company selling it, an independent trial is not a nicety.
Safety looks unremarkable, and that is not the same as proven
AKG is an endogenous metabolite with no signal of serious harm in the human trials that exist, and the ITP reported no adverse effects and no body-weight changes in mice. But the longest randomized human exposure on record is six months, and the calcium salt delivers meaningful supplemental calcium alongside the AKG — worth knowing if you already take calcium or have a history of stones.
You are paying for a dose no trial has completed
Rejuvant runs roughly $1.83 a day, about $55 a month, at one gram. The only completed randomized human trial used six grams. The ABLE trial uses one gram and has not reported. Right now, the commercial dose is supported by no published randomized outcome data in either direction.
"Biological age" is not a regulated claim
No clock is validated as a clinical endpoint, and no regulator recognizes "reduced biological age" as a health outcome. A number from a direct-to-consumer methylation test is a laboratory value, not a diagnosis, and moving it has never been shown to change how long or how well anyone lives. Treat the number as a research instrument you happen to be allowed to buy.
Interesting Molecule, Absent Trial
I am not calling this Marketing Hype, and I want to explain why before I explain the rest. AKG is a real endogenous metabolite with a real mechanism: it is the obligate co-substrate for an entire family of enzymes that includes the ones regulating DNA methylation. It extended lifespan in worms, in flies, and in one respectable mouse study whose morbidity-compression finding would matter enormously if it held. That is a serious scientific case, and dismissing it would be as lazy as swallowing it.
But "Promising" requires human evidence, and there is effectively none. The entire human case for AKG as a longevity intervention consists of two uncontrolled observational analyses of people who had already bought the product — one of 42 people with no control arm, one of 143 people in a cross-section whose own within-person longitudinal analysis came back null. Zero randomized trials of AKG on aging have been published. The one completed randomized trial of AKG in humans is about bone, used six times the commercial dose, moved a resorption marker convincingly, and did not move bone density.
Meanwhile the referee has ruled twice. The NIA's Interventions Testing Program tested AKG from a late start and from an early start, in genetically heterogeneous mice, across three sites, with larger treated groups than the original study — and found no lifespan benefit either time. I will not oversell that, because the second cohort's food assayed at 16% of the intended dose and the program could not detect AKG in plasma at all. A failed replication with a dosing problem is weaker evidence than a clean one. It is still two failures, not zero.
And underneath all of it sits a question nobody has answered: AKG feeds the enzymes that erase the methylation marks these clocks are built from. Until someone shows that a lower clock reading on AKG reflects a slower-aging body rather than a better-fed assay, the headline number is uninterpretable. Insufficient Data is not a hedge here. It is the literal state of the file.
The good news is that this is one of the few supplements where the answer is genuinely coming. ABLE is randomized, placebo-controlled, fully enrolled, and measures grip strength and arterial stiffness alongside the clock. If AKG does something, that trial should show it. I would wait for it. If you are already taking it, it is inexpensive as these things go and appears safe — but do not tell yourself you are buying proven years.
AKG won a leaderboard assembled from people who had already bought it. The mouse program built to referee claims like this has tested it twice and found nothing. The randomized human trial is finished and unpublished. Wait for it.
- 1. Pabis K, … Kennedy BK. Supplements and drugs are associated with biological age in a cohort of exceptionally healthy individuals. Aging Cell. 2026;25(6):e70517. doi:10.1111/acel.70517. Cross-sectional and longitudinal analysis of 4,260 commercial methylation-test purchasers; 84 supplement classes; dAKG n=143 cross-sectional, n=26 longitudinal.
- 2. Chin RM, Fu X, Pai MY, et al. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature. 2014;510(7505):397–401. The C. elegans result that started the field.
- 3. Asadi Shahmirzadi A, Edgar D, Liao CY, et al. Alpha-ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metabolism. 2020;32(3):447–456.e6. C57BL/6, CaAKG from 18 months; female median +16.6%, 90th percentile +19.7%; male +9.6% and +12.8%, not significant.
- 4. Korstanje R, Strong R, Salmon AB, et al., Miller RA. Astaxanthin, meclizine, mitoglitazone, pioglitazone, alpha-ketoglutarate, mifepristone, methotrexate, and atorvastatin-telmisartan do not increase lifespan in UM-HET3 mice. GeroScience. 2026;48(3):3821–3830. doi:10.1007/s11357-026-02201-2. Early-start AKG cohort; achieved dietary dose 3,262 ppm against a 20,000 ppm target (Supplementary Table S3); plasma AKG not quantifiable (Supplementary Table S5).
- 5. Miller RA, Strong R, Harrison DE, et al. Interventions Testing Program report including late-start alpha-ketoglutarate (AKG_Late, C2020 cohort). GeroScience. 2024;46(5):4657–4670. Male median 851 vs 826 days (p=0.58); female 914 vs 906 (p=0.59).
- 6. Islam MS, Leissing TM, Chowdhury R, Hopkinson RJ, Schofield CJ. 2-Oxoglutarate-dependent oxygenases. Annual Review of Biochemistry. 2018;87:585–620. Reference work establishing AKG as obligate co-substrate for the TET and JmjC demethylase families.
- 7. Demidenko O, Barardo D, Budovskii V, et al. Rejuvant, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging, after an average of 7 months of use, in the TruAge DNA methylation test. Aging (Albany NY). 2021;13(22):24485–24499. doi:10.18632/aging.203736. Retrospective, uncontrolled, n=42.
- 8. Bell CG, Lowe R, Adams PD, et al. DNA methylation aging clocks: challenges and recommendations. Genome Biology. 2019;20:249. On the limits of treating clock output as a measure of biological aging.
- 9. Filip R, Pierzynowski S, et al. Alpha-ketoglutarate decreases serum levels of C-terminal cross-linking telopeptide of type I collagen (CTX) in postmenopausal women with osteopenia: six-month study. International Journal for Vitamin and Nutrition Research. 2007;77(2):89–97. Randomized, double-blind, n=76; 6 g AKG + 1.68 g Ca/day vs Ca alone; CTX −37% at 24 weeks (p=0.006); between-group lumbar BMD difference 0.9%, not significant.
- 10. Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE) — intervention study protocol. GeroScience. 2023;45:3229–3241. doi:10.1007/s11357-023-00813-6. ClinicalTrials.gov NCT05706389. Double-blind, placebo-controlled, 120 adults aged 40–60, 1 g sustained-release Ca-AKG, 6 months plus 3-month follow-up.
- 11. Recruitment evaluation of a gerotherapeutic randomized controlled trial testing alpha-ketoglutarate in biologically older, middle-aged adults (ABLE). Experimental Gerontology. 2025. PMID 40819772. 120 enrolled from 467 expressions of interest.
- 12. Evaluation of the efficacy of calcium α-ketoglutarate (AKG-Ca) in improving human aging. ClinicalTrials.gov NCT07114536.
- 13. NIA Interventions Testing Program data portal, Mouse Phenome Database, The Jackson Laboratory. phenome.jax.org/projects/ITP1.
- 14. Koe T. Longevity study: dAKG associated with biological age reversal. NutraIngredients. 1 July 2026. Trade coverage of reference 1, including the Rejuvant subscription-cohort analysis.
- 15. Ponce de Leon Health corporate disclosures and Rejuvant Scientific Advisory Board listings, identifying Brian K. Kennedy as Chief Science Officer. Retrieved August 2026.
- 16. Rejuvant retail pricing, approximately $1.83 per day at the one-gram daily dose (roughly $55 per 30-day supply), with subscription discounting. Manufacturer and major-retailer listings, August 2026.