# Cellular senescence and cell fate/interactions as drivers of Alzheimer's and age-related dementias

> **NIH NIH P01** · BUCK INSTITUTE FOR RESEARCH ON AGING · 2024 · $577,883

## Abstract

PROJECT SUMMARY
Aging is by far the most important driver and risk factor for developing a variety of neurodegenerative diseases,
including the common forms of Alzheimer’s disease (AD) and related dementias. Recent evidence from our
laboratory and others indicate that a cell fate termed cellular senescence is an effective driver of a diverse group
of age-related diseases ranging from neurodegeneration to cancer. Senescent cells increase with age. Owing
to their complex senescence-associated secretory phenotype (SASP), senescent cells can have profound effects
on tissue structure and function, and can foster chronic inflammation, a major contributor to numerous age-
related pathologies. There is also recent, albeit sparse, evidence that senescent cells can contribute to age-
related neurodegeneration, including AD and related dementias. Project 1 of this Program Project Grant (PPG)
will characterize in depth the senescence responses, particularly the SASPs, of human and mouse astrocytes,
microglia and neurons induced to senescent by different stressors. It will then determine how these senescent
cells affect the function of non-senescent cells, using both homotypic and heterotypic cell cultures, and a variety
of endpoints ranging from differentiated functions to metabolic state and single cell analyses of transcriptomes
to understand the heterogeneity of senescent brain cell populations. In addition, the Project will use three
dimensional cortical organoids, including organoids containing human cells with wild-type genotypes and those
with genotypes containing mutations that predispose to early onset AD and related dementias. These cells will
be derived from induced pluripotent stem cells. Finally, Project 1 will take advantage of a novel transgenic mouse
model that permits the selective elimination of senescent cells in order to determine whether and how senescent
cells are causally related to age-related brain function in vivo. These collaborative analyses will complement
experiments proposed by Projects 2 and 3 and rely heavily on Cores B, C and D. Together, these experiments
will provide unprecedented knowledge about senescent cells in the brain, critically test their role in driving AD
and related dementias, and open possibilities for novel interventions into these devasting pathologies.

## Key facts

- **NIH application ID:** 10862755
- **Project number:** 5P01AG066591-04
- **Recipient organization:** BUCK INSTITUTE FOR RESEARCH ON AGING
- **Principal Investigator:** PIERRE-YVES DESPREZ
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $577,883
- **Award type:** 5
- **Project period:** 2021-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862755

## Citation

> US National Institutes of Health, RePORTER application 10862755, Cellular senescence and cell fate/interactions as drivers of Alzheimer's and age-related dementias (5P01AG066591-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10862755. Licensed CC0.

---

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