# Investigating the role of cytosolic mitochondrial double-stranded RNA in cellular senescence and aging

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $507,781

## Abstract

PROJECT SUMMARY/ABSTRACT
This application investigates the relationship between mitochondrial RNA, inflammation, senescence, and aging.
Cellular senescence is a well-established driver of tissue and organismal aging, a process thought to be partly
mediated via the induction of a chronic Senescence-associated secretory phenotype (SASP). Consequently,
there is great interest in selectively targeting senescent cells as a strategy to promote healthy aging. Our work
has demonstrated that mitochondrial dysfunction is a hallmark of cellular senescence and a driver of the SASP
and that by targeting them we may be able to suppress the detrimental SASP known to contribute to aging.
Mitochondrial double-stranded RNA (mtdsRNA) when present in the cytosol is known to be especially
immunogenic and trigger an inflammatory response. We observed that senescent cells contain increased levels
of cytosolic mtdsRNA together with increased expression of RNA sensors. Furthermore, we found that
transfection of cells with mtdsRNA triggers an inflammatory response and inhibition of mitochondrial DNA
transcription in senescent cells, decreases the SASP. Finally, we observed that mtdsRNA requires the cytosolic
DNA sensor cGAS to induce inflammation suggesting an interplay between RNA and DNA sensing pathways in
the process. This led us to hypothesize that cytosolic mdsRNA plays a role in the regulation of the SASP and
may be a novel target for interventions to improve healthspan during aging.
In this project, we will dissect the mechanisms by which mtdsRNA increases in the cytosol of senescent cells as
well as investigate if activation of RNA sensing pathways contributes to the SASP. Additionally, we will explore
the mechanisms mediating the interplay between mitochondrial DNA and RNA in the development of the SASP.
Our ultimate goal is to identify new interventions that target senescent cells to alleviate age-related dysfunction.

## Key facts

- **NIH application ID:** 10929477
- **Project number:** 5R01AG082708-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Joao Passos
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $507,781
- **Award type:** 5
- **Project period:** 2023-09-15 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10929477

## Citation

> US National Institutes of Health, RePORTER application 10929477, Investigating the role of cytosolic mitochondrial double-stranded RNA in cellular senescence and aging (5R01AG082708-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10929477. Licensed CC0.

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