# Reciprocal Modulation of the Microbiome and Cellular Senescence in Metabolic Dysfunction

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $579,640

## Abstract

Research from the last decade has identified cellular senescence and alteration of gut microbial composition as
primary physiological processes that facilitate aging and a wide range of age-related diseases. Because of their
profound impact on health and disease, they represent two promising ideas in developing innovative strategy to
improve health and increase longevity. However, the interplay of the microbiome and cellular senescence in age-
related metabolic dysfunction is largely unknown. The major goal of this proposed study is to elucidate the causal
connection of cellular senescence and the microbiome in older mice under metabolic stress. We showed a high
fat diet (HFD) induced senescent cell loads, increased the abundance of pro-inflammatory gut bacteria, and
aggravated metabolic function. In contrast, caloric restriction (CR) decreased gene expression associated with
senescence in humans and mice. An intermittent fasting (IF) diet that mimics CR improved metabolic function,
and increased the abundance of Akkermansia known to have strong anti-inflammation and anti-aging property.
Using our novel p21-Cre mouse model, we found that depletion of senescent cells expressing high levels of p21
(p21high) profoundly increased the relative abundance of Akkermansia, and improved metabolic dysfunction in
male mice on a HFD. In Aim 1, we will test the hypothesis that cellular senescence modulates the microbiome
composition and function. This will be achieved by directly transplanting or genetic clearance of senescent cells
in older male and female mice, and determine their impact on the gut microbiome and microbial metabolites (Aim
1a). The microbiome changes will be determined at population level and functional level as these have not been
well-defined previously in aging or age-related diseases. Using our novel p21-Cre mouse model, we will further
assess if senescence induced alteration of the microbiome is a novel mechanism by which senescent cells
influence metabolic function. We will also test the hypothesis that SASP mediates the senescence-induced
microbiome changes by inactivating NF-κB in p21high senescent cells (Aim 1b). In Aim 2, we will test the
hypothesis that the gut microbiome modulates senescence development. We will examine development of
senescence in mice receiving fecal microbiota derived from a HFD (Aim 2a). We will determine the potential
suppression of senescent cells by fecal microbiota transplantation of the microbiota derived from IF or mono-
colonization of Akkermansia (Aim 2b). Establishment of reciprocal modulation of the microbiome and cellular
senescence will deepen our fundamental understanding of the pathophysiology of aging and age-related
metabolic diseases, and pave the way to develop robust interventions targeting senescence, microbiome or both
to improve health and increase longevity.

## Key facts

- **NIH application ID:** 10048448
- **Project number:** 1R01AG068860-01
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** Ming Xu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $579,640
- **Award type:** 1
- **Project period:** 2020-09-10 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10048448

## Citation

> US National Institutes of Health, RePORTER application 10048448, Reciprocal Modulation of the Microbiome and Cellular Senescence in Metabolic Dysfunction (1R01AG068860-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10048448. Licensed CC0.

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