Caloric restriction has been associated with increased life span and reduced aging-related disorders and reduces fibrosis in several diseases. Fibrosis is characterized by deposition of excess fibrous material in tissues and organs and is caused by aging, chronic stress, injury, or disease. Myofibroblasts are fibroblast-like cells that secrete high levels of extracellular matrix proteins, resulting in fibrosis. Histological studies have identified many-fold increases of myofibroblasts in aged organs where myofibroblasts are constantly generated from resident tissue fibroblasts and other cell types. However, it remains unclear how aging increases the generation of myofibroblasts. Here, using mouse models and biochemical assays, we show that sirtuin 6 (SIRT6) deficiency plays a major role in aging-associated transformation of fibroblasts to myofibroblasts, resulting in tissue fibrosis. Our findings suggest that SIRT6-deficient fibroblasts transform spontaneously to myofibroblasts through hyperactivation of transforming growth factor β (TGF-β) signaling in a cell-autonomous manner. Importantly, we noted that SIRT6 haploinsufficiency is sufficient for enhancing myofibroblast generation, leading to multiorgan fibrosis and cardiac dysfunction in mice during aging. Mechanistically, SIRT6 bound to and repressed the expression of key TGF-β signaling genes by deacetylating SMAD family member 3 (SMAD3) and Lys-9 and Lys-56 in histone 3. SIRT6 binding to the promoters of genes in the TGF-β signaling pathway decreased significantly with age and was accompanied by increased binding of SMAD3 to these promoters. Our findings reveal that SIRT6 may be a potential candidate for modulating TGF-β signaling to reduce multiorgan fibrosis during aging and fibrosis-associated diseases.

中文翻译：

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Sirtuin 6缺乏症在转录上上调TGF-β信号传导并诱导小鼠纤维化。

热量限制与延长寿命和减少与衰老相关的疾病并减少某些疾病的纤维化有关。纤维化的特征是组织和器官中过多的纤维物质沉积，并且是由衰老，慢性应激，损伤或疾病引起的。肌成纤维细胞是分泌高水平细胞外基质蛋白，从而导致纤维化的成纤维细胞样细胞。组织学研究已经发现，老年器官中成肌纤维细胞的数量增加了许多倍，而常驻组织成纤维细胞和其他细胞类型不断产生成肌纤维细胞。但是，尚不清楚衰老如何增加成肌纤维细胞的生成。在这里，使用小鼠模型和生化分析，我们表明，Sirtuin 6（SIRT6）缺乏在成纤维细胞向成肌纤维细胞的衰老相关转化中起主要作用，从而导致组织纤维化。我们的发现表明，SIRT6缺乏的成纤维细胞通过以细胞自主方式过度激活转化生长因子β（TGF-β）信号转导自发转化为成肌纤维细胞。重要的是，我们注意到SIRT6单倍体不足足以增强成肌纤维细胞的生成，导致衰老期间小鼠多器官纤维化和心脏功能障碍。从机制上讲，SIRT6通过使组蛋白3中的SMAD家族成员3（SMAD3）和Lys-9和Lys-56脱乙酰化，结合并抑制关键TGF-β信号转导基因的表达。随着年龄的增长，SIRT6与TGF-β信号通路中基因启动子的结合显着降低，并伴有SMAD3与这些启动子的结合增加。我们的发现表明，SIRT6可能是调节TGF-β信号传导以减少衰老和纤维化相关疾病中多器官纤维化的潜在候选者。