Tier 2 — strong

Alpha-ketoglutarate supplementation and BiologicaL agE in middle-aged adults (ABLE)—intervention study protocol

Elena Sandalova, Jorming Goh, Zi Xiang Lim, Zhi Meng Lim, Diogo Barardo, Rajkumar Dorajoo, Brian K. Kennedy, Andrea B. Maier

GeroScience 2023 Volume 45, issue 5, pages 2897–2907

Bibliography

DOI: 10.1007/s11357-023-00813-6
PubMed: PMID 37217632
PubMed Central: PMC10643463
Funding: Not present in the extracted manuscript pages. Verify at the Springer publisher site before finalising — likely institutional (NUS / NUHS Healthy Longevity Translational Research Programme).
Competing interests: KB served on the Scientific Advisory Board for Ponce De Leon Health; other authors have no conflict of interest to disclose.

Study snapshot

Design	Single-centre, randomised, parallel-group, double-blind, placebo-controlled RCT protocol
Model	Human — 40 to 60-year-old adults living in Singapore, generally healthy, with DNA methylation age greater than their chronological age
Sample	120 participants (60 Ca-AKG, 60 placebo)
Intervention	1 g/day sustained-release calcium alpha-ketoglutarate (Ponce de Leon Health tablets) vs identical-appearance placebo
Duration	6 months intervention plus 3 months follow-up (visits at baseline, 3 months, 6 months, 9 months)
Endpoints	Primary — change in DNA methylation age (mean of Hannum, Horvath, GrimAge and PhenoAge clocks) from baseline to 6 months; Secondary — inflammatory and metabolic blood parameters; Secondary — handgrip strength and 8-repetition maximum leg extension strength; Secondary — arterial stiffness (carotid-femoral pulse wave velocity); Secondary — skin autofluorescence (advanced glycation end products); Secondary — aerobic capacity (VO₂peak via cardiopulmonary exercise test); Secondary — body composition and lumbar spine bone density (DXA); Post-hoc — gut microbiota profiling; responder vs non-responder DNA methylation analysis

What the study showed, in plain terms

ABLE is the first properly designed clinical trial testing whether a calcium alpha-ketoglutarate (Ca-AKG) supplement can slow biological ageing in healthy middle-aged adults. It is a randomised, double-blind, placebo-controlled trial — the design that produces the strongest evidence in human research.

Run at the National University of Singapore, the trial has recruited 120 people aged 40 to 60 whose DNA methylation clocks read older than their birthdays. Half receive 1 gram of sustained-release Ca-AKG every day for 6 months; the other half receive an identical-looking placebo. Neither participants nor researchers know who is in which group.

The main question is whether Ca-AKG can reduce biological age as measured by four widely used DNA methylation clocks (Hannum, Horvath, GrimAge, PhenoAge). The trial also tracks bone density, arterial stiffness, muscle strength, aerobic fitness, skin ageing markers, blood metabolic parameters, and the gut microbiome. This paper describes only the design and rationale — no results are reported here.

Key findings

ABLE is the first placebo-controlled RCT of a Ca-AKG intervention with DNA methylation age as its primary outcome.
Dose: 1 g/day sustained-release Ca-AKG (the same delayed-release formulation used in the Rejuvant retrospective analysis).
Duration: 6 months of supplementation, 3 months of post-intervention follow-up.
Uniquely, participants are pre-screened to have a DNA methylation age older than their chronological age — enriching for those most likely to show a measurable response.
The primary outcome is the mean of four established epigenetic clocks (Hannum, Horvath, GrimAge, PhenoAge), rather than a single proprietary clock.
Deep secondary phenotyping covers arterial stiffness (cfPWV), muscle strength (handgrip and 8-RM leg extension), aerobic capacity (VO₂peak), bone and body composition (DXA), skin AGEs, and gut microbiota.
Registered at clinicaltrials.gov as NCT05706389; results not yet published as of August 2026.

What this study can and cannot tell us

What this paper can and cannot tell us:

This is a protocol — no efficacy or safety results are reported. Any current statement about ABLE outcomes is premature.
Single-centre design in Singapore may limit generalisability of the eventual results across other populations.
The 120-participant sample size is pragmatic rather than powered by a pre-existing effect estimate; the authors note that the expected effect size of Ca-AKG in healthy individuals is unknown.
Enriching enrolment for participants who are biologically older than chronologically is a design choice that boosts sensitivity but limits generalisation to the general middle-aged population.
The trial's principal investigator (Brian Kennedy) serves on the Scientific Advisory Board of Ponce de Leon Health, the Rejuvant manufacturer supplying the study product — a competing interest disclosed in the paper.
Ca-AKG is Generally Recognised As Safe (GRAS) and no serious adverse events are anticipated, but safety data from this trial will be the first placebo-controlled human safety readout for chronic dosing.

Tier 3

Alpha-ketoglutarate stabilizes redox homeostasis and improves arterial elasticity in aged mice

T. Niemiec et al. · Journal of Physiology and Pharmacology · 2011