# Effect of senescent cells

> **NIH NIH P01** · UNIVERSITY OF MINNESOTA · 2024 · $536,216

## Abstract

Summary
 The induction and maintenance of adaptive immune responses are critical for effective and durable
protection against diverse pathogens and the efficacy of vaccines. Yet it is known that both the homeostasis
and function of adaptive immune cells declines with age – while there may be multiple causes for this, recent
studies (including those from our group) indicate a potentially pivotal role for senescent cells. Diverse cell
types (including immune cells) become senescent with age and in various chronic disease states, and this
state not only affects the replicative potential of the senescent cells (SnC) themselves, but by their production
of a variety of factors (in what is termed the senescence-associated secretory phenotype or SASP), they can
affect other cells, in trans. Many of these SASP factors are pro-inflammatory and can provoke
immunopathology in vulnerable populations (including the aged, as illustrated in the cytokine storm reported in
elderly COVID-19 patients). These “bystander” effects have been demonstrated in experimental mouse
models. Most exciting, ablation of SnC (using senotherapeutic compounds) results in marked improvement of
immune control of pathogens. However, there is a key knowledge gap in understanding what effect SnCs
have on adaptive immune populations, how those effects are mediated and how crosstalk between senescent
and immune cells influences the physiological establishment of senescence with age. We address these in
three Specific Aims. Aim 1 tests how exposure to SnC – as a single variable – influences adaptive immune cell
homeostasis and function in response to defined viral infections, using well defined mouse models to pinpoint
the consequences of SnC introduction vs destruction on naïve and memory T and B cell populations. This
includes functional and single-cell analysis approaches. In Aim 2, we turn the tables by investigating tantalizing
data which indicate certain immune populations (including NK cells) may be capable of SnC destruction during
normal physiology – a feedback loop that we suspect is compromised with age, resulting in SnC build up. The
function of NK cells and other immune populations in culling SnC will be explored. Aim 3 explores how SnC
mediate their inhibitory effects on lymphocytes – by harnessing the power of CRISPR/Cas9 approaches to
ablate receptors for SASP factors and explore the functional significance of immunoregulatory molecules
induced on “young” T cells in the aged environment, as well as test the ability of SASP factors to provoke these
age-related changes, in vitro in both mouse and human cells. The approaches and goals integrate with the
single-cell studies, novel mouse model development and refinement of senotherapeutics conducted in Project
1, and with complementary studies on generation, homeostasis and function of adaptive immune cells
embedded in non-lymphoid tissues, conducted in Project 3. A consistent source of the key mouse models and
pathogens used wil...

## Key facts

- **NIH application ID:** 10767638
- **Project number:** 1P01AI172501-01A1
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** STEPHEN C JAMESON
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $536,216
- **Award type:** 1
- **Project period:** 2024-03-11 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10767638

## Citation

> US National Institutes of Health, RePORTER application 10767638, Effect of senescent cells (1P01AI172501-01A1). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10767638. Licensed CC0.

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