# Role of the steroid hormone ADIOL in learning and memory, aging, and neurodegeneration

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $1,747,068

## Abstract

PROJECT SUMMARY/ABSTRACT
There is currently a paucity of therapeutic approaches for ameliorating cognitive declines that characterize
neurodegenerative disorders such as Alzheimer's Disease (AD) and AD related dementias (ADRDs). Defects in
learning and memory also accompany aging. We have been investigating kynurenic acid, KYNA, a tryptophan
derived metabolite, as a nexus in metabolism, aging, and learning and memory in C. elegans. There is
compelling evidence from multiple species including C. elegans and mice that reductions in KYNA improve
learning and memory while increases in this neuromodulatory metabolite have detrimental effects. In both C.
elegans and mice KYNA accumulates with age. KYNA accumulation also accompanies human aging and
neurodegenerative disorders including AD and ADRDs. Using genetic manipulations, we previously showed
that reducing KYNA levels substantially improves learning and memory in aged C. elegans as well as in C.
elegans models of neurodegeneration. These improvements are due to specific effects of KYNA on the activity
of neurons that express N-methyl D-aspartate receptors (NMDARs), fundamental regulators of learning and
memory across phylogeny. These findings prompted us to seek molecular mechanisms and pharmacological
reagents for reducing KYNA. We have identified androst-5-ene-3β,17β-diol (ADIOL), a C19 steroid hormone, as
a potent reducer of KYNA and enhancer of learning capacity in C. elegans. We have demonstrated that the
effects of ADIOL are dependent on an NHR-91, a transcription factor with both sequence and functional
homology to mammalian estrogen receptor β, ERβ. These findings are intriguing for two key reasons: (i) The
existence of ADIOL has long been recognized in mammals but the physiological functions of this steroid
hormone are extremely poorly understood, (ii) There is compelling evidence that activation of ERβ in
mammals has numerous beneficial effects including improved learning and memory but the underlying
mechanisms are unknown. We hypothesize that ADIOL serves as an endogenous ligand to activate an ERβ-like
nuclear hormone receptor, which in turn causes reductions in KYNA to promote learning and memory. Our
specific aims are to rigorously establish the role of ADIOL in learning and memory during aging and in C.
elegans models of neurodegeneration, devise biochemical strategies for quantitating this steroid hormone from
C. elegans, investigate the role of nhr-91 as a mechanistic link between ADIOL and KYNA, and explore three
hypotheses pertaining to the physiological roles of ADIOL including its role in aging, as a mechanism that links
nutrient sensory pathways to learning and memory via KYNA, and as a mechanism that links development of
reproductive capacity to mechanisms of learning and memory. This investigation employs C. elegans molecular
genetics, imaging, behavioral assays, as well as biochemical measurements of metabolites.

## Key facts

- **NIH application ID:** 10231523
- **Project number:** 1RF1AG068194-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Kaveh Ashrafi
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,747,068
- **Award type:** 1
- **Project period:** 2021-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231523

## Citation

> US National Institutes of Health, RePORTER application 10231523, Role of the steroid hormone ADIOL in learning and memory, aging, and neurodegeneration (1RF1AG068194-01A1). Retrieved via AI Analytics 2026-06-02 from https://api.ai-analytics.org/grant/nih/10231523. Licensed CC0.

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