SummaryAging causes cardiac dysfunction, often leading to heart failure and death. The molecular basis of age‐associated changes in cardiac structure and function is largely unknown. The fruit fly, Drosophila melanogaster, is well‐suited to investigate the genetics of cardiac aging. Flies age rapidly over the course of weeks, benefit from many tools to easily manipulate their genome, and their heart has significant genetic and phenotypic similarities to the human heart. Here, we performed a cardiac‐specific gene expression study on aging Drosophila and carried out a comparative meta‐analysis with published rodent data. Pathway level transcriptome comparisons suggest that age‐related, extra‐cellular matrix remodeling and alterations in mitochondrial metabolism, protein handling, and contractile functions are conserved between Drosophila and rodent hearts. However, expression of only a few individual genes similarly changed over time between and even within species. We also examined gene expression in single fly hearts and found significant variability as has been reported in rodents. We propose that individuals may arrive at similar cardiac aging phenotypes via dissimilar transcriptional changes, including those in transcription factors and micro‐RNAs. Finally, our data suggest the transcription factor Odd‐skipped, which is essential for normal heart development, is also a crucial regulator of cardiac aging.

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Highlights d Flies in microgravity exhibit cardiac constriction, remodeling, and diminished output d Heart defects correlate with reduced sarcomeric and extracellular matrix gene expression d Proteosome gene or protein expression is upregulated, suggesting proteostasis imbalance