02516nas a2200445   4500000000100000000000100001008004100002260001500043653002600058653002500084100002000109700002700129700001300156700001600169700002700185700002100212700001700233700002500250700001700275700001800292700002000310700001300330700002100343700001800364700001800382700002600400700001800426700002000444700002000464700002100484700001800505700001500523700002300538700001800561245007300579856005500652300000900707520134000716022001402056       2026                            d  c2026-08-1910aCellular neuroscience10aNeuronal development1 aIrene Faravelli1 aNoelia Antón-Bolaños1 aAnqi Wei1 aTyler Faits1 aAbhishek Sampath Kumar1 aSophia Andreadis1 aRahel Kastli1 aMarta Montero Crespo1 aMara Steiger1 aDaniel Leible1 aElizabeth Zhang1 aBobae An1 aYaron Meirovitch1 aSayara Silwal1 aSung Min Yang1 aAlexander Kovacsovics1 aXian Adiconis1 aHelene Kretzmer1 aJoshua Z. Levin1 aEdward S. Boyden1 aJeff Lichtman1 aAviv Regev1 aAlexander Meissner1 aPaola Arlotta00aHuman brain organoids record the passage of time over multiple years  uhttps://www.nature.com/articles/s41586-026-10877-x  a1-113 aThe 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.  a1476-4687