Cardiac performance declines with age, but genetic variation within a population makes it difficult to identify the conserved aging mechanisms that negatively impact mechanical function, i.e. mechanogenetics. Over the past 5 years, we have studied cardiac function of the rapidly aging Drosophila melanogaster across many laboratory fruit fly strains. We found that fly strains with age-dependent and heart-specific vinculin up- regulation use it to reinforce and stiffen their costameres and intercalated discs, which helps maintain the crystallinity of their sarcomere lattice and improves contractility. At the cardiomyocyte level, maintaining inter- myofilament spacing prolongs wall shortening velocity and fractional shortening, and systemically, it extends lifespan. Fly strains with decreased basement membrane (BM) protein expression, e.g. laminin, also exhibit similar systemic benefits but due to thinner extracellular matrix, which improves cell-cell coupling between adjacent myocyte layers; importantly, both vinculin up-regulation and BM down-regulation with age appear conserved up through non-human primates. Together these data suggest a new inside-outside aging paradigm that prolongs heart function, i.e. a robust internal contractile apparatus with limited extracellular connections to BM. In this grant application, we propose further aims to determine how these intracellular and extracellular heart perturbations act combinatorially to alter function across cellular-, tissue-, and organ-levels. Preliminary assessments in transgenic fly strains suggest that more efficient cardiomyocyte contraction, may improve substrate utilization and oxygen consumption within fly hearts, and subsequently organ perfusion and systemic metabolism, and better health- and lifespan. In light of this paradigm and the challenges that mechanogenetics present, we have developed new biological and analytical tools for this grant that will improve the feasibility of assessing the age-related mechanical differences of Drosophila myocardium between wild-type and transgenic lines. Thus, this on-going work will continue to improve our understanding of the inside-outside aging paradigm.

Public Health Relevance

Age-induced heart failure significantly impairs and is a cause of death for many thousands in the United States annually. Our novel mechanical assays used in a rapidly aging animal model, e.g. Drosophila melanogaster, have identified specific proteins with significant human homology and critical roles in maintaining heart contractility during aging. We will deepen our understanding of their molecular mechanisms and systemic benefits, which significantly extend lifespan and improve healthspan.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG045428-07
Application #
9786179
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Kerr, Candace L
Project Start
2013-09-30
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
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
Sessions, Ayla O; Min, Peter; Cordes, Thekla et al. (2018) Preserved cardiac function by vinculin enhances glucose oxidation and extends health- and life-span. APL Bioeng 2:
Lo Sardo, Valentina; Chubukov, Pavel; Ferguson, William et al. (2018) Unveiling the Role of the Most Impactful Cardiovascular Risk Locus through Haplotype Editing. Cell 175:1796-1810.e20
Barker, Thomas H; Engler, Adam J (2017) The provisional matrix: setting the stage for tissue repair outcomes. Matrix Biol 60-61:1-4
Sessions, Ayla O; Kaushik, Gaurav; Parker, Sarah et al. (2017) Extracellular matrix downregulation in the Drosophila heart preserves contractile function and improves lifespan. Matrix Biol 62:15-27
Blice-Baum, Anna C; Zambon, Alexander C; Kaushik, Gaurav et al. (2017) Modest overexpression of FOXO maintains cardiac proteostasis and ameliorates age-associated functional decline. Aging Cell 16:93-103
Sessions, Ayla O; Engler, Adam J (2016) Mechanical Regulation of Cardiac Aging in Model Systems. Circ Res 118:1553-62
Happe, Cassandra L; Engler, Adam J (2016) Mechanical Forces Reshape Differentiation Cues That Guide Cardiomyogenesis. Circ Res 118:296-310
Kaushik, Gaurav; Spenlehauer, Alice; Sessions, Ayla O et al. (2015) Vinculin network-mediated cytoskeletal remodeling regulates contractile function in the aging heart. Sci Transl Med 7:292ra99
Kaushik, Gaurav; Engler, Adam J (2014) From stem cells to cardiomyocytes: the role of forces in cardiac maturation, aging, and disease. Prog Mol Biol Transl Sci 126:219-42
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