We recently wrote about a Japanese in-vitro study in which the amino acid glycine rejuvenated older cells. So apparently glycine along is suitable for inclusion in an anti-aging supplement. In 2014 biochemists at the University of California Los Angeles published a study in Nature which could lead you to speculate that glycine AKG might work even better.
AKG is an abbreviation for alpha-ketoglutarate [structural formula shown on the right]. Cells produce this substance when they convert amino acids into energy. The supplements industry sells amino acids that are attached to AKG in the hope that these work better than amino acids on their own.
In their Nature study, the researchers exposed nematodes, Caenorhabditis elegans, to AKG and observed that they lived longer as a result. Each line on the graph represents an individual, but identical experiment.
The optimal concentration was 4-10 millimoles, as the figure above shows.
AKG reduced the concentration of ATP in the nematodes.
When the researchers modified the nematodes genetically so that their cells produced less ATP [atp-2 RNAi], they saw that the nematodes lived longer as a result – and that AKG supplementation no longer had a life-extending effect.
AKG is released during caloric restriction, the researchers write, so supplementation probably imitates the effects of caloric restriction.
“Longevity molecules that delay ageing and extend lifespan have profound implications and have long been a dream of humanity”, the researchers wrote. “Endogenous metabolites such as AKG that can alter Caenorhabditis elegans lifespan suggest that an internal mechanism may exist that is accessible to a myriad of regulations and interventions.”
Wild speculation on our part
It may just be the case that AKG and glycine reinforce each other’s life-extending effects. They are both linked to energy processes in the cell, but not in the same way. In addition, AKG inhibits the breakdown of glycine in the liver, so AKG boosts the bioavailability of glycine. [Arch Biochem Biophys. 1986 Sep;249(2):263-72.]
The metabolite ?-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.
Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits. Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that ?-ketoglutarate (?-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans. ATP synthase subunit ? is identified as a novel binding protein of ?-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution. Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan. We show that ?-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by ?-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells. We provide evidence that the lifespan increase by ?-KG requires ATP synthase subunit ? and is dependent on target of rapamycin (TOR) downstream. Endogenous ?-KG levels are increased on starvation and ?-KG does not extend the lifespan of dietary-restricted animals, indicating that ?-KG is a key metabolite that mediates longevity by dietary restriction. Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.
PMID: 24828042 PMCID: PMC4263271 DOI: 10.1038/nature13264 [PubMed – indexed for MEDLINE]