α-ketoglutarate (CaAKG)

Alpha-ketoglutarate (AKG) is a key intermediate of the tricarboxylic acid (TCA) cycle that also serves as an obligate co-substrate for a large family of dioxygenases — including TET methylcytosine hydroxylases and Jumonji-domain histone demethylases — that regulate the epigenome. Plasma AKG levels decline substantially with age in humans, which has motivated its supplementation in longevity research. In a 2020 mouse study (Asadi Shahmirzadi et al., Cell Metabolism), the calcium salt form (CaAKG) significantly extended median lifespan in female mice (by approximately 17%, with ~20% extension at the 90th percentile) while males showed only a non-significant numerical trend (~10%); frailty was reduced in both sexes, though the trial was conducted in a single cohort rather than through the rigorous multi-site NIA Interventions Testing Program. A small 7-month human RCT using the commercial formulation Rejuvant (Katcher et al., 2021) reported reductions in biological age as estimated by the Horvath epigenetic clock, but the study was industry-funded, small (n=42), and lacked a pre-registered primary endpoint. CaAKG is marketed as a supplement; no drug approval exists for aging indications, and independent replication in humans is absent.