端粒缩短与衰老密切相关，然而端粒在干细胞衰老和相关疾病中的作用远未得到阐明。申请人致力于该领域研究，近年来取得了一系列创新成果：1）阐明了端粒缩短引起干细胞衰老的内在分子机制（Nat Genet 2007, Blood 2014）；2）发现端粒缩短引起血液中细胞因子改变，促进干细胞衰老（Nat Med 2007, Blood 2010, Aging Cell 2012）；3）揭示了端粒缩短、DNA损伤反应和线粒体异常对干细胞功能和组织再生的调控（Cell Stem Cell 2014, Hepatology 2015, Nat Commun 2015）；4）证明了端粒及其相关标记物与人类疾病的发生和发展密切相关（Hypertension 2009, Diabetes Care 2011）。发表SCI论文40篇，总影响因子375。这些发现为衰老研究提供新思路，为干细胞抗衰老策略提供科学依据。

Telomere attrition is closely associated with human aging, however, its role in stem cell aging and related diseases remains elusive. The applicant is committed to the research of telomere and stem cell aging, and has yielded a series of innovative outcomes, e.g. 1) elucidated the intrinsic molecular mechanism of telomere shortening-induced stem cell aging (Nat Genet 2007, Blood 2014); 2) discovered the circulating factors induced by telomere shortening provoke stem cell aging (Nat Med 2007, Blood 2010, Aging Cell 2012); 3) revealed the interplay among telomere dysfunction, DNA damage response and mitochondrial function, and its role in stem cell function and tissue/organ regeneration (Cell Stem Cell 2014, Hepatology 2015, Nat Commun 2015), 4) demonstrated the correlation of telomere shortening and its associated biomarkers with the occurrence and development of aging-related diseases (Hypertension 2009, Diabetes Care 2011). Total of 40 SCI papers (total impact factor of 375) have been published. These findings provided new directions for aging research and experimental evidence for stem cell based anti-aging strategy.

衰老是老年慢病的最大危险因素。理解衰老机制，是从根本上实现老年慢病的早期预警与治疗，实现健康老龄化的关键所在。本项目聚焦衰老机制，利用动物模型，从分子、细胞、组织及整体水平研究衰老机制与有效干预策略。项目执行期间（1）发现Lamin A蛋白直接、特异地与Per2蛋白结合，为从生物节律角度理解人类早衰症治病机理及临床治疗提供了分子基础。（2）围绕衰老/长寿信号通路暨Sirtuin蛋白家族的研究发现，光暗周期（LD cycle）经由“体温-Hsp70-Sirt7-Cry1”轴调控外周组织生物节律，为理解衰老相关生物节律紊乱提供了理论支撑。（3）系统地研究了个体衰老与基因组稳定性、代谢重编程、肿瘤发生发展的关系，发现激活（加强）DNA修复机器（DNA repair machinery）可扭转衰老代谢重编程，增加基因组稳定性，延缓系统衰老，延长寿命。（4）揭示了一个新的SIRT1-PRRX1-KLF4-ALDHA1/A3信号轴，阐明了其调控MET与乳腺癌干性的分子机制。（5）发现了SIRT7调控TGFβ信号通路及乳腺癌肺转移的分子机制，建立了针对乳腺癌肺转移的有效干预策略，为理解增龄伴随的肿瘤高发与低存活率提供了理论基础。本项目的研究成果从不同角度阐释了衰老的分子机制，对于早期预防与临床治疗老年相关疾病具有重要的理论知道意义。