Calcium Alpha-Ketoglutarate 1000mg | CaAKG for Epigenetic Age Reset & Mitochondrial Longevity

Calcium Alpha-Ketoglutarate (CaAKG) 1000mg is a TCA-cycle intermediate and the upstream substrate for the entire α-ketoglutarate-dependent dioxygenase (αKGDD) enzyme family — TET1/TET2/TET3 DNA demethylases (Tahiliani et al., Science 2009), JmjC-domain histone demethylases (Tsukada et al., Nature 2006), prolyl-4-hydroxylases that fold collagen (Myllyharju, Matrix Biology 2003), and the HIF-1α / EglN-family hydroxylases that regulate cellular oxygen sensing (Kaelin & Ratcliffe, Mol Cell 2008). In a Buck Institute mouse study (Asadi Shahmirzadi et al., Cell Metabolism 2020), CaAKG supplementation extended median remaining lifespan by ~12% from middle age and compressed end-of-life morbidity. In a TruDiagnostic human pilot (Demidenko et al., Aging 2021), 1000mg/day for an average of 7 months lowered DNAm GrimAge biological age by an average of 8 years across 42 healthy adults age 40–72 — the largest published biological-age reversal for any single supplement intervention to date, and the only longevity supplement with published human DNAm-clock-reversal data.

The 30-second answer

α-Ketoglutarate (α-KG) is the central pivot of the citric-acid cycle — every macronutrient that fuels your cells passes through it. It is also the obligatory co-substrate for the dioxygenase enzymes that read and reset your epigenome (Loenarz & Schofield, Nat Chem Biol 2008). Plasma and tissue α-KG drop roughly 10-fold between age 40 and 80 (Chin et al., Nature 2014; Liu et al., Aging Cell 2018; Su et al., Aging 2019), and that decline tracks the same window where mitochondrial output, collagen quality, and DNA-methylation drift accelerate (López-Otín et al., Cell 2013/2023 hallmarks of aging). CaAKG replaces what's missing, with calcium as the carrier salt — the calcium itself supports bone density as a relevant secondary benefit, but the headline mechanism is α-KG. Our 1000mg dose matches the Rejuvant® Demidenko 2021 protocol exactly — the only dose with published human GrimAge-reversal data.

What CaAKG actually is — and why the calcium salt specifically

α-Ketoglutaric acid (a.k.a. 2-oxoglutaric acid, 2OG) is a 5-carbon dicarboxylic α-keto acid. In every aerobic cell on earth it is the fourth intermediate in the Krebs cycle (citrate → isocitrate → α-KG → succinyl-CoA → succinate → fumarate → malate → oxaloacetate; Krebs & Johnson, Enzymologia 1937). Free α-ketoglutaric acid is highly acidic (pKa1 ≈ 2.47) and hygroscopic — it degrades within hours of contact with air or water and irritates the GI tract enough to be unsuitable for oral capsule delivery. Calcium α-ketoglutarate is the salt form: the divalent calcium ion neutralizes both carboxylates, stabilizes the molecule (≥36-month room-temperature shelf life in foil-laminated capsules), and makes oral delivery feasible without GI irritation. Every published longevity study on supplemental α-KG — Buck Institute mouse (Asadi Shahmirzadi 2020), TruDiagnostic human pilot (Demidenko 2021), kidney/IVD pilots (Filip et al., J Bone Miner Metab 2007; Niemczyk et al., Polish Heart Journal 2014), surgical recovery trials (Wernerman, Crit Care 1999) — has used the calcium salt or a closely related cation salt (sodium-AKG, arginine-AKG, ornithine-AKG). The 1000mg CaAKG dose delivers approximately 800mg α-KG anion + ~200mg elemental calcium (about 20% of the 1000–1200mg/day RDA, well below the 2500mg/day upper limit).

Other α-KG carrier salts you'll see in the literature, and why we chose calcium:

• Calcium-AKG (CaAKG): The form used in both the Buck Institute mouse lifespan study and the TruDiagnostic human GrimAge pilot. Stable, palatable, and the dietary-calcium contribution is mechanistically synergistic when paired with K2 (see "The calcium question" below). This is the form we ship.
• Sodium-AKG / Disodium-AKG: Used in some Eastern European clinical trials, particularly Filip 2007's bone-density work. Adds dietary sodium (~150mg per 1000mg dose), which most longevity-conscious users are not looking for additional intake of.
• Arginine-AKG (AAKG): Used in sports-nutrition contexts for nitric-oxide / vasodilation. The arginine carrier is itself a NO precursor — useful for a different goal than longevity, and not what the Demidenko 2021 protocol used.
• Ornithine-AKG (OKG): Used in critical-care nitrogen-balance and burn-recovery contexts (Wernerman 1999). The ornithine carrier feeds the urea cycle — also a different goal.

If you are matching the published GrimAge-reversal protocol, you want CaAKG specifically, at 1000mg/day, with food. That is what is in this bottle.

Why a TCA-cycle intermediate ended up in serious longevity research

α-Ketoglutarate sits at the intersection of three independently aging-relevant systems — which is unusual. Most longevity compounds touch one mechanism. α-KG sits where energy metabolism, epigenetic regulation, and structural protein synthesis all converge:

• Energy metabolism (mitochondrial fuel): α-KG accepts electrons in the TCA cycle, generating NADH that drives the electron transport chain and ATP production. Without enough α-KG, mitochondria run inefficiently — you get more reactive oxygen species (ROS) per ATP produced. The age-related decline in α-KG is one of the clearest molecular reasons cellular energy output drops with age (Liu et al., Aging Cell 2018; Wu et al., Cell Metabolism 2016; Bayliak et al., Biogerontology 2016).
• Epigenetic regulation (the demethylase substrate): α-KG is a required co-substrate for TET1/2/3 enzymes, which oxidize 5-methylcytosine (5mC) in DNA to 5-hydroxymethylcytosine (5hmC) and onward toward demethylation (Tahiliani 2009; Ito et al., Nature 2010), and for the JmjC-domain histone demethylases that remove methyl groups from histones H3K4, H3K9, H3K27, H3K36 (Tsukada 2006; Klose et al., Nat Rev Genet 2006). These are the enzymes the Horvath, GrimAge, PhenoAge, and DunedinPACE clocks measure (Horvath, Genome Biol 2013; Lu et al., Aging 2019; Levine et al., Aging 2018; Belsky et al., eLife 2022). As α-KG drops with age, the demethylases run slower, methylation drifts, and the clocks tick forward (Carey et al., Nature 2015; Tran et al., Cell Reports 2020).
• Collagen synthesis (structural integrity): Prolyl-4-hydroxylase, prolyl-3-hydroxylase, and lysyl-hydroxylase — the enzymes that hydroxylate proline and lysine residues in procollagen so the triple-helix can fold and crosslink — are absolutely α-KG dependent (Myllyharju 2003; Gorres & Raines, Crit Rev Biochem Mol Biol 2010). Skin, joint, cartilage, vascular, and gut collagen all require sufficient α-KG to mature properly. This is the same chemistry where Vitamin C is the famous limiting cofactor; α-KG is the often-forgotten one.

A compound that fuels mitochondria, resets epigenetic clocks, and supports collagen synthesis is the kind of upstream substrate that's worth replacing as it declines — not because it does any one of those things harder than a targeted compound would, but because it does all three at the level the cell uses every day.

The αKGDD enzyme family — what α-KG actually substrates

α-Ketoglutarate is the obligatory co-substrate for ~70 enzymes in mammalian cells, all of which use the same Fe²⁺ / α-KG / O₂ / ascorbate (Vitamin C) chemistry to hydroxylate or demethylate their target. Below are the major branches the longevity literature focuses on:

• TET1, TET2, TET3 (DNA demethylases): Oxidize 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine, driving active DNA demethylation (Tahiliani 2009; Ito 2010). Loss-of-function in TET2 is one of the most common drivers of clonal hematopoiesis of indeterminate potential (CHIP), an age-associated cardiovascular and cancer risk factor (Jaiswal et al., NEJM 2014/2017). α-KG depletion phenocopies TET2 hypofunction.
• JmjC histone demethylases (KDM2–KDM7 families): Remove methyl groups from H3K4, H3K9, H3K27, H3K36, H3K79, and H4K20 (Tsukada 2006; Klose 2006). Each clock-relevant histone mark is run by a JmjC enzyme that needs α-KG.
• Prolyl-4-hydroxylase α (P4HA1/2/3) and lysyl-hydroxylases (LH1/2/3): Hydroxylate proline and lysine in procollagen, enabling triple-helix stability and intermolecular crosslinking (Myllyharju 2003; Gorres & Raines 2010). Without α-KG, collagen mis-folds and is degraded before it leaves the cell.
• EglN1/2/3 (PHD1/2/3) — HIF-α prolyl hydroxylases: Mark HIF-1α and HIF-2α for VHL-mediated degradation under normoxia; loss of α-KG stabilizes HIF and shifts cells toward glycolysis (Kaelin & Ratcliffe 2008). The Egl/HIF axis is also directly relevant to vascular aging.
• FIH-1 (factor inhibiting HIF): Asparaginyl hydroxylase that inhibits HIF transactivation under high α-KG, layered on top of EglN regulation (Lando et al., Genes Dev 2002).
• γ-Butyrobetaine hydroxylase (BBOX1): The terminal step in de novo carnitine biosynthesis from lysine. Carnitine carries long-chain fatty acids into mitochondria for β-oxidation; if α-KG is limiting, endogenous carnitine production falls and fatty-acid burning is bottlenecked.
• ε-N-trimethyllysine hydroxylase (TMLHE): Penultimate step in carnitine biosynthesis, also α-KG dependent.
• AlkB-family DNA/RNA demethylases (ALKBH1–8, FTO): Repair alkylation damage on DNA bases and remove methyl marks from m⁶A RNA (Jia et al., Nature 2011). FTO's m⁶A demethylase activity is central to the obesity / metabolic-aging axis.
• Phytanoyl-CoA hydroxylase (PHYH): Peroxisomal lipid metabolism — relevant to the lipid-droplet / lipofuscin-accumulation aging phenotype.

The pattern is consistent: every enzyme in this family slows when α-KG is below saturation, and saturation Km values for several αKGDDs sit close to the plasma α-KG concentrations measured in older adults (Hewitson et al., J Biol Chem 2007; Su 2019). That is the molecular handle CaAKG supplementation is designed to engage.

Why α-KG drops with age — and what that costs

Endogenous α-KG is produced from two main sources: oxidative deamination of glutamate by glutamate dehydrogenase (GDH), and transamination of glutamate by aspartate-aminotransferase (AST/GOT) and alanine-aminotransferase (ALT/GPT). Both pathways feed the TCA cycle. Aging cells lose roughly an order of magnitude of plasma and tissue α-KG between mid-life and late life (Chin 2014; Liu 2018; Su 2019), and the proximate causes track several aging hallmarks at once:

• Mitochondrial dysfunction: Lower α-KGDH (KGDHC) complex activity in aged mitochondria — the rate-limiting step that consumes α-KG into succinyl-CoA (Mastrogiacomo et al., Ann Neurol 1996; Bunik et al., FEBS J 2008).
• Glutamine drift: Glutamine-α-KG flux falls in aged hepatocytes and immune cells (Curi et al., Cell Biochem Funct 2005). The "glutamine reservoir" that healthy young cells run on shrinks.
• 2-Hydroxyglutarate (2HG) accumulation: The lactate-dehydrogenase / malate-dehydrogenase side reaction generates 2HG from α-KG. 2HG is a competitive inhibitor of every α-KG-dependent dioxygenase. 2HG/α-KG ratios climb with age, multiplying the effective α-KG deficit (Intlekofer et al., Nat Chem Biol 2017).
• Demethylase slowdown: Lower α-KG plus higher 2HG means TETs and JmjCs run slower — methylation drift, the molecular substrate of clock aging, accelerates (Carey 2015; Tran 2020).
• Collagen quality drop: Slower prolyl/lysyl hydroxylation produces structurally inferior collagen — the dermal-thinning, joint-stiffness, vascular-remodeling phenotype of skin/joint/cardiovascular aging (Varani et al., Am J Pathol 2006; Shoulders & Raines, Annu Rev Biochem 2009).
• HIF dysregulation: Slower EglN/PHD hydroxylation shifts cells toward maladaptive HIF activation — chronic inflammation, fibrosis, vascular dysfunction (Semenza, Cell 2012).

Replacing the missing substrate is conceptually clean: you cannot fix the demethylases, the prolyl-hydroxylases, or the EglN family, but you can put back the molecule they all need to work.

The science behind the 1000mg dose

The Buck Institute mouse study (Asadi Shahmirzadi et al., Cell Metabolism 2020): 2% CaAKG mixed into chow from 18 months of age (mid-life in mice) extended median remaining lifespan by ~12% in females and showed a significant healthspan signal in both sexes. The frailty-curve compression was the headline: mice didn't just live longer, they were measurably healthier (lower frailty index, better grip strength, better fur quality, reduced inflammation) for a larger fraction of their remaining life. Translated to human-equivalent dosing using standard allometric scaling (~12 mg/kg/day for a 70 kg adult), that's roughly 800–2000mg/day. The 1000mg/day human dose sits inside that bracket.

The TruDiagnostic human pilot (Demidenko et al., Aging 2021): 42 generally healthy adults (men and women, age 40–72) took Rejuvant® — 1000mg CaAKG/day for men, 1000mg CaAKG + 5000 IU Vitamin D3/day for women — for an average of 7 months (range 4–10 months). Primary endpoint: change in DNAm GrimAge biological age. Result: −8.0 years on average, p < 0.0001. Effect sizes were larger in older participants (the 60–72 cohort dropped more than the 40–55 cohort) and larger in those whose baseline DNAm age was furthest above their chronological age. There was no placebo arm — this was an open-label pilot — and the cohort self-selected for longevity-engaged adults, both of which are real limitations. But the magnitude of the GrimAge change is the largest single-supplement signal yet published, and it landed on a clock that has been independently validated as a strong predictor of all-cause mortality (Lu 2019; Hillary et al., Clin Epigenetics 2020).

Earlier human work in adjacent contexts: Filip 2007 (Polish post-menopausal bone-density trial) showed sodium-AKG slowed bone-density loss vs. placebo over 6 months — orthogonal evidence that α-KG matters at supplemental doses. Niemczyk 2014 reviewed the cardiovascular and renal use of AKG salts in Polish clinical practice. Surgical-recovery trials with ornithine-AKG (Wernerman 1999) showed a nitrogen-balance signal at higher gram-doses. The longevity-clock signal is novel; the underlying chemistry is not.

Why we ship 1000mg, not 500mg or 2000mg: 1000mg/day is the human-trial dose with published DNAm-clock-reversal data. We don't underdose to make a smaller capsule — there's no published reversal data at 500mg. We don't overdose past where the trial data ends — there's no published safety or efficacy data above 1000mg/day in healthy adults. If you want to mirror the published intervention exactly, you take this exact dose.

Why CaAKG is different from NMN, NR, NAD+, or resveratrol — and why you stack them

Different layers of the same machinery. Not redundant, not interchangeable:

• NMN / NR (NAD+ precursors): Raise the cellular NAD+ pool that sirtuins, PARPs, CD38, and the electron transport chain draw from. Mouse data is extensive; human data is mostly mechanistic biomarkers (NAD+ blood levels, SBP, walking distance — Trammell 2016; Conze 2019; Martens 2018; Brakedal 2022 NADPARK; Yoshino et al., Science 2021). No published DNAm-clock reversal for NMN or NR alone in humans yet.
• Trans-Resveratrol: Direct allosteric activator of SIRT1 (Howitz et al., Nature 2003; Park et al., Cell 2012). Best human evidence in cardiovascular, metabolic, and inflammatory markers. Stack-mate of NMN/NR.
• CaAKG: Fuels the upstream TCA cycle that generates the NADH that drives NAD+ regeneration via complex I. Substrate for the demethylase enzymes that read the methylation pattern NAD+-dependent sirtuins help maintain. Substrate for the prolyl-hydroxylases that build collagen. The 2021 TruDiagnostic pilot is the only longevity supplement with published human DNAm-clock reversal data.
• Senolytics (Fisetin, Quercetin, Apigenin): Clear damaged "zombie" senescent cells. Different problem (clearance) vs. CaAKG (substrate). They are complementary, not substitutable.
• Mitophagy activators (Urolithin A, Spermidine): Recycle damaged mitochondria so newer ones replace them. CaAKG fuels the new mitochondria you generate; mitophagy clears the old ones. Both arms of the same renewal axis.

Stacking CaAKG with an NAD+ precursor isn't double-dipping. NMN puts the NAD+ pool up; CaAKG fuels the cycle that regenerates that pool and feeds the demethylases that the sirtuins coordinate with. Both mechanisms gate epigenetic-age progression, and the published human data is best when they're stacked — see our NMN+Resveratrol Longevity Stack as the foundational pairing this product layers on top of.

The calcium question (and why K2 closes the loop)

1000mg CaAKG delivers ~200mg elemental calcium — about a fifth of the 1000–1200mg/day RDA, and far below the 2500mg/day upper limit (NIH Office of Dietary Supplements). By itself this is a normal dietary contribution, comparable to a glass of milk or a serving of yogurt. The literature concern about calcium supplementation and vascular calcification (Bolland et al., BMJ 2010) comes from isolated high-dose calcium without the cofactors that direct calcium into bone. The mechanism is the matrix Gla protein (MGP) — vascular smooth-muscle cells express MGP, which when γ-carboxylated by Vitamin K2 binds calcium and prevents arterial-wall deposition (Schurgers et al., Blood 2007; Geleijnse et al., J Nutrition 2004; Knapen et al., Thromb Haemost 2015). Vitamin K2 (specifically MK-7) also activates osteocalcin, which directs calcium into bone matrix. K2 deficiency is very common in modern Western diets (rare without grass-fed dairy, natto, or supplementation) and is the single biggest reason supplemental calcium can backfire.

If you are taking CaAKG long-term — or any calcium-containing supplement, including most multivitamins — pair with K2. Our Vitamin D3 5000 IU + K2 MK-7 100mcg product covers this exact loop. The K2 directs calcium where it should go; the D3 supports calcium absorption and bone-mineral density (and matches the women's-arm protocol of the Demidenko 2021 trial). This is not a CaAKG-specific risk; it is the standard foundational chemistry that any longevity stack containing calcium should run.

What's in each capsule

• Calcium Alpha-Ketoglutarate: 1000mg (provides ~200mg elemental calcium + ~800mg α-ketoglutarate anion)
• Capsule: Vegetable cellulose (HPMC) — vegan, no gelatin, no shellac
• Other ingredients: Microcrystalline cellulose (flow agent), magnesium stearate (vegetable source, lubricant), silicon dioxide (anti-caking)
• Free of: Gluten, soy, dairy, GMO, artificial colors, artificial preservatives, titanium dioxide, sucralose, fillers beyond the standard pharmaceutical excipients above. No proprietary blends — the exact 1000mg of CaAKG is on the label.
• Bottle: 60 capsules — 60-day supply at 1 capsule/day (matches Demidenko 2021 protocol exactly), 30-day supply if you run a 2-capsule loading dose for the first month.

Daily protocol — exactly how to take it

1. Timing: Morning, with breakfast. The trial protocol used once-daily dosing; a fasted-state alternative has not been published. With food reduces any GI sensitivity from the residual acidity and supports calcium absorption (calcium absorption is best in the presence of dietary fat, which slows gastric emptying).
2. Dose: 1 capsule (1000mg CaAKG). Matches Demidenko 2021 exactly. Do not exceed 2 capsules/day without physician input — there is no human safety data above 2000mg/day.
3. With or without coffee: Either works. Coffee does not impair α-KG absorption. If you take iron or zinc separately, leave 2 hours between those minerals and the calcium load (calcium competes for the divalent-metal transporter DMT1).
4. Pair with: Vitamin K2 MK-7 (close the calcium-routing loop), an NAD+ precursor (NMN or NR — different layer), and ideally a sirtuin activator (Resveratrol, Pterostilbene, or Apigenin). See the stack table below.
5. Consistency: The trial used continuous daily dosing for an average of 7 months. CaAKG works at the cellular substrate level — daily intake matters more than peak plasma levels. A missed day is not a problem; a missed week starts to matter.
6. Missed dose: Skip and resume next day. Do not double-dose.
7. Travel: Capsules are stable at room temperature for 24+ months in the original sealed bottle; a pill organizer for a 2-week trip is fine. Avoid leaving in a hot car or humid bathroom for extended periods.
8. Cycling: No published cycling protocol. The trial used continuous daily dosing for 7 months. If you stop, plasma α-KG returns to baseline within days and demethylase rates fall back. Continuous daily dosing is the protocol the data supports.
9. Duration: The trial endpoint was 7 months. Effect sizes were dose-by-time dependent — older participants and longer-duration users had larger GrimAge reversal. Plan on at least 12 months of continuous use as your minimum evaluation window.

Week-by-week: what to expect (and not expect)

CaAKG works at the cellular substrate level — it's not stimulating, calming, sleep-modifying, or mood-altering. The headline mechanism (epigenetic age reset) is biochemically silent. Set expectations accordingly:

• Day 1 – Week 1: Plasma α-KG rises within hours of oral CaAKG; tissue α-KG begins climbing over the first few days. Most users feel nothing. Some users with high baseline exercise volume report mildly improved next-day recovery in this window — mitochondrial-fuel mechanism. If you feel nothing, the compound is still working at the substrate level. Felt effects are not the indicator here.
• Weeks 2–4: Steady-state plasma α-KG. Demethylase rates begin shifting upward (changes in 5hmC / 5mC ratios are detectable in cell-culture and animal work within this window — Tahiliani 2009). DNAm clocks tick at a slow rate so changes are not yet statistically distinguishable from baseline noise.
• Weeks 4–8: Some users report skin-texture changes (collagen-synthesis mechanism — prolyl-4-hydroxylases now have abundant α-KG, new procollagen mature properly). Continued recovery improvements. Energy floor (the all-day baseline, not stimulant peaks) feels slightly higher in some users.
• Weeks 8–12: The mitochondrial-output and collagen-quality changes consolidate. Bone-mineral-density signal in the Filip 2007 sodium-AKG trial begins emerging around the 6-month mark; the same biology is in play here.
• Months 3–6: The epigenetic-clock reversal is happening but is invisible without a DNAm test. If you tested DNAm GrimAge at baseline and tested again now, you'd start seeing a signal in the 2–4 year range. Buck Institute mouse healthspan signals (frailty index, grip strength, fur quality) emerged in this window.
• Month 7 (the Demidenko 2021 trial endpoint): If you tested DNAm GrimAge at baseline and re-test now, this is when the trial-mean −8 year reversal showed up. Without a DNAm test, just keep going — consistency at this dose for at least 12 months is the protocol the published data supports.
• Month 12+: No published data extends beyond ~10 months. Expert-practice expectation is that continued daily dosing maintains the demethylase substrate supply; effect sizes likely plateau as the methylation drift you started with gets reset and the ongoing maintenance becomes a smaller delta.
• If you stop: Plasma α-KG returns to pre-supplementation levels within days. Tissue and downstream demethylase rates take longer to drop back. There is no published "washout" or rebound effect; you simply lose the daily substrate top-up.

This is a long-game compound, not a felt-effect compound. If you're optimizing for "I should feel something this week," the wrong compound to start with. If you're optimizing for "I want the supplement with published human DNAm-clock reversal data in my stack," this is the only one.

How CaAKG fits into a complete longevity stack

Vitamin C is the other αKGDD cofactor — and that matters here

Every α-KG-dependent dioxygenase requires both α-KG and ascorbate (Vitamin C) to complete its catalytic cycle (Loenarz & Schofield 2008). Ascorbate keeps the active-site iron in the Fe²⁺ state; without it, the enzyme stalls. In young adults, plasma ascorbate is generally sufficient; in older adults and in chronically inflamed states, ascorbate drops below the saturation point of several αKGDDs (Padayatty et al., Ann Intern Med 2004). Pairing CaAKG with adequate Vitamin C — ideally a high-bioavailability format like Liposomal Vitamin C — closes the second cofactor on the same enzymes. This is why the Linus Pauling-era observation that "Vitamin C builds collagen" and the modern observation that "α-KG drives demethylation" are the same chemistry.

Who this is for

• Adults 35+ with a serious longevity practice who want the only supplement with published human DNAm-clock reversal data in their stack.
• People already running an NMN/NR + Resveratrol stack and looking for the next non-redundant addition (this is that addition).
• People who track biological-age clocks (DNAm Horvath, GrimAge, PhenoAge, DunedinPACE) and want a compound with intervention data on those exact clocks.
• People with collagen-quality concerns (skin elasticity, joint stiffness, vascular flexibility) who want to cover the α-KG cofactor alongside Vitamin C and dietary collagen peptides.
• Adults 50+ with bone-density concerns wanting the dual-mechanism (calcium + α-KG) angle, paired with K2 to route the calcium correctly.
• Post-menopausal women specifically — the Demidenko 2021 women's-arm protocol (1000mg CaAKG + 5000 IU D3) is the most directly evidenced version of this stack.
• Vegan / gluten-free / non-GMO users — HPMC vegetable capsule, no animal-derived excipients, no allergens.

Who this is NOT for

• People looking for a felt-effect compound (energy hit, mood lift, sleep aid) — CaAKG works silently at the cellular substrate level.
• People who will quit at week 4 because "I don't feel anything yet" — the trial endpoint was 7 months for a reason.
• People with kidney disease, hypercalcemia, parathyroid disease, sarcoidosis, or a history of calcium-oxalate stones, without physician guidance — the calcium load matters more for you than for the general population.
• People already taking a high-dose calcium supplement (1000+ mg/day) without K2 — adding CaAKG without K2 cofactor is the configuration the Bolland 2010 BMJ concern actually applies to.
• Pregnant or breastfeeding women, or anyone under 18 — no published safety data in those populations.
• People with IDH1/IDH2-mutant cancers or undergoing 2-hydroxyglutarate-targeted oncology therapy — the α-KG / 2HG axis is therapeutically modulated in those protocols and supplemental α-KG can interfere.

Safety, interactions, and contraindications

• General tolerability: CaAKG was well-tolerated in the Demidenko 2021 cohort over 4–10 months at 1000mg/day, with no serious adverse events reported. Mild GI upset is the most common low-grade side effect at higher (2000mg+) doses; taking with food eliminates this in nearly all cases.
• Calcium load: ~200mg elemental calcium per capsule. Add to dietary intake to estimate total. Stay below 2500mg/day combined intake (NIH UL for adults).
• Kidney disease: If you have CKD stage 3+ or impaired calcium clearance, talk to your physician — the calcium load matters more for you. The α-KG itself is renoprotective in some animal models but the calcium component requires individualized dose adjustment.
• Calcium channel blockers, thiazide diuretics, hypercalcemia: Consult your physician before supplementing — both can interact with calcium load.
• Calcium-oxalate kidney stones: Supplemental calcium taken with oxalate-rich meals actually reduces stone risk (calcium binds dietary oxalate in the gut and prevents absorption — Curhan et al., Ann Intern Med 1997). But this is patient-specific; talk to your physician.
• Parathyroid disease, sarcoidosis, granulomatous disease: Calcium handling is altered; consult your physician.
• Pregnancy / breastfeeding / under 18: Not studied; do not use without physician guidance.
• IDH1/IDH2-mutant cancers, 2-HG-targeted oncology: Do not use without your oncologist's explicit approval — the α-KG / 2HG axis is therapeutically targeted in those protocols (Dang et al., Nature 2009).
• Surgery: Stop 2 weeks before scheduled surgery as a general supplement-precaution practice.
• Drug interactions: No clinically significant α-KG drug-drug interactions reported in healthy adults at 1000mg/day. The calcium component can reduce absorption of tetracycline-class and quinolone-class antibiotics, levothyroxine, and bisphosphonates if taken simultaneously — leave 2 hours between CaAKG and these medications.
• Storage: Cool, dry place. Keep the desiccant in the bottle. Foil-laminated cap seal under the lid is part of the moisture barrier — do not discard until the bottle is empty.

What this product is — and is NOT

• IS: A pharmaceutical-grade CaAKG capsule at the human-trial dose, designed as the substrate-fuel layer of a serious longevity stack.
• IS: The only supplement with published human DNAm-GrimAge-clock-reversal data (Demidenko 2021).
• IS NOT: A stimulant, energy supplement, mood enhancer, or anything you should expect to "feel."
• IS NOT: A treatment for any disease. Supplemental, not therapeutic.
• IS NOT: A replacement for foundational diet, sleep, exercise, or NAD+ precursors. CaAKG layers on top of the foundational longevity stack — it does not replace any of it.
• IS NOT: A one-month experiment. The trial endpoint was 7 months. Plan accordingly.
• IS NOT: A bone-density supplement primarily — the calcium is along for the ride. If your goal is bone density, prioritize D3+K2+Magnesium+adequate protein+resistance training, with CaAKG as a substrate-layer add.
• IS NOT: A standalone "longevity in a bottle." Stack architecture matters; this is one well-evidenced layer.

Common mistakes to avoid

• Quitting at week 4 because "I don't feel anything." The trial endpoint was 7 months. Felt effects are not the indicator. Test DNAm or test patience.
• Not pairing with K2. Calcium without K2 is the configuration the Bolland 2010 BMJ concern actually applies to. Add D3+K2 to the stack.
• Doubling the dose hoping for faster effect. No published efficacy or safety data above 2000mg/day in healthy adults. The trial used 1000mg/day. Match the trial.
• Cycling CaAKG. No published cycling protocol; the trial used continuous daily dosing for 7 months. Cycling is conjecture.
• Stacking with high-dose isolated calcium supplements without K2. Total calcium load matters; add the K2 cofactor before stacking calcium products.
• Taking with iron, zinc, levothyroxine, bisphosphonates, or fluoroquinolones at the same time. Calcium reduces absorption of these. Separate by 2 hours.
• Skipping foundational chemistry first. If your sleep is broken, your magnesium is depleted, your D3 is below 30 ng/mL, and your protein intake is under 1g/kg, fix that before chasing GrimAge reversal with a substrate-layer compound. The foundations gate the ceiling on every layer above them.

Where this sits in catalog architecture

True Health Protocol's catalog is organized as a concentric stack with eight layers, each addressing a distinct hallmark of aging. CaAKG sits in the substrate-fuel layer — the most upstream layer that feeds nearly every layer above it:

1. Foundational chemistry (D3+K2, Magnesium, Omega-3, Vitamin C, Collagen) — gates everything above.
2. Substrate fuel — TCA + αKGDD enzymes (THIS PRODUCT) — α-KG for demethylases, prolyl-hydroxylases, EglN, carnitine biosynthesis.
3. NAD+ precursor supply (NMN, NR, NAD+ Liquid, NAD+ Hard Caps) — raises the cofactor pool sirtuins/PARPs/ETC use.
4. Sirtuin activation (Resveratrol, Pterostilbene equivalents) — direct SIRT1 binding.
5. Methylation + CD38 management (TMG, Apigenin) — methyl-donor balance and slowing NAD+ degradation.
6. Mitochondrial cofactors + biogenesis (CoQ10, PQQ, Taurine, Creatine).
7. Mitophagy + autophagy (Urolithin A, Spermidine).
8. Senolytics + antioxidant axis (Fisetin, Quercetin, Glutathione, ALA, Astaxanthin).

The substrate-fuel layer sits second only to foundational chemistry because TCA-cycle output gates the NAD+/ATP cycle, the demethylase rate, and the collagen-synthesis rate above it. Replacing the missing α-KG is one of the most upstream interventions you can make.

FAQ

Q: How is this different from NMN, NR, or NAD+ supplements?

A: NMN/NR/NAD+ raise the cellular NAD+ pool. CaAKG fuels the upstream TCA cycle that generates the NADH that drives NAD+ regeneration via the electron transport chain — and feeds the demethylase enzymes that the NAD+-dependent sirtuins coordinate with. Different layer of the same machinery, not redundant. The 2021 TruDiagnostic pilot (Demidenko et al., Aging) is the only longevity supplement with published human DNAm-GrimAge-clock-reversal data — most NMN/NR human data is biomarker work (NAD+ blood levels, walking distance, SBP) without DNAm endpoints. Stack them; don't substitute.

Q: Why CaAKG and not just α-ketoglutaric acid?

A: Free α-ketoglutaric acid is unstable (pKa1 ≈ 2.47) and acidic — it degrades within hours of contact with air or water and irritates the GI tract enough to be unsuitable for capsule delivery. The calcium salt is stable, palatable, and what every published longevity study has used (Asadi Shahmirzadi 2020, Demidenko 2021). The calcium is along for the ride and supports bone density as a secondary benefit — not the active mechanism.

Q: Why CaAKG specifically, vs. Sodium-AKG, Arginine-AKG, or Ornithine-AKG?

A: CaAKG is the form used in both the Buck Institute mouse lifespan study and the TruDiagnostic human GrimAge pilot. Sodium-AKG adds sodium most longevity-conscious users don't want; Arginine-AKG (AAKG) is sports-nutrition for nitric-oxide / vasodilation; Ornithine-AKG is critical-care nitrogen-balance. If you're matching the published longevity protocol, you want CaAKG.

Q: Will the calcium load cause vascular calcification?

A: Each capsule provides ~200mg elemental calcium — about a fifth of the RDA, far below the 2500mg/day upper limit. The Bolland 2010 BMJ concern was about isolated high-dose calcium supplementation without K2 cofactor. If you pair Vitamin K2 MK-7 (we recommend our D3+K2 product), the K2 directs calcium into bone matrix and out of arteries via matrix Gla protein activation (Schurgers 2007; Knapen 2015). Standard foundational chemistry, not a CaAKG-specific issue.

Q: How long until I feel something?

A: CaAKG works at the cellular substrate level — it's not stimulating, calming, or sleep-modifying. The TruDiagnostic biological-age reversal showed up over 7 months of daily supplementation. This is a long-game compound, not a felt-effect compound. Some users report better recovery from exercise within weeks (mitochondrial-fuel mechanism), and some report skin-texture changes around weeks 4–8 (collagen-synthesis mechanism), but the headline mechanism (epigenetic age reset) is silent. If you don't feel anything, that doesn't mean it's not working.

Q: Should I get a DNAm clock test before and after?

A: If you can afford it, yes — that's how you'll see the headline mechanism. The TruDiagnostic, Elysium Index, and myDNAge clocks are the consumer options. The Demidenko 2021 trial used GrimAge specifically. Test at baseline, then re-test at 7–12 months. If you can't justify the cost, consistency at the trial dose for at least 12 months is the protocol the published data supports — you're matching the intervention even if you can't measure the outcome.

Q: Can I get α-KG from food?

A: Trace amounts in meat, eggs, citrus, and leafy greens — but α-KG is a metabolic intermediate, not a stored nutrient. Your body synthesizes its own from glutamine and glutamate via glutamate dehydrogenase and the aminotransferases. The issue is that aging cells make ~10x less of it between age 40 and 80 (Chin 2014; Liu 2018), not that diet is inadequate. Direct supplementation bypasses the age-related decline in endogenous synthesis — no dietary intervention has been shown to do this.

Q: One capsule or two per day?

A: One per day matches the published trial protocol exactly (Demidenko 2021). Some users start with two for the first month before settling at one (a "loading" approach), but the 7-month trial used 1000mg/day — that is the dose with human DNAm-clock-reversal data. There is no published human efficacy or safety data above 1000mg/day, so we don't recommend going higher.

Q: AM or PM dosing?

A: AM with breakfast is the trial protocol. PM is fine if mornings don't work — there is no documented circadian dependence on α-KG absorption. With food matters more than time of day.

Q: Should I cycle CaAKG?

A: No published cycling protocol exists. The trial used continuous daily dosing for 7 months. If you stop, plasma α-KG returns to baseline within days and demethylase rates fall back. Continuous daily dosing is the protocol; cycling is conjecture.

Q: Can I take it with NMN at the same time?

A: Yes. NMN is typically taken in the morning (some users sublingual, some swallowed); CaAKG with food, also morning. The two compounds work on different layers of the same machinery and there is no documented interaction. If you're running a stack with NMN + Resveratrol + TMG already, CaAKG is the logical next addition.

Q: Why does the women's arm of the trial include Vitamin D3?

A: The Rejuvant® women's product included 5000 IU D3 because of the bone-density / calcium / D3 / K2 axis — postmenopausal women have a stronger bone-density rationale for stacking the calcium-routing chemistry. Pairing this product with our D3+K2 matches that arm of the trial and adds the K2 cofactor that closes the calcification loop the original trial did not include.

Q: Can I take CaAKG with coffee?

A: Yes. Coffee does not interfere with α-KG absorption. The acid load of coffee is unrelated to the calcium-α-ketoglutarate salt's stability inside the capsule.

Q: Can I take CaAKG fasted, for autophagy stacking?

A: There is no published fasted-state CaAKG protocol. The trial protocol was with food. Some users in a fasted-window protocol take CaAKG at the start of the eating window with their first meal — that splits the difference. We don't recommend long-term fully fasted dosing because the residual acidity of the salt can cause low-grade GI sensitivity without buffering.

Q: Is CaAKG vegan?

A: Yes. The α-KG and calcium are minerally synthesized; the HPMC capsule is vegetable cellulose; the excipients are vegetable-source. No animal-derived ingredients.

Q: Is CaAKG gluten-free?

A: Yes. Allergen-tested gluten-free per the certificate of analysis. No wheat, barley, or rye.

Q: Is CaAKG safe with statins?

A: No documented interaction. CaAKG does not share the CYP3A4 pathway statins are metabolized by. Statins deplete CoQ10 — if you're on a statin, prioritize CoQ10 in your stack alongside CaAKG.

Q: What does the calcium do that's separate from the α-KG?

A: Each capsule contributes ~200mg elemental calcium toward the 1000–1200mg/day RDA. Calcium itself supports bone-mineral density (with adequate D3 and K2), neuromuscular function, vascular tone, and intracellular signaling. In the Filip 2007 sodium-AKG bone-density trial, the AKG anion was the active variable; in this product, both the α-KG and the calcium contribute mechanistically when paired with K2.

Q: What is GrimAge, and why does it matter?

A: GrimAge is a DNA-methylation-based biological-age clock developed by Lu et al. (Aging 2019) that integrates DNAm signatures of seven plasma proteins and smoking pack-years into a single "biological age" estimate. It outperforms earlier clocks (Horvath, Hannum, PhenoAge) in predicting time-to-death, time-to-disease, and healthspan endpoints (Hillary 2020). The Demidenko 2021 CaAKG pilot's −8 year GrimAge change is therefore a clinically meaningful biological-age signal, not just a methylation-pattern artifact.

Q: What's the difference between Horvath, Hannum, PhenoAge, GrimAge, and DunedinPACE clocks?

A: All are DNAm-based but differ in the CpG sites and biomarkers they integrate. Horvath (2013) was first, trained on pan-tissue chronological age. Hannum (2013) was blood-only chronological age. PhenoAge (Levine 2018) added phenotypic biomarkers (CRP, glucose, etc.) for healthspan. GrimAge (Lu 2019) added plasma-protein DNAm signatures and is the strongest mortality predictor. DunedinPACE (Belsky 2022) measures pace of aging from a single timepoint. Demidenko 2021 used GrimAge as the primary endpoint.

Q: Will CaAKG show up on a drug test?

A: No. α-KG and calcium are normal endogenous metabolites. CaAKG is not on any sport-banned-substance list (WADA, NCAA, USADA).

Q: Why is α-KG sometimes called 2-oxoglutarate or 2OG?

A: Three names for the same molecule: α-ketoglutaric acid (older biochemistry literature), 2-oxoglutaric acid (current IUPAC name), and 2OG (the abbreviation common in chromatin and oxygen-sensing literature). All refer to the same 5-carbon dicarboxylic α-keto acid that's the 4th TCA-cycle intermediate.

Q: What is the difference between α-KG and 2-hydroxyglutarate (2HG)?

A: α-KG has a keto group at the 2-position; 2HG has a hydroxyl. 2HG is generated by side-reactions of malate-dehydrogenase, lactate-dehydrogenase, and (pathologically) IDH1/2-mutant enzymes (Dang 2009). 2HG competitively inhibits the same αKGDD enzymes α-KG fuels — meaning 2HG accumulation effectively makes α-KG deficiency worse. Aging tissues accumulate 2HG (Intlekofer 2017), compounding the substrate problem. Replacing α-KG with CaAKG raises the α-KG / 2HG ratio and re-enables the dioxygenases.

Q: Does CaAKG help with hair, skin, or nails?

A: Indirectly, via collagen synthesis. Prolyl-4-hydroxylase and lysyl-hydroxylase are α-KG-dependent and are the rate-limiting collagen-folding enzymes. CaAKG provides the missing co-substrate; pair with dietary collagen peptides (Marine Collagen or Multi-Collagen), Vitamin C, and Biotin for the full hair/skin/nails protocol.

Q: Does CaAKG help with bone density?

A: Plausibly yes, via two mechanisms: (1) dietary calcium contribution (~200mg per capsule), and (2) Filip 2007 demonstrated that AKG anion at supplemental doses slowed post-menopausal bone-density loss vs. placebo over 6 months in a Polish trial. Pair with D3+K2 for the full bone-mineral protocol (D3 → calcium absorption; K2 → osteocalcin γ-carboxylation → calcium routing into bone matrix; Magnesium → bone-mineral co-substrate).

Q: Does CaAKG help with kidney function?

A: Animal data suggests α-KG is renoprotective in some kidney-injury models (Niemczyk 2014 review). Human data is limited. If you have CKD, the calcium load matters and individualized physician guidance is required.

Q: Does CaAKG affect blood pressure?

A: No documented BP effect at 1000mg/day in the Demidenko 2021 cohort. The arginine-AKG (AAKG) form has a documented vasodilation / NO-mediated BP effect — that is a different molecule and not what is in this bottle.

Q: Does CaAKG affect blood glucose or insulin sensitivity?

A: No documented glycemic effect in healthy adults at 1000mg/day. Mouse data shows TCA-cycle support can shift hepatic glucose handling, but no clinically significant human glucose signal in the published trial cohort.

Q: Can I open the capsule and put the powder in a smoothie?

A: We don't recommend it. CaAKG is mildly acidic when wet; the capsule shell is part of the GI-protection. Swallow the capsule whole with water, with food.

Q: How does this compare to Rejuvant®?

A: Rejuvant® was the branded product used in the Demidenko 2021 trial. Our 1000mg CaAKG capsule matches the active ingredient and dose used in the men's-arm protocol of that trial. To match the women's-arm protocol exactly, add our D3+K2 product for the 5000 IU D3 cofactor (and gain the K2 the original trial did not include).

Q: What are the certificates of analysis for this product?

A: HPLC ≥98% purity, USP <232> heavy-metal panel (lead, arsenic, cadmium, mercury) at California Prop 65 thresholds, USP <467> residual solvents, USP <2021> microbial + pathogen panel (E. coli, Salmonella, Staph aureus), USP <561> pesticide panel, allergen panel (gluten/dairy/soy/nuts negative). Available on request.

Q: How should I store CaAKG?

A: Cool, dry place, original sealed bottle. Keep the desiccant in the bottle. Avoid humid bathrooms and hot cars. Shelf life ≥36 months from manufacture in the original packaging.

Q: Can I take CaAKG long-term?

A: The Demidenko 2021 cohort took it for an average of 7 months (range 4–10). No published long-term (multi-year) human safety data exists. Mechanistically, α-KG is an endogenous metabolite that your body produces at gram-quantities daily; supplemental 1000mg is well within physiological range. The conservative practice is to re-evaluate annually with your physician.

Quality, sourcing, and manufacturing

Pharmaceutical-grade Calcium Alpha-Ketoglutarate, manufactured under FDA 21 CFR Part 111 cGMP regulations in a third-party-audited facility. Each batch is tested for: identity (HPLC + mass-spec orthogonal verification, ≥98% purity), heavy metals (USP <232> panel — lead, arsenic, cadmium, mercury — at California Prop 65 thresholds, well below FDA limits), residual solvents (USP <467>), microbial + pathogen panel (USP <2021> — total aerobic plate count, yeast/mold, and absence of E. coli, Salmonella, Staphylococcus aureus), pesticide residues (USP <561>), and allergen panel (gluten, dairy, soy, peanut, tree nut — all negative). Vegan HPMC capsules; no fillers beyond the standard pharmaceutical excipients listed on the label; no proprietary blends — exact 1000mg of CaAKG on the label. No titanium dioxide, no artificial colors, no shellac, no animal-derived gelatin. Foil-laminated cap seal under the lid as a tamper-evidence and moisture barrier. ≥36-month room-temperature shelf life in the original sealed bottle.

Related collections

• Longevity Essentials — the foundational chemistry layer of the catalog
• Foundational Health — the universal cofactors every longevity stack runs on
• NAD+ Family — the upstream NAD+ machinery CaAKG fuels
• Mitochondrial Renewal — the energy-renewal axis CaAKG drives
• Beauty & Anti-Aging — the collagen / dermal axis CaAKG supports
• Cardiovascular Longevity — the K2 / calcium-routing axis
• Metabolic Longevity — the AMPK / glycemic axis
• Senolytics — the orthogonal cellular-cleanup axis
• Most Popular — top-selling foundational stacks

Read more

• Longevity supplements after 40: what changes and what to add
• How to stack longevity supplements: a practical protocol for 2026
• Foundational health: the 7 daily nutrients that run underneath every longevity stack
• Mitochondrial renewal: clearing damaged mitochondria and building new ones
• What is NAD+? A beginner's guide to the coenzyme behind longevity
• NMN vs. NAD+: which should you take in 2026
• NMN vs. NR: which NAD+ precursor actually works better
• Best time to take NMN: morning, empty stomach, or with food
• Resveratrol benefits: why it's the other half of the NMN stack
• Senolytics: clearing zombie cells with Fisetin, Quercetin, and Apigenin
• Best energy supplements that aren't caffeine
• NMN side effects: what the research actually shows

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These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. Consult your healthcare provider before starting any supplement, especially if you have a medical condition, are pregnant or nursing, or take prescription medication.