Aging is associated with an exponential increase in the incidence of cardiovascular diseases (CVD). Several mechanisms underlying age-associated cardiac changes in fly model and vertebrates have been proposed, for example, decreased cellular quality control, altered calcium handling, increased mitochondria damage, and the production of reactive oxygen species (ROS). Cellular quality control systems, like autophagy, are essential protective mechanisms for the maintenance of tissue homeostasis during cardiac aging. It is well-known that autophagy declines with age. However, the molecular basis for age-dependent dysregulation of autophagy and its contribution to cardiac homeostasis remain largely unknown. Our recent studies uncovered an exciting link between activin and mechanistic target of rapamycin complex 2 (mTORC2) in the regulation of autophagy and cardiac aging. We also noticed that two mTOR complexes (mTORC1 and mTORC2) seem to play distinct roles in autophagy regulation. Furthermore, through genetic screening we identified several activin- regulated systemic factors (e.g., Upd3, the fly homology of mammalian Interleukin 6, IL-6) that can mediate tissue-tissue communication and maintain cardiac homeostasis. In this proposal, we aim to dissect the distinct mechanisms by which activin signaling regulate autophagy and age- dependent cardiac dysfunctions through the interactions with two important pathways, mTORC2 and JAK-STAT. To achieve the overall objective, we propose two specific aims.
Specific Aim 1 : Determine how activin interacts with mTORC2 to regulate autophagy and cardiac aging;
Specific Aim 2 : Determine the role of activin and Upd3 in oenocyte-heart communication during aging. The mechanistic understanding of the tissue specificity and the underlying function of activin in cardiac aging will provide strong justification for its continued development as a novel target for potential therapeutic intervention.

Public Health Relevance

Resolving the contributing mechanisms of heart diseases is a pressing goal of basic and translational aging research. This research aims to delineate novel signaling pathways that regulate heart tissue homeostasis, and to identify circulating factors maintaining cardiac functions with age. This study will contribute to the discovery of activin-related therapy for age- associated cardiac diseases and the medical interventions that restore cardiac health in the elderly.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG058741-01A1
Application #
9662486
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Kerr, Candace L
Project Start
2019-01-15
Project End
2023-11-30
Budget Start
2019-01-15
Budget End
2019-11-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Iowa State University
Department
Genetics
Type
Schools of Arts and Sciences
DUNS #
005309844
City
Ames
State
IA
Country
United States
Zip Code
50011