Understanding and ameliorating ageing through the characterization of novel effectors of senescence.

有证据表明，随着时间的推移，衰老细胞的增加在衰老对器官的有害影响以及癌症、纤维化、糖尿病和阿尔茨海默氏症等许多疾病的症状中起着关键作用。清除累积的老细胞可以大大改善小鼠的健康和寿命，证明这种疗法可能具有临床影响。如果类似的策略可以应用于人类，它可能会改善与老细胞积累有关的病理，提高生活质量，延长寿命。我们描述了一组新的标记，使我们能够使用衰老表面体（衰老细胞表面表位的特定轮廓）选择性地识别衰老细胞。我们将利用这一点来获得有关细胞衰老机制的更多信息，以更好地理解它为什么以及如何发生。此外，我们建议利用这些信息来设计专门针对和杀死老细胞而不影响正常细胞的疗法。一种方法是获得针对这些标记物的抗体，并将它们附着在有毒化合物上。先前的研究表明，当这种修饰的抗体识别并结合到它们的目标时，化学物质被释放出来，细胞被选择性地消灭。基于这一想法的癌症疗法已经被成功地用于治疗患者，我们建议将同样的想法应用于老年细胞。我们还将测试使用纳米技术的类似方法。通过这种新技术产生的化合物比抗体具有成本效益、经济性和更容易制备，并且具有相似的能力。它们可以用来量化组织中衰老细胞的数量，并找到杀死它们的更好方法。最后，我们将使用化学抑制剂来阻止细胞老化过程。这些方法将使我们能够更好地理解细胞衰老的原因，并提出潜在的治疗方法，可以从体内消除衰老细胞，改善我们的健康。

Evidence suggests that the increase with time of old cells plays a critical role in the deleterious effects that ageing has on organs and in symptoms of many diseases, including cancer, fibrosis, diabetes and Alzheimer's. Eliminating old cells as they accumulate substantially improves fitness and longevity in mice, proving that such therapies could have a clinical impact. If a similar strategy could be applied to humans, it could potentially ameliorate pathologies linked to old cell accumulation, increasing the quality of life and extend lifespan.We have characterized a panel of new markers that allow us to selectively identify old cells using the senescent surfaceome (specific profile of surface epitopes of senescent cells). We will use this to obtain more information about the mechanisms involved in the ageing of cells, to better understand why and how it happens. Moreover, we propose to take advantage of this information to design therapies that specifically target and kill old cells without affecting normal ones. One approach is to obtain antibodies against these markers and attach them to a toxic compound. Previous research indicates that when such modified antibodies recognize and bind to their targets, the chemical is released and the cell is selectively eliminated. Cancer therapies based on this idea are already being used to successfully treat patients and we propose to apply the same idea to old cells.We will also test a similar approach using nanotechnology. Compounds generated through this novel technique would be cost-effective, economic and easier to prepare than antibodies and have similar abilities. They could be used to quantitate the number of senescent cells in a tissue and find better ways to kill them. Finally we will use chemical inhibitors that block the cellular ageing process. These approaches will allow us to better understand why cells age and propose potential therapies that could eliminate old cells from the body, improving our health.