Parenchymal damage and myeloid inflammation link the Rag GTPase – mTORC1 axis to mammalian aging [old]

The mechanistic target of rapamycin complex 1 (mTORC1) controls cellular anabolism in response to nutrient sufficiency and growth factor signaling, and genetic and pharmacological inhibition of mTORC1 extends longevity across eukaryotes. Up to date, mouse models to analyze the mechanisms of aging governed by mTORC1 has been limited by detrimental pleiotropic consequences of genetically-increased mTORC1 activity in mice. RragcS74N/+, RragcS74C/+ and RragcT89N/+ knock-in mice endogenously express active mutant variants of RagC, a GTPase that signaling nutrient sufficiency to mTORC1. Rragcmutant/+ mice show an only moderate increase in nutrient signaling to mTORC1, and after one year of life exhibit multiple features of a premature aging phenotype that include prominent senescence in peripheral organs, parenchymal expression of inflammatory and chemo-attractant molecules, increased myeloid inflammation and extensive features of inflammaging. In vivo transplantation and ex vivo functional experiments with bone marrow-derived cells show that myeloid cells are abnormally activated by parenchymal signals evoked from Rragcmut/+ organs, to where myeloid cells extravasate to inflict additional inflammatory damage. Therapeutic suppression of myeloid inflammation in old Rragcmut/+ attenuates features of premature aging and extends longevity. We provide the first genetic link of elevated nutrient – mTORC1 activity and premature aging in mammals, and provide support for a two-component model in which increased nutrient signaling drives parenchymal damage and myeloid inflammation precipitates organ deterioration and accelerated aging. RNA-seq

雷帕霉素机制靶蛋白复合物1（mechanistic target of rapamycin complex 1，mTORC1）可响应营养充足状态与生长因子信号通路，调控细胞合成代谢；对mTORC1进行遗传与药理学抑制，可延长各类真核生物的寿命。迄今为止，用于解析mTORC1调控的衰老机制的小鼠模型，其应用一直受到小鼠体内遗传上调mTORC1活性所引发的有害多效性后果的限制。RragcS74N/+、RragcS74C/+与RragcT89N/+敲入小鼠可内源表达RagC的活性突变体；RagC是一类将营养充足信号传递至mTORC1的GTP酶。Rragcmutant/+小鼠的营养向mTORC1的信号转导仅呈现轻度上调；在饲养至1年龄后，该类小鼠会表现出早衰表型的多种特征，包括外周器官显著衰老、实质细胞表达炎症与趋化分子、髓系炎症加剧以及广泛的炎性衰老（inflammaging）特征。对骨髓来源细胞开展的体内移植与离体功能实验表明，髓系细胞会被Rragcmut/+器官所诱导的实质细胞信号异常激活；髓系细胞会外渗至该类器官中，进而引发额外的炎症损伤。对老龄Rragcmut/+小鼠的髓系炎症进行治疗性抑制，可减轻其早衰表型特征并延长寿命。本研究首次建立了哺乳动物体内营养-mTORC1信号活性上调与早衰之间的遗传关联，并为双组分模型提供了实验依据：即营养信号转导增强会驱动实质细胞损伤，而髓系炎症则会促成器官退化与衰老加速。RNA测序（RNA-seq）