Stanford and Rubedo researchers identify pain-driving neurons with senescent signatures, opening new preclinical therapeutic pathways.
Pain, particularly in older adults, has long been treated as an inevitable symptom of injury or degeneration; however, emerging research from Stanford University suggests it may be more accurately described as the downstream consequence of cellular misbehavior. In a study published in Nature Neuroscience, researchers have identified sensory neurons in the dorsal root ganglia (DRG) that acquire senescent characteristics – altered signaling, inflammation-related gene expression and resistance to cell death – as part of the aging process and following nerve injury [1].
These neurons, though post-mitotic, were shown to exhibit classic senescence markers, as well as hallmarks of the senescence-associated secretory phenotype (SASP), including the chronic production of inflammatory factors [1]. The result is not cellular quietude but pathological hyperactivity; senescent DRG neurons were found to have increased excitability, contributing to persistent pain responses.
How aging alters pain signaling
The DRG sits at a key junction in the sensory nervous system; when a person experiences an injury – a hand on a hot pan, for instance – signals travel from the periphery through the DRG and onward to the spinal cord and brain. The Stanford study revealed that this gateway is not merely a relay station, but a site of profound cellular change during both aging and injury. Senescent neurons in the DRG become sources of IL-6 and other cytokines, amplifying pain signals and promoting sensitization even after the original injury has healed [1].
“This work identifies a new population of pain-driving cells in the peripheral nervous system that can be targeted for the development of future pain therapies,” said Dr Lauren Donovan, postdoctoral scholar in the Tawfik Lab and co-lead author of the study [2].
From senescence markers to therapeutic targeting
Her colleague Dr Vivianne Tawfik, Associate Professor at Stanford and senior author, emphasized the clinical relevance. “Chronic pain continues to be an area with high unmet need, especially among older adults,” she said. “In this study, aging markedly increased the burden of senescent or ‘zombie’ neurons, which in turn worsened neuropathic pain severity. These insights demonstrate that selective targeting of senescent-like neurons may lead to novel strategies for the management of chronic pain [2].”
To probe whether these senescent neurons could be cleared therapeutically, the researchers used navitoclax (ABT263), a small-molecule senolytic known to selectively eliminate senescent cells. Aged mice treated with ABT263 after nerve injury showed a measurable reduction in pain-like behaviors and improved limb function, with no adverse effect on motor or contralateral sensory performance [1].
The findings were further strengthened by analysis of human DRG tissue, which revealed a similar increase in senescence markers with age, along with a conserved pro-inflammatory signature in nociceptors – including elevated expression of factors such as IL-6 in TRPV1-positive neurons, which are commonly associated with the perception of painful stimuli. Together, these results suggest a shared pathological mechanism between mice and humans, reinforcing the role of senescent neurons in age-related pain conditions.
This study forms part of an ongoing collaboration with Rubedo Life Sciences, whose ALEMBIC drug discovery platform contributed to the identification of senescent neuronal phenotypes. “We know that senescent cells, which increase as people age, drive chronic degenerative diseases and conditions,” said Dr Marco Quarta, CSO of Rubedo. “In this study, we were able to show for the first time that neurons can become senescent, fueling neuropathic pain in both mouse models and human dorsal root ganglia tissue [3].”
The implications are potentially wide-reaching. Chronic pain affects millions globally; it is frequently under-treated, especially in older adults. This research offers a mechanistic explanation for why pain may feel different with age, and why recovery from injury can be more protracted. The researchers noted that gaining a clearer picture of how aging alters pain perception – and why older individuals may be more vulnerable to persistent discomfort following injury – could be key to developing more effective treatments across the lifespan.
Longevity.Technology: It’s not often that we glimpse a new therapeutic horizon in real time – but that is just what this study offers. The idea that post-mitotic neurons can enter senescence and contribute directly to chronic pain reframes our understanding of both neurobiology and aging. These ‘zombie’ neurons don’t just sit inert; they’re actively driving dysfunction, making the peripheral nervous system an emerging frontier in geroscience. What was once viewed as inevitable wear and tear now looks strikingly targetable.
And target it we must. That a senolytic intervention could measurably reverse pain behavior in aged mice – and with human data already showing similar hallmarks – is a bold validation of the senotherapeutic strategy. It also highlights the growing power of precision platforms like Rubedo’s ALEMBIC to deconvolute complex cellular ecosystems. We’re not just chasing symptoms anymore – we’re beginning to map, and treat, the cellular architecture of age-related decline. That’s longevity science at its most exciting. To find out more about senescence, neurons and the future of pain therapy, we spoke to Drs Marco Quarta and Vivianne Tawfik.
A new therapeutic angle on chronic pain
Tawfik emphasized that the biggest challenge in translating these findings lies in achieving specificity for senescent neurons without harming normal sensory cells. “We are working on follow-up studies now to home in on potential additional markers expressed by senescent sensory neurons which would allow us to target them more specifically and efficiently,” she said. “The loss of any non-senescent sensory neurons (off target) could have implications for normal sensory function and therefore needs to be avoided.”
Although the team did not use AI methods in this study, it made extensive use of publicly available transcriptomic datasets to validate its findings. “Previously we would not have had access to such datasets to be able to probe them to answer or confirm new/emerging hypotheses,” said Tawfik. She added that future work will include AI-driven bioinformatics to deepen the understanding of neuronal senescence and guide drug development.
Tawfik also sees potential for this research to drive a more tailored approach to chronic pain care. “Right now we unfortunately don’t have a lot of mechanism-based therapies for chronic pain,” she said. “When I see patients in the clinic I am not able to provide a treatment option that is truly personalized – to their type of pain, age, sex, etc. I think our work highlights that age is one important variable to consider in the treatment of chronic pain and I hope that as we move this forward towards translation it will allow us to have such options.”
Rubedo’s next move in senescence targeting
For Rubedo Life Sciences, the study reinforces its strategy of targeting aberrant cell populations in degenerative conditions. “This work lays the foundation for truly novel neuropathic-pain therapies in an area of high unmet need,” said Quarta. “We have identified aberrant senescent sensory neurons as a promising, first-in-class target and have now disclosed a dedicated program in our pipeline to pursue it.”
According to Quarta, neuronal senescence is not a new direction, but one the company has long considered. “Not a strategic pivot, but rather an existing, previously undisclosed program in our pipeline,” he explained. “In fact, when Rubedo was founded, our very first effort – developed in collaboration with Professors Thomas Rando and Tony Wyss‐Coray at Stanford University School of Medicine – focused on neuromusculoskeletal targets.” Skin, he explained, was selected early on as a “low-hanging fruit” to fast-track clinical validation. “We chose GPX4 as our tip-of-the-spear target to fast-track into the clinic and establish proof of concept,” said Quarta, describing the emerging pipeline as one with “substantial opportunities for market expansion and differentiated therapeutic positioning.”
Science, strategy and collaboration
Rubedo’s ALEMBIC platform integrates high-resolution data and experimental workflows to accelerate discovery. “Our proprietary discovery engine was built in-house to work hand-in-glove with our experimental platforms,” said Quarta, “accelerating target identification, validation and optimization.”
He added that the company’s close partnerships with institutions like Stanford, Cedars-Sinai and the Buck Institute have helped “bridge basic research and translational science” and are central to Rubedo’s role in validating new therapeutic cell populations across tissues.
While still in its preclinical phase, the research sets the stage for therapeutic development. The team’s next steps will involve refining how these senescent neurons are targeted, with a focus on delivery, durability and minimizing off-target effects.
As the science of senescence advances, so too does our ability to interrogate and intervene in the cellular narratives that shape how we age. The hope – cautiously held, but grounded in data – is that future pain treatments may not only relieve suffering but do so by restoring cellular health at its roots.
[1] https://www.nature.com/articles/s41593-025-01954-x
[2] https://painnews.stanford.edu/zombie-neurons-link-pain-aging
[3] https://www.businesswire.com/news/home/20250514558243/en/Rubedo-Life-Sciences-Drug-Discovery-Platform-ALEMBIC-Helps-Identify-Senescent-or-Zombie-Neurons-in-New-Study-Linking-Neuropathic-Pain-and-Aging-Published-in-Peer-Reviewed-Scientific-Journal-Nature-Neuroscience
