Evaluation of biomarkers for ageing in populations of the youngest old and the oldest old

Lead Research Organisation: Newcastle University
Department Name: Institute of Cellular Medicine

Abstract

Nearly all major diseases of modern times are age-dependent, that means, high age is the most important risk factor for cardiovascular disease, dementias, many forms of tumours, diabetes and so on. However, biological age can be very different from what is measured in years and days. Everyone knows that some people are ?young for their age?, while others age much faster than suggested by their years. Genes, environmental factors and chance together cause these differences. This tells us two important things: First, ageing is malleable, it is possible to intervene and to slow down human ageing. Secondly, such intervention will not only increase lifespan, but will most probably also postpone the occurrence of major diseases.
The problem with interventions into the ageing process is that their efficiency is very hard to measure. One cannot wait for the death of a person to decide whether a certain combination of nutrients and vitamins was good in slowing down ageing. For that, biomarkers are needed, physical parameters that can be measured today but will tell us not only how old this person is biologically but also how fast he or she will age over, say, the next 10 years. In recent years, improved understanding of the biology of ageing has led to the identification of a number of candidate biomakers of ageing. However, in order to see whether they are really good enough, they need to be tested on large numbers of people of different ages, they need to be tested in combination with each other, and they need to be tested longitudinally, that means we need to know how they change as an individual ages. We propose to do these tests, and we hope to come up with a combination of markers that will improve prediction of risk for major age-related diseases and thus allow early assessment of the efficiency of preventive interventions.
Findings from our research will be vigorously disseminated through contacts with NHS and other stakeholder groups, including older persons? action groups, as represented in the North East Forum on Ageing (?Years Ahead?), and beyond. Findings will also be disseminated through conventional academic publications, conference presentations, web site, other media (as appropriate), and via our networks of collaborators.

Technical Summary

Ageing is the single largest risk factor for death and major diseases. However, biological age can differ significantly from calendaric age. Moreover, the rate of ageing is highly variable between individuals, and this is particularly evident amongst the oldest old. Given the high impact of environmental factors on ageing trajectories, reliable markers of biological age will have great potential in preventive medicine, intervention validation and risk assessment.
?Classical? markers of biological age include systolic blood pressure, hand grip strength, forced respiratory volume, cholesterol and glucose blood levels and cognitive/neuropsychological tests. While these markers are well validated, their prognostic potential is low, even if combined in biomarker batteries. In recent years, many more candidate markers have been discovered on the basis of a greatly improved understanding of the cell and molecular biology of ageing. Telomere length in white blood cells is the best characterized of these so far, but even this has not been sufficiently evaluated in human populations or interlinked with other markers. Moreover, the complex dynamics of the ageing process makes it highly likely that the prognostic power of individual biomarkers varies with age group. However, there are only indirect data available for comparisons between age groups, and longitudinal assessments of intra-individual changes in biomarkers of ageing with time are scarce.
Thus we propose the construction of an interrelated panel of biomarkers of ageing. This will combine ?classical? markers with recent ones developed on the basis of well-established molecular, cellular and physiological ageing mechanisms. We will evaluate these markers both individually and as a panel in two population-based samples ? the MRC National Survey of Health and Development (NSHD), a cohort of the ?youngest old? aged 53-60 years, and the NorthEast 85+ (NE85+) study of the ?oldest old? (aged 85-90 years) ? by testing their association with major health outcomes cross-sectionally and prospectively. Telomere length data obtained in a local population of the ?youngest old? (Newcastle 1000 Families study ? N1000F) will be used to assess and standardize the impact of geographic background between the two main populations. The NE85+ study will immediately allow the examination of longitudinal trajectories of the chosen biomarkers. These population studies will be complemented by a clinical sample of patients at early stages of age-related disease.

Publications

10 25 50
 
Description Office for Life Life Sciences Visit (Kristen McLeod)
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description Why We Age
Geographic Reach Europe 
Policy Influence Type Participation in advisory committee
Impact A road map for future research in ageing in Europe was generated. This is now under active dissemination (e.g. FUTUREAGE and WHYWEAGE European conference Brussels December 2010).
 
Description BBSRC CASE Studentship
Amount £80,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2009 
End 09/2013
 
Description BBSRC CASE studentship
Amount £92,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2010 
End 09/2014
 
Description BBSRC response mode
Amount £588,887 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2011 
End 08/2014
 
Description BHF Funding (Cardiovascular Phenotyping in the Newcastle 85+ study)
Amount £265,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2008 
End 02/2011
 
Description EPSRC CASE studentship
Amount £92,000 (GBP)
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom
Start 10/2009 
End 09/2013
 
Description H2020 Widespread 2014-1
Amount € 500,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 05/2015 
End 05/2016
 
Description MRC Research Grant (The Newcastle 85+ study)
Amount £2,200,000 (GBP)
Funding ID G0500997 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 05/2006 
End 04/2011
 
Description Pioneer Award
Amount £195,251 (GBP)
Funding ID C12161/A24009 
Organisation Cancer Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2017 
End 01/2019
 
Description RCUK New Dynamics of Ageing
Amount £90,000 (GBP)
Organisation Research Councils UK (RCUK) 
Sector Public
Country United Kingdom
Start 09/2008 
End 02/2012
 
Description response mode
Amount £379,371 (GBP)
Funding ID BB/K019260/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2013 
End 08/2016
 
Title Improved assessment of plasma isoprostanes by LC-MS/MS 
Description Quantitative measurement of Isoprostanes by LC-MS/MS in EDTA-plasma samples has been greatly improved by evaluating 2 of the isomers (8-isoprostaglandin F2a and 8,12 iso iPF2a-VI) simultaneously from the same source of plasma and at high throughoutput. This work was done in collaboration with the Medical Toxicology Centre, Newcastle University. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact none yet 
 
Title Improved measurement of telomere length by Q-PCR 
Description Real Time PCR measurement of telomere length in DNA samples has been adapted to a 384-well platform in conjunction with a liquid handling robot system allowing for higher throughoutput and greater accuracy. 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact Improved measurement of telomere length in large cohorts, e.g. HALCyon. 
 
Title Newcastle 85+ Study biomarkers samples bank 
Description Collection of plasma, serum, DNA, RNA and N2 preserved leukocytes samples, from around 800 people 85y old at baseline and 2 repeated sampling intervals of 18 months 
Type Of Material Database/Collection of Data/Biological Samples 
Year Produced 2007 
Provided To Others? Yes  
Impact Samples from this collection have been made available for: - Studies on mitochondrial DNA haplotype to determine whether inherited mtDNA haplogroups are associated with biological ageing and survival. - Studies on Epigenetic DNA methylation to evaluate if increased levels of epigenetic instability may lead to increased susceptibility to age related diseases. Analysis of the outcomes of these studies is in progress. 
 
Title Quantitative analysis of cytokines in blood by MSD technology 
Description Measurement of blood culture IL-6 and TNF-alpha production has been greatly improved with the use of Electrochemiluminescence MSD technology on custom-made 4-spot 96-well plates allowing for a wider range of concentrations to be measured for both cytokines simultaneously and with a significant reduction on the volume of sample required. 
Type Of Material Technology assay or reagent 
Provided To Others? No  
Impact none yet 
 
Description Halcyon 
Organisation University College London
Department MRC Unit for Lifelong Health and Ageing
Country United Kingdom 
Sector Public 
PI Contribution measured telomere length in Halcyon birth cohorts as biomarker of ageing
Collaborator Contribution provided access to multiple British birth cohorts provided access to wide range of ageing-relevant data in these cohorts
Impact papers: 1: Birnie K, Cooper R, Martin RM, Kuh D, Sayer AA, Alvarado BE, Bayer A, Christensen K, Cho SI, Cooper C, Corley J, Craig L, Deary IJ, Demakakos P, Ebrahim S, Gallacher J, Gow AJ, Gunnell D, Haas S, Hemmingsson T, Inskip H, Jang SN, Noronha K, Osler M, Palloni A, Rasmussen F, Santos-Eggimann B, Spagnoli J, Starr J, Steptoe A, Syddall H, Tynelius P, Weir D, Whalley LJ, Zunzunegui MV, Ben-Shlomo Y, Hardy R; HALCyon study team. Childhood socioeconomic position and objectively measured physical capability levels in adulthood: a systematic review and meta-analysis. PLoS One. 2011 Jan 26;6(1):e15564. Review. PubMed PMID: 21297868; PubMed Central PMCID: PMC3027621. 2: Harris SE, Martin-Ruiz C, von Zglinicki T, Starr JM, Deary IJ. Telomere length and aging biomarkers in 70-year-olds: the Lothian Birth Cohort 1936. Neurobiol Aging. 2010 Dec 29. [Epub ahead of print] PubMed PMID: 21194798. 3: Cooper R, Kuh D, Cooper C, Gale CR, Lawlor DA, Matthews F, Hardy R; FALCon and HALCyon Study Teams. Objective measures of physical capability and subsequent health: a systematic review. Age Ageing. 2011 Jan;40(1):14-23. Epub 2010 Sep 15. Review. PubMed PMID: 20843964; PubMed Central PMCID: PMC3000177. a number of additional papers and one book are in preparation. The collaboration is multidisciplinary, including epidemiology and cell biology.
Start Year 2006
 
Description ICM Director's Day, Newcastle University 2018 
Organisation Newcastle University
Department Newcastle University Medical School
Country United Kingdom 
Sector Academic/University 
PI Contribution Multiple presentations across the Institute of Cellular Medicine and other Institutes with a view to cross-institute, cross-faculty, collaborations. Included plenary session by Prof Joris Veltman of the Institute of Genetic Medicine. The day was well attended, enthusiastically received, and good for morale.
Collaborator Contribution Multiple, high quality presentations on latest science from Newcastle.
Impact Multiple cross-functional, multidisciplinary grant submissions in preparation.
Start Year 2018
 
Description Unilever co-funding 
Organisation Unilever
Department Research and Development Colworth
Country United Kingdom 
Sector Private 
PI Contribution validation of biomarker candidates in the Newcastle 85+ population
Collaborator Contribution provision of equipment (activity monitors) evaluation of data (activity monitoring) provision of measurements (isoprostanes by DELFIA)
Impact 2 peer-reviewed publications
Start Year 2007
 
Title Telomeres as prognostic biomarkers for post-stroke dementia 
Description Telomere length in blood is associated with risk of dementia and death following stroke 
Type Diagnostic Tool - Non-Imaging
Current Stage Of Development Initial development
Year Development Stage Completed 2006
Development Status On hold
Impact Intensification of research into telomeres as biomarkers 
 
Description EMEUNET Meeting Lisbon 2016 Immune Tolerance - Where Next? 
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 Immune Tolerance: RA - Where Next?
Year(s) Of Engagement Activity 2016
 
Description NIHR BRC Impact Showcase, Newcastle, 2018 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Showcase event attended by senior figures from the Department of Health and major charities including Versus Arthritis. The CEOs of the Trust and University attended. Musculoskeletal presentations included patient presentations and videos. Ken Baker was awarded a prize for best oral presentation. Sir John Burn and Dame Jackie Daniel presented their vision for Newcastle.
Year(s) Of Engagement Activity 2018
URL https://www.newcastlebrc.nihr.ac.uk/events/nihr-newcastle-biomedical-research-centre-impact-showcase...
 
Description Newspaper interviews 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interviews for various print media

some interviews (e.g. Financial Times 2010) led to widespread international media interest
Year(s) Of Engagement Activity 2007,2008,2009,2010
 
Description Presentation an discussion at Cheltenham Science Festival 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Poster Presentation
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact about 200 people attended a presentaiton about immunsenescence and ageing, leading to intense discussion over 2-3 hours afterwards

unknown
Year(s) Of Engagement Activity 2013
 
Description comment in BMJ "Will your telomeres tell your future?" 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Health professionals
Results and Impact BMJ. 2012 Mar 13;344:e1727. doi: 10.1136/bmj.e1727.
Will your telomeres tell your future?
von Zglinicki T.

unknown
Year(s) Of Engagement Activity 2012
URL http://www.bmj.com/content/344/bmj.e1727?view=long&pmid=22415954
 
Description comment on Biomarker study in BMJ PMID: 25005709 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact responses from colleagues

discussions on biomarkers of ageing within the community
Year(s) Of Engagement Activity 2014
 
Description radio interviews 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Media (as a channel to the public)
Results and Impact explained results to a wide audience

none known
Year(s) Of Engagement Activity 2010,2014