Document Type

Article

Publication Date

5-2022

Publication Title

Genome research

Keywords

JMG, Aging, Animals, Autophagy, Female, Gene Expression Regulation, Male, Mice, Proteostasis, Transcriptome

JAX Source

Genome Res 2022 May; 32(5):838-852

Volume

32

Issue

5

First Page

838

Last Page

852

ISSN

1549-5469

PMID

35277432

DOI

https://doi.org/10.1101/gr.275672.121

Grant

AG038070, GM134500

Abstract

Investigation of the molecular mechanisms of aging in the human heart is challenging because of confounding factors, such as diet and medications, as well as limited access to tissues from healthy aging individuals. The laboratory mouse provides an ideal model to study aging in healthy individuals in a controlled environment. However, previous mouse studies have examined only a narrow range of the genetic variation that shapes individual differences during aging. Here, we analyze transcriptome and proteome data from 185 genetically diverse male and female mice at ages 6, 12, and 18 mo to characterize molecular changes that occur in the aging heart. Transcripts and proteins reveal activation of pathways related to exocytosis and cellular transport with age, whereas processes involved in protein folding decrease with age. Additional changes are apparent only in the protein data including reduced fatty acid oxidation and increased autophagy. For proteins that form complexes, we see a decline in correlation between their component subunits with age, suggesting age-related loss of stoichiometry. The most affected complexes are themselves involved in protein homeostasis, which potentially contributes to a cycle of progressive breakdown in protein quality control with age. Our findings highlight the important role of post-transcriptional regulation in aging. In addition, we identify genetic loci that modulate age-related changes in protein homeostasis, suggesting that genetic variation can alter the molecular aging process.

Comments

The authors thank Matthew Vincent at the Jackson Laboratory for the QTL Viewer web tool. We also thank Heidi Munger and the Genome Technology Service at the Jackson Laboratory for expert assistance with the RNA-seq experiments described in this paper.

This article, published in Genome Research, is available under a Creative Commons License.

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