Tier 4 — mechanistic

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

PubMed
PMID 37217632
PubMed Central
PMC10643463
DOI
10.1007/s11357-023-00813-6
Trial registry
View on ClinicalTrials.gov Registered trial — results not yet published in a peer-reviewed journal.
Funding
No dedicated funding statement appears in the publisher version reviewed.
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

DesignSingle-centre, randomised, parallel-group, double-blind, placebo-controlled RCT protocol
ModelHuman — 40 to 60-year-old adults living in Singapore, generally healthy, with DNA methylation age greater than their chronological age
SamplePlanned n=120 (60 Ca-AKG, 60 placebo)
Intervention1 g/day sustained-release calcium alpha-ketoglutarate (Ponce de Leon Health tablets) vs identical-appearance placebo
Duration6 months intervention plus 3 months follow-up (visits at baseline, 3 months, 6 months, 9 months)
EndpointsPrimary — 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

This paper is the peer-reviewed protocol for ABLE, a single-centre randomized, double-blind, placebo-controlled trial of sustained-release calcium alpha-ketoglutarate (Ca-AKG) in adults aged 40–60 whose DNA-methylation age is greater than their chronological age.

The protocol planned 120 participants, allocated to 1 g/day of sustained-release Ca-AKG or placebo for six months, followed by three months of follow-up. The primary outcome is change in DNA-methylation age using four established clocks; secondary measures include inflammatory and metabolic markers, arterial stiffness, muscle strength, aerobic capacity, skin autofluorescence, body composition and bone density.

This publication contains no treatment results. As of 5 October 2026, later ABLE recruitment/feasibility and operational analyses have appeared, but a primary paper reporting the randomized Ca-AKG efficacy outcome has not been identified.

Key findings

  • The protocol specifies a single-centre, randomized, parallel-group, double-blind, placebo-controlled design.
  • Planned enrollment is 120 adults aged 40–60, with 60 assigned to Ca-AKG and 60 to placebo.
  • The intervention is 1 g/day of sustained-release Ca-AKG for six months, followed by a three-month post-intervention follow-up.
  • The primary outcome is change in DNA-methylation age, assessed using the Hannum, Horvath, GrimAge and PhenoAge clocks.
  • Secondary phenotyping includes arterial stiffness, handgrip and leg-extension strength, VO₂peak, DXA body composition and bone density, skin autofluorescence, blood markers and gut-microbiome analyses.
  • The protocol itself reports no efficacy or safety outcomes.
  • The study is registered as NCT05706389. As of 5 October 2026, later ABLE recruitment/feasibility and operational publications do not provide the primary randomized treatment-efficacy result.

What this study can and cannot tell us

What this paper can and cannot tell us:

  • This is a protocol, not a results paper. It cannot establish that Ca-AKG changes biological age, healthspan, physical performance or clinical outcomes.
  • The planned study is single-centre and based in Singapore, which may limit generalisability of any eventual results.
  • The planned sample size is pragmatic because the expected effect size of Ca-AKG on biological-age measures in generally healthy adults was uncertain when the protocol was written.
  • Eligibility requires DNA-methylation age to exceed chronological age. That enrichment strategy may increase sensitivity to change but limits generalisation to all middle-aged adults.
  • Brian K. Kennedy disclosed service on the Scientific Advisory Board of Ponce de Leon Health, the company associated with the study product; this is a material competing interest.
  • The protocol includes safety monitoring but contains no observed safety results. Regulatory or GRAS status is not evidence that this specific six-month regimen is efficacious or risk-free.

Related papers in the corpus

Tier 3
Alpha-ketoglutarate stabilizes redox homeostasis and improves arterial elasticity in aged mice
T. Niemiec et al. · Journal of Physiology and Pharmacology · 2011

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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