Genetic architecture of cardiac aging: A fly perspective

Risks of cardiovascular diseases increases drastically in aging populations, but its genetic underpinning remains largely unknown. Previous studies characterised the molecular and functional conservation of cardiomyocytes between humans and Drosophila melanogaster. The short life cycle of the fly allowed the study of aging and the identification of common features with mammals: a reduction of cardiac reverse and an increase of arrhythmias. Recently, we published (Saha et al. eLife, 2022, PMID: 36383075) an analysis of the genetic architecture of cardiac performance in young flies and reported correlation between genes associated with cardiac phenotypes in both flies and humans. This supports a conserved genetic architecture regulating adult cardiac function between fly and human. We used Drosophila as a model to decipher the genetic architecture of cardiac aging and elucidate the influence of natural genetic variations on this process. We previously reported GWAS of cardiac performance in young flies using the DGRP. The same population was analysed in aged flies on 196 inbred lines and approx. 4500 individuals. GWAS were performed on the aging of 8 cardiac performance traits to identify genetic variants associated with variability of cardiac senescence. Overall, we identified 293 variants at whole genome Bonferroni correction. The identified genes networks associated with natural variation of cardiac aging were used to gain insight into the molecular and cellular processes affected. Several genetic variants are associated to nuclear genes encoding mitochondrial proteins. Two antagonistic transcription factors are predicted to regulate this set of genes and have themselves variants associated with the natural variations of cardiac aging, suggesting that alterations of the corresponding gene regulatory network play a determining role in cardiac aging. In addition, data mining identifies strong overlap between genes associated to cardiac aging in flies and genes associated to cardio-vascular pathologies in humans, highlighting conserved genetic mechanisms associated with natural variations of cardiac traits from flies to humans. The analysis of natural variations of cardiac aging in Drosophila represents a major advance in understanding the mechanisms underlying the genetic architecture of these complex traits. It holds promise for the identification of the genes and mechanisms underlying cardiac disorders in humans.