衰老是人类疾病研究的重要问题，制定科学的抗衰老策略刻不容缓。Werner综合症（WS）等为研究端粒功能异常所致衰老提供了极佳的研究体系。p16Ink4a（p16）功能缺失逆转衰老表型的作用存在较大争议，可能源于不同的衰老遗传背景。WS背景下p16功能缺失对衰老的作用尚不清楚，解析相关信号通路可帮助我们理解不同早衰背景的调控。我们前期发现，p16功能缺失导致WS细胞逃逸衰老，成为非肿瘤化的永生细胞；而在Wrn-/-细胞内敲除p16可特异地降低端粒损伤应激反应，延迟细胞衰老。因此，本项目拟利用WS与p16基因敲除小鼠杂交,研究p16功能缺失对WS细胞内端粒功能异常、线粒体功能、SIRT-FOXO-p53-PGC通路、小鼠骨髓造血干细胞、胰岛增殖能力、生殖功能及寿限的调控作用，以期初步阐明p16功能缺失在逆转端粒功能异常所致衰老中的作用和分子机制，为人工干预衰老，寻找安全抗衰老策略提供科学依据。

Aging is the important issue for human disease. It is imperative to find a scientific strategy for anti-aging. Werner syndrome (WS) provided an excellent model system for studying aging induced by telomere dysfunction. The role of p16Ink4a (p16) deficiency in reversing aging phenotype remains controversial; this might be due to differences in genetic background of various aging models. The role of p16 deficiency in the background of WS is not clear and dissecting the molecular pathway will help us understand the regulation of aging in progeroid models. Our data have shown that p16 deficiency enabled WS cells to escape from senescence and acquire immortality. Furthermore, knocking out p16 in Wrn-/- cells could down-regulate the telomere DNA damage response and delay cellular senescence. In this study, we will utilize WS mice to cross with p16 null mice. Then study the WS cells with p16 deficiency for telomere dysfunction, mitochondrial function, status of SIRT-FOXO-p53-PGC pathway. In vivo we will study the Hematopoietic stem cells (HSC), the islet cell proliferation potential, the reproductive potential, and the life span of Wrn-/-p16Ink4a-/- mice. We aim to uncover the regulatory role and mechanism of p16 deficiency in reversing aging induced by telomere dysfunction. This study will shed light on the artificial modulation of aging and finding safe anti-aging strategies.