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.

Public Health Relevance

/RELEVANCE Aging is an inevitable consequence of progression through life and age-related disorders such as cardiovascular disease pose an enormous burden on healthcare systems worldwide. Vessel dysfunction is important first event in the development of diseases including atherosclerosis, stroke, heart disease and hypertension. We have identified a group of factors (Kruppel like factors) which influence lifespan in worms and are also present in mammals regulating vessel health during aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
1F30AG054237-01A1
Application #
9190124
Study Section
Special Emphasis Panel (ZRG1-F05-U (20)L)
Program Officer
Velazquez, Jose M
Project Start
2016-06-01
Project End
2019-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
1
Fiscal Year
2016
Total Cost
$43,576
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Hsieh, Paishiun N; Zhou, Guangjin; Yuan, Yiyuan et al. (2017) A conserved KLF-autophagy pathway modulates nematode lifespan and mammalian age-associated vascular dysfunction. Nat Commun 8:914