Kim Chanul, Ofria Luke Daniel, Kshirsagar Anannya, Flores Elizabeth Gomez, Kulkarni Sai, Liu Alan Y, Kirkland James L, Kathuria Annie, Tilton Maryam
Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA.
Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA.
bioRxiv. 2025 Aug 12:2025.08.11.669674. doi: 10.1101/2025.08.11.669674.
Aging is increasingly recognized as a systemic process, yet the mechanisms by which senescent cells' signal from peripheral tissues accelerate brain aging remain poorly defined. Here, we used chronic exposure of human cerebral organoids to the secretome of senescent osteocytes to investigate how peripheral aging signals reshape brain tissue architecture. We combined spatially resolved optical fiberbased interferometry nanoindentation with transcriptomic and immunofluorescence profiling, demonstrating that bone-derived senescence-associated secretory phenotype (SASP) factors induce a biphasic mechanical response, early global tissue softening, followed by the emergence of discrete hyper-stiff microdomains. This spatially heterogeneous biomechanical remodeling was accompanied by upregulation of extracellular matrix (ECM), inflammatory, and senescence pathways, and suppression of neurodevelopmental and synaptic gene networks. Our results reveal that chronic paracrine SASP exposure from senescent osteocytes drives localized ECM reorganization and mechanical vulnerability in human brain tissue, providing mechanistic insight into how peripheral cellular senescence may contribute to regional brain fragility during aging.
