• Alpha-ketoglutarate (AKG), is a signaling molecule, an endogenous intermediary metabolite in the Krebs cycle. • It is involved in multiple metabolic and cellular pathways. • It functions as an energy donor, a precursor in amino acid biosynthesis, as well as a regulator of epigenetic processes and cellular signaling via protein binding. • AKG is a critical nutritional factor in the maintenance of gut homeostasis. • During aging, levels of alpha-ketoglutarate decline. • AKG supplementation extends lifespan in various organisms. •

Because AKG is a key intermediate in the Krebs cycle, it is mainly found in cells (in mitochondria and cytoplasm), but it can also be detected in small quantities (lM) in the bloodstream (Martin et al. 1989; Rocchiccioli et al. 1984; Wagner et al. 2010). 

Interestingly, physiological increases in AKG levels have been observed in the blood of humans after physical exercise (Brugnara et al. 2012), in the liver of starved pigeons (Kaminsky

Your gut bacteria or microbiome is populated by many bacterial strains when you are young. As you get older the number of strains diminishes and the bad bacteria is able to push out the good strains. This result is your body experiences a 10-fold reduction in AKG levels between the ages of 40 and 80.

Alpha-ketoglutarate acid or AKG is required for many healthy cellular processes that we take for granted when we are young. When AKG levels diminish many of those processes start to decline and most significant for older individuals is a loss of muscle and motor control.  AKG has a strong beneficial effect on vascular health. The issue here is not salt, but because it improves your vascular health your body does not see dramatic spikes in blood pressure caused by the constrictions of your vessels in response to salt.

⫸ α-Ketoglutarate (24, 2-oxypentanedioic acid or 2-oxy- glutaric acid) is present in all organisms and is an impor- tant small molecule metabolite in cells. α-Ketoglutarate (AKG) is an intermediate in the tricarboxylic acid cycle (TCA). As an anion of ketoglutaric acid AKG is also involved in the metabolism of nitrogen and amino acid. Numerous studies have demonstrated that intermedi- ates of the TCA cycle show other important physiologi- cal functions in addition to their metabolic roles. They can be considered as gene expression effectors, signal- ing molecules, and stress response regulators [117, 118]. Although AKG is an intracellular metabolite, it is also present in blood plasma. Plasma levels of AKG were found to be obviously lower in older adults compared to younger adults—from 1 mg/mL to a few ng/mL. Given this fact, and given the diversity of AKG physiological functions, reduced endogenous AKG levels may be a marker of aging. Several studies have reported longev- ity effects of AKG supplementation on C. elegans and D. melanogaster because it inhibits TOR kinase, acting on similar effects to that induced by dietary restriction [119, 120]. AKG supplementation has also been found to prolong longevity in yeast and mice [121, 122]. It is believed that aging is associated with dysfunction of the TCA cycle, leading to changes in the proportion of inter- mediates products in the TCA cycle. This, in turn, may cause changes in DNA methylation that initiate aging. AKG-dependent DNA and histone demethylases are part of epigenetic mechanisms that act in the control of aging [123]. In addition, AKG, as an antioxidant, may help to reduce the expression of age-related oxidative stress, alle- viate the adverse effects of stressors through ROS, and simulate dietary restriction.

Oxaloacetate (25) is an intermediate in the citric acid cycle. It is very important for regulating energy and main- taining glucose homeostasis. In C. elegans model, it has been involved in a nutrition-sensing pathway through a mechanism involving FOXO and AMP-activated protein kinases [124]. ⫷ [14]

α-Ketoglutarate (α-KG), a central carbon metabolite in the TCA cycle, is produced from isocitrate by isocitrate dehydrogenase (IDH). Recently, Chin et al. first discovered that α-KG could delay ageing and increase the lifespan of adult C. elegans by inhibiting ATP5B, the beta subunit of the catalytic core of ATP synthase, and the TOR pathway, thereby mimicking the effect of dietary restriction on longevity.[]