Researchers have discovered a potential treatment for post-operative delirium, which accelerates cognitive decline in older people.
A common problem with long-term effects
Roughly a quarter of older people suffer from delirium after surgery [1], which rises to around half if the surgery is particularly invasive or high-risk [2]. This increases the length of hospital stays and roughly triples mortality risk [3].
Furthermore, post-operative delirium is linked to further permanent damage to already damaged brains [4]. Nearly two-thirds of people with existing mild cognitive impairment went on to develop full-blown Alzheimer’s disease within three years of experiencing delirium after surgery [5]. This team noted that little work has been done in analyzing why this occurs.
For their own investigations, they turned to microglia, the immune cells of the brain. Previous research has noted that these cells are overactivated in cases of post-operative delirium [6], which occurs alongside metabolic reprogramming that is linked to Alzheimer’s disease [7]. This is linked to the formation of stress granules, a protective mechanism that goes out of control during neurodegeneration [8].
These researchers have previously discovered that knocking down RUVBL2 increases ATP in cells, leading to more rapid dissolution of these granules and restoring function in a rat model [9]. This paper builds upon that work, focusing on RUVBL2’s role in metabolic reprogramming in the context of post-operative delirium.
Anaesthetic surgery causes hippocampal changes
In their first experiment, the researchers conducted surgery on 8-month- to 9-month-old rats in which they used a 3% sevoflurane anaesthetic for three hours, then conducted cognitive tests to determine its effects. Compared to a control group and a sham surgery group, the pro-inflammatory cytokine IL-1β was increased in the sevoflurane group while the anti-inflammatory cytokine IL-10 was decreased.
The treated rats also had significantly worse performance on the Barnes maze and novel object recognition tests, which occurred alongside metabolic differences in the hippocampus. This brain region was overactivated, with a metabolic shift from oxidative phosphorlylation to glycolysis. Further analysis found that this occurred alongside a more inflammatory profile in the microglia, with fewer microglia branches and an increase in CD86. Unsurprisingly in light of their previous work, the researchers also found increases in RUVBL2 alongside an increase in stress granule formation in the treatment group.
Suppressing RUVBL2 has significant effects
The researchers then chose to investigate RUVBL2 more directly. In an older rat model of mild cognitive impairment, the researchers confirmed the function of two lentiviruses, one of which increases RUVBL2 expression and the other of which decreases it. These rats were then subjected to the same anaesthetic surgery as the younger rats.
As expected, the rats with increased RUVBL2 expression performed worse on the novel object and Barnes maze tests. Suppressing RUVBL2 had dramatic benefits for both tests alongside a significant decrease in inflammation. The glycolytic metabolic shift was attenuated, available ATP was increased, and the number and size of stress granules were decreased. “In conclusion, these data suggest that reduced RUVBL2 expression inhibits metabolic reprogramming progression and effectively alleviates postoperative cognitive deficits in aged MCI rats subjected to sevoflurane anesthesia and surgical trauma.”
With these data in hand, these researchers believe that RUVBL2 is a therapeutic target worthy of further investigation. However, they note the study’s limitations, a major one of which is that microglia are highly heterogenous and that significantly more in-depth study may be required to understand the full effects of anaesthesia on microglial function and how RUVBL2 fits into this dynamic. If a therapy can be created from this line of research, performing significant surgery on older people may become much less dangerous for their long-term cognitive health.
Literature
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[2] Adelaars, S., Te Pas, M. E., Jansen, S. W., van der Linden, C. M., Oosterbos, E., van de Kerkhof, D., … & Bouwman, R. A. (2025). Incidence of delirium post cardiac surgery: Discrepancy between clinical observation, DOS scores, and single‑lead EEG. Journal of Clinical Anesthesia, 106, 111896.
[3] Lander, H. L., Dick, A. W., Joynt Maddox, K. E., Oldham, M. A., Fleisher, L. A., Mazzeffi, M., … & Glance, L. G. (2025). Postoperative delirium in older adults undergoing noncardiac surgery. JAMA Network Open, 8(7), e2519467.
[4] Goldberg, T. E., Chen, C., Wang, Y., Jung, E., Swanson, A., Ing, C., … & Moitra, V. (2020). Association of delirium with long-term cognitive decline: a meta-analysis. JAMA neurology, 77(11), 1373-1381.
[5] Olofsson, B., Persson, M., Bellelli, G., Morandi, A., Gustafson, Y., & Stenvall, M. (2018). Development of dementia in patients with femoral neck fracture who experience postoperative delirium—A three‐year follow‐up study. International journal of geriatric psychiatry, 33(4), 623-632.
[6] Ishii, T., Wang, T., Shibata, K., Nishitani, S., Yamanashi, T., Wahba, N. E., … & Shinozaki, G. (2025). Glial contribution to the pathogenesis of post-operative delirium revealed by multi-omic analysis of brain tissue from neurosurgery patients. bioRxiv, 2025-03.
[7] Guillot-Sestier, M. V., Araiz, A. R., Mela, V., Gaban, A. S., O’Neill, E., Joshi, L., … & Lynch, M. A. (2021). Microglial metabolism is a pivotal factor in sexual dimorphism in Alzheimer’s disease. Communications biology, 4(1), 711.
[8] Cui, Q., Liu, Z., & Bai, G. (2024). Friend or foe: The role of stress granule in neurodegenerative disease. Neuron, 112(15), 2464-2485.
[9] Wang, Z., Yang, C., Wang, X., Liao, H., Liu, X., Liu, H., … & Wang, H. (2025). Knockdown of RUVBL2 improves hnRNPA2/B1‐stress granules dynamics to inhibit perioperative neurocognitive disorders in aged mild cognitive impairment rats. Aging Cell, 24(3), e14418.
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