A conserved KLF-autophagy pathway modulates nematode lifespan and mammalian age-associated vascular dysfunction

Paishiun N. Hsieh, Guangjin Zhou, Yiyuan Yuan, Rongli Zhang, Domenick A. Prosdocimo, Panjamaporn Sangwung, Anna H. Borton, Evgenii Boriushkin, Anne Hamik, Hisashi Fujioka, Ciaran E. Fealy, John P. Kirwan, Maureen Peters, Yuan Lu, Xudong Liao, Diana Ramírez-Bergeron, Zhaoyang Feng () and Mukesh K. Jain ()
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Paishiun N. Hsieh: Case Western Reserve University
Guangjin Zhou: Case Western Reserve University
Yiyuan Yuan: Case Western Reserve University
Rongli Zhang: Case Western Reserve University
Domenick A. Prosdocimo: Case Western Reserve University
Panjamaporn Sangwung: Case Western Reserve University
Anna H. Borton: Case Western Reserve University
Evgenii Boriushkin: Case Western Reserve University
Anne Hamik: Case Western Reserve University
Hisashi Fujioka: Electron Microscopy Facility
Ciaran E. Fealy: Kent State University
John P. Kirwan: Lerner Research Institute
Maureen Peters: Oberlin College
Yuan Lu: Case Western Reserve University
Xudong Liao: Case Western Reserve University
Diana Ramírez-Bergeron: Case Western Reserve University
Zhaoyang Feng: Case Western Reserve University
Mukesh K. Jain: Case Western Reserve University

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Loss of protein and organelle quality control secondary to reduced autophagy is a hallmark of aging. However, the physiologic and molecular regulation of autophagy in long-lived organisms remains incompletely understood. Here we show that the Kruppel-like family of transcription factors are important regulators of autophagy and healthspan in C. elegans, and also modulate mammalian vascular age-associated phenotypes. Kruppel-like family of transcription factor deficiency attenuates autophagy and lifespan extension across mechanistically distinct longevity nematode models. Conversely, Kruppel-like family of transcription factor overexpression extends nematode lifespan in an autophagy-dependent manner. Furthermore, we show the mammalian vascular factor Kruppel-like family of transcription factor 4 has a conserved role in augmenting autophagy and improving vessel function in aged mice. Kruppel-like family of transcription factor 4 expression also decreases with age in human vascular endothelium. Thus, Kruppel-like family of transcription factors constitute a transcriptional regulatory point for the modulation of autophagy and longevity in C. elegans with conserved effects in the murine vasculature and potential implications for mammalian vascular aging.

Date: 2017
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DOI: 10.1038/s41467-017-00899-5

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