Study finds “zombie” neurons in the peripheral nervous system contribute to chronic pain

A new study published in Nature Neuroscience provides evidence that aging and injury lead to the buildup of senescent neurons—commonly referred to as “zombie” cells—in the peripheral nervous system. These neurons, which have stopped dividing but refuse to die, secrete inflammatory signals that increase pain sensitivity. The researchers found that removing these senescent cells with a targeted drug not only reduced markers of inflammation but also improved pain-related behavior in aged mice.

The study was driven by the need to better understand why older adults are more susceptible to chronic pain and why many existing treatments are either ineffective or come with serious side effects. While research has long shown that the central nervous system is affected by aging, much less was known about how aging influences the peripheral nervous system, which includes sensory neurons in the dorsal root ganglia that transmit pain signals. Since these neurons can be damaged by surgery, trauma, or disease, the researchers aimed to investigate whether they too exhibit signs of cellular senescence—and whether these changes contribute to long-term pain.

“Very little is known about underlying causes of pain experienced during aging. The prevalence of chronic pain in aging populations and the lack of effective and non-addictive treatments motivated this exploration into neuronal senescence as a potential mechanism,” said Lauren Donovan, a research scientist at Stanford University.

“There is nothing worse than sitting in front of a patient who is suffering from chronic pain and telling them you have nothing to offer,” added Vivianne Tawfik, an associate professor at Stanford University and board-certified anesthesiologist and pain medicine physician. “That’s why I run a research lab focused on pain mechanisms—so that in the future, there will be better options for my patients.”

For their study, the researchers used both young and aged mice to examine how peripheral nerve injury and age influence the development of cellular senescence in sensory neurons. The team studied the dorsal root ganglia, a cluster of nerve cells that relay sensory signals from the body to the spinal cord. They used molecular and genetic tools to identify markers of senescence—specifically p16 and p21, two proteins commonly found in senescent cells—as well as IL-6, a pro-inflammatory molecule frequently secreted by these cells. By comparing young and old animals, both with and without nerve injury, they assessed how senescence evolves with time and damage.

The researchers began by measuring senescence in aged mice and found a significant increase in dorsal root ganglia neurons expressing p16, p21, and IL-6, compared to young animals. These neurons also displayed activity of β-galactosidase, a commonly used indicator of cellular senescence. Importantly, many of the senescent neurons belonged to a class of small-diameter cells known as nociceptors, which detect painful stimuli. These cells also expressed Trpv1, a receptor associated with the detection of heat and inflammation-related pain.

Injury further amplified the presence of senescent neurons. When the researchers performed a standard nerve injury in young mice, they observed a rapid increase in neurons expressing p21 and IL-6 within the first week, with p16 expression building more gradually over time. The pattern was even more pronounced in aged animals, where senescence markers were elevated earlier and to a greater extent. Interestingly, not only injured neurons showed signs of senescence. Neighboring uninjured neurons also began to express p21 and p16, suggesting a “bystander” effect where inflammatory signals from injured cells may induce senescence in surrounding tissue.

To understand the functional implications of these changes, the team used electrophysiological techniques to study how senescent neurons behave. They discovered that many of these neurons fired more readily and frequently than others, indicating that they were more excitable. When exposed to IL-6, the senescent neurons became even more active. These findings support the idea that senescent neurons are not simply inactive bystanders but actively contribute to heightened sensitivity and pain.

Crucially, the researchers tested whether eliminating senescent cells could improve outcomes. They treated mice with a drug called ABT263, a senolytic compound that targets and destroys senescent cells. Mice received the treatment several weeks after nerve injury, at a time when senescence had already taken hold. In aged mice, the drug significantly improved mechanical pain thresholds and restored more balanced weight-bearing behavior in their limbs. In younger mice, the treatment had more modest effects, reinforcing the idea that age-related senescence plays a larger role in chronic pain.

To validate the relevance of their findings in humans, the researchers analyzed postmortem tissue samples from human donors aged 32 to 65. Similar to mice, human sensory neurons showed increased expression of p16, p21, and IL-6 with age. Many of these senescent cells were also positive for TRPV1, the same nociceptor marker seen in the mouse experiments. Reanalysis of publicly available human gene expression data further confirmed the association between pain-related symptoms and senescence-related gene activity.

These results highlight a previously underappreciated mechanism of age-related pain: the accumulation of senescent neurons that secrete inflammatory molecules and amplify the nervous system’s sensitivity to pain. Unlike traditional pain treatments that often mask symptoms or carry high risk of dependency, targeting the senescence pathway offers a promising strategy to reduce pain at its source.

“The key takeaway for the average person is that as we age, some of our sensory neurons undergo a process called senescence, which may contribute to chronic pain,” Donovan told PsyPost. “In addition, we found that injury can exacerbate senescence in neurons, leading to an additive effect of aging and injury that may enhance pain. This research identifies a new potential target for treating chronic pain, especially in older individuals. It suggests that addressing cellular senescence in the nervous system can lead to new ways of managing pain and sensory dysfunction.

But the study has limitations. The experimental models involved rodents and postmortem human tissue, which cannot fully replicate the complex experience of chronic pain in living humans. The number of human samples analyzed was small, and most came from donors without known chronic pain conditions. While the researchers used multiple rigorous methods to confirm their findings, future studies will need to explore how senescence affects different types of chronic pain, including conditions like arthritis or diabetic neuropathy. There is also a need to determine the long-term safety of using senolytic drugs in humans, as they may also affect beneficial immune responses or other essential cellular functions.

This research opens the door for new approaches to pain management, particularly for older adults who face limited treatment options. As Donovan noted, “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.”

The study, “Aging and injury drive neuronal senescence in the dorsal root ganglia,” was authored by Lauren J. Donovan, Chelsie L. Brewer, Sabrina F. Bond, Aleishai Pena Lopez, Linus H. Hansen, Claire E. Jordan, Oscar C. González, Luis de Lecea, Julie A. Kauer, and Vivianne L. Tawfik.