Tier 2 — strong

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

Oleksandr Demidenko, Diogo Barardo, Valery Budovskii, Robb Finnemore, Francis R. Palmer III, Brian K. Kennedy, Yelena V. Budovskaya

Aging (Albany NY) 2021 Volume 13, issue 22, pages 24485–24499

Bibliography

DOI: 10.18632/aging.203736
PubMed: PMID 34847066
PubMed Central: PMC8660611
Funding: Data for the manuscript was acquired from users of the Rejuvant product from Ponce de Leon Health and DNA methylation analysis provided by TruMe Labs. Data was provided to National University of Singapore for statistical analysis, which provided funding support for this component of the project.
Competing interests: In July of 2019, TruMe entered into a non-exclusive customer service agreement for the DNA methylation testing of Ponce de Leon Health customers taking Rejuvant®. Neither TruMe nor Ponce de Leon Health have any cross ownership or other financial interests to report. B.K.K. is a scientific consultant and Board member for Ponce de Leon Health.

Study snapshot

Design	Retrospective observational cohort analysis of self-selected Rejuvant users with paired pre- and post-supplementation TruAge saliva samples
Model	Human — 42 self-reported healthy adults (28 male, 14 female); chronological age range spanning approximately 40 to 80 years
Sample	42 individuals (28 males on the male CaAKG + vitamin A formulation; 14 females on the female CaAKG + vitamin D formulation); one baseline and one follow-up saliva sample per person
Intervention	Rejuvent® — proprietary sustained-release CaAKG formulation, 2 tablets per day. Female tablets contain CaAKG + vitamin D; male tablets contain CaAKG + vitamin A. Total daily CaAKG dose approximately 1 g per manufacturer disclosure.
Duration	Self-directed supplementation for 4 to 10 months (mean 7 months); no fixed protocol duration
Endpoints	Primary — change in DNA methylation age measured by TruMe TruAge saliva-based proprietary epigenetic clock, baseline vs post-supplementation; Secondary — covariate analysis: baseline chronological age and baseline biological-minus-chronological age difference (diffAge) as predictors of the magnitude of TruAge reduction; Secondary — sex-stratified sub-analysis; Secondary — homogeneous 13-person sub-cohort analysis; Secondary — correlation of treatment duration with magnitude of effect

What the study showed, in plain terms

This is the paper behind the widely repeated claim that Ca-AKG makes you "8 years younger". It looks at 42 people who bought and used Rejuvant, a commercial Ca-AKG supplement, and had their DNA methylation age tested by the same company that makes the test (TruMe). The researchers compared the participants' epigenetic age readings before and after roughly 7 months of Rejuvant use.

On average, the post-supplementation readings were about 8 years lower than the baseline readings. Forty of the 42 people saw their biological age drop. The p-value on the statistical test was extremely small, meaning the difference was very unlikely to be pure chance under the study's own assumptions.

The important context is what this study is not. It is not a randomised controlled trial. There was no placebo group. Participants were self-selected. The epigenetic clock used is a proprietary product from the company reporting the finding. Several authors have financial ties to either TruMe or Ponce de Leon Health. And Rejuvant is a combination product — CaAKG plus vitamins — so even if the effect is real, the contribution of CaAKG alone cannot be separated from the vitamins. The 8-year figure is best treated as a hypothesis-generating observation that made the ABLE trial (a proper RCT) worth running.

Key findings

Mean TruAge biological age reduction of 7.96 years across 42 participants after a mean of 7 months of Rejuvant supplementation (one-sided Welch paired t-test p = 6.538 × 10⁻¹²).
Effect observed in both sexes: male paired mean reduction 8.44 years; female paired mean reduction 6.98 years.
40 of 42 participants (95%) showed a decrease in biological age; only 2 (1 male, 1 female) showed a slight increase.
Linear regression model: Decrease in TruAge = −5.41 + 0.22 × chronological_age − 0.45 × diffAge. Chronologically older and biologically older participants gained more from the intervention.
Treatment duration (within the 4–10 month range studied) did not correlate with magnitude of effect, suggesting the biomarker effect saturates by roughly 7 months.
Baseline TruAge readings were highly correlated with chronological age (adjusted R² = 0.77, p = 2 × 10⁻⁹), consistent with the clock behaving as an ageing biomarker in this cohort.
In a homogeneous 13-person sub-cohort selected via stepwise regression, the paired mean reduction was 10.2 years (p = 7.3 × 10⁻⁵).

What this study can and cannot tell us

What this study can and cannot tell us:

No control group. Without a placebo arm, the observed change cannot be separated from regression to the mean, seasonal variation in DNA methylation, batch effects between the baseline and follow-up sample runs, or lifestyle changes correlated with buying a longevity supplement.
Retrospective self-selected sampling. Participants were people who had voluntarily bought Rejuvant and had TruAge results on file — this is a strong selection bias toward people primed to see or report a positive result.
Single unvalidated proprietary epigenetic clock. TruAge is a TruMe Inc. product, not one of the independently developed and widely validated clocks (Horvath, Hannum, GrimAge, PhenoAge) used in gold-standard biological age research. The 8-year TruAge reduction has not been shown to correspond to any clinical outcome, any change in the independent clocks, or any physiological endpoint.
Small sample size (n=42) with skewed sex distribution (28 male, 14 female).
Industry-conducted throughout. Authors are affiliated with TruMe Inc. (the clock manufacturer) and Ponce de Leon Health (the Rejuvant manufacturer); one further author has separately disclosed a board and equity role at Ponce de Leon Health.
Rejuvant is a compound formulation — CaAKG combined with vitamin A (male formulation) or vitamin D (female formulation). The isolated contribution of CaAKG cannot be determined from this study. Vitamin D alone has been separately associated with lower epigenetic age.
No non-Rejuvant CaAKG comparator arm. Findings on this specific sustained-release formulation should not be extrapolated to generic Ca-AKG capsules.
Baseline and follow-up saliva samples were not necessarily processed together, raising the risk that some or all of the observed change reflects batch effects rather than biological change.
The authors themselves state that a placebo-controlled design is required to validate the finding — that trial is now underway as ABLE (see sandalova-2023-able-trial-protocol).

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