Abstract
Cardiovascular disease accounts for millions of deaths each year and is currently the leading cause of mortality worldwide. The aging process is clearly linked to cardiovascular disease, however, the exact relationship between aging and heart function is not fully understood. Furthermore, a holistic view of cardiac aging, linking features of early life development to changes observed in old age, has not been synthesized. Here, we re-purpose RNA-sequencing data previously-collected by our group, investigating gene expression differences between wild-type mice of different age groups that represent key developmental milestones in the murine lifespan. DESeq2's generalized linear model was applied with two hypothesis testing approaches to identify differentially-expressed (DE) genes, both between pairs of age groups and across mice of all ages. Pairwise comparisons identified genes associated with specific age transitions, while comparisons across all age groups identified a large set of genes associated with the aging process more broadly. An unsupervised machine learning approach was then applied to extract common expression patterns from this set of age-associated genes. Sets of genes with both linear and non-linear expression trajectories were identified, suggesting that aging not only involves the activation of gene expression programs unique to different age groups, but also the re-activation of gene expression programs from earlier ages. Overall, we present a comprehensive transcriptomic analysis of cardiac gene expression patterns across the entirety of the murine lifespan.
Highlights
As the longevity of the human population increases, aging will continue to present one of the most significant risk factors for cardiovascular disease (Go et al, 2014)
This study aimed to investigate gene expression profiles of the aging mouse heart
RNA-sequencing data from wild-type mice of the four different age groups was analyzed to identify gene expression patterns associated with aging
Summary
As the longevity of the human population increases, aging will continue to present one of the most significant risk factors for cardiovascular disease (Go et al, 2014). Age-associated functional changes in the heart manifest as a decrease in left ventricular diastolic function (Desai and Fang, 2008; Keller and Howlett, 2016), reduced systolic function (due to a reduction in cardiac reserve during exercise) (Lakatta and Levy, 2003), and altered electrical functions (Jones, 2006; Strait and Lakatta, 2012) These changes are likely caused by alterations in ventricular and atrial structure; for example, an increase in the left ventricle thickness due to cardiomyocytes hypertrophy (Cheng et al, 2009), Aging Murine Heart Transciptome or atrial hypertrophy and dilatation (Lam et al, 2017). Similar pathological processes within the cardiovascular system have been observed in neurodegenerative disorders (Critchley et al, 2018), including Huntington’s diseaserelated cardiomyopathy, previously identified by our group and others (Mielcarek et al, 2014; Toczek et al, 2016)
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