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

为什么有些人会在早期患上与年龄相关的疾病，如冠状动脉疾病（CAD），而另一些人则会终生不受影响？这个问题的答案对于理解这些疾病以及健康老龄化都非常重要。由于这些疾病与年龄有关，我们认为它们至少在某种程度上是生物学（不同于时间）加速老化的表现。在这个项目中，我们将通过测量一种称为端粒长度（TL）的生物衰老标记来研究这一假设。端粒是覆盖我们染色体两端的结构。人生来就有不同长度的端粒，随着细胞分裂，每次都会丢失少量的端粒。此外，据了解，一些影响某些与年龄有关的疾病风险的因素会增加损失的数量。重要的是，细胞“感觉”到它们的TL，并变得衰老，随后当TL达到临界短值时死亡。因此，TL充当决定细胞行为和寿命的生物钟。把这一点转化为一个完整的人，那些天生端粒较短或端粒磨损较快的人可能比其他人“生物学上”衰老得更快。反过来，这可以解释为什么有些人在较早的年龄发展特定的年龄相关疾病，而其他人可以保持健康，尽管类似的生活暴露到高龄。为了支持我们的假设，在以前的工作中，我们和其他人已经表明，较短的平均TL从血细胞（白细胞）DNA（LTL）和几种慢性疾病，包括CAD的风险之间的关联。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，许多研究结果需要进一步的明确证据，特别是前瞻性的证据，即LTL的变化是否可以预测未来年龄相关疾病的发生。英国生物库为开展此类研究提供了理想的队列。它包括500 000名参与者，年龄在45-69岁之间，在联合王国范围内招募。已经收集了关于每个参与者的大量信息，包括关于饮食、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相联系，还在收集新疾病发生时的信息。每个参与者都使用全基因组阵列进行DNA分型。使用我们优化以实现高通量的方法，我们建议测量所有50万名英国生物库参与者的LTL。一次性对所有参与者进行LTL的标准化测量，将能够探索广泛的假设，并提供英国生物库的长期增强，其价值只会随着更多疾病结局的积累而增加。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。通过使用该项目剩余的DNA样本来测量LTL，我们将避免进一步DNA提取、定量和排列的大量成本，否则将需要这些成本。利用这些数据，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/风险因素以及入选研究后发生的选定心血管疾病结局的相关性。(iii)使用遗传方法测试LTL是否可能是心血管疾病的致病因素，如果是阳性，将支持生物衰老假说，并可能开辟新的预防和治疗策略。(iv)广泛提供数据，使其他研究人员能够测试LTL与其他年龄相关疾病（如痴呆症和癌症）以及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.