# Linking metabolism, neural function, and aging

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2020 · $504,204

## Abstract

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 forgetti...

## Key facts

- **NIH application ID:** 9922835
- **Project number:** 5R01AG046400-07
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Kaveh Ashrafi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $504,204
- **Award type:** 5
- **Project period:** 2014-08-15 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9922835

## Citation

> US National Institutes of Health, RePORTER application 9922835, Linking metabolism, neural function, and aging (5R01AG046400-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9922835. Licensed CC0.

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