Tier 3 — preclinical

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

PubMed
PMID 34952764
DOI
10.1016/j.tem.2021.11.003
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

DesignNarrative review (not systematic; no pre-registered search strategy or quality assessment)
ModelSynthesis of published human clinical trials, cohort studies, and preclinical evidence on AKG supplementation
SampleNot applicable — narrative review synthesising dozens of primary studies
InterventionCovers 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
DurationNot applicable
EndpointsReviews: 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 (AKG) is a tricarboxylic-acid-cycle intermediate with roles in energy metabolism, amino-acid metabolism and 2-oxoglutarate-dependent enzymes. This 2022 narrative review summarizes proposed mechanisms and the then-limited human supplementation literature.

The human evidence reviewed spans several very different settings. A 42-person uncontrolled Rejuvant cohort reported a lower proprietary DNA-methylation age after several months; a small 6-month randomized trial in postmenopausal women found lower CTX with an AKG calcium salt compared with calcium alone; older clinical literature examined ornithine-AKG in hospitalized, burn, renal and other patients. These formulations, indications and endpoints are not interchangeable.

The authors emphasize that much of the human evidence was small, old or uncontrolled and that placebo-controlled longevity trials had not yet reported. The review is therefore a useful mechanistic and clinical-literature overview, not proof that AKG supplementation slows human aging.

Key findings

  • AKG has multiple pleiotropic roles: TCA-cycle intermediate, cellular energy substrate, precursor for amino-acid biosynthesis, antioxidant-related metabolite, epigenetic cofactor context through 2-oxoglutarate-dependent dioxygenases, and nutrient-signaling effects including mTOR-related pathways.
  • Circulating AKG concentrations have been reported to decline with age in some datasets; whether supplementation restores a clinically meaningful 'youthful' state in humans remains unproven.
  • Preclinical longevity findings discussed include roughly 50% lifespan extension in C. elegans (Chin 2014), roughly 8–15% in Drosophila (Su 2019), and sex- and cohort-dependent survival/frailty effects in C57BL/6 mice (Shahmirzadi 2020), where female survival improved but male lifespan was not significantly extended.
  • Human evidence highlighted includes a 6-month randomized double-blind trial in postmenopausal women using an AKG calcium salt providing 6 g/day AKG plus 1.68 g/day calcium versus calcium alone, with a larger CTX reduction but no significant between-group lumbar-spine BMD difference; and the uncontrolled 42-person Rejuvant cohort reporting a roughly 8-year TruAge change.
  • Older clinical literature reviewed included ornithine-AKG in hospitalized older adults, severe burns and other catabolic settings; those results concern different AKG salts/formulations and disease contexts rather than modern Ca-AKG longevity supplementation.
  • The review also discusses intravenous AKG in cardiac-surgery contexts and metabolic studies in renal or hepatic disease, which should not be extrapolated directly to oral Ca-AKG use in healthy adults.
  • Human tolerability data summarized by the review are limited and formulation-specific; gastrointestinal adverse effects have been reported at higher intakes.
  • AKG has a short plasma half-life and extensive intestinal/first-pass metabolism, complicating direct translation from experimental exposure to oral supplement dosing.

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.

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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