On the benefits of the tryptophan metabolite 3-hydroxyanthranilic acid in Caenorhabditis elegans and mouse aging

Hope Dang, Raul Castro-Portuguez, Luis Espejo, Grant Backer, Samuel Freitas, Erica Spence, Jeremy Meyers, Karissa Shuck, Emily A. Gardea, Leah M. Chang, Jonah Balsa, Niall Thorns, Caroline Corban, Teresa Liu, Shannon Bean, Susan Sheehan, Ron Korstanje and George L. Sutphin ()
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Hope Dang: Molecular & Cellular Biology, University of Arizona
Raul Castro-Portuguez: Molecular & Cellular Biology, University of Arizona
Luis Espejo: Molecular & Cellular Biology, University of Arizona
Grant Backer: The Jackson Laboratory
Samuel Freitas: Molecular & Cellular Biology, University of Arizona
Erica Spence: Molecular & Cellular Biology, University of Arizona
Jeremy Meyers: Molecular & Cellular Biology, University of Arizona
Karissa Shuck: Molecular & Cellular Biology, University of Arizona
Emily A. Gardea: Molecular & Cellular Biology, University of Arizona
Leah M. Chang: Molecular & Cellular Biology, University of Arizona
Jonah Balsa: Molecular & Cellular Biology, University of Arizona
Niall Thorns: Molecular & Cellular Biology, University of Arizona
Caroline Corban: The Jackson Laboratory
Teresa Liu: The Jackson Laboratory
Shannon Bean: The Jackson Laboratory
Susan Sheehan: The Jackson Laboratory
Ron Korstanje: The Jackson Laboratory
George L. Sutphin: Molecular & Cellular Biology, University of Arizona

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Tryptophan metabolism through the kynurenine pathway influences molecular processes critical to healthy aging including immune signaling, redox homeostasis, and energy production. Aberrant kynurenine metabolism occurs during normal aging and is implicated in many age-associated pathologies including chronic inflammation, atherosclerosis, neurodegeneration, and cancer. We and others previously identified three kynurenine pathway genes—tdo-2, kynu-1, and acsd-1—for which decreasing expression extends lifespan in invertebrates. Here we report that knockdown of haao-1, a fourth gene encoding the enzyme 3-hydroxyanthranilic acid (3HAA) dioxygenase (HAAO), extends lifespan by ~30% and delays age-associated health decline in Caenorhabditis elegans. Lifespan extension is mediated by increased physiological levels of the HAAO substrate 3HAA. 3HAA increases oxidative stress resistance and activates the Nrf2/SKN-1 oxidative stress response. In pilot studies, female Haao knockout mice or aging wild type male mice fed 3HAA supplemented diet were also long-lived. HAAO and 3HAA represent potential therapeutic targets for aging and age-associated disease.

Date: 2023
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DOI: 10.1038/s41467-023-43527-1

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