3 research outputs found
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 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
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The Current Role of Kynurenine Pathway Interventions in Oxidative Stress and Redox Homeostasis in the Context of Aging and Cancer
Cancer is the second-leading cause of death in the United States and in Europe. Age is the single highest risk factor for developing cancer, and more than half of cancer diagnoses occur after age 70. Most cancer therapeutics are studied in younger and healthier individuals, excluding the impact that age-related comorbidities may have in the initiation and progression of cancer. There is clearly a gap in knowledge in the cancer field about the complex relationship between the development of the disease and the molecular environment in old individuals. In recent years, the kynurenine pathway –the main route to metabolize tryptophan in the cell– has emerged as a therapeutic target in several age-related diseases, including cancer. Intermediate metabolites in the kynurenine pathway have immunological and redox properties that have been associated with cancer initiation, progression, and metastasis. Increased flux of tryptophan metabolism towards the kynurenine pathway has been positively correlated with age and age-related diseases. The necessity of building the bridge between aging and cancer research using this shared metabolic pathway will create new knowledge in the understanding of age-driven cancer development.
My goal is to investigate the intricacies of the kynurenine pathway and its role in the initiation and progression of cancer at an advanced age. The long-term goal of my career is to develop therapeutic targets that prevent or delay the onset of cancer by improving cell fitness by targeting mechanisms in the underlying aging process. Delaying aging-associated decline is not only going to improve the wellbeing of older adults, but also reduces the burden costs of public health associated to the treatment of age-related comorbidities. The results of this project will provide, at an academic level, a deeper understanding of the correlation between age and cancer and, at a clinical level, the possibility of preventing cancer development by targeting the underlying biological processes that drive cellular and physiological functional decline with age