Generating new knowledge to support reversability interventions

Lead Research Organisation: King's College London
Department Name: Social Genetic and Dev Psychiatry Centre

Abstract

This proposal responds to a call for research on the "mid-life reversibility of early-established bio-behavioral risk factors" (RFA-AG-14-006). Population aging increases the public-health burden of age-related conditions, such as cardiovascular disease, type 2 diabetes, and dementia. It is now known that the pathogenesis of such age related diseases involves gradually accumulating damage to organ systems, beginning in the first half of the life course, particularly in people exposed to early-life adversity. It is also known that age-related diseases and early mortality are portended by a variety of adverse experiences in early life. Although these facts imply that it is desirable to prevent early-life adversities, adversity cannot be fully prevented (and it is too late to prevent early life adversity for the baby-boomer generation). Therefore there is growing interest in interventions for midlife adults, to reverse the damage done by early-life adversity. This interest lends new scientific significance to existing studies that have followed cohorts from childhood to midlife, because they can provide an evidence base to inform and speed the development of novel intervention strategies. The RFA extends a call for such studies. We propose to undertake data analyses in one such study, the NIA-funded Dunedin Multidisciplinary Health & Development Study, a longitudinal birth-cohort study of both problematic and positive processes of lifelong development. Our data resource comprises in-clinic assessments at birth and ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, and most recently 38 years, with 95% retention as the cohort enters midlife. The data combine demographic/economic surveys, clinical-quality health assessments, a bio-bank, genome-wide SNP data, and administrative-record linkage. First, we will generate outcome measures to detect individual differences in
decline of biomarkers for organ systems in the general population at early midlife, the stage when future reversibility interventions will be applied. Second, we will compare the performance of retrospective versus prospective measures of early-life adversity. Future reversibility interventions will have to rely on midlife participants' retrospective reports of adversity, so there is a need to know how well this is going to work. Third, we will test how the connection between early-life adversity and midlife aging relates to polygenic genetic risk and family history of age-related diseases. Will genotype or family history influence responsiveness to reversibility interventions? Fourth, we will identify potentially reversible behavioral and social factors that mediate the connection from early-life adversity to midlife biological aging. Findings are expected to support the design of future randomized clinical trials of midlife interventions intended to reverse the effects of early-life adversity, prevent age-related diseases, and enhance wellbeing in late life.

Planned Impact

n/a

Publications

10 25 50
publication icon
Belsky DW (2015) Quantification of biological aging in young adults. in Proceedings of the National Academy of Sciences of the United States of America

publication icon
Moffitt TE (2017) The Longitudinal Study of Aging in Human Young Adults: Knowledge Gaps and Research Agenda. in The journals of gerontology. Series A, Biological sciences and medical sciences

 
Description 1. We followed 1000 members of a birth cohort while collecting a panel of biomarkers from them every 6 years, and used the repeated measures dataset to create a method to measure how rapidly or slowly any individual is aging. Belsky et al 2015. PNAS
2. We found that intelligence measured in early childhood, middle childhood, and midlife correlated significantly with perceived facial age, the NHANES biomarker algorithm, and Framingham heart age. Correlations between intelligence and telomere length were more modest. Study members with lower intelligence at age three had more advanced biological age at midlife. Schaefer et al 2016, J of Gero.
3. We tested whether associations between adverse childhood experiences (ACEs; e.g., abuse, neglect, parental loss, etc.) are the same for prospective and retrospective ACE measures in the Dunedin Longitudinal Study. Retrospective and prospective measures of adversity showed only moderate agreement. Retrospective ACEs showed stronger associations with life outcomes that were subjectively assessed, and weaker associations with life outcomes that were objectively assessed. More agreeable and neurotic dispositions bias retrospective ACE measures toward miss-estimating the impact of adversity on health outcomes. Reuben et al. 2016. JCPP
4. We found that individuals exposed to childhood victimization had pervasive impairments in clinically-relevant cognitive functions including general intelligence, executive function, processing speed, memory, perceptual reasoning, and verbal comprehension in adolescence and adulthood. However, the observed cognitive deficits in victimized individuals were largely explained by cognitive deficits that predated childhood victimization and by confounding genetic and environmental risks. Danese et al 2017. AM J of Psychiatry
5. We report that personal-history characteristics of familial longevity, childhood social-class, adverse childhood experiences, and childhood health, intelligence, and self-control all predicted differences in cohort members' adulthood Pace of Aging. Accumulation of more personal-history risks predicted faster Pace of Aging. Belsky et al 2017. in review
6. Our argument is that gero-prevention can best be attained by studying and measuring the pace of aging in young-to-mildlife adults. this argument is summarised in Moffit et al 2017, J of Gero.
Exploitation Route Our measure of the pace of aging can be used as a sensitive outcome measure in randomised clinical trials of therapies to prevent aging-related disease and disability. It works with people in their twenties to forties, allowing anti-aging therapies to be implemented in young adults before disease onset.

Because trials of anti-aging therapies will need to ascertain personal histories retrospectively, we replicated results using cohort members' retrospective personal-history reports made in adulthood. Because many trials recruit participants from clinical settings, we replicated results in the cohort subset who had recent health-system contact according to electronic medical records. Quick, inexpensive measures of trial participants' early personal histories can enable clinical trials to study who volunteers for trials, who adheres to treatment, and who responds to anti-aging therapies.
Sectors Healthcare

URL http://www.moffittcaspi.com
 
Description This award was for only 2 years and the budget was under 150,000 pounds, and it ended only a year ago, so it is not clear how much impact ought to be expected. However, I think the project did quite well. One of the impacts to come soon from this ESRC-funded research will be a Nuffield Council on Bioethics Policy Brief: the Search for a Treatment for Ageing. This Brief is in part based on our ESRC-funded work, and Moffitt was asked to preview and comment on it in her role as a Nuffield Trustee. Narrative: We undertook this project in response to a call for research on the "Mid-life reversibility of early-established bio-behavioral risk factors" (NIA RFA-AG-14-006). The rationale behind the call was as follows: Population aging is increasing the burden of age-related conditions, such as cardiovascular disease, type 2 diabetes, and dementia. Such age-related diseases are caused by gradual damage to organ systems, and this damage process begins already in the first half of the life course, particularly in people who suffered adversity as children. Adverse experiences in early life also lead to early death. Although these facts imply that it is highly desirable to prevent early-life adversities, adversity cannot always be prevented. It is part of life. As a result, there is growing interest in developing new anti-aging therapies for midlife adults, to reverse the damage done by early-life adversity and slow their aging. NIA's call for projects asked, what new information do we need to develop the best therapies for mid-life adults? To answer this call, we undertook analyses of data from the Dunedin Multidisciplinary Health & Development Study, which is a longitudinal birth-cohort study of 1000 people all born in 1972. The Dunedin Study comprises in-depth clinical assessments at birth and ages 3, 5, 7, 9, 11, 13, 15, 18, 21, 26, 32, and most recently 38 years, with 95% retention. We explained that knowledge to help develop anti-aging therapies can best be attained by studying young-to-midlife adults, because they will be the target recipients of anti-aging therapies (Our explanation was published as Moffitt et al. 2017, J of Gerontology). We had already followed the 1000 members of the Dunedin birth cohort while collecting a panel of 18 biomarkers from them every 6 years, and we used this unique data set of repeated biomarker measurements to create a method for measuring how rapidly or slowly any individual is biologically aging during the first half of adult life. We called this new measure the Pace of Aging (This was published as Belsky et al. 2015, PNAS). This new measure can now be calculated for anyone. It can be used to test which anti-aging therapies are able to slow aging. Second, we found that differences between people in their adulthood Pace of Aging can be predicted by their personal characteristics, including their history of adverse childhood experiences, familial longevity of grandparents, childhood social-class, and their childhood health, cognitive ability, and self-control. People who accumulate more of these risks begin to age faster already by midlife (This was published as Belsky et al. 2017, Aging Cell). In particular, we found that people who have lower cognitive ability as young as age three have an older biological age at midlife (This was published as Schaefer et al, 2016, J of Gerontology). However, childhood adversity does not lead to lower intelligence, rather low cognitive ability is present before children experience adversity (This was published as Danese et al 2017. American J of Psychiatry). This means that when new anti-aging therapies are tested, each participant's personal background and cognitive ability level will have to be taken into account, because these factors might affect how participants are able to respond to the therapy. Third, future anti-aging therapeutic programs will have to rely on midlife participants' retrospective reports to know if they experienced adversity in their childhoods, and if the effects of this adversity need to be reversed by therapies. Participants' reports will have to be based on their long-term memory, and memory is fallible, so there is a need to know how well this is going to work. We compared people's retrospective memories of adverse childhood experiences reported at age 38 against our prospective data on their actual adverse childhood experiences, as documented in the 1970's when they were children. We found that retrospective and prospective measures of childhood adversity are not in good agreement. Retrospective memories of childhood adversity also show only weak associations with objectively tested adult health, such as lab test results or cognitive testing. We found that a person's personality biases their memories of childhood. Adults with neurotic personalities tend to remember more childhood adversities and also to believe their adult health is poor, while people with optimistic personalities tend to remember fewer childhood adversities and also to believe their adult health is good. These findings suggest that if future research and clinical therapies need to ask adults to remember and report their childhood adversities this is going to pose validity problems (This was published as Reuben et al. 2016, JCPP). Fourth, many different methods of measuring biological age have been put forward in the field, but each has its own small separate literature, and what was needed was a comparison of these measures in the same sample of humans. We published the first comparison of 11 different measures, including competing epigenetic methylation clocks, telomeres, Pace of Aging, and Bio-age. Correlations ranged from nil to very small, a surprising finding that suggests each measures something different. The field needs to work this out, as obviously all of these measures cannot be claimed to be "biological aging." (This was published as Belsky et al. in press, 2017). Our findings from this ESRC grant are expected to support the design of future randomized clinical trials of midlife interventions intended to reverse the effects of early-life adversity, slow aging, prevent age-related diseases, and enhance wellbeing in late life. Talks: Our team members gave 30 talks at ageing conferences and other international venues, including an invited address at a 2017 NIH research network focused on reversing the effects of childhood adversity. Publications: The RESEARCHFISH site unfortunately seems to scrape the internet and add papers that do not belong to grants, and we cannot seem to stop this happening, so for your convenience we list the SIX primary publications that fulfilled the aims from this ESRC grant here: Moffitt TE, Belsky DW, Danese A, Poulton R, Caspi A. (2017). The longitudinal study of aging in human young adults: Knowledge gaps and research agenda. Journal of Gerontology Series A: Biological Sciences and Medical Sciences and Journal of Gerontology: Psychological Sciences. Belsky DW, Caspi A, Houts R, Cohen HJ, Corcoran D, Danese A, Harrington HL, Israel S, Levine ME, Schaefer J, Sugden K, Williams B, Yashin A, Poulton R, Moffitt TE. (2015). Quantification of biological aging in young adults. Proceedings of the National Academy of Sciences of the United States of America. 77, 601-617. Belsky DW, Caspi A, Cohen HJ, Kraus WE, Ramrakha S, Poulton R, Moffitt TE. (2017). Impact of Early Personal History Characteristics on the Pace of Aging: Implications for Clinical Trials of Therapies to Slow Aging and Extend Healthspan. Aging Cell. Belsky DW, Moffitt TE, Cohen AA, Corcoran DL, Levine ME, Prinz J, Schaefer J, Sugden K, Williams B, Poulton R, Caspi A. (in press). Telomere, epigenetic clock, and biomarker-composite quantifications of biological aging: Do they measure the same thing? American J of Epidemiology. Reuben, Aaron, T. E. Moffitt, A Caspi, D W. Belsky, HL Harrington, F Schroeder, S Hogan, S Ramrakha, R Poulton, & A Danese, (2016). Lest we forget: Comparing retrospective and prospective assessments of adverse childhood experiences in the prediction of adult health. J of Child Psychology and Psychiatry Danese A., Moffitt TE, Arseneault, L, Bleiberg B, Dinardo P, Gandleman S, Houts R, Ambler,A, Fisher, H, Poulton R, Caspi A, (2016). The origins of cognitive deficits in victimized children: Implications for neuroscientists and clinicians. American Journal of Psychiatry. There are also more than a dozen subisidary papers that benefitted from grant resources and are credited to this grant. Thank you, Terrie Moffitt and colleagues
First Year Of Impact 2015
Sector Healthcare
Impact Types Policy & public services

 
Description Adult ADHD paper selected by NEJM as in top 10 findings of psychiatry in 2015
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
URL http://www.jwatch.org/na39791/2015/12/28/nejm-journal-watch-psychiatry-top-stories-2015?
 
Description Prime Mininster's speech, plus Annual Report of the Chief Medical Officer 2012, Our Children Deserve Better: Prevention Pays."
Geographic Reach National 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact From Jo Jenkinson at the UK MRC: "Your research is everywhere in the public domain at the moment with the Prime Ministers's speech on child and adolescent mental health and the new MQ publicity campaign. In the Annual Report of the Chief Medical Officer 2012, Our Children Deserve Better: Prevention Pays." Used Kim-Cohen et al. 2003. Prior juvenile diagnoses in adults with mental disorder.
 
Description Science News named our paper the 4th best science story of 2015
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
Impact not sure yet
URL https://www.sciencenews.org/article/top-stories-2015-pluto-gene-editing-new-hominid-and-more
 
Description NIA Neuroimaging grant
Amount $7,000,000 (USD)
Funding ID 2 R01 AG032282-06 
Organisation National Institute on Aging 
Sector Public
Country United States
Start 07/2015 
End 06/2020
 
Description Data sharing from the Dunedin Study 
Organisation University of Otago
Country New Zealand 
Sector Academic/University 
PI Contribution we collect and share the data
Collaborator Contribution The Dunedin Study data set is shared among a consortium of 6 research teams, from Canada, Australia, New Zealand, and us, in the UK. Via our Unit based at the Univ of Otago in New Zealand, we share the data with more than 80 other research teams outside the Study group, including with 23 universities in the USA. This study has been ongoing since 1972, has a 32 year dataset, and has had 12 assessments.
Impact more than 1200 scientific publications since 1973
 
Description Duke University Geriatrics School of Medicine 
Organisation Duke University
Department School of Medicine Duke
Country United States 
Sector Academic/University 
PI Contribution coauthor papears
Collaborator Contribution coauthor papers
Impact PNAS publication
Start Year 2014
 
Description The Dunedin Multidisciplinary Health & Development Study, Otago School of Medicine 
Organisation University of Otago
Department Dunedin Multidisciplinary Health & Development Research Unit
Country New Zealand 
Sector Academic/University 
PI Contribution We raised funds and designed protocols and analysed the data
Collaborator Contribution the Unit at Otago runs the cohort study and undertakes data-collection waves
Impact over 1000 publications
 
Description 3-page story about our research in the journal: Science. 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact 3-page feature article about our careers in the Dunedin Study.
Year(s) Of Engagement Activity 2018
URL http://science.sciencemag.org/content/359/6375/510.full
 
Description media coverage of our research in 2015 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Print coverage
Cosmopolitan Magazine: http://www.cosmopolitan.com/health-fitness/news/a35586/what-your-social-life-is-doing-to-your-body/
Daily Mail 20.01.2015 - p13
http://www.dailymail.co.uk/health/article-2918139/Do-suffer-social-jetlag-two-hour-lie-weekend-increases-risk-OBESE-scientists-warn.html
Daily Telegraph - 20.01.2015 - p14
http://www.telegraph.co.uk/news/science/science-news/11358195/Social-jet-lag-is-driving-obesity-and-illness-say-scientists.html
The Independent - 20.01.2015 - p15
http://www.independent.co.uk/life-style/health-and-families/fancy-a-liein-on-weekends-new-study-finds-it-could-lead-obesity-and-diabetes-9990661.html
The Times - 20.01.2015 - p14
The Sun - 20.01.2015 - p25
Online
https://www.sciencenews.org/blog/scicurious/weekly-grind-social-jetlag-could-be-weighty-issue
NHS choices - http://www.nhs.uk/news/2015/01January/Pages/Social-jet-lag-linked-to-obesity-and-unhealthy-metabolism.aspx
Diabetes.co.uk - http://www.diabetes.co.uk/news/2015/jan/sleeping-late-at-the-weekend-linked-to-obesity-and-type-2-diabetes-97385674.html
Yahoo News UK - https://uk.lifestyle.yahoo.com/blogs/icymi/no-more-weekend-lie-ins--study-finds-they-re-making-us-sick-and-fat-112510799.html
Huffington Post UK - http://www.huffingtonpost.co.uk/2015/01/21/obesity-social-jet-lag-sleep_n_6514568.html
Shape Magazine US - http://www.shape.com/weight-loss/weight-maintenance/how-your-sleep-schedule-affects-your-weight-gain-and-disease-risk
Australian's Women Weekly - http://www.aww.com.au/diet-health/health-news/2015/1/do-you-have-social-jet-lag/
New Kerala India - http://www.newkerala.com/news/2015/fullnews-9245.html
Zee News India - http://zeenews.india.com/news/health/health-news/heres-how-social-jet-lag-can-affect-your-weight-gain-and-disease-risks_1534053.html
Why Some People May Be Harder Hit by Daylight Saving Time http://www.livescience.com/50078-daylight-saving-time-unhealthy.html
Broadcast
BBC Radio 5 Live - 21.01.2015 - 51:30, http://www.bbc.co.uk/programmes/b04yg8l4
BBC Radio Scotland - 21.01.2015 - 55:44, http://www.bbc.co.uk/programmes/b04ykb7n
BBC Radio Kent - 21.01.2015 - 01:28:12. http://www.bbc.co.uk/programmes/p02gh8ys
BBC Radio Sheffield - 21.01.2015 - 52:44, http://www.bbc.co.uk/programmes/p02grdyy
BBC Hereford and Worcestershire - 22.01.2015 - 02:05:40, http://www.bbc.co.uk/programmes/p02ghczy
VIDEO: (http://today.duke.edu/2015/01/low-incomeboys )
Live interview: http://live.huffingtonpost.com/r/segment/mixed-income-housing-bad-for-low-income-boys/54c911e078c90a46e8000567
Op-Ed: http://theconversation.com/poor-doors-highlight-social-costs-of-growing-up-in-the-shadow-of-wealth-39846

NPR National Public Radio: http://wunc.org/post/mixed-income-housing-pros-cons

This article got lots of news coverage, among the best articles are:
http://www.economist.com/news/britain/21641283-unnervingly-poor-children-seem-fare-better-poor-neighbourhoods-paradox-ghetto
http://www.newrepublic.com/article/120827/study-low-income-boys-perform-worse-mixed-income-housing
http://www.washingtonpost.com/blogs/wonkblog/wp/2015/01/23/the-surprising-cost-of-growing-up-poor-in-the-shadow-of-wealth/
http://www.bbc.com/news/education-30950523 http://www.thetimes.co.uk/tto/education/article4331786.ece
http://www.medicaldaily.com/antisocial-behavior-higher-low-income-boys-living-beside-wealthier-neighbors-319126
http://psychcentral.com/news/2015/01/24/low-income-boys-fare-worse-in-wealthier-neighborhoods/80336.html
http://scienceblog.com/76599/low-income-boys-fare-worse-wealths-shadow/#g06vMtXvculJIBLH.97

MacArthur Foundation Housing Matters SmartBrief: http://www2.smartbrief.com/servlet/encodeServlet?issueid=1A250F3E-8760-4701-9E62-1B6EF2AF1E8B&sid=8d9444c2-87b5-4506-9421-0f6344afc31d


http://johnraissmd.com/blog/?p=64
Selected at CME for American Psychiatirc Association. (1 Continuing Medical Education credit)
NEJM Journal watch: http://www.jwatch.org/na38100/2015/06/05/how-related-are-adult-and-childhood-adhd?query=topic_substabuse
http://www.psychcongress.com/article/adult-adhd-may-be-separate-childhood-adhd-22824
http://alert.psychnews.org/2015/06/adult-adhd-may-be-distinct-from.html
http://www.healio.com/psychiatry/add-adhd/news/online/%7B08ca3e86-938b-4576-9f5b-66db4e6eeb02%7D/adults-with-adhd-may-not-have-had-onset-of-disorder-in-childhood
http://www.medwirenews.com/47/106298/Psychiatry/Adult_ADHD_could_be_distinct_condition.html

BBC WORLD NEWS interview: http://www.bbc.co.uk/programmes/p002vsnk/episodes/downloads

ALTMETRICS: tracking all internet mentions: http://pnas.altmetric.com/details/4248247/news

VIDEO Wall St. Journal: http://www.wsj.com/articles/how-quickly-are-you-growing-old-1436808166
ScitechNow: http://scitechnow.org/technology/old-really/#

http://thedoctorweighsin.com/predicting-the-speed-of-aging/
http://www.theonion.com/americanvoices/researchers-people-age-different-rates-50802
http://www.haaretz.co.il/news/science/.premium-1.2678930
http://www.maariv.co.il/news/world/Article-487817
http://www.corriere.it/salute/15_luglio_08/invecchiamento-inizia-giovani-non-uguale-tutti-10c41f7e-2545-11e5-85c7-ee55c, 78b3bf9.shtml

A summary of coverage links is here:
USA
Print
Wall Street Journal (with video), Washington Post, LA Times, TIME, US News and World Report
Radio/TV
CBS News (with video), NBC News (with video), Science Friday (audio @7:45 min in), Voice of America, BBC News Hour (audio)

UK
BBC News, The Guardian, The Telegraph, The Times, Daily Mail,

EU & AUSTRALIA
Deutche Welle, Der Spiegel, El Pais, Science et Avenir, Le Science, Australian Broadcasting Corp.

OTHER
Al Jazeera America, Jerusalem Post, Haaretz, Times of India, The Hindu, Gazete Istambul

INTERNET
NEJM Journalwatch, Huffington Post, Yahoo News, Medical News Today, MedPage Today, Medical Xpress, WebMD, The Conversation, SciTech, SciTech Today, Big Think, Science World Report, The Mermaid's Tale, IFLS, The Onion.
http://www.thedailymash.co.uk/news/science-technology/number-of-years-youve-been-alive-tells-you-how-old-you-really-are-20150907101749


enormous interest in five of our publicatons this year
Year(s) Of Engagement Activity 2015