The human brain takes nearly two decades to fully mature, a lengthy process that has been difficult to study in animal models. As in vitro models, human brain organoids could previously only simulate early developmental stages. Now, a Harvard University research team has published a breakthrough study in bioRxiv: they successfully cultivated human brain organoids in the laboratory for a full five years.

## Time Leaves Its Mark in Organoids

The research team optimized culture conditions, enabling the survival of excitatory neurons beyond previously known limits. By analyzing expression patterns of maturation-related genes, they discovered that these organoids exhibited "aging" signs at the transcriptional level over years of cultivation, specifically related to cell types.

Genome-wide methylation analysis more precisely showed that organoids collected at different time points from 3 months to 5 years had epigenetic ages highly correlated with their in vitro culture time, and this process paralleled the epigenetic aging of in vivo brains.

## "Old" Cells Remember Their Age

The most intriguing finding came from chimeric organoid experiments. When researchers mixed neural progenitor cells from "aged" organoids with progenitor cells from "young" organoids, the "old" cells rapidly produced late-stage neuron types, skipping early neuron production stages. Meanwhile, "young" cells in the same culture environment progressed through the complete developmental process as usual.

This suggests that aging progenitor cells in organoids retain "culture time memory" and can execute late-stage developmental programs appropriate to their "age."

## Ethical Boundaries and Scientific Value

This research naturally sparked ethical discussions. Some netizens questioned: "How can this be considered ethical science?" But as researchers clarified, these are not complete brains but laboratory-cultivated cell clusters, without involvement of human subjects.

The scientific community currently generally believes that existing brain organoids lack the complexity, size, and vascular system needed for consciousness or pain perception. They are more like advanced tissue cultures rather than sentient beings.

The value of this technology lies in providing an unprecedented model system for studying human-specific brain development processes, neuropsychiatric diseases, and personalized medicine, while potentially reducing the use of experimental animals.

Paper link: [Human brain organoids record the passage of time over multiple years in culture](https://www.biorxiv.org/content/10.1101/2025.10.01.679721v1)