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Peer-reviewedCC BY-NC-NDNature

Human brain organoids record the passage of time over multiple years

  • Irene Faravelli1,2,3
  • Noelia Antón-Bolaños2,4,3
  • Anqi Wei2,3
  • Tyler Faits2,3
  • Abhishek Sampath Kumar2,3
  • Sophia Andreadis2,3
  • Rahel Kästli2,3
  • Marta Montero‐Crespo2,3
  • Mara Steiger5,6
  • Daniel Leible7
  • Enxi Zhang7
  • Bobae An7
12 more authors
  • Yaron Meirovitch8
  • Sayara Silwal2
  • Sung Min Yang2,3
  • Alexander Kovacsovics5
  • Xian Adiconis9,3
  • Helene Kretzmer5,6
  • Joshua Z. Levin9,3
  • Edward S. Boyden7
  • Jeff William Lichtman8
  • Aviv Regev10,9
  • Alexander Meissner11,5
  • Paola Arlotta12,13
13 affiliations
  1. 1Department for Clinical Sciences and Community Health (DISCCO), University of Milan, Milan, Italy
  2. 2Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA
  3. 3Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  4. 4Department of Translational Neuroscience, University Medical Center Utrecht (UMCU), Brain Center, Utrecht University, Utrecht, The Netherlands
  5. 5Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Berlin, Germany
  6. 6Digital Health Cluster, Hasso Plattner Institute for Digital Engineering, Digital Engineering Faculty, University of Potdsdam, Potsdam, Germany
  7. 7McGovern Institute, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA
  8. 8Department of Molecular and Cellular Biology and The Center for Brain Science, Harvard University, Cambridge, MA, USA
  9. 9Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA
  10. 10Genentech, San Francisco, CA, USA
  11. 11Broad Institute of MIT and Harvard, Boston, MA, USA
  12. 12Department of Stem Cell & Regenerative Biology, Harvard University, Cambridge, MA, USA. [email protected]
  13. 13Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
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Abstract

The human brain develops and matures over an exceptionally prolonged period of time that spans nearly two decades of life. Processes that govern species-specific aspects of human postnatal brain development are difficult to study in animal models1. While human brain organoids offer a promising in vitro model, they have thus far been shown to largely mimic early stages of brain development. Here we develop human brain organoids for 5 years in culture, optimizing growth conditions to extend excitatory neuron viability beyond previous limits. Using maturation-associated modules derived from endogenous human brain, we show that brain organoids transcriptionally age with cell type specificity over years in culture. Whole-genome methylation profiling reveals that the predicted epigenomic age of organoids correlates precisely with time spent in vitro, and parallels epigenomic ageing in vivo. Notably, we show that in chimeric organoids generated by mixing neural progenitors of different ages, old progenitors rapidly produce late neuronal fates, skipping the production of earlier neuronal progeny, therefore showing that progenitors that age in organoids retain a memory of the time spent in vitro. The data indicate that human brain organoids can continue to mature and record the passage of time over many years in culture. Human brain organoids were developed for over five years in culture to demonstrate that brain cells can continue to mature and record the passage of time, following human-specific endogenous programs, even outside the context of the organism.

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Cite

BibTeXRIS
BibTeX
@article{faravelli2026human,
  title = {{Human brain organoids record the passage of time over multiple years}},
  author = {Irene Faravelli and Noelia Antón-Bolaños and Anqi Wei and Tyler Faits and Abhishek Sampath Kumar and Sophia Andreadis and Rahel Kästli and Marta Montero‐Crespo and Mara Steiger and Daniel Leible and Enxi Zhang and Bobae An and Yaron Meirovitch and Sayara Silwal and Sung Min Yang and Alexander Kovacsovics and Xian Adiconis and Helene Kretzmer and Joshua Z. Levin and Edward S. Boyden and Jeff William Lichtman and Aviv Regev and Alexander Meissner and Paola Arlotta},
  journal = {Nature},
  year = {2026},
  month = aug,
  doi = {10.1038/s41586-026-10877-x},
  url = {https://doi.org/10.1038/s41586-026-10877-x},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Human brain organoids record the passage of time over multiple years
AU  - Irene Faravelli
AU  - Noelia Antón-Bolaños
AU  - Anqi Wei
AU  - Tyler Faits
AU  - Abhishek Sampath Kumar
AU  - Sophia Andreadis
AU  - Rahel Kästli
AU  - Marta Montero‐Crespo
AU  - Mara Steiger
AU  - Daniel Leible
AU  - Enxi Zhang
AU  - Bobae An
AU  - Yaron Meirovitch
AU  - Sayara Silwal
AU  - Sung Min Yang
AU  - Alexander Kovacsovics
AU  - Xian Adiconis
AU  - Helene Kretzmer
AU  - Joshua Z. Levin
AU  - Edward S. Boyden
AU  - Jeff William Lichtman
AU  - Aviv Regev
AU  - Alexander Meissner
AU  - Paola Arlotta
PY  - 2026
DA  - 2026/08/19
JO  - Nature
DO  - 10.1038/s41586-026-10877-x
UR  - https://doi.org/10.1038/s41586-026-10877-x
AB  - The human brain develops and matures over an exceptionally prolonged period of time that spans nearly two decades of life. Processes that govern species-specific aspects of human postnatal brain development are difficult to study in animal models1. While human brain organoids offer a promising in vitro model, they have thus far been shown to largely mimic early stages of brain development. Here we develop human brain organoids for 5 years in culture, optimizing growth conditions to extend excitatory neuron viability beyond previous limits. Using maturation-associated modules derived from endogenous human brain, we show that brain organoids transcriptionally age with cell type specificity over years in culture. Whole-genome methylation profiling reveals that the predicted epigenomic age of organoids correlates precisely with time spent in vitro, and parallels epigenomic ageing in vivo. Notably, we show that in chimeric organoids generated by mixing neural progenitors of different ages, old progenitors rapidly produce late neuronal fates, skipping the production of earlier neuronal progeny, therefore showing that progenitors that age in organoids retain a memory of the time spent in vitro. The data indicate that human brain organoids can continue to mature and record the passage of time over many years in culture. Human brain organoids were developed for over five years in culture to demonstrate that brain cells can continue to mature and record the passage of time, following human-specific endogenous programs, even outside the context of the organism.
SN  - 0028-0836
SN  - 1476-4687
ER  -