The Wnt-chromatin axis in ageing

发达国家的人口活到极端高龄是人类历史上的一个显著现象。这一变化主要是通过改善公共卫生、降低儿童死亡率和减少传染病来实现的。然而，发达国家人口平均年龄的稳步增长付出了可怕的代价：与年龄有关的疾病，如心血管疾病、中风、糖尿病、骨质疏松症、癌症和阿尔茨海默病的负担日益加重。因此，过去导致预期寿命延长的公共卫生努力，使发达国家的人们能够活得足够长，经历一种或经常是几种退化性和肿瘤性疾病，这些疾病现在已成为主要的死亡原因。虽然衰老过程的标志是组织功能和稳态下降，但细胞、组织和生物体衰老的分子基础仍然知之甚少。这严重阻碍了开发治疗方法以对抗衰弱性年龄相关病理的努力。这个应用程序探索细胞，组织和有机体衰老的基本机制。具体来说，我们将测试三个不同的模型或老龄化机制的协调。其中有两个是成熟的老龄化理论。根据细胞“衰老”理论，衰老是由于细胞的增殖能力有限，因此最终会衰竭，无法更新。根据“染色质”理论，衰老是DNA包装到细胞核中的累积变化的结果。这些理论并不相互排斥，但都不能单独令人满意。最近，我们获得了第三种理论的证据。具体来说，衰老是由一种已知的组织发育和维持所需的途径（即所谓的“Wnt信号传导”途径）的活性下降引起的。我们的初步数据表明，这三种衰老理论可以统一为一个单一的“Wnt-染色质-衰老”信号通路，这是衰老的关键决定因素。本应用程序的目标是测试这一新的假设。我们将使用一系列方法来验证这一假设，包括细胞培养、动物模型、对老年人和狒狒组织的分析以及最先进的全基因组分析。这个项目的进展将提高我们对老年退行性疾病的认识，从而促进治疗方法的发展，以对抗这些疾病，提高老年人的生活质量。

The survival of populations in developed nations into extreme old age is a remarkable phenomenon in human history. This change has come about largely through improved public hygiene, decreased child mortality and a decrease in infectious disease. However, the steady increases in the average age of the populations of developed countries have come at a terrible price: an ever-increasing burden of age-associated diseases, such as cardiovascular maladies, stroke, diabetes, osteoporosis, cancer and Alzheimer's disease. Thus, public health efforts that resulted in past increases in life expectancy have made it possible for people in developed nations to live long enough to experience one, or quite frequently several, of the degenerative and neoplastic diseases that have now become the dominant causes of death. Although a hallmark of the aging process is declining tissue function and homeostasis, the molecular basis of cell, tissue and organismal aging is still very poorly understood . This severely hinders efforts to develop therapies to combat debilitating age-associated pathologies. This application explores the basic mechanisms of cellular, tissue and organismal ageing. Specifically, we will test a reconciliation of three separate models or mechanisms of ageing. Two of these are well established as theories of ageing. According to the theory of cell 'senescence', ageing results from a finite proliferative capacity of cells, and hence their ultimate exhaustion and failure to renew. According to the theory of 'chromatin', ageing results from accumulated changes in the packaging of DNA into the cell nucleus. These theories are not mutually exclusive, but neither is satisfactory on its own. Recently, we have obtained evidence for a third theory. Specifically, that ageing results from a decline in activity of a pathway that is known to be required for tissue development and maintenance, the so-called 'Wnt signaling'pathway. Our preliminary data suggest that these three theories of ageing can be unified into a single 'Wnt-chromatin-senescence' signaling pathway which is a key determinant of ageing. The goal of this application is to test this novel hypothesis. We will test this hypothesis using a range of approaches, including cell culture, animal models, analysis of tissues from very old humans and baboons and state-of-the-art whole genome analysis. Progress on this project will enhance our understanding of degenerative age-associated diseases, and so facilitate development of therapies to combat these diseases and increase the quality of life in old age.