Conserved transcriptional regulation of autophagy and lifespan by the Kruppel-like Factors

Case Western Reserve University, Cleveland OH

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Abstract

PROJECT SUMMARY/ABSTRACT Aging is an inevitable consequence of life. Globally, age-related disorders such as cardiovascular disease pose an increasing burden on healthcare systems. Accumulating evidence suggest that dysfunction of the vascular endothelium underlies a number of cardiovascular diseases of aging including hypertension (vessel tone), atherosclerosis, and calcification. Genetic studies in simple organisms (C. elegans) as well as mammals (M. musculus) have identified key cellular processes such as autophagy, energy metabolism, and nutrient sensing as critical to lifespan regulation which are coordinately orchestrated by nodal transcription factors in a complex circuitry. However, our understanding of the pathways that govern these physiologic processes that influence lifespan remains incomplete. Nascent observations in our lab identify klf-3 as a novel regulator of longevity in C. elegans. Overexpression of klf-3 extends lifespan of C. elegans worms, increases autophagy, and klf-3 may be required for lifespan extension by caloric restriction. A conserved KLF exists in mammals, KLF4, which shares sequence homology to C. elegans klf-3, that may regulate in vitro autophagy and in vivo vascular physiology. These findings provide the basis for our central hypothesis that a conserved KLF-autophagy pathway regulates longevity and vascular health. In the proposed studies, we aim to examine whether KLFs are nodal regulators of longevity in C. elegans through a mechanism involving autophagy, KLF regulation of autophagy is maintained in mammalian endothelial biology and KLFs serve an essential role in vascular health and aging. Our studies not only provide crucial scientific knowledge concerning the molecular mechanisms of the aging process, but provide the foundation for interventions which target age-associated debility and disease with the hope of delaying their incidence.