Calcium Alpha-Ketoglutarate (Ca-AKG)
Ca-AKG is a central Krebs-cycle intermediate that acts as obligate cofactor for TET and JmjC demethylases. Shahmirzadi 2020 (Cell Metabolism) reported +16.6% median lifespan in female mice and 41-46% frailty reduction; the human ABLE RCT (NCT05706389) is still pending.
Calcium Alpha-Ketoglutarate (Ca-AKG) scored 6.8 / 10 (π Worth trying) on the BioHarmony scale as a Substance β Vitamin / Mineral / Nutrient.
What It Is
Type: Nutrient supplement (calcium alpha-ketoglutarate; Krebs-cycle metabolite).
Calcium alpha-ketoglutarate is the calcium salt of alpha-ketoglutarate, a central Krebs-cycle intermediate that doubles as an epigenetic signaling molecule. Endogenous AKG declines roughly 50% between youth and senescence, a gradient that Brian Kennedy's lab and others have flagged as a likely driver of age-associated epigenetic drift. The calcium salt form is used because free AKG is unstable in the gut; calcium chelation creates a shelf-stable, orally bioavailable delivery vehicle.
Three mechanisms make it one of the more interesting longevity candidates. First, AKG is the obligate cofactor for TET1/2/3 DNA demethylases and JmjC histone demethylases (KDM4, KDM6A/B), meaning low intracellular AKG directly compromises the cell's ability to resolve repressive methylation marks on active genes. Second, Chin 2014 (Nature) showed AKG non-competitively inhibits ATP-synthase subunit Ξ² and co-inhibits mTORC1 in C. elegans, a dual caloric-restriction mimetic mechanism that extended worm lifespan roughly 50%. Third, Shahmirzadi 2020 (Cell Metabolism) demonstrated Ca-AKG elevates systemic IL-10 in mouse T-cells; IL-10 knockouts lost all frailty and lifespan benefit, confirming the inflammation node is required rather than incidental.
Despite this mechanistic profile, Ca-AKG is rarely included in multi-ingredient longevity formulas. It appears disproportionately on sophisticated individual stacks (Bryan Johnson's Blueprint runs 2 g/day) and almost never on mainstream retail shelves. The landscape is divided between generic Ca-AKG at $15-30/month and the branded Rejuvant formula at roughly $150/month; the price delta is defended entirely by one uncontrolled retrospective study (Demidenko 2021) that the field is still waiting to see replicated in the ABLE trial.
Terminology
- AKG: Alpha-ketoglutarate, a central intermediate in the Krebs (citric acid) cycle and obligate cofactor for TET and JmjC demethylases.
- TET1/2/3: Ten-Eleven Translocation methylcytosine dioxygenases, the enzyme family that initiates DNA demethylation by oxidizing 5-methylcytosine. AKG is their obligate cofactor.
- JmjC: Jumonji C domain-containing histone demethylases (including KDM4 and KDM6A/B), which remove repressive methylation marks from histones. AKG is their cofactor.
- mTORC1: Mechanistic Target of Rapamycin Complex 1, the central nutrient-sensing kinase complex that drives anabolic signaling. AKG inhibits mTORC1 non-competitively per Chin 2014.
- IL-10: Interleukin-10, an anti-inflammatory cytokine. Shahmirzadi 2020 showed IL-10 knockout mice lose all lifespan and frailty benefits from Ca-AKG.
- CTX: C-terminal telopeptide of type I collagen, a serum biomarker of bone resorption. Filip 2007 showed CTX β37% on 6 g/day AKG + Ca.
- CAC: Coronary Artery Calcification, a CT-measurable biomarker of cardiovascular risk. MESA linked supplemental Ca >400 mg/day to +22% CAC progression.
- GrimAge / DunedinPACE / TruAge: Epigenetic clocks that estimate biological age from DNA methylation patterns. ABLE uses a composite of GrimAge, PhenoAge, Horvath, and Hannum.
- ABLE: Alpha-ketoglutarate for Biological age reduction: a Longevity Evaluation (NCT05706389), the 6-month DBRCT pending results.
- IDH: Isocitrate dehydrogenase, the enzyme that produces AKG in the Krebs cycle. IDH1/2 mutations (recurrent in glioma and AML) produce oncometabolite 2-HG and are the mechanistic basis for the oncology precaution.
- Rejuvant: Branded Ca-AKG product from Ponce de Leon Health containing 1 g Ca-AKG plus either Vitamin A (men's) or Vitamin D3 (women's) at above-UL doses.
Dosing & Protocols
Dosing information is summarized from published research and community reports. This is not a prescribing guide. Consult a healthcare provider before starting any protocol.
View 1 route and 4 protocols
Routes & Forms
| Route | Form | Clinical Range | Community Range |
|---|---|---|---|
| 1-2 g/day (longevity); 6 g/day (bone, Filip protocol) | 1-2 g/day AM fasted; Blueprint 2 g/day |
Protocols
Conservative longevity protocol (default) Clinical
- Dose
- 1 g/day generic Ca-AKG oral
- Frequency
- AM fasted
- Duration
- indefinite
Pair with K2 MK-7 180 mcg. No additional supplemental Ca elsewhere. Lowest-risk mechanism bet.
Blueprint protocol (Bryan Johnson) Anecdotal
- Dose
- 2 g/day oral
- Frequency
- AM fasted
- Duration
- indefinite
Stacked with 60+ interventions. Highest public single-person n. Claimed epigenetic reduction confounded by co-interventions.
Rejuvant label protocol (Ponce de Leon) Clinical
- Dose
- 1 g/day Ca-AKG + 25,000 IU Vit A (men) OR 5,000 IU D3 (women)
- Frequency
- daily
- Duration
- 6-12 months minimum
Demidenko 2021 regimen. Vit A dose is above UL (10,000 IU) and warrants retinol monitoring. Backed by one uncontrolled n=42 study.
Bone-preserving protocol (Filip 2007 derivative) Clinical
- Dose
- 6 g/day AKG + calcium
- Frequency
- daily
- Duration
- 24 weeks minimum
Postmenopausal osteopenic women. Only direct bone-endpoint RCT. 6x longevity dose, delivers ~1,200 mg elemental calcium daily. K2 co-admin mandatory.
How this score is calculated →
Upside (1.76 / 5.00)
| Dimension | Weight | Score | Visual | Weighted |
|---|---|---|---|---|
| Efficacy | 25% | 2.8 | 0.700 | |
| Breadth of Benefits | 15% | 3.2 | 0.480 | |
| Evidence Quality | 25% | 2.8 | 0.700 | |
| Speed of Onset | 10% | 2.0 | 0.200 | |
| Durability | 10% | 2.0 | 0.200 | |
| Bioindividuality Upside | 15% | 3.2 | 0.480 | |
| Total | 2.760 |
Upside Rationale
Efficacy (2.8/5.0). Mouse data is striking; human data is thin. Shahmirzadi 2020 (Cell Metabolism, male + female C57BL/6 mice, Ca-AKG in chow from 18 months) reported +16.6% median lifespan in females and +19.7% 90th-percentile lifespan, with composite frailty scores cut 41 to 46%. Filip 2007 (n=76, 24-week DBRCT in postmenopausal osteopenic women) showed serum CTX bone-resorption down 37% on 6 g/day AKG + Ca, but that dose is 6Γ the longevity protocol. Demidenko 2021 (n=42, uncontrolled, retrospective) reported TruAge biological age down ~8 years after 7 months on Rejuvant 1 g/day plus Vit A or D3; the effect survives neither the missing placebo arm nor the Vit D3 confound nor the Ponce de Leon funding trail. Effect size for aging endpoints in humans remains genuinely unknown pending ABLE (NCT05706389). Score reflects "plausibly real but unquantified in humans."
Breadth of Benefits (3.2/5.0). Mitochondrial energy flux (TCA substrate), DNA and histone demethylation (TET + JmjC cofactor), IL-10-mediated inflammation resolution, bone remodeling (Filip RCT), muscle maintenance (frailty data), and hippocampal plasticity (Navakkode 2025 APP/PS1 Alzheimer's mice, LTP and synaptic tagging improved, female response stronger). Most of these are mechanistic inferences rather than demonstrated human endpoints. Bone and frailty are the two human-adjacent pillars; cognition remains preclinical.
Evidence Quality (2.8/5.0). One weak human longevity study (Demidenko), one solid human bone RCT at 6Γ dose (Filip), one pending human DBRCT (ABLE), strong mouse lifespan data (Shahmirzadi), strong C. elegans data (Chin), emerging Alzheimer's mouse data (Navakkode). No meta-analysis. No Cochrane review. The defining evidence-integrity flag is that Brian Kennedy is simultaneously the field's primary academic champion AND an advisor/board member at Ponce de Leon Health, which manufactures Rejuvant. Per v0.5 evidence-integrity rules this is an industry-funding-concentration case β β0.5 penalty applied (default), not β1.0, because there is no burial signal or failed replication, just dependence on non-independent work. Net score 2.8 (would otherwise be 3.3).
Speed of Onset (2.0/5.0). TruAge changes in the Demidenko data were apparent by 4 months and maxed at 7 months. Filip bone CTX markers reached significance at 12 weeks and peaked at 24 weeks. Subjective effects are muted. Most users do not feel Ca-AKG the way they feel creatine, taurine, or caffeine. It is a trust-the-mechanism supplement on a months-to-years timescale, not a daily felt tool.
Durability (2.0/5.0). No published washout data in humans. Biological plausibility favors chronic dosing since endogenous AKG depletion is the state being corrected; stop supplementing and the declining age-curve resumes. ABLE includes a 3-month post-intervention follow-up designed to answer the washout question, unpublished as of April 2026.
Bioindividuality Upside (3.2/5.0). Older adults with depleted endogenous AKG and elevated epigenetic age are the clean responder profile. Female mice showed stronger lifespan, IL-10, and neurological effects than males in both Shahmirzadi and Navakkode, but human sex-stratified data does not exist. High-baseline-inflammation individuals theoretically respond more via the IL-10 node. Young users with pristine mitochondrial function likely see the smallest marginal benefit. Vegetarians on protein-restricted diets with lower endogenous AKG from glutamine cycling may respond more than omnivores.
Downside (0.61 / 5.00)
| Dimension | Weight | Score | Visual | Weighted |
|---|---|---|---|---|
| Safety Risk | 30% | 1.8 | 0.540 | |
| Side Effect Profile | 15% | 1.5 | 0.225 | |
| Financial Cost | 5% | 2.2 | 0.110 | |
| Time/Effort Burden | 5% | 1.2 | 0.060 | |
| Opportunity Cost | 5% | 1.5 | 0.075 | |
| Dependency / Withdrawal | 15% | 1.0 | 0.150 | |
| Reversibility | 25% | 1.2 | 0.300 | |
| Total | 1.460 | |||
| Harm subtotal Γ 1.4 | 1.701 | |||
| Opportunity subtotal Γ 1.0 | 0.245 | |||
| Combined downside | 1.946 | |||
| Baseline offset (constant) | −1.340 | |||
| Effective downside penalty | 0.606 |
Downside Rationale
Safety Risk (1.8/5.0). No intrinsic catastrophic adverse event has surfaced in RCT data, FAERS, CAERS, or longitudinal forum tracking across a decade of human use. Riedel 1996 documented 4.5 g/day tolerated for 36 months in dialysis patients without SAE. The two real considerations are calcium load and oncology-theoretical risk. Each gram of Ca-AKG delivers approximately 200 mg elemental calcium; at 1 g/day this is trivial, but at 2+ g/day users enter the supplement-derived calcium range that MESA 10-year follow-up (Anderson 2016, n=2,742) associated with a 22% increased coronary artery calcification risk. The AKG-in-cancer question is unresolved: AKG is substrate for TET2 and IDH enzymes recurrently mutated in glioma and AML, a theoretical flag for active IDH-mutant malignancy but not a documented supplementation harm. Per v0.5 catastrophic-floor rules: no intrinsic 4.0 trigger β the calcium-load concern is dose-dependent and interaction-mediated (supplemental calcium stacking), not an intrinsic AKG signal.
Side Effect Profile (1.5/5.0). Mild GI (loose stool, nausea) at higher doses. Rare lightheadedness consistent with a calcium bolus in sensitive individuals. One forum-level signal of fatigue at 1 g/day, heavily confounded by saturated-fat diet context. No muscle stiffness reports anywhere in community tracking. No rash, no headache, no mood signals above placebo background. Lower side-effect burden than most longevity compounds.
Financial Cost (2.2/5.0). Generic Ca-AKG powder runs $15-30/month at 1-2 g/day (DoNotAge, Kirkman Labs, Renue By Science liposomal). Rejuvant premium at roughly $150/month is widely regarded as unjustified given the uncontrolled study backing it. Per v0.5 accessible-channel cost rules, scored at the generic bulk channel β the 10Γ price premium for Rejuvant's single retrospective n=42 Vit-A-confounded paper is a weak value proposition when generic Ca-AKG delivers the same molecule.
Time/Effort Burden (1.2/5.0). One oral dose daily, AM fasted is the modal preference among longevity users. Mixes with other AM stack items (NAD precursors, taurine, glycine). Total daily commitment under 30 seconds. No cycling, no timing complexity, no food-pairing requirements.
Opportunity Cost (1.5/5.0). Rarely displaces other stack items; slots alongside NAD precursors, taurine, and glycine rather than replacing them. The main friction is that Vitamin A in the Rejuvant formula can stack into toxicity if users scale the dose without tracking retinol from other sources (cod liver oil, organ meats, pre-formed A in multivitamins). The calcium load also argues against stacking Ca-AKG with high-dose supplemental calcium. Per v0.5 audience-vs-indication rules, scored for the indicated population (adults 50+ with depleted endogenous AKG); for healthy young users with pristine mitochondrial function, the marginal benefit is smaller but the opportunity cost framing belongs in Verdict, not the dimension score.
Dependency/Withdrawal (1.0/5.0). None demonstrated. No receptor down-regulation, no HPA-axis involvement, no tolerance development in any published data or community reports. Per v0.5 dependency-vs-addiction framework, this is the substrate-class floor: stopping produces no rebound, no craving, no withdrawal.
Reversibility (1.2/5.0). Fully reversible in the primary sense: stopping returns endogenous AKG to whatever baseline age and diet produce. No adaptation must be unwound. The only theoretical non-reversibility is the CAC question: if supplemental calcium contributes to vascular calcification, that deposition is not easily reversed even after stopping, which is why the >2 g/day dose range carries asymmetric risk and earns a mild bump above the 1.0 floor.
Verdict
β Best for: Adults over 50 with elevated epigenetic age (measured via GrimAge, DunedinPACE, or TruAge). Postmenopausal women with documented osteopenia or osteoporosis (where the Filip 2007 bone-resorption data actually applies). Individuals with chronically elevated inflammatory markers (CRP, IL-6) who might benefit from the IL-10 mechanism. Disciplined longevity stack builders who accept the uncertainty of pending RCT data and price the intervention accordingly (generic, not Rejuvant). Pair with vitamin K2 (MK-7 180 mcg or MK-4 45 mg) to direct the calcium load to bone rather than vasculature. Stack alongside taurine, glycine, and NAD precursors.
β Avoid if: Primary hyperparathyroidism (additive hypercalcemia risk). Active coronary artery calcification or advanced atherosclerosis where supplemental calcium is contraindicated. Severe CKD with eGFR <30 (calcium clearance compromised). Active IDH-mutant malignancy (glioma, AML; precautionary via TET/IDH substrate mechanism). Pregnancy or lactation (insufficient data). Competitive athletes in weight-restricted sports sensitive to the ~200 mg calcium per gram load. Anyone expecting felt subjective effects β Ca-AKG is a mechanism-trust supplement, not a lived-experience supplement. If you need to feel it work, skip it.
Use Case Breakdown
The overall BioHarmony score reflects the intervention's primary evidence profile. These subratings are independent assessments per use case.
| Use Case | Score | Summary |
|---|---|---|
| πͺ Geriatric / Aging Population | 7.5 | Cleanest responder phenotype: adults 50+ with depleted endogenous AKG. Shahmirzadi frailty data directly targets this population. |
| πͺ Bone / Joint Health | 7.4 | Filip 2007: CTX bone resorption β37% at 24 weeks in postmenopausal women (6 g/day AKG + Ca). |
| πͺ Healthspan | 7.2 | Shahmirzadi frailty β41 to β46% in aged mice. Aligns with mechanism. Human translation pending. |
| πͺ Longevity / Lifespan | 7.0 | Shahmirzadi 2020: +16.6% median lifespan (β mice), +19.7% 90th-percentile. Human data pending ABLE. |
| πͺ Methylation Support | 7.0 | Direct TET/JmjC cofactor. Low intracellular AKG compromises demethylation of active genes. Core mechanism. |
| π Anti-Inflammatory | 6.8 | IL-10 mechanism confirmed in Shahmirzadi 2020 via IL-10 KO rescue failure. Human CRP/IL-6 translation untested. |
| π Telomere / DNA Repair | 6.4 | Demidenko 2021 TruAge β8y but n=42 uncontrolled and Vit D3 confounded. ABLE pending. |
| π Mitochondrial | 6.2 | TCA cycle substrate; indirect NAD/AMPK support. Chin 2014 ATP-synthase inhibition is CR-mimetic mechanism. |
| π Immune Function | 6.2 | IL-10 modulation is bidirectional; net benefit in inflammaging contexts per Shahmirzadi mechanism. |
| π Recovery / Repair | 6.0 | Mechanistic via TCA substrate; ties to Nick's personal performance note. No controlled RCTs. |
| π Cellular Senescence | 5.8 | Frailty data suggests downstream senescence impact; mechanism indirect. |
| π Memory | 5.8 | Preclinical hippocampal LTP and synaptic tagging signal; no human RCTs. |
| π Neuroplasticity | 5.8 | JmjC histone demethylase cofactor role is neuroplasticity-adjacent; mechanism solid, human data absent. |
| π Endurance / Cardio | 5.8 | Plausible via ATP cycling; no RCT in trained athletes. |
| βοΈ Cognition / Focus | 5.6 | No human data; Navakkode 2025 LTP improvement in APP/PS1 mice (female response stronger). |
| βοΈ Neuroprotection | 5.6 | Navakkode APP/PS1 Alzheimer's mice show LTP rescue. Preclinical only. |
| βοΈ Antioxidant / Oxidative Stress | 5.5 | Indirect via TCA substrate support and NADH cycling; no direct antioxidant RCTs. |
| βοΈ Autophagy | 5.5 | mTORC1 inhibition (Chin 2014) is an autophagy-favorable signal; no direct flux data. |
| βοΈ Strength / Power | 5.5 | Indirect via frailty-reversal signal; no RCT in trained athletes. |
| βοΈ Energy / Fatigue | 5.4 | Mechanistic TCA substrate rationale but no direct human energy endpoints. Nick notes subjective performance benefit. |
| βοΈ Metabolic Health | 5.4 | No direct human data; TCA substrate logic only. |
| βοΈ Skin / Beauty | 5.4 | Mechanism via fibroblast epigenetic remodeling; anecdotal only. |
| βοΈ Kidney Function | 5.4 | Riedel 1996: 4.5 g/day tolerated 36 months in dialysis patients without SAE. No benefit endpoint. |
| βοΈ Blood Sugar / Glycemic Control | 5.2 | No direct glucose RCTs in humans. |
| βοΈ Cardiovascular | 5.2 | Mechanism neutral; calcium-load concern at >2 g/day (MESA +22% CAC at supplemental Ca >400 mg/day). |
| βοΈ Stress / Resilience | 5.2 | Indirect via IL-10 inflammaging attenuation. |
| βοΈ Muscle Growth / Hypertrophy | 5.2 | No hypertrophy RCT data. |
| βοΈ Sleep Quality | 5.0 | No signal in literature or community reports. |
| βοΈ Stem Cell Support | 5.0 | No direct stem-cell data. |
| βοΈ Liver / Detoxification | 5.0 | No direct liver data. |
| βοΈ Body Composition / Fat Loss | 5.0 | No direct body comp data. |
| βοΈ Mood / Emotional Regulation | 5.0 | No mood signal in literature or forums. |
| βοΈ Anxiety | 5.0 | No direct evidence. |
| βοΈ Hormonal / Endocrine | 5.0 | No direct hormonal data. |
| βοΈ Hair / Nail Health | 5.0 | No data. |
| βοΈ Wound Healing | 5.0 | No direct evidence. |
| βοΈ Injury Recovery | 5.0 | No direct evidence. |
| βοΈ VO2 Max | 5.0 | No direct VO2 data. |
| βοΈ Chronic Pain Management | 5.0 | Anti-inflammatory mechanism is chronic-pain-adjacent but no direct pain RCTs. |
| βοΈ Depression | 4.8 | No signal. |
| βοΈ HRV / Vagal Tone / Autonomic Balance | 4.8 | No direct evidence. |
| βοΈ Flexibility / Mobility | 4.8 | No direct evidence. |
| βοΈ Gut Health / Microbiome | 4.8 | No direct gut evidence. |
| β Sleep Architecture (Deep/REM) | 4.5 | No direct evidence. |
| β Circadian Rhythm / Chronobiology | 4.5 | No direct evidence. |
| β Heavy Metal / Toxin Burden | 4.5 | No direct evidence. |
| β Nerve Regeneration | 4.5 | No direct evidence. |
| β Traumatic Brain Injury | 4.5 | No direct evidence. |
| β Flow State / Peak Mental Performance | 4.5 | No direct evidence. |
| β Creativity / Divergent Thinking | 4.5 | No direct evidence. |
| β Reaction Time / Coordination | 4.5 | No direct evidence. |
| β Libido / Sexual Health | 4.5 | No direct evidence. |
| β Fertility (Male) | 4.5 | No direct evidence. |
| β Fertility (Female) | 4.5 | No direct evidence. |
| β Pediatric Use | 4.5 | No pediatric evidence. |
| β Respiratory | 4.5 | No direct evidence. |
| β Eye / Vision Health | 4.5 | No direct evidence. |
| β Lymphatic / Drainage | 4.5 | No direct evidence. |
| β Cold / Heat Tolerance / Hormesis | 4.5 | No evidence. |
| β Acute Pain Relief | 4.5 | No evidence. |
| β Social Bonding / Empathy | 4.0 | Not applicable. |
| β Spiritual / Consciousness Expansion | 4.0 | Not applicable. |
| β Hearing / Auditory | 4.0 | No evidence. |
| β Dental / Oral Health | 4.0 | No evidence. |
| β Electromagnetic / Frequency Therapy | 4.0 | Not applicable. |
Frequently Asked Questions
What is calcium alpha-ketoglutarate and how does it work?
Ca-AKG is the calcium salt of alpha-ketoglutarate, a central Krebs-cycle intermediate that is also an obligate cofactor for TET1/2/3 DNA demethylases and JmjC histone demethylases. Chin 2014 in Nature showed AKG non-competitively inhibits ATP-synthase Ξ² and co-inhibits mTORC1, producing a dual caloric-restriction mimetic signature that extended C. elegans lifespan ~50%. Endogenous AKG drops ~50% between youth and senescence.
Does Ca-AKG really reduce biological age?
The claim rests on one uncontrolled study: Demidenko 2021 (n=42, retrospective) reported TruAge biological age down ~8 years after 7 months on Rejuvant plus Vit A or D3. The effect is large but lacks a placebo arm, co-administers D3 (itself an epigenetic modifier), and comes from Ponce de Leon-funded research. The properly controlled ABLE RCT (NCT05706389, n=120) is pending.
Is Rejuvant worth the premium over generic Ca-AKG?
Probably not. Generic Ca-AKG powder from DoNotAge or Kirkman Labs runs $15-30/month; Rejuvant runs ~$150/month. The 10Γ premium is defended entirely by Demidenko 2021, an uncontrolled retrospective n=42 study that also co-administered Vitamin A (at 25,000 IU, above the 10,000 IU UL) or Vitamin D3. Generic Ca-AKG delivers the identical molecule at a fraction of the cost.
What are the side effects of Ca-AKG?
Mild GI (loose stool, nausea) at higher doses. Rare lightheadedness consistent with a calcium bolus. The main quantitative concern is calcium load: each gram of Ca-AKG delivers ~200 mg elemental calcium, and MESA 10-year follow-up (Anderson 2016) associated supplemental Ca >400 mg/day with +22% coronary artery calcification progression. At 1 g/day Ca-AKG the load is trivial; at 2+ g/day, co-dose K2 to direct calcium to bone.
Who should not take Ca-AKG?
Avoid in: primary hyperparathyroidism (additive hypercalcemia), active coronary artery calcification (supplemental calcium contraindicated), severe CKD with eGFR <30, active IDH-mutant malignancy (glioma, AML β TET/IDH substrate concern), and pregnancy or lactation (data insufficient). Competitive athletes in weight-restricted sports sensitive to calcium load should weigh the ~200 mg Ca per gram.
How long before Ca-AKG works?
Most users do not feel Ca-AKG subjectively. Bone CTX markers reach significance at 12 weeks and peak at 24 weeks (Filip 2007). TruAge reductions in uncontrolled data appeared at 4 months and maxed at 7 months (Demidenko 2021). It is a mechanism-trust supplement on a months-to-years timescale, not a daily felt tool.
Can I take Ca-AKG with other longevity supplements?
Yes. Ca-AKG stacks cleanly with NAD+ precursors (NMN, NR), taurine, glycine, and rapamycin protocols β no known interaction conflicts. The primary stacking constraint is calcium load: avoid combining Ca-AKG with other high-dose supplemental calcium sources, and co-dose vitamin K2 (MK-7 180 mcg or MK-4 45 mg) to direct calcium into bone rather than vasculature.
Is Ca-AKG different from AAKG (arginine-AKG)?
Yes, fundamentally. Calcium-AKG is studied for longevity and bone endpoints. Arginine-AKG (AAKG) is a different salt studied mostly for nitric-oxide-mediated pump and performance effects in sport. They are not interchangeable and have distinct evidence bases. When the research discusses Ca-AKG or Rejuvant, it specifically refers to the calcium salt form.
How This Score Could Change
BioHarmony scores are living assessments. New research, regulatory changes, or personal context can shift the score up or down. These are the most likely scenarios that would change this intervention's rating.
| Scenario | Dimension shifts | New score |
|---|---|---|
| ABLE RCT confirms β₯2-year epigenetic-age reduction | Evidence 2.8β4.0, Efficacy 2.8β3.5 | 7.6 / 10 (πͺ Strong recommend) |
| ABLE RCT null on composite epigenetic endpoint | Evidence 2.8β2.0, Efficacy 2.8β2.3 | 6.3 / 10 (π Worth trying) |
| Independent RCT confirms CRP/IL-6 reduction in humans | Evidence 2.8β3.5, Breadth 3.2β3.8 | 7.3 / 10 (πͺ Strong recommend) |
| Head-to-head vs Ca citrate placebo shows benefit is the calcium, not AKG | Efficacy 2.8β2.0, Evidence 2.8β2.3 | 6.1 / 10 (π Worth trying) |
| Large observational confirms CAC signal at >2 g/day dose range | Safety 1.8β2.6 | 6.4 / 10 (π Worth trying) |
| Kennedy/Ponce de Leon COI resolved via fully independent replication | Evidence 2.8β3.6 (COI adjustment released) | 7.1 / 10 (πͺ Strong recommend) |
Key Evidence Sources
- Shahmirzadi AA, et al. 2020. Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice. Cell Metabolism 32(3):447-456. β Primary mammalian lifespan paper. +16.6% median lifespan β, frailty β41 to β46%, IL-10 KO rescue failure confirms mechanism.
- Chin RM, et al. 2014. The metabolite Ξ±-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510(7505):397-401. β Established dual AMPK/mTORC1 CR-mimetic mechanism. +50% C. elegans lifespan.
- Demidenko O, et al. 2021. Rejuvant, a potential life-extending compound formulation with alpha-ketoglutarate and vitamins, conferred an average 8 year reduction in biological aging. Aging (Albany NY) 13(22):24485-24499. β n=42, uncontrolled, retrospective, 7-month Rejuvant + Vit A/D3. Ponce de Leon Health funded. Kennedy COI flag is defining.
- Filip RS, et al. 2007. Effects of calcium and alpha-ketoglutarate acid supplementation on the treatment of postmenopausal osteoporosis. Adv Med Sci 52:171-175. β n=76 DBRCT, 6 g/day AKG + Ca, CTX β37% at 24 weeks. Strongest human RCT, dose 6x longevity protocol.
- ABLE Trial NCT05706389. Alpha-ketoglutarate for Biological age reduction: a Longevity Evaluation. 6-month DBRCT, n=120. β Composite primary endpoint: GrimAge, PhenoAge, Horvath, Hannum clocks. Registered 2023, results unpublished as of April 2026.
- Navakkode S, et al. 2025. Alpha-ketoglutarate improves hippocampal long-term potentiation and synaptic tagging in APP/PS1 Alzheimer's mice. β Female response stronger. Preclinical cognition/AD signal.
- Anderson JJB, et al. 2016. Calcium Intake From Diet and Supplements and the Risk of Coronary Artery Calcification (MESA 10-year follow-up). J Am Heart Assoc 5(10):e003815. β Supplemental Ca +22% CAC progression at >400 mg/day. Dose-relevant at >2 g/day Ca-AKG.
- Riedel E, et al. 1996. Correction of amino acid metabolism by alpha-ketoglutarate in hemodialysis patients. Kidney Int Suppl 55:S108-S110. β 4.5 g/day tolerated 36 months in dialysis, no SAE. Long-term tolerability data.
- Tang S, et al. 2023. Alpha-ketoglutarate and cellular reprogramming: review. Frontiers in Molecular Biosciences. β Review of TET/JmjC cofactor role and epigenetic aging.
- Su Y, et al. 2019. Alpha-ketoglutarate extends Drosophila lifespan by inhibiting mTOR and activating AMPK. Aging (Albany NY) 11(12):4183-4197. β Drosophila lifespan confirmation of Chin 2014 C. elegans mechanism.
- Tian Q, et al. 2014. Dietary alpha-ketoglutarate promotes beige adipogenesis and prevents obesity in middle-aged mice. Aging Cell. β Mouse metabolic data; thermogenesis mechanism.
Other interventions for Geriatric
See all ratings βπ How BioHarmony scoring works
BioHarmony translates a weighted expected-value calculation into a reader-facing 0β10 score. 5.0 is neutral (benefits and risks balance). Above 5 = benefits outweigh risks; below 5 = risks outweigh benefits.
Harm-type downsides (safety risk, side effects, reversibility, dependency) carry a 1.4× precautionary multiplier. Harm weighs more than benefit. Opportunity-type downsides (financial cost, time/effort, opportunity cost) are subtracted at face value.
Use case subratings are independent assessments of how well the intervention addresses specific health goals. They are not components of the overall score. Each subrating reflects the scorer's judgment based on use-case-specific evidence, safety, and effect sizes.
Every dimension is evaluated on a 1–5 scale, and the baseline (1) is subtracted before weighting. A perfect intervention with zero downsides contributes zero penalty rather than a residual floor, so top-tier scores are actually reachable.
EV = Upside − Downside
EV = 1.760 − 0.610 = 1.150
EV ranges from −5 to +5. Adding 7 shifts to 2–12, dividing by 12 normalizes to 0–1, then ×10 gives the 0–10 score.
Score = ((1.150 + 7) / 12) × 10 = 6.8 / 10
Further reading
4 Best AKG Supplements: Benefits, Dosage, & Review of Alpha-Ketoglutarate
Alpha-ketoglutarate is a natural longevity nutrient used to extend healthspan, enhance athletic performance, and boost overall wellbeing.
Control Your Genetics: A Deep Dive Into Epigenetic Testing, Biological Age Clocks, Longevity Protocols, Therapies & Supplementation
What if aging was optional? Or that you could actually have control over your genetics or genetic dispositions to diseases and the like. Inβ¦
