# The pathogenic effects of senescent cells on their microenvironments and their role in human brain aging

> **NIH NIH R21** · UNIVERSITY OF TEXAS HLTH SCIENCE CENTER · 2024 · $223,622

## Abstract

PROJECT SUMMARY
Senescent cells were hypothesized to contribute to development of Alzheimer’s Disease and Related
Dementias (ADRD) by secreting inflammatory factors in their surrounding microenvironments. However,
the exact role of senescent neurons in brain aging and effective ways to mitigate their contribution to
ADRD development are unknown. To address this gap in knowledge, we need high-resolution spatial
omics data, which covers hundreds of genes and potentially have the information on how a cell impacts its
microenvironment.
In this study, the Orr Lab generates spatial omics data from ADRD brains and the corresponding mouse
models. The Zare Lab uses deep learning and other machine learning techniques to fully leverage the
spatial aspects of these data. In the R21 phase, we identify molecular changes in the microenvironment of
senescent neurons compared to healthy neurons. In Aim 1, we identify the general molecular markers of
senescent neurons while Aim 2 is focused on their role specifically in neuronal death in brain aging and
ADRD.
The rationale for this study is the accumulating evidence by our team, and others, that demonstrate a
mechanistic link between cellular senescence and ADRD. Specifically, a) in a seminal study, the Orr Lab
identified senescent neurons in human Alzheimer’s disease that were mechanistically linked to
neurodegeneration using tau transgenic mice, b) by analyzing transcriptome data of 140K single nuclei
derived from 76 human brains with various levels of ADRD pathology, the Zare Lab identified cyclin-
dependent kinase inhibitor 2D (CDKN2D/p19) as a marker for senescent neurons. Using p19 and other
markers, we showed that senescent neurons have a significant overlap with neurofibrillary tangle (NFT)
pathology in the human brain, and c) we have recently discovered that Fas receptor (CD95), which
induces apoptosis, is overexpressed in the microenvironment of senescent neurons in ADRD brains
compared to normal brains.
 The R33 phase has a mechanistic approach aiming at limiting negative effects of neural senescence on
brain aging. In Aim 3, the Zare Lab uses deep models to simulate deregulation of a particular gene in
senescent neurons to predict its effects on other genes in the microenvironment. In Aim 4, we use a
similar approach to determine the most promising treatment that can possibly mitigate the negative effects
of neural senescence. The Orr Lab determines their mechanistic role in pathogenesis using mouse
models for ADRD.
The expected outcomes of this study includes the discovery of negative senescence effects in brain aging
and possible novel treatments for ADRD that mitigate these effects.

## Key facts

- **NIH application ID:** 10933770
- **Project number:** 1R21AG087907-01
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
- **Principal Investigator:** Miranda Ethel Orr
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $223,622
- **Award type:** 1
- **Project period:** 2024-09-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933770

## Citation

> US National Institutes of Health, RePORTER application 10933770, The pathogenic effects of senescent cells on their microenvironments and their role in human brain aging (1R21AG087907-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10933770. Licensed CC0.

---

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