# Project 1: Thymic and peripheral Aspects of T cell Aging and Rejuvenation

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2020 · $245,360

## Abstract

Preventing, delaying, or reversing aging-related thymic involution is a widely sought-after therapeutic goal
with the potential to significantly improve immune function and health-span in aging humans. Thymic involution
initiates in childhood, and is progressive thereafter, continuing to produce T cells that develop in a deteriorating
microenvironment and raising the possibility that the process of involution itself may produce sub-functional T
cells. Studies of involution that compare old with young mice investigate only the end stage of involution. The
thymus is also highly sensitive to many kinds of stress. The very different life histories of mice in a controlled
environment and humans living in the world could significantly influence the rate and degree of thymus
involution, and the capacity for rebound. There is accumulating evidence that changes in the expression of the
FOXN1 transcription factor may directly regulate initial involution. Our preliminary data show that the Atf3
stress response gene is suppressed by FOXN1, up-regulated in thymic epithelial cells (TEC) with aging, and
may mediate some key aspects of thymic involution. These data directly implicate stress as a potentially
important aspect of involution that is understudied in animal models, but may impact efforts to modulate
involution in humans.
 This project is based on the premise that developing mouse models of thymic involution and
immunosenesensce to include parameters that more accurately mimic the human condition will generate more
relevant data for devising therapeutic strategies in humans. Based on this premise we propose to use novel
computational approaches to generate a data-driven comparison of human and mouse thymic involution, to
test whether a mouse strain with accelerated involution better mimics the effects of thymic involution on
peripheral T cells in humans, and to investigate the effects of stress on age-associated involution. We will also
test the hypothesis that the TEC response to repeated stress compromises the capacity for rebound with
aging, and that the Atf3 stress response gene is up regulated with aging and promotes key aspects of thymus
involution. These experiments will directly address the differences between mouse and human lifespan and life
history, to develop and test new models for investigating thymic involution and its effects on peripheral T cell
changes with aging. Together with Projects 3 and 4 and Cores A-C, the human-mouse comparisons will
generate the Human-Mouse Timeline that will be not only a key resource to the Program, but a valuable
reference for the community. This and other aspects of this Project will synergize with other Project outcomes
and inform the design and interpretation of interventions testing in Core D.

## Key facts

- **NIH application ID:** 9967949
- **Project number:** 5P01AG052359-04
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Nancy R Manley
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $245,360
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967949

## Citation

> US National Institutes of Health, RePORTER application 9967949, Project 1: Thymic and peripheral Aspects of T cell Aging and Rejuvenation (5P01AG052359-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9967949. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*