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Calcium Alpha Ketoglutarate

Calcium α-Ketoglutarate (Ca-aKG)

Ageing is a natural process that is characterised by a functional decline in cells and tissues as organisms age, resulting in an increased risk of disease and mortality. To this end, many efforts have been made to control ageing and increase lifespan and healthspan. These efforts have led to the discovery of several anti-ageing drugs and compounds such as rapamycin and metformin. Recently, alpha-ketoglutarate (aKG) has been introduced as a potential anti-ageing metabolite that can control several functions in organisms, thereby increasing longevity and improving healthspan.

 

What is Ca-aKG?

α-Ketoglutarate (also called 2-oxoglutarate) is a five-carbon keto-acid intermediate of the tricarboxylic acid (TCA) cycle or also known as the Krebs Cycle, in mitochondria, which processes fuels (glucose, fats, amino acids) to generate energy. Alpha-ketoglutarate (aKG) is at the nexus of carbon and nitrogen metabolism. aKG is a key metabolite in the tricarboxylic acid (TCA) cycle, a series of reactions that is vital for oxygen-dependent energy derivation. As the alpha-keto acid of glutamate, it is an important component of amino acid metabolism and is an obligate partner in aminotransferase reactions. It directly or indirectly contributes to a host of catabolic and anabolic pathways. Given its broad influence, aKG may be viewed as a fundamental metabolic intermediate (Asadi Shahmirzadi et al., 2020).  In the TCA cycle, aKG is produced from isocitrate and is further oxidised to succinyl-CoA, generating NADH and ATP equivalents. The cycle thus not only produces energy but also provides NADH (the reduced form of NAD⁺) for the electron transport chain. NAD⁺ itself is an essential cofactor in many metabolic reactions, and its cellular levels decline with age (Lautrup et al., 2024). By influencing the NAD⁺/NADH balance, α-ketoglutarate (αKG) can indirectly affect the redox state and metabolic homeostasis (Wang et al., 2020).

Ca-aKG is simply the calcium salt of aKG, making it stable and orally absorbable. In biological systems, aKG has pleiotropic roles beyond energy metabolism. It is the α-keto acid of glutamate and a precursor for glutamine and other amino acids. aKG is an obligatory co-substrate for all 2-oxoglutarate–dependent dioxygenases, a family of enzymes that catalyse hydroxylation reactions. This includes prolyl-4-hydroxylases that hydroxylate proline residues in collagen (important for connective tissue and bone), and the prolyl hydroxylase domain enzymes that regulate hypoxia-inducible factor (HIF) (Zdzisińska et al., 2017). Critically, aKG is a cofactor for epigenetic enzymes, including the ten-eleven translocation (TET) DNA demethylases and Jumonji C (KDM/JmjC) histone demethylases (Zdzisińska et al., 2017).

In short, Ca-aKG feeds into the TCA cycle and serves in multiple fundamental pathways: metabolic energy production, amino acid biosynthesis, collagen (bone) synthesis, redox balance (NAD⁺/NADH), and epigenetic gene regulation. By replenishing aKG, Ca-aKG can influence these processes that are intimately tied to ageing.

Mitochondrial Energy Metabolism:

In brain cells, αKG restores mitochondrial membrane potential (the voltage across the mitochondrial membrane that drives ATP synthesis), improves ATP and NAD⁺/NADH balance (key energy and redox carriers), and lowers mitochondrial reactive oxygen species or ROS (damaging oxygen by-products), while at the same time suppressing the growth-promoting kinase mTOR (mechanistic target of rapamycin) and enhancing autophagy, the cell’s self-cleaning of damaged components; together these changes reduce neuronal senescence, which provides a mechanistic template for how Ca-aKG could protect the aging brain via mitochondrial metabolism (Guan et al., 2025).

At a systems level, Naeini et al. show that αKG can directly interact with mitochondrial ATP synthase and the alpha-ketoglutarate dehydrogenase complex, slightly lowering respiration rate and ATP/ADP ratio in a way that reduces ROS production and downregulates mTOR, mimicking dietary restriction and extending lifespan and health span in multiple species, which positions Ca-aKG as an anti-ageing intervention that “retunes” mitochondrial energy flux toward a lower-stress, longevity-supporting state.

Meng et al. integrate clinical and preclinical data and describe aKG (often given as Ca-aKG) as a mitochondrial metabolic regulator that improves cardiac and vascular ageing phenotypes by promoting mitophagy (selective removal of damaged mitochondria), strengthening antioxidant defences, and reducing mitochondrial ROS, while also supporting intestinal epithelial energy status and barrier integrity through its role in the TCA cycle. Through these mechanisms, Ca-aKG’s organ-level anti-ageing benefits emerge from better mitochondrial quality control and more efficient energy metabolism.

In skeletal muscle, Zhang et al. show that aKG combats sarcopenia-like muscle aging in mice by increasing superoxide dismutase (SOD, a key antioxidant enzyme), activating the SIRT1–PGC-1α–Nrf2 pathway that drives mitochondrial biogenesis and antioxidant gene expression, lowering ROS, and directly improving mitochondrial function and ATP-linked oxidative capacity, which translates into better muscle mass, fibre size, and strength. Taken together, these findings support a coherent picture in which Ca-αKG, by supplying αKG to the mitochondrial TCA cycle, recalibrates mitochondrial energy production, reduces oxidative and mTOR-driven stress, and maintains mitochondrial quality in the brain, muscle, and other tissues, thereby contributing to slower functional decline and an anti-ageing phenotype.

Inflammation and immune modulation:

Inflammaging is the term used to describe the chronic, low-grade, largely sterile inflammation that tends to occur as people age. It is marked by a small but persistent rise in circulating pro-inflammatory cytokines such as interleukin 6 (IL 6), tumour necrosis factor α (TNF α) and interleukin 1β (IL 1β), along with changes in innate and adaptive immune cells, and it is now seen as a major risk factor for most age-related diseases and late-life mortality.

  • Ca-aKG suppresses systemic inflammaging by reducing pro-inflammatory cytokine signalling. It lowers circulating IL-6, TNF-α, IL-1β and other age-elevated cytokines, while simultaneously enhancing IL-10 secretion from T cells. IL-10 is a potent anti-inflammatory mediator that restrains immune overactivation, and this shift toward an IL-10–dominant profile helps counter chronic low-grade inflammation that accelerates ageing (Asadi Shahmirzadi et al., 2020).
  • It deactivates microglia and reduces neuroinflammatory cytokine output in ageing-relevant brain regions. Ca-aKG suppresses microglial expression of IL-1β, IL-6, TNF-α and IFN-γ, decreases activation markers such as CD68 (Cluster of Differentiation 68), and restores a resting microglial morphology. By limiting microglial-driven inflammation, Ca-aKG helps protect neurons from age-linked inflammatory stress, a key contributor to neurodegeneration (Zhang et al., 2023).
  • It reduces inflammation-driven bone turnover and supports a less catabolic bone–immune environment. Ca-aKG decreases CTX (C-terminal telopeptide of type I collagen), a biochemical marker of inflammatory osteoclast activity (Filip et al., 2007), and improves mineral–endocrine balance by normalising phosphate and parathyroid hormone levels in chronically inflamed individuals (Zimmermann et al., 1996). Evidence from recent mechanistic reviews further shows that α-ketoglutarate, often administered as its calcium salt, alleviates bone-tissue inflammation and counters age-related skeletal degeneration (Wu et al., 2025).
  • Ca-aKG is associated with reduced biological age in humans, consistent with systemic inflammation modulation. Sustained-release Ca-aKG supplementation lowers DNA-methylation biological age by an average of eight years (Demidenko et al., 2021), a change aligned with the cytokine-reducing and immune-balancing effects seen in animal models of inflammaging (Naeini et al., 2023).

 

mTOR and AMPK signalling:

mTOR (mechanistic target of rapamycin) is a nutrient-sensing pathway that promotes cellular growth and protein synthesis, and its chronic activation accelerates aging by reducing autophagy and increasing the accumulation of cellular damage, whereas AMPK (Adenosine Monophosphate activated protein kinase) functions as an energy-stress sensor that activates repair processes such as autophagy, mitochondrial renewal, and antioxidant defense, thereby slowing aging by shifting cells toward a maintenance-focused state. By dissociating into bioactive aKG in vivo, Ca-aKG can engage conserved nutrient-sensing pathways in the same way aKG does in model organisms, where aKG has been shown to activate AMPK, inhibit mTOR, and extend lifespan (Su et al., 2019; Chin et al., 2014). In mammalian systems, aKG consistently suppresses mTOR signalling, which is the growth-promoting “mechanistic target of rapamycin” pathway, and it also enhances autophagy, the cell’s internal clean-up and recycling process, in ageing or stress-exposed neurons. At the same time, aKG reduces senescence markers, which indicate that cells have entered an aged, non-dividing state. Together, these effects provide a neuronal template for how Ca-aKG could protect the ageing brain by lowering mTOR activity and improving cellular stress resistance. (Guan et al., 2025). The AMPK–PGC-1α–Nrf2 axis is a signalling chain in which the energy sensor AMPK turns on PGC-1α, a master regulator of mitochondrial biogenesis, and Nrf2, a key transcription factor for antioxidant genes. In parallel, aKG directly activates the AMPK–PGC-1α–Nrf2 axis in the liver, improving mitochondrial function and antioxidant defences, which illustrates the AMPK side of the same longevity pathway that Ca-aKG would be expected to trigger systemically (Cheng et al., 2024). Importantly, in an Alzheimer’s disease mouse model, Ca-aKG itself restores synaptic function, helping neurons communicate more effectively. It also enhances autophagy in the hippocampus, and this occurs in an mTOR-dependent context. These findings support the idea that Ca-aKG provides geroprotective effects in the ageing brain by supplying aKG that activates AMPK-linked energy-stress responses. At the same time, Ca-aKG reduces mTOR-driven growth signals. Together, these combined actions shift cells into a maintenance-focused, anti-ageing state. (Navakkode et al., 2025).

Cellular Senescence/SASP:

SASP (Senescence-Associated Secretory Phenotype) is the inflammatory secretory profile produced by senescent cells. These cells no longer divide, but they remain metabolically active and start releasing Pro-inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α), Chemokines (e.g., CCL2), Matrix-remodelling enzymes (e.g., MMP3), Growth factors and Proteases. Cellular senescence contributes to ageing by releasing SASP factors that create chronic, low-grade inflammation, which gradually impairs tissue repair and accelerates functional decline. In senescent fibroblasts, aKG shifts cells toward a less inflammatory phenotype by lowering core SASP factors such as IL-1β, IL-6, CCL2, and MMP3 while leaving classical senescence markers largely unchanged, indicating selective suppression of SASP-driven inflammatory signalling (Asadi Shahmirzadi et al., 2020). Evidence from mesenchymal stem cells further shows that sustained aKG availability delays cellular senescence and reduces SASP output in aged tissues, linking aKG-regulated SASP control to tissue-level anti-ageing effects (Cao et al., 2025). This SASP-focused mechanism is also reflected in patent filings that identify aKG and its salts, including Ca-aKG, as agents capable of modulating SASP-associated inflammatory pathways in age-related contexts (patent - CA3142781A1). Taken together, these findings support the view that Ca-aKG promotes anti-ageing benefits by elevating aKG and suppressing SASP-mediated chronic inflammation across senescent and stem-cell populations.

 

Epigenetic Regulation: 

Epigenetic regulation, particularly DNA methylation and histone modifications, changes with age and helps drive functional decline across tissues, a process that can be quantified using DNA methylation “epigenetic clocks” that predict healthspan and mortality (Unnikrishnan et al., 2019; Horvath, 2013; Hannum et al., 2013). Alpha-ketoglutarate (aKG) is a Krebs-cycle metabolite that directly feeds epigenetic enzymes as a co-substrate for TET DNA demethylases (Ten-Eleven Translocation (TET) family of dioxygenases that modify DNA) and Jumonji histone demethylases, thereby linking cellular metabolism to chromatin state and epigenetic remodelling. Consistent with this role, aKG can reprogram macrophage activation via an aKG–JMJD3–H3K27me3 pathway, showing that physiological changes in aKG levels are sufficient to drive metabolic and epigenetic reprogramming of gene expression (Liu et al., 2017). In this pathway, aKG serves as an essential cofactor for the Jumonji demethylase JMJD3, enabling the removal of the repressive H3K27me3 histone mark and thereby promoting the activation of genes involved in cellular differentiation and immune regulation. Because Ca-aKG dissociates to release bioactive aKG and is a clinically used salt form, it is expected to engage the same aKG-dependent DNA and histone demethylases while offering a practical way to modulate these epigenetic pathways in humans (Zimmermann et al., 1996). Animal and mechanistic studies further show that aKG levels decline with age and that supplementation supports stem-cell function, improves skeletal ageing, and aligns with the rejuvenation of the ageing epigenome. Translating this to humans, a Ca-aKG–based formulation (Rejuvant) has been associated with a several-year reduction in biological age as measured by DNA methylation clocks, providing direct evidence that Ca-aKG can beneficially shift epigenetic ageing signatures in vivo (Demidenko et al., 2021). Building on these findings, the ABLE randomised trial (Alpha-ketoglutarate supplementation and Biological Age in middle-aged adults) is explicitly testing Ca-aKG as a geroprotective intervention with change in DNA methylation age as its primary outcome, positioning Ca-aKG as an anti-ageing strategy that acts through epigenetic regulation of biological age (Maier et al., 2023). The ABLE trial enrols older adults and assesses whether daily Ca-aKG supplementation over 12 months can slow or reverse epigenetic ageing markers and improve key functional measures of healthspan. A related patent (AU2018260646A1) describing Ca-aKG-containing compositions for promoting healthy ageing is consistent with this framework, treating Ca-aKG as a geroprotective agent that targets molecular hallmarks of ageing in humans. Taken together, the mechanistic, preclinical, clinical and patent evidence support a coherent model in which Ca-aKG supplies aKG to epigenetic dioxygenases, reshapes DNA methylation and histone marks, and, as a result, slows or partially reverses epigenetic ageing trajectories.