Intestinal Snakeskin Limits Microbial Dysbiosis during Aging and Promotes Longevity

Anna M Salazar; Martin Resnik-Docampo; Matthew Ulgherait; Rebecca I Clark; Mimi Shirasu-Hiza; D Leanne Jones; David W Walker

doi:10.1016/j.isci.2018.10.022

Intestinal Snakeskin Limits Microbial Dysbiosis during Aging and Promotes Longevity

iScience. 2018 Nov 30:9:229-243. doi: 10.1016/j.isci.2018.10.022. Epub 2018 Oct 24.

Authors

Anna M Salazar¹, Martin Resnik-Docampo², Matthew Ulgherait³, Rebecca I Clark⁴, Mimi Shirasu-Hiza³, D Leanne Jones⁵, David W Walker⁶

Affiliations

¹ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
² Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
⁴ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Biosciences, Durham University, Durham DH1 3LE, UK.
⁵ Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Broad Stem Cell Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁶ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: davidwalker@ucla.edu.

Abstract

Intestinal barrier dysfunction is an evolutionarily conserved hallmark of aging, which has been linked to microbial dysbiosis, altered expression of occluding junction proteins, and impending mortality. However, the interplay between intestinal junction proteins, age-onset dysbiosis, and lifespan determination remains unclear. Here, we show that altered expression of Snakeskin (Ssk), a septate junction-specific protein, can modulate intestinal homeostasis, microbial dynamics, immune activity, and lifespan in Drosophila. Loss of Ssk leads to rapid and reversible intestinal barrier dysfunction, altered gut morphology, dysbiosis, and dramatically reduced lifespan. Remarkably, restoration of Ssk expression in flies showing intestinal barrier dysfunction rescues each of these phenotypes previously linked to aging. Intestinal up-regulation of Ssk protects against microbial translocation following oral infection with pathogenic bacteria. Furthermore, intestinal up-regulation of Ssk improves intestinal barrier function during aging, limits dysbiosis, and extends lifespan. Our findings indicate that intestinal occluding junctions may represent prolongevity targets in mammals.

Keywords: Functional Aspects of Cell Biology; Microbiome; Model Organism; Molecular Mechanism of Behavior.

Abstract

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