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

Nature Communications, Oct 2017

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.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://www.nature.com/articles/s41467-017-00899-5.pdf

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

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. Introduction The maintenance of cellular and organismal homeostasis determines the progress of aging. On a cellular level, homeostasis is maintained, in part, through macroautophagy (hereafter referred to as autophagy), a conserved mechanism by which a cell achieves multiple goals, including clearance of misfolded proteins and organelle turnover with subsequent recycling of degraded constituents. As cells age, their ability to perform these functions declines. This likely leads to an unsustainable accumulation of protein aggregates, which ultimately present an obstacle to cellular survival1,2,3. Indeed, 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. Notably, the inhibition of autophagy in any model of longevity mediated through the mTOR, IIS, or AMPK nutrient sensing pathways strongly suppresses lifespan4, 5. In mammals, global defects in autophagy are lethal postnatally, while tissue-restricted deficiencies produce age-associated pathologic features, including accumulation of inclusion bodies containing ubiquitinylated proteins, deformed mitochondria, ER stress, and appearance of lipofuscin positive vesicles5. These local defects in autophagy usually result in organ-specific dysfunction, likely due to the diverse functional roles of autophagy; tissue-restricted autophagy defects have been investigated in some tissues (hepatocytes, neurons, skeletal and cardiac muscle, immune cells)5. Regulation of autophagy by conserved signaling pathways is primarily understood at post-translational levels; relatively few transcriptional regulators that operate broadly downstream of nutrient sensing pathways to regulate autophagy have been identified6. How autophagy is transcriptionally regulated under diverse upstream stimuli therefore remains unclear. Pha-4/FoxA is required for lifespan extension in the C. elegans eat-2 mutant model of dietary restriction and regulates autophagy, but is dispensable in other models such as IIS signaling-deficient nematodes or other modes of dietary restriction7,8,9. A recently identified TFEB ortholog, HLH-30, has been shown to attenuate lifespan across multiple C. elegans longevity models and to regulate autophagy; it remains to be seen whether TFEB has any direct influence on mammalian aging6. In mammals, substantial work has been performed on the transcriptional regulation of autophagy. Among others, β-catenin, C/EBPβ, FOXO1/3, GATA1, HIF1, NF- κB, p53, and SREBP2 have been reported to be regulators of autophagy, primarily through direct transcriptional activation of autophagy genes10. Additionally, 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) network11, 12. Their roles in the connection between autophagy and mammalian aging largely remain to be explored, although variants of FOXO3A in humans have been linked to longevity in seven cohorts globally13. The Kruppel-like transcription factors (KLFs) are a subfamily of zinc finger transcriptional regulators with highly characterized roles in proliferation, survival, metabolism, and response to stress. While 18 exist in mammals, in C. elegans 3 klf encoding genes (klf-1, klf-2 and klf-3) have been identified with roles in fat metabolism, cell survival (...truncated)


This is a preview of a remote PDF: https://www.nature.com/articles/s41467-017-00899-5.pdf

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, Mukesh K. Jain. A conserved KLF-autophagy pathway modulates nematode lifespan and mammalian age-associated vascular dysfunction, Nature Communications, 2017, Issue: 8, DOI: 10.1038/s41467-017-00899-5