GENETIC AND ENVIRONMENTAL INFLUENCES ON AGEING WELL IN THE UK BIOBANK

英国生物库中遗传和环境对健康老龄化的影响

• 批准号: MR/M023095/1
• 负责人: David Melzer
• 金额: $ 58.92万
• 依托单位: UNIVERSITY OF EXETER
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM023095%2F1
• 关键词: GENETIC; ENVIRONMENTAL; INFLUENCES; AGEING; WELL

Human ageing is characterised by wide variation in lifespan and the period people remain healthy and active, with some older people becoming frail in their sixties while others remain fit into their nineties and beyond. Although these differences have a significant genetic component, the underlying mechanisms in humans are still unclear. Conventional risk factors such as smoking are important, but there is uncertainty about many other conventional risk factors in later life. If we understood why some people age well we should be able to help those who age less well to remain disability free and active for longer. At the laboratory level there is increasing evidence that the onsets of many age-related conditions can be simultaneously delayed or even partially reversed in mice. Centenarian groups show delayed onsets of the common conditions of ageing and this health advantage is partially inherited in offspring. In previous work we showed that the offspring of long lived parents have strikingly lower incidence rates of cancers, heart disease, diabetes and cognitive impairment in later life. The aim of this project is to identify novel risk factors and genetic variants associated with ageing well. Our underlying aim is to find new ways of helping those who age less successfully by applying insights gained from those who age well. We propose two main work packages (WP), both focussing on the 215,000 respondents aged 60 to 69 years old in UK Biobank study baseline: WP1: Identifying factors associated with the best health status in the seventh decade of life: We will define those at best health status (i.e. ageing well) as those free of major diseases (cardiovascular disease, stroke, diabetes, depression or cancer) and who are consistently in the healthiest range of measures of muscle strength, cognition, lung function, bone mineral density and blood pressure. WP2: Identifying factors associated with parental longevity: We have identified data on Biobank respondents who are the offspring of two long lived (non-adoptive) parents or one long lived and one intermediate lived parent. We will include only those who are free of cancer, myocardial infarction, stroke or diabetes (yielding 15,000 disease free offspring of longer lived parents and over 50,000 respondents with intermediate lived parents at baseline). We will examine all the major measured factors available in the Biobank data, including measures of early life circumstances and health behaviours. Genome wide association studies (GWAS) will identify associated variants. Independent replication will be carried out through already agreed collaborations with EPIC-Norfolk and the Framingham Heart Study. Fine characterisation of top findings will be carried out in ageing cohorts with genomic data and samples and very detailed health measures. The investigator team brings together experienced scientists from the Universities of Exeter and Cambridge. This group will be supported by international leaders in the relevant fields, who have both agreed to serve as consultants for the project and will collaborate in the replication of findings in independent population studies. By building on UK Biobank and other existing ageing studies we have greatly reduced the costs of this project. Outputs will include robust estimates of a wide range of conventional markers associated with ageing well, providing for a firmer basis for prevention. We expect to detect novel genetic variants, which should provide new clues to the biological influences on the timing of onset of common age related diseases. According to the UK Health and Social Care Information Centre, people aged 65 and over account for 54% of inpatient bed days, 60% of all prescribed items and 67% of social care clients. Even small improvements in ageing trajectories could have very major impacts on older people (our 'future selves'), carers, plus health and social care systems.

人类老龄化的特点是寿命变化很大，人们保持健康和活跃的时期，一些老年人在六十多岁时变得虚弱，而另一些人则在九十多岁及以后保持健康。虽然这些差异具有重要的遗传成分，但人类的潜在机制仍不清楚。传统的风险因素，如吸烟是重要的，但有许多其他传统的风险因素在以后的生活中是不确定的。如果我们理解为什么有些人老得很好，我们应该能够帮助那些年龄较小的人保持无残疾和更长时间的活跃。在实验室水平上，越来越多的证据表明，许多与年龄有关的疾病的发作可以同时延迟甚至部分逆转。百岁老人群体表现出延迟的常见衰老条件的发病，这种健康优势部分遗传给后代。在之前的研究中，我们发现长寿父母的后代在晚年患癌症、心脏病、糖尿病和认知障碍的发病率明显较低。该项目的目的是确定与衰老相关的新风险因素和遗传变异。我们的基本目标是通过应用从那些年龄好的人那里获得的见解，找到帮助那些年龄不太成功的人的新方法。我们提出了两个主要的工作包（WP），都集中在215，000名年龄在60至69岁的受访者在英国生物银行研究基线：WP 1：确定与生命的第七个十年的最佳健康状况相关的因素：我们将定义那些处于最佳健康状态的人（即老得好），（心血管疾病，中风，糖尿病，抑郁症或癌症），并始终处于肌肉力量，认知，肺功能、骨密度和血压。WP 2：识别与父母寿命相关的因素：我们已经确定了生物银行受访者的数据，他们是两个长寿（非收养）父母或一个长寿和一个中间寿命父母的后代。我们将只纳入那些没有癌症、心肌梗死、中风或糖尿病的人（在基线时产生15，000名长寿父母的无疾病后代和超过50，000名中等寿命父母的受访者）。我们将检查生物银行数据中可用的所有主要测量因素，包括早期生活环境和健康行为的测量。全基因组关联研究（GWAS）将确定相关的变异。独立的复制将通过已经同意的合作EPIC-诺福克和心脏病研究。将利用基因组数据和样本以及非常详细的健康措施，在老龄化队列中对主要发现进行精细表征。研究团队汇集了来自埃克塞特和剑桥大学的经验丰富的科学家。该小组将得到有关领域的国际领导人的支持，他们都同意担任该项目的顾问，并将合作复制独立人口研究的结果。通过建立在英国生物银行和其他现有的老龄化研究，我们大大降低了这个项目的成本。产出将包括对与油井老化有关的各种常规标志物的可靠估计，为预防提供更坚实的基础。我们期望检测到新的遗传变异，这将为常见年龄相关疾病发病时间的生物学影响提供新的线索。根据英国健康和社会护理信息中心的数据，65岁及以上的人占住院天数的54%，所有处方项目的60%和社会护理客户的67%。即使是老龄化轨迹的微小改善也可能对老年人（我们的“未来自己”），护理人员以及健康和社会护理系统产生非常重大的影响。

项目成果

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women.

• DOI: 10.1038/s41467-021-20918-w
• 发表时间: 2021-01-28
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Jones G;Trajanoska K;Santanasto AJ;Stringa N;Kuo CL;Atkins JL;Lewis JR;Duong T;Hong S;Biggs ML;Luan J;Sarnowski C;Lunetta KL;Tanaka T;Wojczynski MK;Cvejkus R;Nethander M;Ghasemi S;Yang J;Zillikens MC;Walter S;Sicinski K;Kague E;Ackert-Bicknell CL;Arking DE;Windham BG;Boerwinkle E;Grove ML;Graff M;Spira D;Demuth I;van der Velde N;de Groot LCPGM;Psaty BM;Odden MC;Fohner AE;Langenberg C;Wareham NJ;Bandinelli S;van Schoor NM;Huisman M;Tan Q;Zmuda J;Mellström D;Karlsson M;Bennett DA;Buchman AS;De Jager PL;Uitterlinden AG;Völker U;Kocher T;Teumer A;Rodriguéz-Mañas L;García FJ;Carnicero JA;Herd P;Bertram L;Ohlsson C;Murabito JM;Melzer D;Kuchel GA;Ferrucci L;Karasik D;Rivadeneira F;Kiel DP;Pilling LC
• 通讯作者: Pilling LC

Vitamin D levels and risk of delirium A mendelian randomization study in the UK Biobank

• DOI: 10.1212/wnl.0000000000007136
• 发表时间: 2019-03-19
• 期刊: NEUROLOGY
• 影响因子: 9.9
• 作者: Bowman, Kirsty;Jones, Lindsay;Melzer, David
• 通讯作者: Melzer, David

A genome-wide association study of the frailty index highlights brain pathways in ageing.

• DOI: 10.1111/acel.13459
• 发表时间: 2021-09
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Atkins JL;Jylhävä J;Pedersen NL;Magnusson PK;Lu Y;Wang Y;Hägg S;Melzer D;Williams DM;Pilling LC
• 通讯作者: Pilling LC

Genome-wide meta-analysis of muscle weakness identifies 15 susceptibility loci in older men and women

肌肉无力的全基因组荟萃分析确定了老年男性和女性的 15 个易感位点

• DOI: 10.1101/2020.05.14.20100354
• 发表时间: 2020
• 作者: Jones G

Impact of Low Cardiovascular Risk Profiles on Geriatric Outcomes: Evidence From 421,000 Participants in Two Cohorts.

• DOI: 10.1093/gerona/gly083
• 发表时间: 2019-02-15
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Atkins JL;Delgado J;Pilling LC;Bowman K;Masoli JAH;Kuchel GA;Ferrucci L;Melzer D
• 通讯作者: Melzer D