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Lessons from inducible pluripotent stem cell models on neuronal senescence in aging and neurodegeneration

Nature Aging volume 4, pages 309–318 (2024)Cite this article

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Abstract

Age remains the central risk factor for many neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease and amyotrophic lateral sclerosis. Although the mechanisms of aging are complex, the age-related accumulation of senescent cells in neurodegeneration is well documented and their clearance can alleviate disease-related features in preclinical models. Senescence-like characteristics are observed in both neuronal and glial lineages, but their relative contribution to aging and neurodegeneration remains unclear. Human pluripotent stem cell-derived neurons provide an experimental model system to induce neuronal senescence. However, the extensive heterogeneity in the profile of senescent neurons and the methods to assess senescence remain major challenges. Here, we review the evidence of cellular senescence in neuronal aging and disease, discuss human pluripotent stem cell-based model systems used to investigate neuronal senescence and propose a panel of cellular and molecular hallmarks to characterize senescent neurons. Understanding the role of neuronal senescence may yield novel therapeutic opportunities in neurodegenerative disease.

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Fig. 1: Established hallmarks of cellular senescence and those commonly identified in aged neurons and neurodegenerative neurons.
Fig. 2: Summary of PSC models and associated aging phenotypes.
Fig. 3: Hypothetical mechanisms of neuronal senescence that could be implicated in neurodegenerative disease.

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Acknowledgements

We thank D. Snyder, C. Mendes and S. Oakeley for their invaluable administrative support. This Review was funded by the joint efforts of The Michael J. Fox Foundation for Parkinson′s Research (MJFF) and the Aligning Science Across Parkinson′s (ASAP) initiative. MJFF administers the grant ASAP-020370 on behalf of ASAP and itself. The work of the authors was funded by grants ASAP-000472, ASAP-000592, ASAP-020566 administered through MJFF. All figures were created with BioRender.com. For the purpose of open access, the authors have applied a CC BY public copyright license to the author accepted manuscript version arising from this submission.

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Authors and Affiliations

  1. The Center for Stem Cell Biology and Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, NY, USA

    Isabelle R. de Luzy & Lorenz Studer

  2. Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, MD, USA

    Isabelle R. de Luzy, Michael K. Lee, William C. Mobley & Lorenz Studer

  3. Department of Neuroscience, University of Minnesota, Minneapolis, MN, USA

    Michael K. Lee

  4. Institute for Translational Neuroscience, University of Minnesota, Minneapolis, MN, USA

    Michael K. Lee

  5. Department of Neurosciences, University of California, San Diego, San Diego, CA, USA

    William C. Mobley

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Conceptualization: I.D.L., M.L., W.B. and L.S. Manuscript preparation: I.D.L. and L.S. Manuscript editing: I.D.L., M.L., W.B. and L.S.

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Correspondence to Isabelle R. de Luzy or Lorenz Studer.

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L.S. is a scientific cofounder and consultant of BlueRock Therapeutics and Dacapo Brainscience. The remaining authors declare no competing interests.

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de Luzy, I.R., Lee, M.K., Mobley, W.C. et al. Lessons from inducible pluripotent stem cell models on neuronal senescence in aging and neurodegeneration. Nat Aging 4, 309–318 (2024). https://doi.org/10.1038/s43587-024-00586-3

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