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

Paishiun N Hsieh,Anna H Borton,Domenick A Prosdocimo,Diana Ramírez-Bergeron,Zhaoyang Feng,Yuan Lu,John P Kirwan,Ciaran E Fealy,Maureen Peters,Panjamaporn Sangwung,Yiyuan Yuan,Hisashi Fujioka,Guangjin Zhou,Anne Hamik,Rongli Zhang,Evgenii Boriushkin,Mukesh K Jain,Xudong Liao

doi:10.1038/s41467-017-00899-5

Paishiun N Hsieh, Anna H Borton + Show 16 more

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https://doi.org/10.1038/s41467-017-00899-5

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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.

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Loss of protein and organelle quality control secondary to reduced autophagy is a hallmark of aging
Combinatorial deficiency achieved by knockdown of one klf in the background of a second klf mutant nematode revealed that knockdown of klf-2 in both a klf-1(tm731) mutant and klf-3(ok1975) mutant did not affect lifespan, while the converse, single knockdowns of klf-1 or klf-3 in a klf-2(ok1043) mutant, reduced mean lifespan significantly, a result which may reflect the differential response of an organism to acute vs. chronic loss of a klf gene (Supplementary Fig. 1B, C, E, F; Supplementary Tables 1 and 2)
Our findings demonstrate that klf-1 and klf-3 are required for normal lifespan in C. elegans

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Loss of protein and organelle quality control secondary to reduced autophagy is a hallmark of aging. Studies of the distinct signaling networks in C. elegans that modulate lifespan have provided evidence of a central role for autophagy in many known longevity paradigms These pathways include the highly conserved mechanistic target of rapamycin (mTOR), insulin/IGF-1 like (IIS), and 5′ AMP-activated protein kinase (AMPK) pathways. TFEB, an activator, and ZKSCAN3, a repressor, have been reported to bind directly to promoter regions of target lysosomal and autophagy genes to regulate autophagosome and lysosome biogenesis in an organized pattern of control known as the coordinated lysosomal expression and regulation (CLEAR) network[11, 12] Their roles in the connection between autophagy and mammalian aging largely remain to be explored, variants of FOXO3A in humans have been linked to longevity in seven cohorts globally[13]. While KLF4 has profound pleiotropic effects in multiple cell types, it functions to regulate autophagy in vascular endothelial cells and modulate blood vessel aging

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