Essential amino acid L-threonine prolongs healthspan thanks to ferritin

Caloric restriction, which is the coordinated reduction of intake of all nutritional ingredients except vitamins and minerals, is proven to extend the lifespan of aging model organisms and improve healthspan. During caloric restriction, most metabolic processes and intermediates are reduced. A research team from Sungkyunkwan University School of Medicine, Suwon, Korea, hypothesized that those metabolites that have increased concentrations during caloric restriction might be involved in attenuating age-associated decline. To test their hypothesis, researchers screened for elevated metabolites in the worm Caenorhabditis elegans.

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The team identified several metabolic intermediates whose concentration was altered, of which the essential amino acid L-threonine increased the most. Recent studies imply that regulation of dietary amino acid levels can prolong healthspan and give motivation to further investigation of the effects of essential amino acids on senescence and age-related diseases. Threonine metabolism is crucial for stem cell maintenance. It is also a component of mucins and plays an important role in maintaining mucosal integrity, barrier constitution, and immune function regulation. Impaired threonine catabolism also promoted the healthspan of C. elegans.

The Korean study has proven that L-threonine supplementation increased the healthspan of worms. The results suggested it happens by attenuating ferroptosis in a ferritin-dependent manner. Ferroptosis is a programmed cell death type which is dependent on iron, while ferritin is an iron-storing protein able to release it in a controlled fashion. 

Transcriptomic analysis showed that L-threonine supplementation in worms increased expression of the gene FTN-1 encoding ferritin. It suggests that ferritin is an essential mediator of longevity promotion. The levels of ferritin are positively correlated with chronological aging, but the iron storage capacity of ferritin is compromised by age and senescence. The escape of iron from ferritin in the aging worms increases ROS generation, possibly leading to age-associated ferroptosis and diseases. The article stated that L-threonine supplementation protected against age-associated ferroptosis. Higher threonine levels upregulated FTN-1 renewal through the transcription factors DAF-16 and HSF-1. This process, in turn, reduced the hallmarks of ferroptosis, the redox-active iron level, and blocked the generation of ROS.

In humans, there is ferritin heavy chain 1 (FTH-1), whose expression is induced by activating the human homolog of DAF-16 called FoxO3. It suggests that threonine levels might also regulate human ferritin expression by activating the FoxO3 transcription factor. Ferritin imbalance stands behind iron-deficiency anemia, hypothyroidism, porphyria, and celiac disease in the case of deficiency. 

So far, most of the positive effects of threonine are linked to enhanced immunity through mucus formation and stimulation of pluripotency of embryonic stem cells. The above-mentioned research suggests a new mechanism of attenuation of cellular ferroptosis by threonine, which can improve health- and lifespan. Therefore, these optimistic results should be taken into human studies as soon as possible.

Source: Kim, J., Jo, Y., Cho, D. et al. L-threonine promotes healthspan by expediting ferritin-dependent ferroptosis inhibition in C. elegans. Nat Commun 13, 6554 (2022). https://doi.org/10.1038/s41467-022-34265-x

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