Cardiac performance declines with age and has been attributed to the accumulation of abnormal gene changes. The cardiac aging paradigm has postulated that these changes ultimately perturb myocyte stiffness and cytoskeletal organization leading to systolic and/or diastolic dysfunction. However efforts to understand dysfunction have been stymied by at least three factors: 1) mechanogenetics, i.e. the genetic variation within a model organism affecting mechanical function making it difficult to identify conserved aging mechanisms, 2) geometric complexity of model organisms, and 3) extremely gradual aging. We have developed novel approaches to measure the passive and active mechanics and physiology of fruit flies, i.e. Drosophila melanogaster, a model system that rapidly ages from juvenile to geriatric in 6 weeks. Using these new analysis methods and the high throughput nature of the Drosophila model, we will examine how genotypic variation influences cardiac aging, and we will also identify what mammalian-conserved genes are most responsible for these detrimental changes leading to dysfunction via microarrays, qPCR, and western blotting. Using targeted molecular genetics, we will subsequently assess the influence of these specific genes on age-related myocyte remodeling, e.g. changes in expression of sarcomeric, costameric, and junctional proteins, as well as how they alter adhesion between the adjacent ventral muscle and heart tube. Importantly, we will also assess how these genes alter fly heart physiology and function. Comparison with aging databanks of conventional models will ensure that these Drosophila data provide meaningful predictions for the genes responsible in part for age- related dysfunction. This Drosophila work will provide the first in vivo analysis and dissection of the mechanics and function of rapidly aging myocardium in a high throughput fashion and it will also identify genetic modulators and potential therapeutic targets that could improve cardiovascular aging.

Public Health Relevance

As a significant cause of death in the United States, age-induced heart failure from diastolic dysfunction has spawned the need for novel techniques to understand its molecular origins;by better identifying genes responsible for the condition, we can combat the disease more effectively. However, slow aging and complicated myocardial geometry have limited our ability to characterize cardiac changes over time. With new detection methods well suited for a rapidly aging animal model, e.g. Drosophila melanogaster, we have used quantitative genetics to assess how different fly strains undergo cardiac aging and found remarkable variation. Using strains specifically with and without a cardiac aging phenotype, i.e. age-induced stiffening and decreased force-velocity output, fractional shortening, and diastolic diameter, we will investigate cytoskeletal, extracellular matrix, and junctional molecular mechanisms of cardiac aging in flies noting proteins with significant homology to humans. These data will be correlated with pre-existing rat cardiac aging data to demonstrate the predictive power of the fly when assessing cardiac aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG045428-01
Application #
8563410
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Kohanski, Ronald A
Project Start
2013-08-01
Project End
2018-06-30
Budget Start
2013-08-01
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$302,497
Indirect Cost
$72,077
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Nishimura, Mayuko; Kumsta, Caroline; Kaushik, Gaurav et al. (2014) A dual role for integrin-linked kinase and ?1-integrin in modulating cardiac aging. Aging Cell 13:431-40