GENETIC AND ENVIRONMENTAL INFLUENCES ON AGEING WELL IN THE UK BIOBANK

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.

The onsets of age-related conditions can be simultaneously delayed in mice by calorie restriction and by targeting pathways including nutrient sensing, mTOR signalling and clearance of senescent cells. Much less is known about determinants of ageing trajectories in humans. We propose two main work packages for identifying conventional markers and for genome wide association study analysis, both focussing on the 215,000 respondents aged 60 to 69 years old in UK Biobank:

WP1: Identifying factors associated with best health status in the seventh decade of life:
We will define this ageing well group as those free of major diseases 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 will apply an empirical classification of relative parental longevity, using reported ages of death of parents.

The novel aspects of the proposal include:
1. A focus on the timing of onset of major disease or impairment in ageing. Disease specific studies are likely to be less sensitive to ageing effects, so our project should help account for unexplained variance.
2. Our two ageing well phenotypes will identify groups more accurately and in much larger numbers than possible thus far.
3. Ability to estimate the heritability of the chosen phenotypes using the Biobank array data, allowing improvement in the classification for SNP discovery.
4. We have arranged replication in independent cohorts.
5. We are planning fine characterisation of top genetic findings in transcriptomic and methylomic datasets linked to very detailed phenotypic data, plus transcriptomic studies in human tissue panels.
5. We have exceptionally strong agreed consultant collaboration from international leaders in this field.

This project should have a major impact on the field in clarifying the roles of many conventional risk factors in the seventh decade of life, and in identifying genetic contributions to ageing well.
.
At present there is much debate over the role of many conventional risk factors with advancing age. The planned work should result in better models of conventional risks during the key period of early old age, when there is still great scope for decreasing health risks and avoiding disability. People in their sixties are often motivated to reduce health risks and the risk of dependency. The baby boom generation are more likely than previous generations to see ageing as a modifiable process and not be fatalistic. We will work with AgeUK to engage with the public and identify the important outputs from this study. We will aim to include this project on the AgeUK information websites and publications, building on much existing work supported by AgeUK and the agreed support for the current project by the Age UK research director.

Professors Brayne and Melzer co-lead the NIHR National School for Public Health Research Ageing Well programme, which is focussed on cardiovascular prevention in later life. The NIHR School has an established network of contacts with the Department of Health, Public Health England and local authorities,
We plan to use these channels to engage the field in the current project, which will add value to the existing work.

Better evidenced models of risk in early old age should be useful in primary care, for targeting advice and health checks to the right patients. The investigators will work closely with primary care colleagues to scope out the potential impacts. The PI has links to two primary care software companies, and will explore the scope for developing and testing the addition of ageing well risk algorithms for GP or web software analysis of clinical records, to highlight the potential ageing well gains from risk reduction. This could be done in health terms that matter more to middle aged people than the current models which tend to focus on the avoidance of single diseases.

Better risk measures for ageing well could have major impacts on policy models, as dependency in later life is a very major factor in current and future NHS and social care costs. The investigators will ensure that this project is taken into account in the NIHR School for Public Health Research policy model work on ageing, and in other channels to influence policy.

The genomics results should provide new mechanistic insights and clarify the roles of known variants on ageing outcomes. These results should help clarify the pathways involved, inform discussions about the relevance of existing laboratory models, and provide new ideas for intervention. The project consultants at the US National Institute on Aging (at NIH) and the Framingham Heart study are very well placed to help with the interface with basic and translational science internationally. Results may be of great interest for basic scientists and the development of more relevant laboratory models of human ageing. The results may point to potential interventions, e.g. by the pharmaceutical sector and may help identify opportunities for the development of biomarkers (i.e. the test sector). Better biomarkers of human ageing would have major impacts on improving the monitoring of ageing changes, the measurement of the effects of interventions and the estimation of prognosis, all of which are at present very limited.