中国科学院昆明动物研究所机构知识库

根据第六次全国人口普查数据显示，2015年中国老年人口占总人口的16.15%，预计到21世纪中叶，中国老年人口将达到5亿人，人口老龄化程度到达顶峰。随着人口老龄化越来越严重，患老年相关慢性疾病（阿尔兹海默症、骨质疏松、白内障、糖尿病等）的人也越来越多，无论对个人还是社会医疗都造成极大负担。因此如何让老年人健康生活是现在抗衰老领域面临的最大挑战。而从病理学上看，促进年龄相关慢性疾病发生的一个重要过程就是细胞衰老。因此，对于衰老细胞的干预或许可以作为治疗和预防各种年龄相关疾病的一种重要方式。近年来，选择性清除衰老细胞（senolytics）已经成为一种有效干预机体衰老的方法。目前，通过动物实验已经证实清除小鼠体内的衰老细胞后能够延长“健康寿命周期”（Healthy Lifespan），同时改善造血干细胞、肌肉干细胞功能，改善骨质疏松、动脉粥样硬化等老年相关疾病的症状。虽然已有的几种小分子化合物如ATB263都展现出清除体内衰老细胞的潜力，但尚未发现一种安全有效无副作用的药物。数千年来，传统中药(traditional Chinese medicine , TCM)在亚洲地区的疾病诊断和治疗中占有主导地位。然而，在过去由于缺乏科学且系统研究，天然产物的药用价值未能完全被挖掘。近半个多世纪以来，随着对天然药物发掘与研究的日益深入，部分天然药物已走向临床，比如抗癌药物紫杉醇和高三尖杉酯碱（分别来自Taxus brevifolia和Cephalotaxus harringtonii），抗疟药青蒿素（来自Artemisia annua）和用于治疗阿尔茨海默病的乙酰胆碱酯酶抑制剂加兰他敏（来自Galanthus spp），这些药物在临床上的成功应用为进一步挖掘天然产物的其他药用功能提供了前景。然而目前中药在抗衰老领域仅限于一些复方、单方的基础探索，既没有系统研究某种药抗衰老的作用机理，也没有大规模寻找潜在的抗衰老药物，更没有任何从众多中药中寻找选择性清除衰老细胞药物的研究。 利用细胞衰老模型筛选抗衰老药物是抗衰老药物研发常用的手段，目前细胞衰老模型包括自然衰老模型、辐射衰老模型、DNA损伤衰老模型、癌基因诱导衰老模型、过氧化氢衰老模型等。然而这些模型由于无法进行大规模培养或者衰老细胞不稳定而无法用于抗衰老药物的高通量筛选，因此需要一种合适的细胞衰老模型对众多的天然产物进行高通量筛选，以探究天然产物中是否含有能够选择性清除衰老细胞而对人无副作用的药物。以往的研究表明过表达P16能诱导细胞衰老，但仅限于P16蛋白质的功能研究，未考虑建模的问题。本课题首次将过表达P16诱导细胞衰老建立为一种构建细胞衰老模型的方式，首次将建模方式建立在TET诱导的慢病毒系统中，仅在DOX存在下才能诱导衰老的发生。通过该方法建立的细胞衰老模型能进行大规模的培养和保种，且衰老细胞能稳定存在，满足高通量的条件，能够对众多的天然产物进行抗衰老药物的高通量筛选，为抗衰老的研究拓宽了途径。本课题通过该细胞衰老模型从天然产物分离的9276个组分中筛选出了7个具有选择性杀伤衰老细胞能力的组分。同时通过构建的癌基因和DNA损伤诱导的共计六种细胞衰老模型，验证了这7个组分的选择性杀伤衰老细胞的能力，其中六个均有可重复性，表明通过高通量平台筛选出的抗衰老药物具有广谱性。而通过初步机制探究表明，这些组分可能通过凋亡途径杀伤衰老细胞。通过以上实验证明了天然产物中确实存在能够选择性清除衰老细胞的成分，为中草药抗衰老提供了一个可行的细胞模型。 

According to the data from the sixth National Census, China's elderly population accounted for 16.15 percent of the total population in 2015. It is expected that by the middle of the 21st century, China's elderly population will reach 500 million, with the population aging reaching its peak. As the aging population becomes more and more serious, there are more and more people suffering from age-related chronic diseases such as Alzheimer's disease, osteoporosis, cataract, diabetes and so on. The current medical level and treatment ability are not enough to meet such a large-scale medical needs, it is a great burden on both individuals and social health care. So how to make the elderly live a healthy life has become a great challenge. An important process that promotes the development of age-related chronic diseases is cellular senescence. Therefore, the intervention of senescence cells may be an important way to treat and prevent various age related diseases.In recent years, selective elimination of senescence cells (also known as ‘senolytics’) has become an effective way to interfere with aging. At present, animal experiments have confirmed that the elimination of senescence cells in mice can prolong the healthy lifespan, and improve the function of hematopoietic stem cells, muscle stem cells, ameliorate osteoporosis, atherosclerosis and other related diseases. Although several small molecular compounds, such as ATB263, have shown the potential to clear senescence cells in vivo, no safe and effective drug has been found.Traditional Chinese medicine (TCMs) has played a leading role in the diagnosis and treatment of diseases in Asia for thousands of years. However, in the past, due to the lack of scientific and systematic research, the medicinal value of natural products has not been fully exploited. Nearly half a century, along with the discovery and study of natural medicine increasingly deepening, some natural drugs have been used to clinic, such as anti-cancer drug paclitaxel and homoharringtonine, anti-malarial artemisinin and acetylcholinesterase inhibitors galanthamine treatment for Alzheimer's disease. These successful clinical applications provide a prospect for further exploring other medicinal functions of natural products. However, at present, the traditional Chinese medicine in the field of anti-aging is limited to some compound, unilateral basic exploration. There is no systematic study of the antiaging mechanism of a drug, nor is there a large-scale search for potential anti-aging drugs. Therefore, there is no any research on selective elimination of senescence cells from many traditional Chinese medicines. Researchers often use cell aging models to develop anti-aging drugs. At present, the cell senescence model mainly includes natural replication aging model, radiation aging model and DNA damage senescence model, oncogene induced senescence model, hydrogen peroxide aging model and so on. However, these models cannot be used for high-throughput screening of anti-aging drugs because they cannot be cultured on a large scale or because aging cells are unstable. Therefore, a suitable model of cell senescence is needed for high-throughput screening of many natural products, in order to find out whether the natural products contain drugs that can selectively elimination aging cells and have no side effects on human beings. Previous studies have shown that overexpression of P16 can induce cell senescence, but it is limited to the functional study of P16 protein and does not consider the construction of model. For the first time, we used overexpression of P16 to induce cell senescence as a way of building a model of cell senescence. This is also the first time that a modeling approach has been built into a lentivirus system containing TET to induce senescence through DOX. The model of cell senescence established by this method can carry out a large number of culture and conservation, and the aging cells can exist stably and satisfy the high-throughput condition. This will enable high-throughput screening of many natural products for anti-aging drugs, thus broadening the way for anti-aging research.Through this cell senescence model, we selected 7 components with selective killing ability from 9276 components isolated from natural products. At the same time, we constructed a total of six cell senescence models induced by oncogene and DNA damage, and verified the selective killing ability of the seven components, six components have repeatability. The results showed that the anti-aging drugs selected by high-throughput platform had broad spectrum. The preliminary mechanism suggests that these components may kill senescent cells through apoptosis. This experiment proved that there are some components in Chinese herbal medicine which can selectively remove aging cells and provide a cell model which can be used in high-throughput screening. It provides a feasible research direction for anti-aging of Chinese herbal medicine.