# Validation of neuronal senescence as a target for chronic pain in aging

> **NIH NIH RF1** · STANFORD UNIVERSITY · 2024 · $2,249,392

## Abstract

Project Summary
Aging is a major risk factor for the development of chronic pain with 50% of adults over the age of 65 suffering
from at least one chronic pain condition. Unfortunately, there is a major knowledge gap regarding the interaction
between age and pain. There is an urgent need for basic research using aged animal models to validate targets
relevant to chronic pain treatment in this specific population.
As humans and animals age, senescent cells accumulate in tissues throughout the body, and if not effectively
cleared by the immune system, can disrupt homeostasis. Certain senescent cells secrete factors that induce
inflammation, known collectively as the senescence-associated secretory phenotype (SASP), and include
cytokines, chemokines, and proteases. Interestingly, several of these SASP factors are known pain-inducing
cytokines released in the dorsal root ganglion (DRG) where primary sensory neuron cell bodies reside and drive
hyperexcitability. Senescent cells therefore warrant investigation within the pain circuit in aged mice, and even
in young mice after peripheral nerve injury. Our central hypothesis is that age-and injury-induced senescent
neurons promote DRG hyperexcitability through production of SASP factors, causing persistent pain following
peripheral injury. This hypothesis is founded on our robust preliminary evidence confirming: 1) Induction of
senescent neurons within the DRG after peripheral nerve injury, 2) Increased senescent cell burden in the DRG
of aged compared to young mice with and without injury as indicated by increased expression of senescent
markers, p21 and p16, and 3) Localization of the SASP factor and pain mediator, IL6, to senescent neurons.
Additionally, we have preliminary data demonstrating that treatment with a senolytic (anti-senescence) drug
improves spared nerve injury (SNI)-induced mechanical allodynia while maintaining overall sensory function in
young adult and aged mice. Therefore, a potential mechanism underlying enhanced pain susceptibility following
injury in aged mice may be the combination of age-related and injury-induced senescent cells. The overall goal
of this proposal is to rigorously validate senescent cells as a target for future therapeutic development. We will
pursue validation by genetically, functionally, and phenotypically characterizing deleterious SASP-producing
senescent DRG neurons using cross-disciplinary approaches across multiple laboratories. Our approach will
leverage three clinically-relevant mouse models (SNI, paw incision and orthopaedic trauma) as well as human
post-mortem DRG tissue to strengthen the evidence that our target is likely to be robust in translation. This
research will be the first of its kind to investigate and validate cellular senescence in pre-clinical mouse models
and has the potential to open a new therapeutic avenue, using senolytic agents, to alleviate pain.

## Key facts

- **NIH application ID:** 10941246
- **Project number:** 1RF1AG088052-01
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Vivianne L Tawfik
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $2,249,392
- **Award type:** 1
- **Project period:** 2024-09-15 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941246

## Citation

> US National Institutes of Health, RePORTER application 10941246, Validation of neuronal senescence as a target for chronic pain in aging (1RF1AG088052-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10941246. Licensed CC0.

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