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Necrosis as a fundamental driver of loss of resilience and biological decline: what if we could intervene?

Oncogene volume 44, pages 1893–1904 (2025)Cite this article

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Abstract

Necrosis is uncontrolled cell death that marks the irreversible threshold of biological degeneration. Rooted in the Greek nekros (death), it is a pivotal mechanism underlying numerous diseases, including cancer, as well as renal, cardiac, neuronal, and hepatic disorders, and more broadly, the aging process. Despite its profound impact on morbidity and mortality, necrosis remains untreatable and has long been viewed as a chaotic, unavoidable aspect of biology. This review examines the mechanisms of necrosis and outlines its far-reaching impact on health, as revealed by emerging evidence. Furthermore, we explore its potential as a game-changing therapeutic target. Inhibiting necrosis could revolutionize treatments for acute and chronic age-related conditions like cancer, kidney disease, cardiovascular disease (including heart attacks and strokes), and neurodegeneration, while also preserving resilience—and even slowing aging itself. Beyond Earth, where microgravity, cosmic radiation, and oxidative stress accelerate cellular decline, targeting necrosis may also hold the key to preserving astronaut resilience and health on long-duration space missions, offering insights that could reshape human longevity both on and off the planet.

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Fig. 1: General cellular changes associated with unprogrammed cell death necrosis.
Fig. 2: Chain of events at the molecular, cell, tissue, and physiological levels associated with aging [20].
Fig. 3: Cell necrosis is at the heart of kidney disease.
Fig. 4: Overview of changes in age-related conditions and age-related disease as well as accelerated aging.

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Acknowledgements

This work did not receive any funding from public, commercial, or not-for-profit organizations. Figures were created partially in BioRender. Kern, C.(2025) and partially using images under license from iStock.com.

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Authors and Affiliations

  1. LinkGevity, Babraham Research Campus, Cambridge, UK

    Carina Kern, Bill Davis, Halime Karakoy & Nikodem Grzesiak

  2. Division of Renal Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Joseph V. Bonventre

  3. Harvard Stem Cell Institute, Harvard, Boston, MA, USA

    Joseph V. Bonventre

  4. Harvard-MIT Health Sciences and Technology, Cambridge, MA, USA

    Joseph V. Bonventre

  5. MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK

    Alexander W. Justin

  6. Division of Nephrology and Hypertension, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA

    Kianoush Kashani

  7. Starburst Aerospace, El Segundo, CA, USA

    Elizabeth Reynolds

  8. NASA Human Research Program, Microsoft and Translational Research Institute for Space Health Space-H Program, Houston, CA, USA

    Elizabeth Reynolds

  9. London Tubular Centre, Royal Free Hospital, London, UK

    Keith Siew

  10. UCL Centre for Kidney and Bladder Health, University College London, London, UK

    Keith Siew

  11. Bexorg Inc, New Haven, CT, USA

    Damian Miles Bailey

  12. Neurovascular Research Laboratory, Faculty of Life Sciences and Education, University of South Wales, Pontypridd, UK

    Damian Miles Bailey

  13. Life Sciences Working Group, European Space Agency, Paris, France

    Damian Miles Bailey

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  1. Carina Kern
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  2. Joseph V. Bonventre
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Contributions

All authors contributed equally to the manuscript. CK, JVB, AWJ, KK, ER, KS, BD, HK, NG, and DMB jointly conceptualized, drafted, and revised the manuscript.

Corresponding author

Correspondence to Carina Kern.

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Competing interests

CK is CEO of LikGevity. BD is Head of R&D of LinkGevity and formerly held senior leadership positions, inc. director of scientific operations, at GlaxoSmithKline (GSK). JB holds equity in LinkGevity; is Director of Health Sciences and Technology at Massachusetts General Hospital, Harvard, USA; Chair of Renal Medicine, Harvard; Chief, Renal Division; Chief, Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard; Past President, American Society of Nephrology; and Member of the Kidney Cancer Program at the Dana-Farber/Harvard Cancer Center. ER is Managing Director, Starburst Aerospace, USA and Director of NASA Human Research Program, Microsoft and Translational Research Institute Space-Health (Space-H) Program, USA. NG is CTO at LinkGevity. HK is a LIDO student at LinkGevity. DMB is Editor-in-Chief of Experimental Physiology; Chair of the Life Sciences Working Group, European Space Agency; Member of the Human Spaceflight and Exploration Science Advisory Committee to the European Space Agency; Member of the Space Exploration Advisory Committee to the UK and Swedish National Space Agencies; and Member of the National Cardiovascular Network for Wales and South-East Wales Vascular Network. DMB is also affiliated to Bexorg, Inc. (USA) focused on the technological development of novel biomarkers of cerebral bioenergetic function and structural damage in humans.

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Kern, C., Bonventre, J.V., Justin, A.W. et al. Necrosis as a fundamental driver of loss of resilience and biological decline: what if we could intervene?. Oncogene 44, 1893–1904 (2025). https://doi.org/10.1038/s41388-025-03431-y

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