# New mechanistic insights into how the gut metabolite urolithin A extends lifespan and prevents AD

> **NIH NIH RF1** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2022 · $461,518

## Abstract

PROJECT SUMMARY/ABSTRACT
The parent award proposes to assess the potential neuroprotective effects of the gut metabolite urolithin A
(UA) in the 3xAD Tg model of Alzheimer’s disease (AD). Aim 3 of the grant centers on the hypothesis that
reductions in age-related gut microbiota involved in the production of UA from its dietary precursor ellagic acid
may contribute to increased neuropathology associated with the 3xAD model and can be prevented by
restoration of a more youthful microbiome.
In addition to its direct impact on neurons (the subject of the parent grant), UA potentially may also have
indirect effects via its ability to maintain gut integrity and function which can have ‘knock on’ effects on
neuronal integrity via the gut-brain axis. In order to get a better handle on potential mechanisms that may
underlie gut inflammation and influence the development of AD-related neuropathology in these mice, we
initiated a collaboration with Dr. Dan Winer at the Buck, an expert on the role of the adaptive immune system in
controlling metabolic tissue inflammation. Bacterial profiling was performed and revealed a clear difference in
the levels of pro-inflammatory bacteria in the AD mouse colon, coinciding with a striking enrichment in the level
of CD4+Tbet+ (Th1) immune cell populations previously linked to reduced gut barrier function and dysbiosis.
Additional studies as part of the funded parent grant demonstrated that UA-fed 3xAD mice show significant
reductions in Aß neuropathology and improvement in behavioral deficits. As postulated in the original grant,
this may be in part due to direct effects on neuronal cells in the CNS. However, it may also involve the
compound’s ability to maintain gut integrity and function and reduce gut inflammation. The purpose of this
supplement is to provide us with funds to allow us to determine whether UA’s neuroprotective effects are due
in part to its ability to influence gut health.

## Key facts

- **NIH application ID:** 10614896
- **Project number:** 3RF1AG062280-01S1
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** Julie Kay Andersen
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $461,518
- **Award type:** 3
- **Project period:** 2018-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10614896

## Citation

> US National Institutes of Health, RePORTER application 10614896, New mechanistic insights into how the gut metabolite urolithin A extends lifespan and prevents AD (3RF1AG062280-01S1). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/10614896. Licensed CC0.

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