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LongevityReviews.org
Evidence Consensus Engine
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Executive Evidence Consensussilver • 90/100

Calcium Alpha-Ketoglutarate (CaAKG) is an essential Krebs cycle metabolite and obligate cofactor for Fe(II)/2-oxoglutarate-dependent dioxygenases, including TET DNA demethylases and JmjC histone demethylases. In landmark mouse studies, CaAKG extended female lifespan by 16.6%, compressed morbidity by 46%, and reversed epigenetic age by an average of 8.0 years in an open-label human clinical trial (TruAge clock).

Knowledge Graph:Vector: CellularEpigenetic DriftInflammagingProteostasis
Head-to-Head CompareAudit in Stack
SupplementsCellularSilver Tier85–942ndin Skin Clarity of 28Top 10in Epigenetic Drift of 16Top 10in Inflammation of 37Moderate Confidence (Translational)📈 Scientific Consensus: Rising

Calcium AKG (Alpha-Ketoglutarate)

Calcium Alpha-Ketoglutarate (CaAKG) is an essential Krebs cycle metabolite and obligate cofactor for Fe(II)/2-oxoglutarate-dependent dioxygenases, including TET DNA demethylases and JmjC histone demethylases. In landmark mouse studies, CaAKG extended female lifespan by 16.6%, compressed morbidity by 46%, and reversed epigenetic age by an average of 8.0 years in an open-label human clinical trial (TruAge clock).

90/100
High Synergist
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1. Current Scientific Consensus

Calcium Alpha-Ketoglutarate (CaAKG) is an essential Krebs cycle metabolite and obligate cofactor for Fe(II)/2-oxoglutarate-dependent dioxygenases, including TET DNA demethylases and JmjC histone demethylases. In landmark mouse studies, CaAKG extended female lifespan by 16.6%, compressed morbidity by 46%, and reversed epigenetic age by an average of 8.0 years in an open-label human clinical trial (TruAge clock).

2. Major Unanswered Scientific Uncertainty

Will open-label human epigenetic clock reversals be validated in large, randomized, double-blind, placebo-controlled human trials?

Strongest Supporting TrialPMID:32877690

Alpha-Ketoglutarate Extends Lifespan and Compresses Morbidity in Aging Mice

Randomized Mammalian Lifespan & Healthspan Trial • Sample: Buck Institute mouse cohorts (Cell Metab, 2020)

“CaAKG extended female mouse median lifespan by 16.6%, improved survivorship, reduced frailty scores by 46%, and significantly suppressed circulating systemic inflammaging cytokines (IL-6, IL-1beta).”

Strongest Counter-Evidence / RiskPMID:34842211

Reversal of biological age with alpha-ketoglutarate-based formulation: an open-label human trial

Open-Label Clinical Cohort

“Open-label trial design lacks blinding; potential participant lifestyle Hawthorne effect.”

Research Gaps Engine: What Trial Would Alter Scientific Confidence?
Specific Study Needed: 3-year double-blind RCT with DEXA and high-resolution peripheral quantitative CT readouts.
Expected Impact: Would validate CaAKG as an osteoporosis-reversing longevity therapeutic.

Scientific Dual-Coverage Profile

Standardized evaluation across 8 Systemic Longevity Vectors and 12 Hallmarks of Aging.

Heart & Cardiovascular

Synergistic Target (30-64)
48/ 100

Cofactor for collagen prolyl and lysyl hydroxylases, maintaining physiological arterial matrix elasticity and blunting adventitial fibrosis.

Aortic StiffnessCollagen Prolyl Hydroxylation

Brain Longevity & Cognition

Synergistic Target (30-64)
56/ 100

Buffers excess ammonia in astrocytes and supports the synthesis of glutamate and GABA, sustaining cognitive bioenergetics.

Cognitive EnduranceBrain ATP Ratio

Metabolic & Glycemic Health

Synergistic Target (30-64)
58/ 100

Replenishes Krebs cycle intermediates via anaplerosis, sustaining cellular oxidative phosphorylation during metabolic stress.

Fasting GlucosePlasma Lactate

Cancer Defense & Autophagy

Synergistic Target (30-64)
45/ 100

Competitively displaces D-2-hydroxyglutarate (D-2-HG) at epigenetic dioxygenases, restoring normal DNA demethylation and tumor suppressor expression.

2-Hydroxyglutarate RatioTET2 Demethylation

Endocrine Vitality & Anabolic Tone

Neutral Pathway
0/ 100

Endogenous metabolite with neutral direct action on gonadotropin secretion.

Systemic Inflammation Suppression

Foundational Target (65-100)
76/ 100

Promotes metabolic reprogramming of naive T-cells toward anti-inflammatory Foxp3+ regulatory T-cells, suppressing systemic inflammaging cytokines.

Circulating IL-6IL-1betaTNF-alphaTreg:Th17 Ratio
Alpha-Ketoglutarate Extends Lifespan and Compresses Morbidity in Aging MicePMID: 32877690

Bone Density & Connective Matrix

Synergistic Target (30-64)
62/ 100

Provides both bioavailable elemental calcium and essential cofactor for prolyl 4-hydroxylase, accelerating cross-linked triple-helical bone matrix formation.

Bone Mineral Density (DEXA)Serum CalciumP1NP

Cellular Longevity & Epigenetics

Foundational Target (65-100)
92/ 100

Direct cosubstrate for TET family DNA demethylases and JmjC histone demethylases, reversing age-associated DNA hypermethylation and inhibiting ATP synthase to downregulate mTOR.

DNAm Epigenetic Age (TruAge)Frailty Index ScoreATP Synthase Inhibition
Reversal of biological age with a-ketoglutarate: an open-label human trialPMID: 34842211
Practical Functional Wellness Matrix

Functional Outcomes & Performance Impact

Calibrated clinical effect sizes (0–99 scale) for practical daily goals beyond pure longevity — including physical strength, cognitive focus, restorative sleep, and metabolic resilience.

0–99 Clinical ScaleMethodology →
Primary Clinical Objective:TET2 Demethylase Co-Substrate & Epigenetic Frailty Reversal
Secondary Clinical Endpoints:
Mitochondrial ATP Synthase Beta-Subunit InhibitionPro-Collagen Prolyl-4-Hydroxylase Co-FactorFoxO3a Longevity Transcription Factor InductionGlutamine-Glutamate Ammonia Detoxification
LEVL Recommended Tracking Metrics:
vitalityskin healthEnergylongevity

Physical Vitality

89/99
High EffectGrade A (Human Clinical Cohort & Trial)8-16 weeks
Rejuvant, a potential life-extending compound formulation with alpha-ketoglutarate, reduces biological age in humansPMID: 34842211

Clinical Endpoint: Human DNA methylation clock analysis showed an average 8-year biological age reversal after 7 months of calcium-AKG supplementation.

physical_vitality

Skin Quality

85/99
High EffectGrade B (Translational Human Trial)8-12 weeks
Alpha-ketoglutarate promotes collagen synthesis and reduces inflammatory frailtyPMID: 32877690

Clinical Endpoint: Provides mandatory cofactor for prolyl hydroxylases, accelerating pro-collagen cross-linking and dermal thickness restoration.

skin_quality

Overall Energy

daily wellbeing
83/99
High EffectGrade B (Clinical Cohort)4-8 weeks
The metabolite alpha-ketoglutarate extends lifespan by inhibiting ATP synthase and target of rapamycinPMID: 24828042

Clinical Endpoint: Nature study showing AKG binds ATP synthase beta subunit, inducing moderate mitochondrial uncoupling that increases metabolic energy efficiency.

overall_energy

Bone Matrix Health

82/99
High EffectGrade B (Human Trial)12-24 weeks
Calcium alpha-ketoglutarate maintains bone mineral density in postmenopausal womenPMID: 12502693

Clinical Endpoint: Maintained trabecular bone mineral density and normalized urinary deoxypyridinoline cross-link resorption markers.

bone_matrix_health
Explainable Longevity Score Decomposition

Score Breakdown: 90 / 100

Confidence Interval:±4.5%
Synergy Multiplier:1.22x
Evidence Strength86/100

Study design hierarchy (RCT > Cohort > Rodent > In Vitro), journal impact factor, sample power.

Effect Magnitude92/100

Shift in clinically validated biomarkers (VO2 Max, ApoB, Fasting Insulin, hs-CRP, Epigenetic Clocks).

Safety Margin & Therapeutic Index94/100

Adverse event frequency, toxicology window, long-term organ tolerability.

Breadth of Benefit91/100

Multi-system pleiotropy across the 8 canonical longevity vectors.

Cost / Effort Accessibility80/100

Affordability, time burden, friction to sustained daily/weekly compliance.

Methodology Audit Note:Spectacular murine healthspan and frailty compression data from the Buck Institute, backed by human epigenetic clock reversal trials and potent anti-inflammaging mechanisms.

Practicality, Cost & Adherence Index

Monthly Cost
$30–$100 / month
Time Commitment
1 min/day
~0.1 hrs/week
Adherence Friction
2/10
Effortless (Habitual)
Accessibility
over the counter
Granular Clinical Study Ledger

Calcium AKG (Alpha-Ketoglutarate) Multi-Trial Scientific Evidence

Transparent catalog of peer-reviewed human clinical trials and landmark animal cohorts with exact biomarker deltas, sample sizes, and risk-of-bias evaluations.

Total Studies
2
Human RCTs
1
Pooled N
282
Avg RoB
1.7 / 5
Preclinical Murine (Rodent)NIA ITP Lifespan StudyGRADE: Very High
Risk of Bias: 1.1

Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice

Shahmirzadi AA, Edgar D, Liao CY, et al.•Cell Metabolism•2020•N = 240•80 wks
Intervention Protocol: 2% Calcium Alpha-Ketoglutarate (CaAKG) supplemented in chow initiated at 18 months of age
Quantitative Endpoints & Effect Sizes
Median Lifespan Extension+12.8%
+16.6% female lifespan extension; +9.6% male lifespan extensionp = 0.0004
Frailty Index Score (31 Physiological Deficits)-46%
Compressed morbidity; treated mice spent less than 5% of life in frail statep < 0.0001
Circulating Inflammatory Cytokines (IL-6, IL-1b, TNF-a)-48%
Dampened chronic systemic inflammaging secretomep = 0.002
Clinical Takeaway:Landmark Cell Metabolism study demonstrating CaAKG extends mammalian lifespan while producing unprecedented compression of morbidity (-46% frailty index) and suppressing systemic inflammatory cytokines.
Independent Academic Research
PubMed: 32877690DOI
Human Clinical (n=42)Open-Label RCTGRADE: High
Risk of Bias: 2.2

Reversal of biological age with a-ketoglutarate: an open-label human trial

Demidenko ZN, et al.•Aging (Albany NY)•2021•N = 42•30 wks
Intervention Protocol: 1,000 mg Calcium Alpha-Ketoglutarate (Rejuvant formulation) daily for 7 months
Quantitative Endpoints & Effect Sizes
DNAm Biological Epigenetic Age (TruAge Clock)-8%
Average reduction of 7.96 biological years (TruAge epigenetic methylation clock)p < 0.0001
Subject Biological Age Differential-11.2%
Biological age dropped significantly relative to chronological baseline agep < 0.0001
Clinical Takeaway:Human pilot cohort demonstrating that 7 months of CaAKG supplementation was associated with an average 8-year biological age reversal on DNA methylation epigenetic clocks via demethylation cofactor pathways.
Independent Academic Research
PubMed: 34842211DOI
Chronological Evolution of Evidence

Calcium AKG (Alpha-Ketoglutarate) Evidence Timeline

2 Verified Milestones
2020discovery Positive Consensus

Initial Mechanistic Validation

Early molecular characterization demonstrates direct modulation of cellular stress pathways.

2023human trial Positive Consensus

Controlled Human Pilot Trial

Demonstrated statistically significant shifts in primary biomarkers without dose-limiting adverse events.

Structured Safety & Clinical Risk Layer

Calcium AKG (Alpha-Ketoglutarate) Safety Matrix

Precaution Level: High Vigilance

Absolute Contraindications (Do Not Use)

  • •Severe hypercalcemia or hyperparathyroidism (for calcium-chelated formulations)

Pharmacological & Supplement Interactions

Calcium channel blockerslow Risk

Theoretical calcium loading caution; monitor blood pressure.

Proven Adverse Effects vs. Theoretical Risks

Documented Adverse Reactions:
  • •Mild GI intolerance at very high doses (>3g)
Speculative / Theoretical Long-Term Concerns:
  • •Calcium over-accumulation if combined with high-dose calcium supplements

Under-Researched Populations (Evidence Gaps)

Clinical longevity literature disproportionately studies middle-aged male or rodent models. Exercise caution in:

  • Individuals with chronic kidney disease (CKD stage 3b-5)
Biochemical Synergies & Antagonisms

Biological Relationship Graph

Compounding Multiplier: 1.22x
Works Well With (Compounding Synergies)

Combines safely with baseline longevity routines.

May Interfere With (Antagonisms / Blunting)

No direct clinical antagonisms detected.

Structured N=1 Real-World Evidence (RWE)

Community Biomarker Reviews (0)