Directly Reprogrammed Human Neurons Retain Aging-Associated Transcriptomic Signatures and Reveal Age-Related Nucleocytoplasmic Defects

Aging is a major risk factor for many human diseases, and in vitro generation of human neurons is an attractive approach for modeling aging-related brain disorders. However, modeling aging in differentiated human neurons has proved challenging. We generated neurons from human donors across a broad range of ages, either by iPSC-based reprogramming and differentiation or by direct conversion into induced neurons (iNs). While iPSCs and derived neurons did not retain aging-associated gene signatures, iNs displayed age-specific transcriptional profiles and revealed age-associated decreases in the nuclear transport receptor RanBP17. We detected an age-dependent loss of nucleocytoplasmic compartmentalization (NCC) in donor fibroblasts and corresponding iNs and found that reduced RanBP17 impaired NCC in young cells, while iPSC rejuvenation restored NCC in aged cells. These results show that iNs retain important aging-related signatures, thus allowing modeling of the aging process in vitro, and they identify impaired NCC as an important factor in human aging. [Display omitted] •Human iPSCs erase aging signatures and hiPSC-derived neurons remain rejuvenated•Directly converted iNs preserve donor age-dependent transcriptomic signatures•Nuclear transport receptor RanBP17 is decreased in aged human cells and iNs•Aged and RanBP17-depleted cells show nucleocytoplasmic compartmentalization defects Mertens and colleagues compare transcriptomes of human fibroblasts, induced neurons (iNs), iPSCs, iPSC-derived neurons, and brain samples from a broad range of aged donors, finding that iNs retain donor aging signatures, while iPSCs are rejuvenated. RanBP17 was consistently decreased during aging, leading to compromised nucleocytoplasmic compartmentalization in aged human cells.