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.

中文翻译：

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全基因组转录本和蛋白质分析强调了蛋白质稳态在衰老小鼠心脏中的作用


由于饮食和药物等混杂因素，以及健康老龄个体组织的获取机会有限，研究人类心脏衰老的分子机制具有挑战性。实验室小鼠为在受控环境下研究健康个体的衰老提供了理想的模型。然而，之前的小鼠研究只检查了在衰老过程中形成个体差异的一小部分遗传变异。在这里，我们分析了 185 只 6、12 和 18 个月龄的遗传多样性雄性和雌性小鼠的转录组和蛋白质组数据，以表征衰老心脏中发生的分子变化。转录本和蛋白质揭示了与胞吐作用和细胞运输相关的途径随着年龄的增长而激活，而涉及蛋白质折叠的过程则随着年龄的增长而减少。其他变化仅在蛋白质数据中显而易见，包括脂肪酸氧化减少和自噬增加。对于形成复合物的蛋白质，我们发现其组成亚基之间的相关性随着年龄的增长而下降，这表明与年龄相关的化学计量损失。受影响最严重的复合物本身参与蛋白质稳态，这可能会导致蛋白质质量控​​制随着年龄的增长逐渐崩溃的循环。我们的研究结果强调了转录后调控在衰老中的重要作用。此外，我们还确定了调节与年龄相关的蛋白质稳态变化的遗传位点，这表明遗传变异可以改变分子衰老过程。