Aging Immune Signal Identified as a Conserved Brake on Nerve Regeneration

Peripheral nerves lose much of their ability to repair themselves as bodies age, and a new comparative genomics study points to a single immune-cell pathway as a shared culprit in humans and mice. Writing in the Journal of Translational Medicine, a research team led by Canbin Zheng reports that macrophage STING signaling—a DNA-sensing inflammatory pathway—is consistently switched on in aged sciatic nerves across both species, and that silencing it in aged mice markedly improves axonal regrowth and remyelination after injury. The finding matters because the authors argue that understanding molecular mechanisms conserved between humans and mice is critical for translating promising preclinical nerve-repair results into clinical strategies; here, at least one regenerative brake appears to be conserved.

The study began with bulk RNA sequencing of sciatic nerve tissue collected from young and aged human donors and from young and aged mice. Cross-species transcriptomic analysis identified 14,855 one-to-one orthologous gene pairs—genes descended from a common ancestor that can be matched directly between the two genomes—and found that their expression patterns were broadly conserved with aging. Within that conserved landscape, the team screened age-associated pathways for those behaving the same way in both species. Macrophage STING signaling stood out: pathway activity was elevated in aged nerves in humans and mice alike, and immunofluorescence and Western blot analyses confirmed that the activation was not merely a transcriptional signal but was detectable at the protein level in macrophages within the aged nerves.

To test whether this conserved activation was causally involved in poor regeneration rather than a bystander of aging, the researchers turned to a pharmacological approach in aged mice. Animals received a STING inhibitor beginning four weeks before sciatic nerve injury, with the duration of post-injury dosing tailored to each experimental endpoint. The result was a significant improvement in both axonal regeneration and remyelination following injury, suggesting that chronic STING activity in aged nerve tissue actively restrains the repair response rather than simply accompanying it.

The complementary experiment worked in the opposite direction. In laboratory co-culture assays, the team evaluated what happens when macrophage STING is activated in the presence of neurons. Using human motor ganglion sensory neurons as well as mouse neurons, they found that STING activation in macrophages suppressed axonal outgrowth in both human-derived and mouse neuronal preparations. That convergence is the translational heart of the paper: the same macrophage pathway that lights up with age in nerve tissue, when experimentally engaged, dampens the extension of axons from neurons of both species in vitro. Together with the inhibition results in aged mice, the authors conclude that macrophage STING signaling functions as a conserved and potent inhibitor of axonal regeneration during aging, and that targeting the pathway may represent a promising therapeutic approach to enhance peripheral nerve repair and restore regenerative capacity in older individuals.

The evidence, however, arrives with important boundaries. The human component consists of transcriptomic and protein-level observations from donor tissue, not interventions in people; the functional proof comes from a mouse injury model with pre-injury drug dosing, a timing regimen that would be difficult to reproduce clinically where injuries are unpredictable. The in vitro co-culture findings, while consistent across human-derived and mouse neurons, cannot capture the full complexity of an injured nerve in a living body. The team also notes that the work was shared as an accepted manuscript subject to further edits before the final version of record. Even so, the study offers a concrete molecular target for a problem that has resisted one: if macrophage STING signaling proves to be as influential in human nerve repair as the comparative data suggest, blocking it could become a strategy to help aging nerves regenerate.

Subject of Research: Macrophage STING signaling as a conserved inhibitor for axonal regeneration with aging: insights from comparative human-mouse transcriptomics

Article Title: Macrophage STING signaling as a conserved inhibitor for axonal regeneration with aging: insights from comparative human-mouse transcriptomics

Article References: Liao, F., Gu, C., Pang, Q., Yin, S., Chen, S., Li, X., Wu, Y., Zhou, R., Wang, B., Zeng, J., Qi, F., Jiang, Y., Wang, S., Dong, H., Zhu, Q., & Zheng, C. (2026). Macrophage STING signaling as a conserved inhibitor for axonal regeneration with aging: insights from comparative human-mouse transcriptomics. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09118-6

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09118-6

Keywords: Macrophage, STING, signaling, conserved, inhibitor, axonal, regeneration, aging, insights, comparative, human-mouse, transcriptomics