Stanford researchers identify “zombie-like” pain-sensing neurons that link pain and aging, published in Nature Neuroscience
A groundbreaking study from Stanford’s Dr. Vivianne L. Tawfik, MD, PhD and lead scientist Dr. Lauren J. Donovan, PhD has demonstrated that sensory neurons in the periphery can take on a new “zombie-like” state called cellular senescence, after nerve injury or with age, characterized by altered signaling and production of inflammatory factors. Their results, published this week in Nature Neuroscience, establish a mechanism linking age and injury, establishing senescent neurons as a translational target for new pain therapeutics.
After a pain-causing injury, signals travel from the periphery (for example, the hand) to the central nervous system through the dorsal root ganglia (DRG). In this study, Donovan et al used a mouse model of nerve injury to establish that senescent neurons accumulate in the DRG after injury, with a larger accumulation seen in aged mice. The team also tested a drug called ABT263 (navitoclax), which is a senolytic, a type of drug that selectively destroys senescent cells. They found significant improvement in pain after nerve injury in aged subjects, suggesting that senolytics may be a promising treatment for chronic pain
“This discovery could lead to new treatments for chronic pain, particularly by using drugs which target senescent cells (senolytics) which are already being developed for other age-related diseases”
“This discovery could lead to new treatments for chronic pain, particularly by using drugs which target senescent cells (senolytics) which are already being developed for other age-related diseases,” says Donovan. By targeting senescent neurons, doctors may be able to prevent or treat chronic pain more effectively.
"We still know very little about why pain becomes chronic, which makes it hard to focus treatments on the root cause," says Tawfik. "This study offers a step toward personalized, mechanism-based care for people living with chronic pain."
The team received valuable bioinformatics support from Marco Quarta, Chief Scientific Officer of Rubedo Life Sciences, and his team, in particular bioinformatician and Chief Technology Officer Alexander Laslavic, using open source codes integrated in their broader proprietary multi-OMICS drug discovery platform ALEMBIC™. Their expertise in aging science, cellular senescence and regenerative medicine was key to re-analyzing existing mouse and human transcriptomic datasets, providing further evidence for the key finding that sensory neurons can take on the senescent “zombie-like” cell state.
Why It Matters
Chronic pain is a widespread health issue that affects millions of people. Yet it remains undertreated, especially in older adults. This study helps explain why pain can feel different as we age, and why older adults may experience more persistent pain. Understanding how aging contributes to pain, or increases the susceptibility to pain after injury, is an important step toward improving treatment for all age groups.
What’s Next
The team will continue investigating how to best target senescent neurons to relieve chronic pain, with their work still at the pre-clinical phase, there is a lot of groundwork to do. The ultimate goal is to create treatments that can help manage pain while preserving healthy nerve function. “We may see a shift towards tailoring pain therapies based on a patient's age, with older individuals receiving treatments that specifically target senescent neurons,” concludes Donovan.
Contact:
Vivianne Tawfik, MD, PhD
Associate Professor, Principal Investigator
Department of Anesthesiology, Perioperative & Pain Medicine
vivianne@stanford.edu
