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.

Boston University School of Medicine, Center for Regenerative Medicine · biorxiv

Paper

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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Research summary

The paper claims that iPSC-derived neurons from centenarians exhibit unique resilience signatures that promote healthy aging and stress responses. This research is relevant as it explores the underlying mechanisms of resilience in centenarians, potentially addressing root causes of aging and contributing to the understanding of longevity.

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