[R01] Linking metabolism, neural function, and aging
Ente: National Institute on Aging
Scadenza: 2031-03-31
Importo max: 540.373 EUR
Paese: US
Descrizione
PROJECT SUMMARY/ABSTRACT
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. In our previous funding cycle, we discovered that the
steroid hormone androst-5-ene-3β,17β-diol (ADIOL) links metabolic state to neuronal function by reducing
levels of KynA and its precursor, kynurenine (Kyn). In C. elegans, these effects require the homolog of estrogen
receptor β (ERβ). Although ADIOL was identified in humans nearly a century ago, it has been largely overlooked
as a biosynthetic intermediate. Notably, in mammals, ADIOL is also a ligand for ERβ, though little is known
about its broader molecular or physiological roles. 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 proposal aims to define the mechanisms underlying these interactions across three key areas: i)
the regulatory interplay between ADIOL, N-acyl-phosphatidylethanolamines, and KP metabolites, testing the
hypothesis that ADIOL coordinates these signaling lipids to control neural KynA levels; ii) the interaction
between ADIOL, the KP, and transcriptional programs regulated by the aryl hydrocarbon receptor (AhR) and
hypoxia-inducible factor-1 (HIF-1), given that AhR activation by excess KP intermediates impairs cognition in
AD. We will test the hypothesize that ADIOL mitigates the negative effects of AhR activation by reducing levels
of its endogenous agonists, Kyn and KynA, and iii) the impact of KP activity on brain energetics and resilience.
As declining neural energetics underlie aging and cognitive decline, we hypothesize that elevated Kyn and KynA
disrupt neural energetics, and that ADIOL counters these deficits. Together, this work will advance our
understanding of how aging and proteostasis stress impair neuronal function via the KP and explore the
therapeutic potential of the long-neglected h
Istituzione: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
PI: Kaveh Ashrafi
Progetto: 2R01AG046400-11A1
Settori: National Institute on Aging
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