3-hydroxyanthranilic acid (3HAA) for Extending Healthy Lifespan [george sutphin]

#1

George sutphin has a paper (he used to be in Kaeberlein lab

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

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 Haaoknockout 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.

Open access paper:

https://www.nature.com/articles/s41467-023-43527-1

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note quinolinic acid is neurotoxic…

Our data demonstrate that 3HAA is protective against ROS in the context of aging C. elegans. 3HAA has a complex history with oxidative stress, with earlier studies linking 3HAA to ROS generation and/or oxidative damage28,29,30,31 and more recent studies reporting antioxidant properties for 3HAA32,33,34,35,36,37,38,39. These studies vary widely in the oxidant properties examined, presence of added metals, cell type, and cellular context. 3HAA can auto-oxidize under specific conditions, including the presence of Cu2+, Fe3+ or alkaline pH28. Each of these variables is likely critical to understanding redox properties of 3HAA in the context of aging, and the particular importance of copper and pH were recently confirmed in silico15. Our data that 3HAA can both directly degrade H2O2 and promote endogenous H2O2 production suggest that both sides of this debate are likely correct in context. Given both that 3HAA is protective against oxidative stress and the complex interaction between haao-1 and genes in other aging pathways (Fig. 1g), we speculate that 3HAA may also impart protection against other forms of cellular stress.

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#2

The Emerging Role of 3-Hydroxyanthranilic Acid on C. elegans Aging Immune Function

3-hydroxyanthranilic acid (3HAA) is considered to be a fleeting metabolic intermediate along tryptophan catabolism through the kynurenine pathway. 3HAA and the rest of the kynurenine pathway have been linked to immune response in mammals yet whether it is detrimental or advantageous is a point of contention. Recently we have shown that accumulation of this metabolite, either through supplementation or prevention of its degradation, extends healthy lifespan in C. elegans and mice, while the mechanism remained unknown. Utilizing C. elegans as a model we investigate how 3HAA and haao-1 inhibition impact the host and the potential pathogens. What we find is that 3HAA improves host immune function with aging and serves as an antimicrobial against gram-negative bacteria. Regulation of 3HAA’s antimicrobial activity is accomplished via tissue separation. 3HAA is synthesized in the C. elegans hypodermal tissue, localized to the site of pathogen interaction within the gut granules, and degraded in the neuronal cells. This tissue separation creates a new possible function for 3HAA that may give insight to a larger evolutionarily conserved function within the immune response.

and:

EXTENDING A HEALTHY LIFESPAN WITH 3-HYDROXYANTHRANILIC ACID

Metabolism of tryptophan by the kynurenine pathway is increasingly linked to aging. Kynurenine pathway enzymes and metabolites influence a range of molecular processes critical to healthy aging, including regulation of inflammatory and immune responses, cellular 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—kynu-1, tdo-2, and acsd-1—for which decreasing expression extends lifespan in invertebrates. More recently we discovered that knockdown of haao-1, a fourth kynurenine pathway gene encoding the enzyme 3-hydroxyanthranilic acid 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 3-hydroxyanthranilic acid (3HAA). Aging mice fed a diet supplemented with 3HAA are similarly long-lived. The mechanism of action liking 3HAA to aging is complex and partially overlaps with multiple pathways previously implicated in aging. We recently identified activation of the Nrf2/SKN-1 oxidative stress response and alterations to iron homeostasis as key players in the benefits 3HAA. Ongoing work explores the relationship between 3HAA, Nrf2/SKN-1, and iron in C. elegans and mammalian aging, age-associated immune decline, and cancer. This works provides a foundation for detailed examination of the molecular mechanisms underlying the benefits of 3HAA, and how these mechanisms interact with other anti-aging interventions. We anticipate that these findings will bolster growing interest in developing pharmacological strategies to target tryptophan metabolism to improve health aging.

Open access paper:

#3

Lustgarten and kyneurine toooo

The enzymes converting tryp to 3HAA also divert the flux from 5HT/melatonin…

The pathway is surrounded by toxic metabolites…

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