Aging manifests as progressive deterioration in cellular and systemic homeostasis, requiring systems-level perspectives to understand the gradual molecular dysregulation of underlying biological processes. Here, we report systems-level changes in the molecular regulation of biological processes under multiple lifespan-extending interventions in mice and across age in humans. In mouse cohorts, Differential Rank Conservation (DIRAC) analyses of liver proteomics and transcriptomics show that mechanistically distinct prolongevity interventions tighten the regulation of aging-related biological modules, including fatty acid metabolism and inflammation processes. An integrated analysis of liver transcriptomics with mouse genome-scale metabolic model supports the shifts in fatty acid metabolism. Additionally, the difference in DIRAC patterns between proteins and transcripts suggests biological modules which may be tightly regulated via cap-independent translation. In a human cohort spanning the majority of the adult lifespan, DIRAC analyses of blood proteomics and metabolomics demonstrate that regulation of biological modules does not monotonically loosen with age; instead, the regulatory patterns shift according to both chronological and biological ages. Our findings highlight the power of systems-level approaches to identifying and characterizing the biological processes involved in aging and longevity.

中文翻译：

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在长寿干预和跨生物年龄的情况下，生物过程中的系统级模式发生了变化

衰老表现为细胞和系统稳态的逐渐恶化，需要系统层面的观点来理解潜在生物过程的逐渐分子失调。在这里，我们报告了在小鼠和人类跨年龄的多种延长寿命干预下，生物过程的分子调控的系统级变化。在小鼠队列中，肝脏蛋白质组学和转录组学的差异秩守恒 (DIRAC) 分析表明，机械上不同的长寿干预措施加强了对衰老相关生物模块的调节，包括脂肪酸代谢和炎症过程。肝脏转录组学与小鼠基因组规模代谢模型的综合分析支持脂肪酸代谢的变化。此外，蛋白质和转录物之间 DIRAC 模式的差异表明生物模块可能通过不依赖帽的翻译受到严格调节。在一个跨越大部分成年人寿命的人类队列中，DIRAC 对血液蛋白质组学和代谢组学的分析表明，生物模块的调节不会随着年龄的增长而单调放松。相反，监管模式会根据实际年龄和生物学年龄而变化。我们的研究结果强调了系统级方法在识别和表征衰老和长寿所涉及的生物过程方面的力量。血液蛋白质组学和代谢组学的 DIRAC 分析表明，生物模块的调节不会随着年龄的增长而单调放松。相反，监管模式会根据实际年龄和生物学年龄而变化。我们的研究结果强调了系统级方法在识别和表征衰老和长寿所涉及的生物过程方面的力量。血液蛋白质组学和代谢组学的 DIRAC 分析表明，生物模块的调节不会随着年龄的增长而单调放松。相反，监管模式会根据实际年龄和生物学年龄而变化。我们的研究结果强调了系统级方法在识别和表征衰老和长寿所涉及的生物过程方面的力量。