Calcium α-ketoglutarate (Ca-AKG): epigenetic regulation, energy, and healthy ageing
Calcium-α-ketoglutarate (Ca-AKG) is a bioactive form of α-ketoglutarate (α-KG), a molecule that occurs naturally in the human body and plays a central role in the citric acid cycle, the core process by which cells produce energy. Unlike many targeted supplements, Ca-AKG does not act on a single symptom, but supports several fundamental biological processes involved in aging. As a result, Ca-AKG affects several Hallmarks of Aging, including disrupted nutrient sensing, epigenetic changes, and inflammaging.
At the cellular level, α-ketoglutarate functions not only as an energy metabolite, but also as a cofactor for α-KG-dependent dioxygenase enzymes. These enzymes are essential for DNA demethylation and histone demethylation, processes that determine which genes are active or inactive. As we grow older, this epigenetic regulation becomes disrupted more often, which can contribute to accelerated “biological aging” of cells. The role of α-ketoglutarate in this epigenetic regulation, especially as a cofactor of TET and JmjC enzymes, has been described in detail in recent scientific reviews.¹
In addition, α-ketoglutarate appears to play an important role in regulating inflammatory processes and immune function. In preclinical research, α-KG has been shown to inhibit the activation of pro-inflammatory pathways and thus help reduce low-grade chronic inflammation, a core mechanism behind inflammaging.²
Interest in Ca-AKG within longevity science increased markedly after the publication of an animal study in Cell Metabolism by Shahmirzadi et al. (2020). In this study, Ca-AKG not only extended the lifespan of mice, but also improved several aspects of their healthspan. The treated animals showed less chronic inflammation, better physical performance, and a slower decline in bone and muscle function.³ This is relevant because it shows that Ca-AKG affects not only lifespan but, above all, quality of life during aging.
Human data are still developing, but the first indications are promising. In an observational analysis by Demidenko et al. (2021), users of a Ca-AKG supplement showed a reduction in DNA methylation-based biological age markers. Although this was not a randomized study, it supports the hypothesis that Ca-AKG can influence epigenetic features of aging in humans.⁴
Taken together, these findings outline a coherent biological narrative. Ca-AKG supports cellular energy production, helps keep epigenetic processes in balance, and may help temper chronic inflammation. This combination makes Ca-AKG particularly interesting within a longevity strategy aimed at slowing biological aging rather than fighting separate symptoms.
Ca-AKG is therefore not a quick fix, but a fundamental building block for those who want to invest in healthy aging at a deep biological level. Within a broader approach, in which diet, exercise, and recovery are central, Ca-AKG can help maintain resilience, energy, and functional health in the long term.
Sources:
- Codomo CA et al. (2020)
Metabolic regulation of gene expression by α-ketoglutarate-dependent dioxygenases. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748998/ - Liu et al. (2019)
α-Ketoglutarate orchestrates macrophage shifts through metabolic and epigenetic regulation. https://www.nature.com/articles/ni.3796 - Shahmirzadi et al. (2020)
Alpha-Ketoglutarate, an endogenous metabolite, extends lifespan and compresses morbidity in aging mice. Cell Metabolism, 32(8):1380-1393.e6.
https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30417-4 -
Demidenko et al. (2021)
Rejuvant® treatment … reduces biological aging in humans based on DNA methylation. https://pmc.ncbi.nlm.nih.gov/articles/PMC8660611/
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