Innate immune restoration after major surgery in the elderly: functional adaptation for maintaining immune reactivity

Diana Boraschi; Paola Italiani; Maria Laura Manca; Daniela Melillo; Thomas B. Dschietzig; Georg Winterer; Anika Müller; Aldo Tagliabue; Paola Migliorini; Claudia D. Spies; on behalf of the BioCog Consortium

doi:10.59717/j.xinn-med.2026.100223

The Innovation Medicine > 2026 Vol. 4 > No. 3 > 100223

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Innate immune restoration after major surgery in the elderly: functional adaptation for maintaining immune reactivity

1.
Laboratory of Immunology, Faculty of Pharmacological Sciences, Shenzhen University of Advanced Technology, Shenzhen 518055, China
2.
Laboratory of Inflammation and Vaccines, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
3.
China-Italy Joint Laboratory of Pharmacobiotechnology for Medical Immunomodulation, Shenzhen 518055, China
4.
Institute of Biochemistry and Cell Biology, National Research Council, Napoli 80131, Italy
5.
Stazione Zoologica Anton Dohrn, Napoli 80121, Italy
6.
Department of Clinical and Experimental Medicine and Department of Mathematics, University of Pisa, and Hospital-University of Pisa, Pisa 56100, Italy
7.
Immundiagnostik AG, Bensheim 64625, Germany
8.
Department of Anesthesiology and Intensive Care Medicine, Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin 10117, Germany
9.
Pharmaimage Biomarker Solutions GmbH, Berlin 13125, Germany
10.
Department of Internal Medicine, University of Pisa, and Hospital-University of Pisa, Pisa 56100, Italy
11.
These authors contributed equally
12.
These authors share last senior authorship
13.
In addition to Diana Boraschi, Thomas B. Dschietzig, Georg Winterer, Anika Müller, and Claudia D. Spies, the BioCog Consortium includes Friedrich Borchers, Insa Feinkohl, Fatima Halzl-Yürek, Gunnar Lachmann, Kwaku Ofosu, Maria Olbert, Rudolf Mörgeli, Tobias Pischon, Alissa Wolf, Norman Zacharias (Charité–Universitätsmedizin Berlin, Germany), Jürgen Gallinat, Simone Kühn (University Medical Center Hamburg, Germany), Jeroen de Bresser, Edwin van Dellen, Jeroen Hendrikse, Ilse M.J. Kant, Simone J.T. van Montfort, Arjen J.C. Slooter (University Medical Center Utrecht, The Netherlands), David K. Menon, Laura Moreno-López, Jacobus Preller, Emmanuel Stamatakis, Stefan Winzeck (University of Cambridge, UK), Giacomo Della Camera (National Research Council, Napoli, Italy), Roland Krause, Reinhard Schneider (University of Luxembourg), Karsten Heidtke, Peter Nürnberg (ATLAS Biolabs GmBH, Berlin, Germany), Franz Paul Armbruster, Axel Böcher, Ina Diehl, Bettina Hafen, Katarina Hartmann, Anja Helmschrodt, Jana Ruppert, Marion Kronabel, Marius Weyer (Immundiagnostik AG, Bensheim, Germany), Malte Pietzsch, Simon Weber (Cellogic GmbH, Berlin, Germany), Ariane Fillmer, Bernd Ittermann (Physikalisch-Technische Bundesanstalt, Berlin, Germany)

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Corresponding author: diana.boraschi@gmail.com
Received Date: January 17, 2026

Accepted Date: May 20, 2026

Published Online: May 21, 2026

The Innovation Medicine 4(3), https://doi.org/10.59717/j.xinn-med.2026.100223 | Cite this article

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PUBLIC SUMMARY
1. A new reactivity index allows to group elderly subjects into immunologically competent vs. anomalous.
  
  After major physical stress (surgery), over 50% of initially anomalous subjects normalize.
  
  Constitutively inflamed subjects do not normalize.
  
  Normalization is due to active reprogramming of the production of inflammatory vs. anti-inflammatory factors.
  
  Stress-induced generation of innate memory is suggested as adaptation mechanism to attain immune competence.

ABSTRACT

ABSTRACT

Innate immune memory reflects the capacity of innate immune cells to undergo functional reprogramming after challenges. Given its importance as protective immune mechanism in the elderly, in this study we aimed to characterize the development of protective functional innate memory upon major surgery in elderly patients. In a prospective cohort of 102 elderly patients undergoing major surgery, innate immune reactivity was measured as blood leukocyte response to bacterial LPS one day before surgery and 3 months post-operatively, using free active IL-1β as reactivity index. Based on their response, patients were initially classified into four functional response categories: Normal (n=53), Anergic (n=18), Hyperreactive (n=18), and Inflamed (n=13). Thirty-two circulating biomarkers and 29 clinical parameters were analyzed for association with immune state and trajectory. Three months post-surgery, substantial improvement occurred, with 55% Anergic and 67% Hyperreactive patients reaching immune normalization, although some patients maintained abnormal response and some adopted an abnormal reactivity. Irrespective of trajectory, the post-surgical reactivity index was the result of a re-directioning of the production of inflammatory vs. anti-inflammatory factors, suggestive of the establishment of functional innate immune memory. Among clinical and biochemical variables, age emerged as the only significant predictor of immune trajectory in initially Normal patients, with individuals >75 years showing a higher risk of post-operative anergy. This study suggests for the first time that surgery-related stress could induce a functional cell-intrinsic memory-like immune modulation that improves subsequent immune responsiveness in elderly individuals. Thus, surgery-induced innate memory can be considered as an adaptation mechanism for maintaining/attaining optimal immune functionality. The maladaptive post-operative immune reactivity observed in some individuals stresses the need for future personalized interventions to re-establish the capacity of optimal adaptation.

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Boraschi D., Italiani P., Manca M., et al. (2026). Innate immune restoration after major surgery in the elderly: functional adaptation for maintaining immune reactivity. The Innovation Medicine 4:100223. https://doi.org/10.59717/j.xinn-med.2026.100223

Boraschi D., Italiani P., Manca M., et al. (2026). Innate immune restoration after major surgery in the elderly: functional adaptation for maintaining immune reactivity. The Innovation Medicine 4:100223. https://doi.org/10.59717/j.xinn-med.2026.100223

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Innate immune restoration after major surgery in the elderly: functional adaptation for maintaining immune reactivity

GRAPHICAL ABSTRACT

PUBLIC SUMMARY

ABSTRACT