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Supplements and Drugs Are Associated With Biological Age in a Cohort of Exceptionally Healthy Individuals

Kamil Pabis, Weilan Wang, Kumar Selvarajoo, Yelena V. Budovskaya, Vincenzo Sorrentino, Jan Gruber, Brian K. Kennedy
Aging Cell 2026 Volume 25, issue 6, article e70517

Bibliography

PubMed
PMID 42166733
PubMed Central
PMC13239866
DOI
10.1111/acel.70517
Funding
V.S. is supported by the NUHS Internal Grant Funding under NUS Start-up grant NUHSRO/2022/047/Startup/11, and an MOE Tier 2 grant T2EP30124-0014. B.K.K., V.S., and K.P. are supported by a Healthy Longevity Catalyst grant (HLCA25Jan-0012). TruMe Labs provided access to proprietary data but had no role in the interpretation of the data or the final decision to publish the manuscript. The authors otherwise state that they have nothing to report regarding funding.
Competing interests
The published Conflicts of Interest statement reads: "The authors declare no conflicts of interest." However, the Acknowledgments section discloses that B.K.K. (Brian K. Kennedy, senior author) is a scientific advisor and board member of PDL Health, the company that produces the Rejuvant delayed-release calcium-α-ketoglutarate supplement analysed as the primary finding of this paper. Co-author Y.V. Budovskaya is affiliated with TruMe Inc., the company that manufactures the saliva-based epigenetic clock used as the primary biomarker in the study, and TruMe Labs provided access to the proprietary participant dataset. Participants recruited via PDL Health received free epigenetic test vouchers upon Rejuvant purchase, which the authors acknowledge as a potential source of recruitment bias.

Study snapshot

DesignCross-sectional observational cohort with longitudinal subset analysis; no randomisation, no placebo control
ModelHuman — convenience sample of 4260 "health enthusiast" adults (mean age 53.5 ± 13.2 years; 59% male; 96% non-smokers; predominantly White/Caucasian), recruited between 2020 and 2025 via supplement companies and telehealth clinics; unusually low prevalence of smoking (4% vs 18% in NHANES) and poor/fair self-rated health (12% vs 25% in NHANES)
Sample4260 unique participants provided a valid date of birth and epigenetic test; 3628 provided complete questionnaire data for multivariate analysis; 755 provided ≥2 tests for the longitudinal subset; 143 self-declared dAKG users, 294 dAKG subscribers identified via order history
InterventionSelf-reported use of 84 supplement categories and 22 medication classes; primary supplement of interest was delayed-release calcium-α-ketoglutarate (dAKG, Rejuvant, containing added vitamin A for men or vitamin D3 for women). Additional named supplement analyses: any AKG (dAKG plus non-delayed formulations), coenzyme Q10, vitamin D, NAD+ precursors (NMN, NR, niacin), carotenoids, calcium, curcumin, and others. Dose, frequency, and duration were not recorded.
DurationCross-sectional snapshot; longitudinal subset had mean 367 days (range 0–1741 days) between epigenetic tests
EndpointsAge Residual (residual from linear regression of Biological Age on Chronological Age); Age Delta (Biological Age minus Chronological Age); Odds ratio of improvement in Age Residual over time in the longitudinal subset; Biological Age measured via proprietary 9-CpG saliva-based TruAge epigenetic clock (mean absolute error 5.4 years)

What the study showed, in plain terms

This 2026 observational study analyzed 4,260 mostly health-conscious adults who completed saliva epigenetic-age testing and reported supplement use. The investigators compared 84 supplements using a proprietary 9-CpG clock and an Age Residual measure.

Users of a proprietary delayed-release calcium-AKG formulation combined with vitamin A for men or vitamin D3 for women had a 1.8-year lower Age Residual cross-sectionally; after matching, the difference was 1.27 years. Plain non-delayed AKG did not show a significant association.

The longitudinal dataset included 755 participants. A subscription-defined delayed-release AKG subgroup showed an initial signal, but it was no longer significant after accounting for baseline Age Residual/regression to the mean. The design is observational, so the study cannot establish that delayed-release AKG reverses biological aging.

Key findings

  • Among 4,260 cross-sectional participants, delayed-release calcium-AKG plus sex-specific vitamins was associated with an average 1.8-year lower Age Residual.
  • After propensity-style matching, delayed-release AKG users had a 1.27-year lower Age Residual than matched controls (p<0.01).
  • Plain non-delayed AKG showed a smaller, non-significant association.
  • The saliva clock used nine CpG sites and had a reported mean absolute error of about 5.4 years for chronological age.
  • The longitudinal sample included 755 participants. A subscription-defined delayed-release AKG subgroup (n=294) showed an initial association with improvement, but the signal was not significant after correction for baseline Age Residual/regression to the mean.
  • A self-reported delayed-release AKG subgroup was small (n=26) and did not show a significant longitudinal benefit.
  • Because treatment was not randomized and supplement use was self-selected, all effect estimates are associative rather than causal.

What this study can and cannot tell us

This was a convenience sample of health enthusiasts with substantial supplement use, creating strong healthy-user and self-selection biases. The cohort was not representative of the general population.

Supplement exposure was largely self-reported or inferred from customer/subscription records; frequency and dose were not reliably available. The delayed-release product also contained sex-specific vitamins, so the Ca-AKG contribution cannot be isolated.

The biological-age endpoint was a proprietary 9-CpG saliva clock. Clock movement is a biomarker, not a clinical endpoint, and measurement error/regression to the mean are especially important in repeated testing.

The cross-sectional association persisted through covariate adjustment and matching but remains vulnerable to unmeasured confounding. In longitudinal analysis, the delayed-release AKG signal did not remain significant after baseline Age Residual/regression-to-the-mean correction.

This study is not directly comparable with Demidenko 2021. Demidenko's uncontrolled 42-person before-after Rejuvant cohort reported roughly an 8-year TruAge change, whereas Pabis found a 1.8-year cross-sectional Age Residual association, attenuating to 1.27 years after matching. The designs and estimands differ, so the effect sizes should not be treated as estimates of the same causal quantity; neither observational study establishes reversal of biological aging.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology