The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
Vividion Therapeutics, San Diego, California 92121, USA.
Genome Res. 2022 May;32(5):838-852. doi: 10.1101/gr.275672.121. Epub 2022 Mar 11.
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.
研究人类心脏衰老的分子机制具有挑战性，因为存在饮食和药物等混杂因素，以及获取健康衰老个体组织的有限性。实验室小鼠为在受控环境中研究健康个体的衰老提供了理想的模型。然而，之前的小鼠研究仅考察了塑造衰老过程中个体差异的遗传变异的一个狭窄范围。在这里，我们分析了 185 只具有不同遗传背景的雄性和雌性小鼠在 6、12 和 18 月龄时的转录组和蛋白质组数据，以描述衰老心脏中发生的分子变化。转录物和蛋白质揭示了与胞吐和细胞运输相关的途径随着年龄的增长而被激活，而与蛋白质折叠相关的过程随着年龄的增长而减少。仅在蛋白质数据中才会出现其他变化，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，我们看到随着年龄的增长，其组成亚基之间的相关性下降，这表明与年龄相关的化学计量比损失。受影响最大的复合物本身就参与了蛋白质的动态平衡，这可能导致随着年龄的增长，蛋白质质量控制的逐渐崩溃的循环。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，我们确定了调节蛋白质动态平衡与年龄相关变化的遗传位点，这表明遗传变异可以改变分子衰老过程。
