Telomere length measurement in UK Biobank: advancing understanding of biological ageing and age-related diseases

为什么有些人很早就患上了与年龄有关的疾病，比如冠状动脉疾病（CAD），而有些人一辈子都没有受到影响？这个问题的答案对于理解这些疾病和健康老龄化都非常重要。由于它们的年龄相关性，我们提出，这些疾病，至少在某种程度上，是加速的生物（不同于实际）衰老的表现。在这个项目中，我们将通过测量被称为端粒长度（TL）的生物衰老标记来研究这一假设。端粒是覆盖在染色体两端的结构。人们生来就有不同长度的端粒，当细胞分裂时，每次都会丢失少量的端粒。此外，已知一些影响某些与年龄有关的疾病风险的相同因素会增加损失的数量。重要的是，细胞“感知”它们的TL，并在TL达到临界短值时衰老并随后死亡。因此，TL就像一个生物钟，决定着细胞的行为和寿命。从整体上看，那些生来端粒较短或端粒损耗更快的人，可能在“生物学”上比其他人衰老得更快。反过来，这可以解释为什么有些人在较早的时候就患上了特定的与年龄相关的疾病，而另一些人尽管经历了类似的生活，却能保持健康到高龄。为了支持我们的假设，在之前的工作中，我们和其他人已经表明，来自血细胞（白细胞）（LTL）的DNA中较短的平均TL与几种慢性疾病（包括CAD）的风险之间存在关联。其他研究表明，LTL与饮食、生活方式特征和疾病风险因素（如肥胖和吸烟）之间存在相关性。然而，许多发现需要进一步明确的证据，特别是前瞻性的证据，即LTL的变化是否预测未来与年龄相关的疾病的发生。英国生物银行为开展此类研究提供了一个理想的群体。它包括50万名参与者，注册时年龄在45-69岁之间，在英国范围内招募。收集了每个参与者的大量信息，包括饮食、生活方式、行为和风险因素以及现有疾病的数据。通过与各种与健康有关的记录联系，还在新疾病发生时收集信息。每个参与者都将使用全基因组阵列对他们的DNA进行分类。使用我们优化的方法来实现高通量，我们建议测量所有50万英国生物银行参与者的LTL。一次性对所有参与者的LTL进行标准化测量，将能够探索广泛的假设，并提供英国生物银行的长期增强，其价值只会随着时间的推移而增加，因为更多的疾病结果会累积。此外，我们将利用英国生物银行正在进行的基因分型项目提供的一次性机会。通过使用本项目剩余的DNA样本来测量LTL，我们将避免进一步的DNA提取，定量和阵列的大量成本，否则将需要。使用这些数据，我们将：(i)确定与LTL相关的个人、环境和生活方式因素，这些因素可能是LTL的决定因素。（ii）描述LTL与心血管特征/危险因素的关联，以及与入选研究后发生的特定心血管疾病结局的关联。（三）利用遗传方法测试LTL是否可能是心血管疾病的一个致病因素，如果结果为阳性，将支持生物老化假说，并可能开辟新的预防和治疗战略。㈣广泛提供数据，使其他研究人员能够检验长寿与其他与年龄有关的疾病，如痴呆和癌症，以及与健康老龄化和长寿的可能性之间的关系。

Why do some individuals develop age-associated diseases such as coronary artery disease (CAD) early while others go through their entire life without being affected? The answer to this question is profoundly important for both understanding these diseases as well as healthy ageing. Because of their age-association, we have proposed that these diseases, at least to some extent, are manifestations of accelerated biological (as distinct from chronological) ageing. In this project, we will investigate this hypothesis by measuring a marker of biological ageing called telomere length (TL). Telomeres are structures that cap our chromosomes at each end. People are born with telomeres of different lengths and as cells divide a small amount of telomere is lost each time. Furthermore, the amount lost is known to be increased by some of the same factors that influence the risk of some age-related diseases. Importantly, cells "sense" their TL and become senescent and subsequently die when TL reaches a critically short value. Thus, TL acts as a biological clock that determines cell behaviour and lifespan. Translating this to a whole person, those born with shorter telomeres or whose telomeres attrition faster may "biologically" age more quickly than others. In turn, this could explain why some people develop specific age-associated diseases at an earlier age while others can remain healthy to an advanced age despite similar life exposures.In support of our hypothesis, in previous work we and others have shown an association between shorter mean TL in DNA from blood cells (leucocytes) (LTL) and risk of several chronic diseases, including CAD. Other studies have shown correlations between LTL and diet, life-style characteristics and disease risk factors such as obesity and smoking. However, many of the findings require further definitive evidence especially of a prospective nature i.e. whether variation in LTL predicts future occurrence of age-related disease. UK Biobank provides an ideal cohort to undertake such research. It comprises 500,000 participants, aged 45-69 years at enrolment, recruited UK-wide. A vast amount of information has been collected on each participant including data on diet, lifestyle, behaviour and risk factors and on existing diseases. By linkage to a variety of health-related records, information is also being collected on new diseases as they occur. Each participant is having their DNA typed using a genome-wide array.Using a method that we have optimised to achieve high throughput, we propose to measure LTL of all 500,000 UK Biobank participants. Standardised measurement of LTL in all participants in one go will enable a wide-range of hypotheses to be explored and provide a long-term enhancement of UK Biobank whose value will only increase with time as more disease outcomes accrue. Furthermore, we will be taking advantage of a one-off opportunity that has presented itself from an ongoing genotyping project in UK Biobank. By using the residual DNA samples left over from this project to measure LTL, we will avoid the substantial costs of further DNA extraction, quantification and arraying that would otherwise be required. Using the data we will:(i) Identify personal, environmental and life-style factors that correlate with LTL, which may be determinants of LTL. (ii) Characterise associations of LTL with cardiovascular traits/risk factors as well as with selected cardiovascular disease outcomes that occur after enrolment into the study.(iii) Test whether LTL is likely to be a causative factor in cardiovascular diseases using genetic methods, which, if positive, would support the biological ageing hypothesis and potentially open up new strategies for prevention and treatment. (iv) Make the data widely available to enable other researchers to test the association of LTL with other age-associated diseases, such as dementia and cancers, and with the likelihood of healthy ageing and longevity.