# Reversing Age Related Inflammation

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $490,171

## Abstract

Project Summary
Systemic elevation in chronic, low grade inflammation is seen across almost all peripheral organ systems with
aging. This systemic “inflammaging” has a major impact on brain function and leaves the brain vulnerable to
injury. The main goal of this proposal is to investigate and manipulate the mechanisms by which chronic
inflammation impacts the response to ischemic stroke, the leading cause of long-term disability in the elderly.
Experimental, clinical, and epidemiological studies demonstrate that peripheral immune challenges lead to
detrimental effects in the central nervous system (CNS) such as sickness behavior and delirium. Conversely,
although much more recently recognized, a primary CNS insult can also trigger dramatic changes in the
periphery. We hypothesize that increased peripheral inflammation contributes to the high mortality and poor
functional recovery seen after stroke in aged animals. Reversing peripheral “inflammaging” by manipulation
of peripheral factors will decrease the number of activated T cells found in the aged CNS and reduce microglia
activation, leading to enhanced recovery after experimental stroke. This hypothesis is supported by recent
studies demonstrating that age-related deficits in neurogenesis and memory can be reversed by
administration of systemic factors found in young blood and from our own data that shows rejuvenation of the
aged peripheral immune system with young bone marrow reduces mortality and enhances behavioral
recovery after stroke.
Using animal models, we will examine the relationship between age-related changes in cellular and humoral
inflammation and ischemic stroke outcome, which will allow for the identification of novel age-appropriate
therapeutic targets. Our preliminary data suggests the pro-inflammatory phenotype seen in aged mice
contributes to poor stroke outcome, and that this can be reversed by bone marrow transplantation (BMT)
from a young donor. We will first determine whether this rejuvenation phenotype leads to long-lasting
functional improvements after stroke. The effects of BMT on the phenotype/function of age-related CNS
resident immune cells (CD8+ T cells and microglia) will be then examined in chimeras developed from mice
lacking mature lymphocytes. Heterochronic parabiosis results in a similar “rejuvenation” phenotype in models
of age-related cognitive decline. We will combine this technique with proteomic screens and RNA sequencing
to identify novel “pro-rejuvenation” factors (Aim 2a) and investigate how these interact with intrinsic CNS
immune cells. Finally plasma exchange will be investigated to determine if these therapeutic benefits can be
recapitulated without replacement of cellular elements (Aim 2b).

## Key facts

- **NIH application ID:** 9906276
- **Project number:** 5R01NS094543-05
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Louise D. McCullough
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $490,171
- **Award type:** 5
- **Project period:** 2016-06-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9906276

## Citation

> US National Institutes of Health, RePORTER application 9906276, Reversing Age Related Inflammation (5R01NS094543-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9906276. Licensed CC0.

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