Laboratory of Integrative Systems Physiology, Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne 1015, Switzerland.
Department of Genetics, Genomics and Informatics, University of Tennessee, Memphis, TN 38163, USA.
Cell Rep. 2020 Sep 29;32(13):108203. doi: 10.1016/j.celrep.2020.108203.
Many genes and pathways have been linked to aging, yet our understanding of underlying molecular mechanisms is still lacking. Here, we measure changes in the transcriptome, histone modifications, and DNA methylome in three metabolic tissues of adult and aged mice. Transcriptome and methylome changes dominate the liver aging footprint, whereas heart and muscle globally increase chromatin accessibility, especially in aging pathways. In mouse and human data from multiple tissues and regulatory layers, age-related transcription factor expression changes and binding site enrichment converge on putative aging modulators, including ZIC1, CXXC1, HMGA1, MECP2, SREBF1, SREBF2, ETS2, ZBTB7A, and ZNF518B. Using Mendelian randomization, we establish possible epidemiological links between expression of some of these transcription factors or their targets, including CXXC1, ZNF518B, and BBC3, and longevity. We conclude that conserved modulators are at the core of the molecular footprint of aging, and variation in tissue-specific expression of some may affect human longevity.
许多基因和途径与衰老有关，但我们对其潜在的分子机制仍了解甚少。在这里，我们测量了成年和老年小鼠三种代谢组织中转录组、组蛋白修饰和 DNA 甲基化组的变化。转录组和甲基化组的变化主导了肝脏衰老的特征，而心脏和肌肉则普遍增加了染色质可及性，尤其是在衰老途径中。在来自多个组织和调控层的小鼠和人类数据中，与年龄相关的转录因子表达变化和结合位点富集都集中在假定的衰老调节剂上，包括 ZIC1、CXXC1、HMGA1、MECP2、SREBF1、SREBF2、ETS2、ZBTB7A 和 ZNF518B。通过孟德尔随机化，我们确定了这些转录因子或其靶基因（包括 CXXC1、ZNF518B 和 BBC3）表达与长寿之间可能存在的一些流行病学联系。我们的结论是，保守的调节剂是衰老分子特征的核心，而某些组织特异性表达的变化可能会影响人类的长寿。
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