Ageing is the single greatest cause of disease and death worldwide, and understanding the associated processes could vastly improve quality of life. Although major categories of ageing damage have been identified—such as altered intercellular communication, loss of proteostasis and eroded mitochondrial function 1 —these deleterious processes interact with extraordinary complexity within and between organs, and a comprehensive, whole-organism analysis of ageing dynamics has been lacking. Here we performed bulk RNA sequencing of 17 organs and plasma proteomics at 10 ages across the lifespan of Mus musculus , and integrated these findings with data from the accompanying Tabula Muris Senis 2 —or ‘Mouse Ageing Cell Atlas’—which follows on from the original Tabula Muris 3 . We reveal linear and nonlinear shifts in gene expression during ageing, with the associated genes clustered in consistent trajectory groups with coherent biological functions—including extracellular matrix regulation, unfolded protein binding, mitochondrial function, and inflammatory and immune response. Notably, these gene sets show similar expression across tissues, differing only in the amplitude and the age of onset of expression. Widespread activation of immune cells is especially pronounced, and is first detectable in white adipose depots during middle age. Single-cell RNA sequencing confirms the accumulation of T cells and B cells in adipose tissue—including plasma cells that express immunoglobulin J—which also accrue concurrently across diverse organs. Finally, we show how gene expression shifts in distinct tissues are highly correlated with corresponding protein levels in plasma, thus potentially contributing to the ageing of the systemic circulation. Together, these data demonstrate a similar yet asynchronous inter- and intra-organ progression of ageing, providing a foundation from which to track systemic sources of declining health at old age. Bulk RNA sequencing of organs and plasma proteomics at different ages across the mouse lifespan is integrated with data from the Tabula Muris Senis , a transcriptomic atlas of ageing mouse tissues, to describe organ-specific changes in gene expression during ageing.

中文翻译：

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衰老标志表现出器官特异性的时间特征


衰老是全世界疾病和死亡的最大原因，了解相关过程可以极大地提高生活质量。尽管已经确定了衰老损伤的主要类别，例如细胞间通讯改变、蛋白质稳态丧失和线粒体功能受损1，但这些有害过程与器官内部和器官之间异常复杂的相互作用，并且对衰老动态进行全面的、整体的有机体分析。缺乏。在这里，我们对小家鼠整个生命周期中 10 个年龄的 17 个器官和血浆蛋白质组学进行了批量 RNA 测序，并将这些发现与随附的 Tabula Muris Senis 2（或“小鼠衰老细胞图谱”）的数据相结合，该图谱是原始数据的基础白板 3 。我们揭示了衰老过程中基因表达的线性和非线性变化，相关基因聚集在具有连贯生物学功能的一致轨迹组中，包括细胞外基质调节、未折叠蛋白结合、线粒体功能以及炎症和免疫反应。值得注意的是，这些基因组在组织中表现出相似的表达，仅在表达的幅度和开始年龄上有所不同。免疫细胞的广泛激活尤其明显，并且首先在中年时期的白色脂肪库中检测到。单细胞 RNA 测序证实了脂肪组织中 T 细胞和 B 细胞的积累（包括表达免疫球蛋白 J 的浆细胞），这些细胞也在不同的器官中同时积累。最后，我们展示了不同组织中的基因表达变化如何与血浆中相应的蛋白质水平高度相关，从而可能导致体循环的老化。 总之，这些数据表明了相似但异步的器官间和器官内衰老进程，为跟踪老年健康状况下降的系统根源提供了基础。对小鼠生命周期中不同年龄的器官和血浆蛋白质组学进行批量 RNA 测序，与来自衰老小鼠组织转录组图谱 Tabula Muris Senis 的数据相结合，以描述衰老过程中器官特异性基因表达的变化。