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July 17th, 2025
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University of Southern California
genomics
biorxiv

A multi-omics analysis of human fibroblasts overexpressing an Alu transposon reveals widespread disruptions in aging-associated pathways

Bravo, J. I.Open in Google Scholar•Tewelde, E.Open in Google Scholar•King, C. D.Open in Google Scholar•Bons, J.Open in Google Scholar•Shah, S.Open in Google Scholar•Rose, J.Open in Google Scholar•Campisi, J.Open in Google Scholar•Schilling, B.Open in Google Scholar•Benayoun, B. A.Open in Google Scholar

During aging and cellular senescence, repetitive elements are frequently transcriptionally derepressed across species and cell types. Among these, the most abundant repeats by copy number in the human genome are Alu retrotransposons. Though Alu elements are often studied for their mutagenic potential, there is increasing appreciation for their contributions to other biological functions, including pro-inflammatory signaling and mitochondrial dysfunction. However, a comprehensive analysis of Alu-driven molecular changes remains to be conducted, and Alu\'s potential contributions to aging features remain incompletely characterized. Here, we show that overexpression of an AluJb transposon in human primary IMR-90 fibroblasts leads to large-scale alterations across the transcriptome, cellular proteome, and secretome. Functional genomics analyses reveal alterations in aging/senescence pathways, broadly, and mitochondrial metabolism, proteostasis, cell cycle, and extracellular matrix pathways, more specifically. Our results demonstrate that Alu transcriptional upregulation is sufficient to drive widespread disruptions to cellular homeostasis that mirror aging-associated alterations.

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