# The role of senescence in severe COVID-19

> **NIH NIH R21** · UNIVERSITY OF PENNSYLVANIA · 2024 · $243,750

## Abstract

ABSTRACT
Preexisting obesity and non alcoholic steatohepatitis (NASH) are strongly associated with COVID-
19 cytokine storm and severe outcome. SARS-CoV-2 virions are present in the patient adipose
tissue and liver at low levels and it is not known if they play a major functional role in severe
COVID-19 pathology. The Raabe lab has derived for the first time organoids from livers of patients
with NASH and shown that they are senescent and exhibit a senescence associated secretory
phenotype (SASP) and thus model the known senescence of hepatocytes and other liver cells in
end stage NASH liver. Further, SARS-CoV-2 has been shown recently to induce senescence and
an SASP in infected lung cells that spreads through senescence associated secretion of
chemokines and cytokines including chemokine CXCL10, interferon IFN and cytokine TNF to
attract macrophages and activate them to a pro inflammatory state. The Raabe lab will study the
hypothesis that genetic or chemical removal of senescent cells in SARS-CoV-2 infected obesity
or NASH mouse models or in human adipose tissues derived cells and NASH patient liver derived
organoids will alleviate NASH related severe COVID-19 symptoms. In Aim 1 we will induce
obesity and NASH senescence in mouse models and infect these with SARS-CoV-2. Prior or
after infection we will remove senescence promoting factor p16 expressing cells either genetically
or chemically and then determine if this alleviates severe obesity or NASH COVID-19 symptoms.
In Aim 2 primary human lung cells will be infected with SARS-CoV-2 and the supernatant
containing the SASP and virus will be added to primary human adipocytes or NASH liver derived
organoid cultures. We will remove senescent cells chemically using established senolytics to
study if their removal alleviates inflammatory responses. Readout will be RNA-Seq, IHC and
ELISA to study the effect on senolytics on the SASP.

## Key facts

- **NIH application ID:** 10871494
- **Project number:** 1R21AI183111-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Tobias D. Raabe
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $243,750
- **Award type:** 1
- **Project period:** 2024-07-02 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10871494

## Citation

> US National Institutes of Health, RePORTER application 10871494, The role of senescence in severe COVID-19 (1R21AI183111-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10871494. Licensed CC0.

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