National Institute on Aging 2R56AG046400-11

Linking metabolism, neural function, and aging

This award funds research investigating the kynurenine pathway's role in aging and cognitive function, particularly its impact on neurodegenerative diseases like Alzheimer's. Using C. elegans models, the study explores how metabolic factors and steroid hormones influence learning and memory through modulation of KP metabolites, aiming to uncover therapeutic targets for age-related cognitive decline.

Description

Maintaining cognitive and physiological health during aging is vital for a healthy lifespan. In mammals, most tryptophan is converted to kynurenine pathway (KP) metabolites, now recognized as signaling molecules linked to neurodegenerative conditions like Alzheimer’s Disease (AD). Disruptions in KP metabolite levels are a hallmark of AD and related disorders (ADRD), thought to contribute to significant pathologies in these disorders, and targeting the KP has recently gained traction as a therapeutic strategy, especially in AD. Using C. elegans as an experimental model, we have explored the connections between the KP, metabolism, aging, and learning and memory. Our findings reveal that the benefits of caloric or dietary restriction on learning and memory result from lowered levels of kynurenic acid (KynA), a KP metabolite. In turn, we showed that the accumulation of KynA contributes significantly to learning deficits in aged C. elegans and in models of proteostasis stress. We identified specific neurons as the production sites of KynA that impact learning and memory through modulation of N-methyl-D-aspartate receptor (NMDAR) activity. As an NMDAR antagonist, KynA interferes with learning and memory processes, a mechanism conserved in mammals. During the last funding cycle, we discovered that the steroid hormone androst-5-ene-3β,17β-diol (ADIOL) links metabolic state to cognitive function by reducing KynA and its precursor, kynurenine (Kyn). In C. elegans, the beneficial effects of ADIOL require the homolog of estrogen receptor β (ERβ). Our work shows that ADIOL can modulate Kyn and KynA levels, creating a new regulatory pathway that links metabolic state, aging, conditions of proteostasis stress that characterize AD/ADRD, and cognitive health.

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