皮下脂肪线粒体在progerin敲入早老小鼠中延缓衰老进程研究

Aging and its related diseases make a heavy burden to China due to the increasing aging population. Aging is an independent factor of many lethal diseases, including cardiovascular disease, cancer, Alzheimer’s disease and etc. Since the investigation on normal aging requires a long period, recently accelerated aging animal model is widely accepted and used. Lipodystrophy, especially loss of subcutaneous fat, is a significant feature of aging. The degeneration of subcutaneous fat was accompanied with the loss of brown adipocyte, which is abundant with mitochondria. This project aims to investigate whether subcutaneous fat is the targeted organ of aging and whether mitochondria dysfunction regulated the degeneration of subcutaneous fat. Finally, we will explore the possibility of the improvement of mitochondrial function in subcutaneous fat to slow down the aging process. Preliminary results demonstrated the average life span of progerin knock in mice is as short as 34 weeks. Mitochondrial oxidative phosphorylation enzyme activities changes with age, which indicate the importance of oxidative phosphorylation chain in aging development. The biogenesis of mitochondria was also regulated by the abnormal Lamin A processing. The significance of this project is to firstly elucidate the regulatory effects of mitochondrial dysfunction on the degeneration of subcutaneous fat and aging progress and to provide a new research direction and new therapeutic target.

随着人口老龄化加剧，衰老及老年疾病爆发带来了沉重的社会负担。衰老是多种致死疾病的独立发病因素，包括心脑血管疾病、癌症、阿尔海默氏疾病等。由于衰老研究面临周期长见效慢的特点，快速衰老模型被广泛接受并用于抗衰老研究。皮下脂肪萎缩退化是正常衰老的明显特征之一，并伴随有褐色脂肪细胞含量减少，提示线粒体含量的变化。本课题拟利用早老小鼠（progerin敲入小鼠）作为动物模型，从器官层面上研究皮下脂肪作为衰老靶器官，并从细胞水平上研究线粒体对皮下脂肪退化的调控作用，并通过靶向改善皮下脂肪线粒体功能，观察对早老小鼠机体衰老进程的影响。前期实验表明progerin敲入小鼠平均寿命只有34周，线粒体受Lamin A代谢和小鼠年龄的调控，提示线粒体功能在衰老进程中的重要作用。本课题从动物和细胞学层面阐明线粒体功能对progerin敲入小鼠皮下脂肪衰老的调节作用，并探讨能否通过改善皮下脂肪脂肪代谢增而延缓衰老。

脂肪衰老是人体衰老进程中最明显的变化。同时国内外研究指出线粒体是推动衰老进程的关键因素。本项目致力于验证脂肪组织尤其是是脂肪中的线粒体对整体衰老进程的影响，确立脂肪组织在整体衰老进程中的推动作用，以及线粒体作为治疗靶点的有效性。.本课题的创新点在于首次利用早老小鼠模型进行器官特异性的研究，建立了脂肪特异性表达早老素的小鼠模型，观察其表型并确定脂肪衰老的推动地位，以及脂肪作为治疗靶点的可行性探究。具体来说：1）建立早老素表达引起的早老小鼠模型以及脂肪特异性表达早老素小鼠模型；2) 脂肪特异性表达早老素小鼠的表型观察，尤其对皮下脂肪棕色化进行了深入研究；3）对脂肪特异性表达早老素小鼠中的三种解剖部位脂肪进行研究，尤其是从分子生物学层面进行研究；4）利用芯片技术，对脂肪特异性表达早老素小鼠的整体炎症情况进行评估；5）利用生物信息学技术，对该小鼠中的皮下脂肪进行研究，研究皮下脂肪中易感信号通路；6）研究脂肪组织作为治疗靶点的可行性，通过药物刺激改善脂肪功能结构，从而降低衰老相关疾病的致命性；7）利用细胞模型和药物刺激研究改善线粒体功能能否延缓衰老进程。