Centre for Immunobiology and Regenerative Medicine, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Turner Street, London, E1 2AD, UK.
Department of Life Science, South Kensington Campus, Imperial College London, London, SW7 2AZ, UK.
Sci Rep. 2018 Aug 14;8(1):12148. doi: 10.1038/s41598-018-29809-5.
Cellular senescence is often associated with irreparable DNA double strand breaks (IrrDSBs) which accumulate with chronological age (IrrDSBsen). The removal of senescent cells ameliorates several age-related diseases in mice but the translation of these findings into a clinical setting would be aided by the characterisation of non-invasive biomarkers of senescent cells. Several serum metabolites are independent indicators of chronological age and some of these accumulate outside senescent fibroblasts independently of cell cycle arrest, repairable DNA breaks and cell size (the extracellular senescence metabolome, or ESM). The post-mitotic phase of senescence is dynamic, making the detection of senescent cells in vivo difficult. An unbiased metabolomic screen of the IrrDSBsen fibroblast ESM also showed differences in the times of initiation and maintenance of different metabolites but generally the ESM altered progressively over the 20 day study period unlike the reported transcriptional profiles. This more detailed analysis of IrrDSBsen identified several new ESM metabolites that are associated with chronological ageing. Targeted analysis of citrate confirmed the dynamic nature of this metabolite in two cell lines and revealed its independence from the senescence effector p16. These data will aid our understanding of metabolic signatures of ageing and their relationship to cellular senescence and IrrDSBs.
细胞衰老通常与不可修复的双链 DNA 断裂 (IrrDSBs) 相关，这些断裂会随着年龄的增长而积累 (IrrDSBsen)。清除衰老细胞可以改善小鼠的几种与年龄相关的疾病，但要将这些发现转化为临床应用，就需要对衰老细胞的非侵入性生物标志物进行特征描述。一些血清代谢物是年龄的独立指标，其中一些代谢物在细胞周期停滞、可修复的 DNA 断裂和细胞大小之外独立于衰老成纤维细胞积累 (细胞外衰老代谢组或 ESM)。衰老的有丝分裂后阶段是动态的，使得体内衰老细胞的检测变得困难。对 IrrDSBsen 成纤维细胞 ESM 的无偏代谢组学筛选也显示了不同代谢物的起始和维持时间的差异，但通常 ESM 在 20 天的研究期间逐渐改变，与报告的转录谱不同。对 IrrDSBsen 的更详细分析确定了几个与年龄相关的新 ESM 代谢物。对柠檬酸的靶向分析证实了这种代谢物在两种细胞系中的动态特性，并揭示了其与衰老效应因子 p16 的独立性。这些数据将有助于我们理解衰老的代谢特征及其与细胞衰老和 IrrDSBs 的关系。
