Linking metabolism, neural function, and aging

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PROJECT SUMMARY/ABSTRACT A general characteristic of aging is diminution of cognitive functions. Aging is also one of the greatest risk factors for the development of neurodegenerative disorders. Dietary restriction, DR, and molecular mechanisms that mimic aspects of it, DR mimetics, are under intense investigation as they delay some of the cognitive declines of aging and neurodegenerative disorders. These perturbations generally extend lifespan in several species. In C. elegans, we have discovered that DR and some DR mimetics also enhance a simple form of learning, whose molecular underpinnings are involved in learning in mammals. We have discovered that changes in a single, neuromodulatory metabolite, kynurenic acid (KYNA), account for the beneficial effects of DR and multiple DR mimetics on learning in C. elegans. We have identified the specific neural sites of KYNA production as well as N-methyl D-aspartate receptor (NMDAR)-expressing neurons whose activity is regulated by KYNA in the context of learning. These findings are consistent with KYNA serving as an NMDAR antagonist. Additionally, we have discovered that a significant portion of age-onset decline in learning is due to age-dependent accumulation of KYNA. We have also found evidence that learning defects caused by a disease variant of tau, a protein associated with neurodegeneration, may be, in part, due to unanticipated increases in KYNA. Significantly, despite being intertwined with aging, changing KYNA levels does not affect lifespan. Thus, we have pinpointed a direct link between a variety of metabolic and stress perturbations and mechanism of neural plasticity. KYNA has desirable attributes as a potential therapeutic strategy as reducing KYNA levels, even when initiated in adults, blunts learning declines in worms. Existing data support the notion that KYNA affects mammalian cognition and that KYNA accumulates with age. Our goal here is to understand the factors that regulate KYNA accumulation, especially during aging. A particular challenge in both C. elegans and mammals is that despite ubiquitous availability of tryptophan, neural KYNA can be produced in highly localized spaces yet be influenced by distant tissues through effects on substrate availability. To achieve our goals, we will combine behavioral assays with molecular genetic, neural imaging, and direct biochemical metabolite measurements to investigate the intersection of aging, stress, and metabolic pathways with KYNA-dependent learning. We will investigate a candidate transporter that may play a regulatory role through its transport of the substrate needed to make KYNA. We will explore the provocative hypothesis that protein folding stress affects flux through the kynurenine pathway cell non-autonomously with detrimental effects on learning. Finally, we will investigate the molecular relationship of KYNA to conserved mechanisms of memory acquisition as well as newly discovered mechanisms that actively promote forgetting.