# Novel mechanism of intestinal stem cell aging

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $505,734

## Abstract

Abstract
Many mammalian organs with high cellular turnover (e.g. skin, intestine and blood) are composed of short-lived
cells that require continuous replenishment by somatic stem cells. Aging results in the inability of these tissues
to maintain homeostasis. Evidence accumulated over the past decade has found measurable and successive
age-dependent decline in stem cell activity from adulthood to old age, in various organs, including
hematopoietic, intestinal and muscle. This age-associated decline in stem cell function leads to a decline in the
regenerative capacity in humans and mice, which may limit lifespan. Identifying mechanisms under which aged
stem cells become phenotypically and functionally similar to young stem cells may be a first step towards
designing rationale approaches to ameliorate stem cell aging in the clinics. Based on our preliminary results we
hypothesize that the declining beta-catenin signaling and associated microbiota changes play a causal role in
ISC functional changes upon aging in both mice and humans. To pursue this hypothesis, we will perform three
aims. In aim 1, we will determine the extend of changes in beta-catenin signaling in single ISCs upon aging via
single-cell sequencing approaches and the impact of Wnt expression changes on beta-catenin signaling and a
decline in the function of ISCs upon aging. In aim 2, we will investigate the contribution of various niche cells to
aging-associated changes in beta-catenin signaling in ISCs in vivo. In aim 3, we will determine the role of
microbiota in Wnt ligand expression in the niche cells and in regulating beta-catenin signaling and the function
of ISCs upon aging. The proposed studies will unveil a new mechanism of changes in associating beta-catenin
signaling and microbiota with the physiologic aging process of intestinal stem cells and alterations in tissue
homeostasis. The findings of the proposal may lead to future therapeutic interventions preventing or reversing
tissue aging.

## Key facts

- **NIH application ID:** 10263330
- **Project number:** 5R01AG063967-02
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** YI ZHENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $505,734
- **Award type:** 5
- **Project period:** 2020-09-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263330

## Citation

> US National Institutes of Health, RePORTER application 10263330, Novel mechanism of intestinal stem cell aging (5R01AG063967-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10263330. Licensed CC0.

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