Human brain organoids transcriptionally and epigenomically age with cell type specificity over years in culture, retaining a memory of time spent in vitro and continuing to mature beyond previously demonstrated limits.
Key Findings
Methods
Human brain organoids were successfully cultured and maintained for 5 years in vitro with optimized growth conditions that extended excitatory neuron viability beyond previous limits.
The study developed human brain organoids for 5 years in culture, representing an extension beyond prior in vitro brain organoid development timelines.
Growth conditions were specifically optimized to support long-term excitatory neuron survival.
The organoids were shown to largely mimic early stages of brain development in prior work, but this study extended their developmental maturation window.
Results
Brain organoids transcriptionally age with cell type specificity over years in culture, as assessed using maturation-associated modules derived from endogenous human brain.
Maturation-associated transcriptional modules were derived from endogenous human brain tissue to serve as a reference for aging.
Transcriptional aging was observed to be cell type-specific, meaning different cell populations within organoids aged at distinct rates or patterns.
The transcriptional aging trajectory in organoids paralleled developmental progression seen in vivo in the human brain.
Results
Whole-genome methylation profiling revealed that the predicted epigenomic age of organoids correlates precisely with time spent in vitro and parallels epigenomic ageing in vivo.
Epigenomic age was predicted using whole-genome methylation profiling across multiple organoid time points.
The correlation between predicted epigenomic age and actual time in culture was described as precise.
The epigenomic aging trajectory in organoids was shown to parallel the in vivo epigenomic aging process in the human brain.
Results
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.
Chimeric organoids were generated by mixing neural progenitors of different chronological ages.
Older progenitors, when placed in a younger environment, did not revert to producing early neuronal fates but instead continued to generate late-stage neuronal types.
This skipping of earlier neuronal progeny demonstrates that progenitors retain a memory of the time they spent in vitro.
This finding indicates that the aging state of neural progenitors is cell-intrinsically encoded and not readily reset by environmental context.
Results
Neural progenitors that age in organoids retain a memory of time spent in vitro, as evidenced by their continued production of age-appropriate neuronal fates in chimeric conditions.
The chimeric organoid experiment directly tested whether the aging state of progenitors was reversible or environmentally determined.
Old progenitors maintained their temporal identity even when mixed with younger progenitors, producing late neuronal fates rather than reverting to early ones.
This provides evidence that time-dependent fate specification is encoded within the progenitor cells themselves rather than being solely governed by external signals.
Conclusions
Human brain organoids can continue to mature and record the passage of time over many years in culture.
Both transcriptomic and epigenomic data converged to support the conclusion that organoids undergo progressive maturation over a multi-year period.
The study demonstrates that organoids are not static models but actively record elapsed time through molecular changes.
These findings suggest organoids may serve as valid models for studying prolonged, species-specific aspects of human postnatal brain development that are difficult to recapitulate in animal models.
What This Means
This research suggests that miniature human brain models grown in the laboratory — called brain organoids — can age and mature over multiple years, recording the passage of time in ways that closely mirror how the actual human brain develops after birth. By growing these organoids for up to 5 years (longer than previously achieved) and analyzing their gene activity and DNA chemical modifications, the researchers found that the organoids progressively change in ways that match the timeline of real human brain maturation. This means these lab-grown brain models are not simply frozen at an early developmental stage but continue to develop over time.
One of the most striking findings involves what happens when researchers mixed young and old brain progenitor cells together in the same organoid. The older cells did not 'reset' to behave like younger cells — instead, they continued producing the types of neurons appropriate for their age, effectively skipping over earlier developmental steps. This shows that the cells have an internal memory of how long they have been developing, and that this memory is encoded within the cells themselves rather than being controlled entirely by their surrounding environment.
This research matters because the human brain takes nearly two decades to fully develop, and this prolonged process is very hard to study in animals or with conventional lab tools. Brain organoids that can authentically age over years could provide a powerful new way to study diseases that emerge during brain development or maturation, and to better understand what makes human brain development uniquely prolonged compared to other species.
Faravelli I, Antón-Bolaños N, Wei A, Faits T, Kumar A, Andreadis S, et al.. (2026). Human brain organoids record the passage of time over multiple years.. Nature. https://doi.org/10.1038/s41586-026-10877-x