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IPSC-based modeling of resiliency in centenarians reveals longevity-specific signatures

Dowrey, T. W.; Cranston, S. F.; Skvir, N. J.; Lok, Y.; Bock, P.; Kharitonova, E. K.; MacDonald, E.; Zeldich, E.; Gabel, C. V.; Tyshkovskiy, A.; Monti, S.; Gladyshev, V. N.; Sebastiani, P.; Perls, T. T.; Andersen, S.; Murphy, G. J.

2025-10-11 molecular biology
10.1101/2025.10.10.681757 bioRxiv
Show abstract

Centenarians represent a human model of resilience to age-related decline, yet resiliency mechanisms remain elusive. Here, we establish an induced pluripotent stem cell (iPSC)-based platform to interrogate resilience signatures in centenarians. IPSC-derived neurons from centenarians exhibit transcriptional programs promoting synaptic integrity, calcium homeostasis, and cholesterol biosynthesis, while suppressing proteostatic stress pathways. Functionally, these neurons maintain stable calcium dynamics, reduced baseline mitochondrial activity, and energy-efficient homeostasis. Upon challenge, centenarian-derived neurons mount a robust stress response, in contrast to attenuated responses in non-centenarian controls. This resilience signature parallels adaptations in long-lived mammals and aligns with healthy brain aging, while showing erosion in Alzheimers disease and cancer. Our platform provides a scalable human model for dissecting resilience biology offering a framework to extend healthspan and mitigate age-related decline.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.