Dichotomy between the transcriptomic landscape of naturally versus accelerated aged murine hearts

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 proteincoding 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. The perception of old age as a merciless and unavoidable perpetrator of the decay of the human body has been a common theme among ancient and modern artists. Oscar Wilde in his novel "The Picture of Dorian Gray" conveys the idea of the fading of youth coming with age as a despicable plague, as an illness consuming the body. Even the geneticist Richard Benedict Goldschmidt, yet with less harsh and colorful images, described aging as the unresolved, ultimate disease of the body; of Goldschmidt are the words "I have accumulated a wealth of knowledge in innumerable spheres and enjoyed it as an always ready instrument for exercising the mind and penetrating further and further. Best of all, mine has been a life of loving and being loved. What a tragedy that all this will disappear with the used-up body!" 1. From a biological perspective, aging still remains an unresolved dilemma: it is generally regarded as a complex process resulting from several causes, as epigenetic, proteotoxic and oxidative stresses, telomere shortening and unresolved DNA damages, all synergistically contributing to altering the functionality of cells, organs and ultimately of the entire organism 2-6. The most recent theories on aging hypothesize that the ultimate responsible for organismal senescence is the cumulative contribution of damages to DNA, proteins, lipids and organelles, produced either by intrinsic stress,

Cardiac Molecular Analysis Reveals Aging-Associated Metabolic Alterations Promoting Glycosaminoglycans Accumulation Via Hexosamine Biosynthetic Pathway

“…The translatability of murine models to understand humans cardiac aging transcriptomics is very limited due to significant developmental, structural and functional cardiovascular differences, including oxygen consumption, adrenergic receptor ratios, and heart rate [29]. Furthermore, the use of senescence-induced animal models lacks reliability due to the non-physiological and uncoordinated promotion of aging mechanisms [28]. While the use of rodent models represents a significant limitation to human translation, the temporal analysis based on classes also compromises the analytical power, causality testing, and effect evaluation.…”

“…However, the aging-related cellular mechanisms that lead to ECM remodeling and to cardiac hypertrophy, and CVD are not well understood. Initial studies of aging-related cardiac transcriptomics use a traditional comparison of two time points (young vs. old animals) [10,12,27] or more than two specific time points in rodents [28]. The translatability of murine models to understand humans cardiac aging transcriptomics is very limited due to significant developmental, structural and functional cardiovascular differences, including oxygen consumption, adrenergic receptor ratios, and heart rate [29].…”