New Technology Developed to Induce Aging in Human iPS Cell-Derived Neurons

A joint research group including Professor Kazuto Kobayashi and Associate Professor Keiichi Ishikawa of the Genome and Regenerative Medicine Center at Juntendo University Graduate School of Medicine, along with Keio University, the University of Tokyo, and Showa University, has developed a technology to induce characteristics of senescent cells in human iPS cell-derived neurons using the ATM kinase inhibitor KU60019. While human iPS cell-derived neurons are useful for studying neurological diseases, it has been challenging to replicate age-related pathology in iPS cells because their aging information is reset during the induction process, which is problematic for late-onset diseases such as Parkinson's and Alzheimer's diseases. In this study, KU60019 successfully reproduced senescence-like states in Alzheimer's and Parkinson's disease iPS cell models, significantly shortening the period for detecting disease-related phenotypes. Furthermore, as it induces senescence-like changes in skin fibroblasts collected from young individuals, applications for cellular senescence research are also expected. The paper was published online in the journal Stem Cell Reports on June 11, 2026.

Highlights of this research: - Inducing a cellular senescence-like state in human iPS cell-derived neurons using the ATM kinase inhibitor KU60019. - Shortening the time to replicate disease phenotypes in neurodegenerative disease iPS cell models through KU60019 treatment. - KU60019 also induces senescence-like changes in cultured cells such as skin fibroblasts, presenting possibilities for applications in cellular senescence research.

Our research group performed compound screening to identify compounds that promote maturation and aging-related changes in human iPS cell-derived neurons, identifying the ATM kinase inhibitor KU60019. Treatment of human iPS cell-derived dopamine neurons with KU60019 promoted neurite outgrowth and electrical activity without significantly affecting differentiation efficiency. Furthermore, several characteristics associated with cellular senescence were observed, such as an increase in SA-βGal-positive cells (a marker of cellular senescence), changes in DNA damage response, nuclear envelope structural abnormalities, autophagy dysfunction, and a decrease in the NAD/NADH ratio. This effect was also observed in skin fibroblasts derived from young individuals, showing that they approached the gene expression patterns of skin fibroblasts derived from elderly individuals. In addition, KU60019-induced senescence-like cells were reduced by HSP90 inhibitors and BCL-2 family inhibitors, suggesting that they are maintained dependent on specific cell survival pathways similar to known senescent cells. Furthermore, in Alzheimer's disease iPS cell models with mutations in the PSEN1 gene, an increase in Aβ42 and phosphorylated tau, and a decrease in cell survival were observed earlier. Disease phenotypes were also clearly observed in Parkinson's disease models. These results indicate that KU60019 treatment is a useful method for efficiently detecting disease-related phenotypes of age-related neurodegenerative diseases. Future validation in glial cells and other cell types is expected.