Abstract
We investigated the transcriptomic landscape of the murine myocardium along the course of natural aging and in three distinct mouse models of premature aging with established aging-related cardiac dysfunction. Genome-wide total RNA-seq was performed and the expression patterns of protein-coding genes and non-coding RNAs were compared between hearts from naturally aging mice, mice with cardiac-specific deficiency of a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity and mice with reduced telomere length. Our results demonstrate that no dramatic changes are evident in the transcriptomes of naturally senescent murine hearts until two years of age, in contrast to the transcriptome of accelerated aged mice. Additionally, these mice displayed model-specific alterations of the expression levels of protein-coding and non-coding genes with hardly any overlap with age-related signatures. Our data demonstrate very limited similarities between the transcriptomes of all our murine aging models and question their reliability to study human cardiovascular senescence.
Highlights
We investigated the transcriptomic landscape of the murine myocardium along the course of natural aging and in three distinct mouse models of premature aging with established aging-related cardiac dysfunction
The first model of accelerated aging we included in the study is the one we address as the Harlequin (Hq) model: these are male mice on a B6CBACa-Aw-J/A (B6CBA) background between 17 and 20 weeks of age which present a proviral insertion in the first intron of Apoptosis inducing factor mitochondria associated 1 (Aifm1) in hemizygosity that reduces for the 80% the expression of this gene[15]
To study the effects of natural aging on the genomic features of the heart, we performed total RNA sequencing on hearts from naturally aged mice of 12, 52 and 104 weeks of age and of three mouse models of accelerated aging: Ercc[1] heart specific knock-out mice, Telomerase Reverse Transcriptase (Tert) knock-out mice and mice harboring the Hq mutation characterized by haploinsufficiency of Aifm[1] (Fig. 1a)
Summary
We investigated the transcriptomic landscape of the murine myocardium along the course of natural aging and in three distinct mouse models of premature aging with established aging-related cardiac dysfunction. Our results demonstrate that no dramatic changes are evident in the transcriptomes of naturally senescent murine hearts until two years of age, in contrast to the transcriptome of accelerated aged mice. These mice displayed model-specific alterations of the expression levels of protein-coding and non-coding genes with hardly any overlap with age-related signatures. Longitudinal and cross-sectional studies on human aging are merely observational and not mechanistic in nature, making unavoidable the use of model organisms For this purpose, rodents represent the unsurpassed gold-standard: mice and rats have a relative short lifespan (approximatively two years) which makes them easier to be used rather than long-lived animals[8]. This can cause pitfalls in the interpretation of the translational value of the findings in the current model organisms
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