# Translational Studies of Age-Associated Arterial Dysfunction, Western Diet and Aerobic Exercise: Role of the Gut Microbiome

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2020 · $719,929

## Abstract

Project Summary
Age-related arterial dysfunction is the main risk factor for cardiovascular diseases (CVD). Recently, we have
used short-term and lifelong studies in mice to determine how a Western-style diet (WD; high fat and sugar,
low fiber and nutrient density) and aerobic exercise (EX), common lifestyle factors, interact with aging to
influence endothelial dysfunction and stiffening of the large elastic arteries. We found that WD accelerates, and
EX prevents, these key features of arterial aging via changes in oxidative stress and inflammation.
The gut microbiome is a strong modulator of host metabolic health and inflammation that is influenced by
age, diet and EX, but there is no information about its effects on arterial function in these or other settings.
Our integrative hypothesis is that dysregulation of the gut microbiome (gut dysbiosis) with primary aging
and WD consumption, coupled with increased intestinal permeability that allows gut-derived particles to leak
into circulation, may act to impair arterial function via changes to adverse gut-derived metabolites such as
atherosclerosis-linked trimethylamine-N-oxide (TMAO), and stimulation of toll-like receptor 4-induced pro-
inflammatory signaling, whereas chronic aerobic exercise protects against these effects.
The purpose of this application is to determine the potential causal role of the gut microbiome in the effects
of aging, WD and EX on arterial function, and gain insight into the underlying metabolomic and inflammatory
mechanisms. We will employ 3 highly innovative, complementary translational approaches:
1. Mouse studies that allow us to discern cause-and-effect: a) by assessing arterial function with aging ± WD
in the presence vs. absence of the gut microbiome and associated signaling; and b) by determining if vascular
phenotypes associated with aging, WD and EX can be transferred via the gut microbiome. We also will explore
possible mechanisms using pharmacological inhibition and/or knock-out of suspected pathways.
2. Human studies assessing the time course (temporal associations) of diet (WD vs. non-WD)-induced
changes in the gut microbiome vs. arterial function in young and older exercising and non-exercising healthy
adults, using a randomized, single-blind, controlled feeding crossover study design.
3. Combined mouse/human studies employing “humanized” mice to determine if the characteristics
present in the human gut microbiome with age, WD and EX predictably influence arterial function.
These studies will determine not only changes to gut microbe presence and relative abundance with aging,
WD and EX, but also the functional effects of those changes, allowing us to gain novel insight into the role
of the gut microbiome in modulating vascular function with aging and these common lifestyle
influences. The expected results have the potential to establish the gut microbiome as a key mechanism and
therapeutic target for age-related arterial dysfunction, and to identify lifesty...

## Key facts

- **NIH application ID:** 9841433
- **Project number:** 5R01HL134887-04
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** DOUGLAS R SEALS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $719,929
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9841433

## Citation

> US National Institutes of Health, RePORTER application 9841433, Translational Studies of Age-Associated Arterial Dysfunction, Western Diet and Aerobic Exercise: Role of the Gut Microbiome (5R01HL134887-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9841433. Licensed CC0.

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