Sleep disruption increases with age and is associated with adverse outcomes, yet the molecular mechanisms remain unclear. Here, integrative analyses of human and mouse transcriptomic and proteomic datasets identify proteostasis pathways whose aging trajectories align with responses to chronic sleep disruption across tissues, cell types, and molecular layers. Mouse brain and human blood analyses independently recover heat shock factor 1 (HSF1)-associated proteostasis as a recurrent feature of sleep-aging convergence.
Components of the HSF1-associated network display diminished inducibility with age despite increased molecular demands imposed by acute sleep deprivation. This attenuation is particularly pronounced in neurons. Spatial and single-cell analyses map this vulnerability to hippocampal circuits during aging and to glutamatergic cortical neurons in Alzheimer’s disease.
These findings support a model in which repeated sleep disruption and aging both contribute to progressive loss in proteostasis-induction capacity, potentially linking sleep stability and molecular aging. A.B.R. acknowledges funding from the Perelman School of Medicine, University of Pennsylvania, the Institute for Translational Medicine and Therapeutics (ITMAT) at the University of Pennsylvania. This work was supported also by NIH R35GM161590.
Department of Systems Pharmacology & Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA Chronobiology and Sleep Institute (CSI), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA A.B.R. and S.Y. are inventors on a filed patent relating to HSF1 modulation for sleep therapy. A.B.R. is a founder of Pyrellia LLC. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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