National Institute on Aging 2R01AG046400-11A1

Linking metabolism, neural function, and aging

This award funds research investigating the kynurenine pathway's role in linking metabolism, neural function, and aging, particularly its impact on learning and memory deficits related to Alzheimer's disease and aging, using C. elegans as a model organism.

Description

Maintaining cognitive and physiological health during aging is essential for a healthy lifespan. In mammals, most tryptophan is metabolized through the kynurenine pathway (KP), producing signaling molecules increasingly recognized for their roles in neurodegenerative disorders such as Alzheimer’s disease (AD). Disruptions in KP metabolite levels are a hallmark of AD and related dementias (ADRD), contributing to disease pathology and prompting recent interest in targeting the KP for therapeutic intervention. Using C. elegans as a model, we have investigated how the KP links metabolism, aging, and fundamental mechanisms of learning and memory. We found that the learning and memory benefits of caloric or dietary restriction are mediated by reduced levels of kynurenic acid (KynA), a KP metabolite. In turn, we showed that accumulation of KynA contributes to age-related learning deficits and to impairments caused by proteostasis stress. We identified specific neurons that produce KynA and showed that KynA impairs learning by antagonizing NMDA receptor (NMDAR)-dependent neural activity—a mechanism conserved across species. Our work demonstrates that ADIOL modulates Kyn and KynA levels, establishing a new regulatory axis connecting metabolic state, aging, proteostasis stress, and cognitive function. This research aims to define the mechanisms underlying these interactions and explore the therapeutic potential of ADIOL in preserving nervous system function.

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