Metabolomic and omic assessment of biological ageing across the life-course (METAGE)

Lead Research Organisation: Imperial College London
Department Name: School of Public Health

Abstract

Both genetic and environmental factors affect the ageing process, leading to differences in ageing rates. Therefore, a person's "biological age", or overall physiological state, may differ from what is expected given their actual (chronological) age. Differences in biological aging rates mean some people die earlier and have more health problems in later life.
We aim to develop blood-based measures of biological age that provides improved prediction, over chronological age itself, of ill health and premature mortality in adults and developmental outcomes in children.

We will existing metabolomics (whole sets of small molecules) and other 'omics' (whole sets of molecules related to gene control and function) data from multiple population based cohort studies in the UK, Europe and the USA. We will develop blood tests of biological age composed of measurements of multiple molecules using advanced statistics. Three approaches will be pursued:
i) Using targeted metabolomics on over 200 molecules in approximately 35,000 people (aged 7-99 years);
ii) Using untargeted metabolomics on several thousand molecules in approximately 7,000 people (aged 20-95 years). Predictive metabolites will be identified, and the new blood test will tested with newly measured data in an independent population;
iii) Using metabolomic and omics data in 1,200 children (aged 6-11 years) to develop blood tests of biological development.

We will then assess whether 'age acceleration', the difference between predicted age (from metabolomic and omic age blood tests) and chronological age, is predictive of cardiovascular disease and premature death in adults and associated with height, weight, and mental development in children. We will identify the key environmental and genetic causes of age acceleration and the biological pathways underlying the ageing process.

Planned Impact

The development of affordable biomarkers of biological age, improved knowledge of the biological of ageing in humans, and identification of risk factors of faster biological ageing rate may impact the following beneficiaries:

-Industry, including pharmaceutical companies
-Policy makers
-Public health campaigners
-Doctors
-Carers
-The general public

They may benefit in the following ways:

Pharmaceutical companies benefit from stratified selection of patients into drug trials, greatly reducing the number of patients needed to treat to observe an effect - and greatly reducing the costs of trials. Improved knowledge of the biology of ageing may identify the processes and sites most amenable to therapeutic targeting, potentially leading to new drugs to reduce the risk of age-associated morbidity. Other commercial areas include the burgeoning personal health field, where by customers often use apps to track their health and may pay a subscription for advanced services such as in-depth medical tests. These new development will contribute to the economic competitiveness of
the UK

Policy makers will benefit from a stronger evidence base regarding key determinants of faster biological ageing, allowing the development of evidence-based policy to improve healthy ageing for all sectors of society. Similarly, public health campaigns and messaging can target the reduction of risk factors of unhealthy ageing.

In the primary care setting, providing biological age tests to patients may provide a greater impact than current clinical tests and provide greater motivation to follow healthier life habits. in clinical practice, an affordable clinical test may be used to identify individuals most at risk of co-morbidities, potentially within early life where interventions may be most effective.

Ultimately, the general public will benefit from all these actions to improve ageing outcomes. With increasing lifespans and later retirement ages, increasing health and well-being in later life is one of the greatest challenges we face today. This will lessen the burden on carers and health services and extend productive lives, providing an overall benefit to the global economic performance

Publications

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Alfano R (2022) Perspectives and challenges of epigenetic determinants of childhood obesity: A systematic review. in Obesity reviews : an official journal of the International Association for the Study of Obesity

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De Prado-Bert P (2021) The early-life exposome and epigenetic age acceleration in children in Environment International

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Handakas E (2021) Cord blood metabolic signatures predictive of childhood overweight and rapid growth. in International journal of obesity (2005)

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Handakas E (2022) A systematic review of metabolomic studies of childhood obesity: State of the evidence for metabolic determinants and consequences. in Obesity reviews : an official journal of the International Association for the Study of Obesity

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Lau CE (2021) DNA methylation age as a biomarker for cancer. in International journal of cancer

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Robinson O (2021) Metabolic profiles of socio-economic position: a multi-cohort analysis. in International journal of epidemiology

 
Description In the workstream using Nuclear Magnetic Resonance Spectroscopy (NMR) based metabolomics in blood samples, we have assembled data from 38,000 people from 14 cohort studies covering ages 20-90 years. We have investigated various multivariate modeling strategies to test whether chronological can be predicted using this data, giving a correlation range of 0.5 -0.8 depending on model used. We then defined "age acceleration (AA)" as the difference between chronological and predicted age.
We found that for some models, AA was with associated with mortality and cardiovascular disease, suggesting that this approach does capture biological ageing processes. Furthermore this metabolomic AA score was robustly, associated with biomarkers of biological aging within the inflammatory, lung, kidney and circulatory systems. We found risk of age acceleration to include obesity, diabetes, physical inactivity and low education level. We found that certain metabolites including docosahexaenoic acid, citrate, creatinine, albumin and histidine had clear relationships with age over the lifespan. However for metabolites such as docosahexaenoic acid which increases with age, appeared to also be associated with longer lifespan.
Within the workstream using untargeted liquid chromatography - mass spectrometry (LC-MS), which provide much greater coverage than NMR metabolomics, we have harmonizing a database of existing untargeted LC-MS datasets - including six cohorts for around 8,000 people. Through ongoing annotation work with partners at the National Phenome Centre, we now have around 500 metabolites which we will take forward for age modelling work. We have initiated a partnership with the Irish Longitudinal Study of Ageing and are currently running LC-MS acquisitions for 1,900 samples from people aged over 50 years from across Ireland, including 500 repeat samples, to validate these models and test associations with physical markers of aging such as frailty.

In the workstream in children we have found that AA derived from epigenetic models of age is associated with developmental outcomes such as height, fat mass, onset of puberty, and behavioral problems. We have developed further aging (development) models using protein, metabolite and gene expression data.
Exploitation Route This information and the biological age models can be used by other researchers exploring biological aging in human studies
Sectors Healthcare

 
Description AIRWAVE study 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of data provided by AIRWAVE cohort. We are re-processing and performing additional annotation experiments to enrich the existing metabolomic database
Collaborator Contribution Provision of data collected in the AIRWAVE cohort. Intellectual contribution to research design and interpretation.
Impact Untargeted metabolomics study database doi: 10.1111/acel.13149
Start Year 2020
 
Description ALSPAC cohort study 
Organisation University of Bristol
Department Bristol Research Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of data
Collaborator Contribution Provision of data from the ALSPAC birth coohort
Impact Child study database Targeted metabolomics database doi: 10.1093/ije/dyaa188
Start Year 2020
 
Description FINGER 
Organisation National Institute for Health and Welfare
Country Finland 
Sector Public 
PI Contribution We will analyze the metabolomic data generated from the FINGER trial to develop age models and test whether intervention slows biological aging
Collaborator Contribution They have provided metabolomic and covariate data from the FINGER trial
Impact none to report yet
Start Year 2021
 
Description GRAPHIC study 
Organisation University of Leicester
Country United Kingdom 
Sector Academic/University 
PI Contribution We will analyze metabolomic and covariate data from The Genetic Regulation of Arterial Pressure of Humans In the Community (GRAPHIC) Study
Collaborator Contribution Provide metabolomic data and covariates
Impact None yet
Start Year 2022
 
Description Generation 21 Study 
Organisation University of Porto
Department University of Porto Medical School
Country Portugal 
Sector Academic/University 
PI Contribution Analysis of data collected in the Generation 21 Birth Cohort
Collaborator Contribution Provision of data collected in the Generation 21 Birth Cohort and intellectual contribution to research design and interpretation
Impact Child study database
Start Year 2020
 
Description HELIX/Athlete exposome study 
Organisation Barcelona Institute for Global Health
Country Spain 
Sector Multiple 
PI Contribution The research team are analysing data collected in EU HELIX Exposome study of European children. In addition we are performing a glucocorticoid steroid profiling assay (in collaboration with our laboratory research partners) of hair and urine samples from the study. Additionally we contribute intellectually to the working group on biological aging in this study.
Collaborator Contribution The partners are providing data and biological samples to meet our project aims. Intellectual contribution to research design and interpretation
Impact Child study database
Start Year 2020
 
Description Lolipop Study 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of data provided by Lolipop cohort.
Collaborator Contribution Provision of data from the Lolipop study. Intellectual contribution
Impact Untargeted metabolomics database
Start Year 2020
 
Description Multi-Ethnic Study of Atherosclerosis (MESA) 
Organisation National Institutes of Health (NIH)
Department National Heart, Lung, and Blood Institute (NHLBI)
Country United States 
Sector Public 
PI Contribution Analysis of data provided by MESA cohort. We are re-processing and performing additional annotation experiments to enrich the existing metabolomic database
Collaborator Contribution Provision of data collected in the MESA cohort. Intellectual contribution to research design and interpretation.
Impact Untargeted metabolomics study database
Start Year 2020
 
Description Northern Finnish Birth Cohort 
Organisation University of Oulu
Department Biocenter Oulu
Country Finland 
Sector Academic/University 
PI Contribution Analysis of data collected in the Northern Finnish Birth Cohort
Collaborator Contribution Provision of data collected in the Northern Finnish Birth Cohort and intellectual contribution to research design and interpretation
Impact Targeted metabolomics database doi: 10.1093/ije/dyaa188
Start Year 2020
 
Description Rotterdam study 
Organisation University Medical Center Rotterdam
Country Netherlands 
Sector Hospitals 
PI Contribution Analysis of data provided by the Rotterdam study. We are re-processing and performing additional annotation experiments to enrich the existing metabolomic database
Collaborator Contribution Provision of data from the Rotterdam study. Intellectual contribution
Impact Untargeted metabolomics database
Start Year 2020
 
Description TILDA 
Organisation Trinity College Dublin
Department The Irish Longitudinal Study on Ageing
Country Ireland 
Sector Academic/University 
PI Contribution We are analyzing 1,700 blood samples provided by the TILDA using four liquid-chromatography mass-spectrometry platforms
Collaborator Contribution They are providing samples and covariate data and intellectual contribution to downstream data analysis
Impact Laboratory analysis underway so not outputs to report yet
Start Year 2021
 
Description UCLEB consortium 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We are analysing data accessed through the UCL-LSHTM-Edinburgh-Bristol (UCLEB) Consortium, a network of UK based cohorts, that have provided data through the UCLEB data infrastructure.
Collaborator Contribution The UCLEB consortium is providing access and a security controlled infrastructure to analyse data from six cohorts: The MRC National Survey of Health and Development (NSHD), the Caerphilly Prospective Study (CaPS), the British Women's Heart and Health Study (BWHHS), the Southall and Brent Revisited Study (SABRE), the Whitehall-II study (WHII) and the UK Collaborative Trial of Ovarian Cancer Screening Longitudinal Women's Cohort (UKCTOCS).
Impact Targeted metabolomics database doi: 10.1093/ije/dyaa188
Start Year 2020
 
Description Young Finns Study 
Organisation University of Turku
Country Finland 
Sector Academic/University 
PI Contribution Analysis of data collected in the Young Finns Study
Collaborator Contribution Provision of data collected in the Young Finns Study and intellectual contribution to research design and interpretation
Impact Targeted metabolomics database doi: 10.1093/ije/dyaa188
Start Year 2020
 
Description "World Cafe" webinar on epigenetic and metabolomic determinants of childhood obesity 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact As part of a webinar series on childhood obesity, I reported recent advances in metabolomic and epigenetic research in to causes of childhood obesity and how this is related to my own work assessing development in children using these molecular markers. The webinar was attended by stakeholders of four European project and and around 200 participants were on the call.
Year(s) Of Engagement Activity 2021
URL https://www.fhi.no/en/studies/co-create/news2/world-cafe---lets-talk-about-childhood-obesity/
 
Description An online presentation open to all and advertised on ICL website, hosted by the Imperial College Bioinformatics Group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Approximately 80 participants attended the microsoft Teams meeting where I presented an update on the project, as part of a regular series of meetings on Bioinformatics. Many questions were asked including from participants outside Imperial College London
Year(s) Of Engagement Activity 2020
URL https://www.imperial.ac.uk/events/117239/biomarkers-of-development-and-ageing-across-multiple-popula...
 
Description International meeting of the CAD-GWAS project, Imperial College London 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Presentation of project aims and preliminary results at the international meeting of the CAD-GWAS project, a consortium including cohorts providing data to this project. The event was an opportunity to strengthen collaboration with American partners, and provided very helpful discussion for the project direction.
Year(s) Of Engagement Activity 2020
 
Description Nordic UK-Brain Network Seminar series 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Provided an overview of metabolomics-based approaches for generation of biomarker profiles across the life course; with a focus on biological ageing, and also in relation to AD/dementia development, to network of research in biomarker based dementia prevention
Year(s) Of Engagement Activity 2021
URL https://sites.uef.fi/neuro/uef-nordic-uk-brain-network/
 
Description TILDA Seminar Series 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Seminar given to researchers and collaborators involved in the Irish Longitudinal Study of Ageing, as part of a regular seminar series
Year(s) Of Engagement Activity 2021