Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Single Nuclei Sequencing of old and young mice hearts under senolytica (Ageing impairs the neuro-vascular interface in the heart)

ABSTRACT: Aging is a major risk factor for impaired cardiovascular health. The aging myocardium is characterized by microcirculatory and diastolic dysfunction and increased susceptibility to arrhythmias. Nerves align with vessels during development. However, the impact of aging on the cardiac neuro-vascular interface is entirely unknown. Here, we report that aging reduces nerve density specifically in the left ventricle and dysregulates vascular-derived neuro-regulatory genes. Aging leads to a down-regulation of miR-145 and de-repression of the neuro-repulsive factor Semaphorin-3A. miR-145 deletion, which increased Sema3a expression, or endothelial Sema3a overexpression reduced axon density, thus mimicking the observed aged heart phenotype. Removal of senescent cells, which accumulated with chronological age in parallel to the decline in nerve density, rescued age-induced denervation, reduced Sema3a expression, preserved heart rate variability and reduced electrical instability. These data suggest that senescence-associated regulation of neuro-regulatory genes is associated with reduced nerve density and, thereby, contributes to age-associated cardiac dysfunction.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: David John

PROVIDER: E-MTAB-13093 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Background: Skin aging is associated with intrinsic processes that compromise structure of the extracellular matrix while promoting loss of functional and regenerative capacity. These processes are accompanied by a large-scale shift in gene expression, but underlying mechanisms are not understood and conservation of these mechanisms between humans and mice is uncertain. Results: We used genome-wide expression profiling to investigate the aging skin transcriptome. In humans, age-related shifts in gene expression were sex-specific. In females, aging increased expression of transcripts associated with T-cells, B-cells and dendritic cells, and decreased expression of genes in regions with elevated Zeb1, AP-2 and YY1 motif density. In males, however, these effects were contrasting or absent. When age-associated gene expression patterns in human skin were compared to those in tail skin from CB6F1 mice, overall human-mouse correspondence was weak. Moreover, inflammatory gene expression patterns were not induced with aging of mouse tail skin, and well-known aging biomarkers were in fact decreased (e.g., Clec7a, Lyz1 and Lyz2). These unexpected patterns and weak human-mouse correspondence may be due to decreased abundance of antigen presenting cells in mouse tail skin with age. Conclusions: Aging is generally associated with a pro-inflammatory state, but we have identified an exception to this pattern with aging of CB6F1 mouse tail skin. Aging therefore does not uniformly heighten inflammatory status across all mouse tissues. Furthermore, we identified both intercellular and intracellular mechanisms of transcriptome aging, including those that are sex- and species-specific. We used Affymetrix microarrays to evaluate genome-wide expression in tail skin from young (5 month) and old (30 month) CB6F1 mice (males and females). Genome-wide expression was evaluated in tail skin from young (5 months) and old (30 months) CB6F1 mice of both sexes. Samples were collected simultaneously but RNA samples were processed in two separate batches.

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Single Nuclei Sequencing of old and young mice hearts under senolytica (Ageing impairs the neuro-vascular interface in the heart)

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