Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
Cell. 2018 Nov 29;175(6):1575-1590.e22. doi: 10.1016/j.cell.2018.10.012. Epub 2018 Nov 8.
During aging, stromal functions are thought to be impaired, but little is known whether this stems from changes of fibroblasts. Using population- and single-cell transcriptomics, as well as long-term lineage tracing, we studied whether murine dermal fibroblasts are altered during physiological aging under different dietary regimes that affect longevity. We show that the identity of old fibroblasts becomes undefined, with the fibroblast states present in young skin no longer clearly demarcated. In addition, old fibroblasts not only reduce the expression of genes involved in the formation of the extracellular matrix, but also gain adipogenic traits, paradoxically becoming more similar to neonatal pro-adipogenic fibroblasts. These alterations are sensitive to systemic metabolic changes: long-term caloric restriction reversibly prevents them, whereas a high-fat diet potentiates them. Our results therefore highlight loss of cell identity and the acquisition of adipogenic traits as a mechanism underlying cellular aging, which is influenced by systemic metabolism.
在衰老过程中，基质功能被认为是受损的，但目前还不清楚这是否源于成纤维细胞的变化。本研究使用群体和单细胞转录组学以及长期谱系追踪，研究了在影响长寿的不同饮食条件下，生理衰老过程中，皮肤成纤维细胞是否发生改变。研究结果表明，老年成纤维细胞的身份变得不确定，年轻皮肤中存在的成纤维细胞状态不再明显区分。此外，老年成纤维细胞不仅降低了细胞外基质形成相关基因的表达，而且获得了脂肪生成特性，反常地变得更类似于新生的前脂肪生成成纤维细胞。这些改变对全身代谢变化敏感：长期热量限制可使其可逆地恢复，而高脂肪饮食则可使其增强。因此，我们的研究结果强调了细胞身份丧失和获得脂肪生成特性作为细胞衰老的一种机制，这种机制受全身代谢的影响。
