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.
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.
?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

Adams J
(2007)
No association between socio-economic status and white blood cell telomere length.
in Aging cell

Adamson AJ
(2009)
Nutrition in advanced age: dietary assessment in the Newcastle 85+ study.
in European journal of clinical nutrition


Alfred T
(2013)
Genetic variants influencing biomarkers of nutrition are not associated with cognitive capability in middle-aged and older adults.
in The Journal of nutrition

Alfred T
(2014)
Associations between APOE and low-density lipoprotein cholesterol genotypes and cognitive and physical capability: the HALCyon programme.
in Age (Dordrecht, Netherlands)

Anderson KN
(2014)
Assessment of sleep and circadian rhythm disorders in the very old: the Newcastle 85+ Cohort Study.
in Age and ageing


Arasaradnam RP
(2010)
DNA methylation of ESR-1 and N-33 in colorectal mucosa of patients with ulcerative colitis (UC).
in Epigenetics

Aw D
(2008)
Architectural changes in the thymus of aging mice.
in Aging cell

Basterfield L
(2010)
Intestinal tumours, colonic butyrate and sleep in exercised Min mice.
in The British journal of nutrition
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 | Public |
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 | MIA - Multidisciplinary Institute for Ageing Portugal |
Amount | € 15,000,000 (EUR) |
Organisation | European Commission H2020 |
Sector | Public |
Country | Belgium |
Start | 01/2020 |
End | 12/2026 |
Description | MRC Research Grant (The Newcastle 85+ study) |
Amount | £2,200,000 (GBP) |
Funding ID | G0500997 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
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 | Academic/University |
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 | 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 |