Tier 2 — strong

Alpha-Ketoglutarate dietary supplementation to improve health in humans

Gyanwali B, Lim ZX, Soh J, Lim C, Guan SP, Maier AB, Goh J, Kennedy BK

Trends in Endocrinology and Metabolism 2022 Volume 33, issue 2, pages 136–146

Bibliography

DOI: 10.1016/j.tem.2021.11.003
PubMed: PMID 34952764
Funding: This work was supported by the National University of Singapore (Start-up Grant DPRT, R183000413133, and Interventions for Healthy Longevity Grant, R-171-000-083-750) and the National University Health System, Centre for Healthy Longevity Grant (SPOT20AHS3O).
Competing interests: B.K.K. is a board member and equity holder at Ponce de Leon Health, a company aimed at developing nutritional supplements for aging, which manufactures several products related to AKG. All authors declare no competing interest regarding this manuscript.

Study snapshot

Design	Narrative review (not systematic; no pre-registered search strategy or quality assessment)
Model	Synthesis of published human clinical trials, cohort studies, and preclinical evidence on AKG supplementation
Sample	Not applicable — narrative review synthesising dozens of primary studies
Intervention	Covers AKG in multiple forms (Ca-AKG, O-AKG, Na-AKG, arginine-AKG) at doses ranging from 3.6 g/day to 30 g/day, delivered orally or intravenously across clinical contexts
Duration	Not applicable
Endpoints	Reviews: lifespan/healthspan; muscle mass and protein turnover; bone density and CTX; cognitive and neurological outcomes; cardiovascular and renal function; liver disease; wound healing; cancer; gastrointestinal health; nutritional status in older adults

What the study showed, in plain terms

Alpha-ketoglutarate is a small molecule the body produces in every cell as part of the Krebs cycle — the pathway that turns food into usable energy. Its levels drop with age, and this review from Brian Kennedy's Singapore longevity group synthesises what is known about supplementing AKG to slow ageing and improve health in humans.

The authors walk through the evidence organ system by organ system. In animal models AKG extends lifespan across worms, flies, and mice. In humans, one retrospective study (Rejuvant, 42 people) reported an 8-year reduction in biological age measured by DNA methylation after roughly 7 months of Ca-AKG supplementation. A 6-month randomised trial in postmenopausal women showed a 37% drop in a bone breakdown marker. Older hospitalised patients gained weight and appetite on ornithine-AKG. Burn patients showed lower protein loss and faster wound healing. Kidney and liver disease patients showed improved metabolic markers.

The authors are appropriately measured: much of the human evidence is from small trials, several are decades old, and no completed placebo-controlled longevity RCT existed at publication (the ABLE trial was still recruiting). AKG shows an impressive breadth of biological activity — antioxidant, epigenetic, anti-inflammatory, mTOR-inhibiting — but the human clinical evidence base is still thin. The review is the most comprehensive single reference on the topic in the recent literature.

Key findings

AKG has multiple pleiotropic effects: TCA cycle intermediate, cellular energy substrate, precursor for amino acid biosynthesis, antioxidant, epigenetic regulator (via 2-oxoglutarate-dependent dioxygenases), and inhibitor of the mTOR pathway.
Serum AKG concentrations decline with age; supplementation is proposed to restore youthful metabolic signalling.
Animal lifespan data are robust: Ca-AKG extended C57BL/6 mouse lifespan 9.6–12.8% and healthspan 16.6–19.7% (Shahmirzadi 2020); C. elegans lifespan extended ~50% (Chin 2014); Drosophila lifespan extended 8–15% (Su 2019).
Human evidence highlighted: 6-month RCT in postmenopausal women showed 37% CTX reduction with 6 g/day Ca-AKG (Filip 2007); retrospective cohort (Rejuvant, Ca-AKG plus vitamins) reported 8-year biological age reduction over ~7 months (Demidenko 2021).
In hospitalised older adults, 10 g/day O-AKG for 4 months increased appetite, body weight, and albumin/transferrin, and reduced healthcare costs (Brocker 1994).
In severe burn patients, 20–30 g/day O-AKG reduced protein catabolism and shortened wound healing time from 90 to 70 days.
In cardiac surgery, 28 g intravenous AKG in cardioplegic blood reduced ischaemic biomarkers and post-operative acute renal failure risk.
AKG has been safely used at up to 6 g/day for 6 months. Gastrointestinal adverse effects (nausea, dyspepsia) can occur at higher doses.
Pharmacokinetics: AKG has a short plasma half-life (< 5 min), poor membrane permeability, and only ~40% is absorbed intact through the intestine — most is metabolised first-pass to glutamate, proline, and other amino acids.

What this study can and cannot tell us

This is a narrative review, not a systematic review or meta-analysis. The authors did not use pre-registered search strategies, formal risk-of-bias tools, or GRADE-style quality assessment. Individual claim strengths cannot be graded uniformly from the paper alone; readers should treat the synthesis as informed expert commentary.

The corresponding and senior author (B.K.K.) discloses board membership and equity in Ponce de Leon Health, the company that markets Rejuvant — the Ca-AKG product featured in the retrospective biological-age study cited prominently in the review. This is a substantive commercial interest and is disclosed clearly, but the review's overall framing of AKG as a promising longevity supplement aligns with that commercial interest.

Much of the reviewed human evidence is from small, old, and often uncontrolled studies. Several key clinical claims (hospitalised older adults, burn patients, kidney and liver disease) draw on trials from the 1980s and 1990s with small sample sizes and idiosyncratic outcome measures.

The 8-year Rejuvant biological-age reduction (Demidenko 2021) is a retrospective, uncontrolled cohort of 42 self-supplementing individuals — this is described in the review but not always with the caveats it warrants.

No completed placebo-controlled human RCT of Ca-AKG for longevity or biological age had reported results at publication. The ABLE trial and other RCTs referenced were still recruiting.

Tier 3

Alpha-Ketoglutarate Ameliorates Synaptic Plasticity Deficits in APP/PS1 Mice Model of Alzheimer's Disease

Navakkode S et al. · Aging Cell · 2025

Tier 2

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 et al. · Aging (Albany NY) · 2021