Linking metabolism, neural function, and aging

PROJECT SUMMARY/ABSTRACT
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). Though ADIOL was identified in humans decades ago, it has been largely overlooked
as merely a steroid intermediate. With the notable exception that in mammals ADIOL is also a ligand for ERβ,
little is known about the molecular or physiological roles of this steroid. 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. This proposal aims to deepen the
mechanistic understanding of these connections by examining three key areas: i) The regulatory interplay
between ADIOL, N-acyl-phosphatidylethanolamines, and KP metabolites, testing the hypothesis that ADIOL
orchestrates these signaling lipids to modulate neural KynA levels, ii) the interactions between ADIOL, the KP,
and transcriptional processes regulated by the aryl hydrocarbon receptor (AhR) and hypoxia factor-1
transcription factors, given that aberrant AhR activation in AD impairs cognitive function. We hypothesize that
ADIOL may alleviate the negative impacts of aberrant AhR activation on neural functions, and iii) the impact of
KP on brain energetics and resilience, considering that declining brain energetics underlies aging and AD-related
cognitive decline. We hypothesize that increased levels of Kyn and KynA disrupt neural energetics and that
ADIOL can counter these negative effects. This work advances our understanding of how aging and proteostasis
stress influence learning memory through KP modulation and the potential of the neglected hormone ADIOL in
mitigating the negative impacts of this KP modulation.

Grant Number: 2R56AG046400-11
NIH Institute/Center: NIH
Principal Investigator: Kaveh Ashrafi