New research by Daniel Belsky quantifies the pace of biological aging through a blood test

Tuesday, May 5, 2020

Novel research led by Columbia Aging Center faculty member Daniel Belsky, PhD, together with Avshalom Caspi and Terrie Moffitt at Duke University published today in the journal eLife reports a new blood test to measure the pace of biological aging. People with faster aging measured by the blood-test, called “DunedinPoAm”, showed more rapid decline in physical and cognitive functioning and increased risk for chronic disease and mortality.  A fact sheet about the findings follows.

***

 

Quantification of the pace of biological aging in humans through a blood test,  The DunedinPoAm DNA methylation algorithm

A research team led by Dan Belsky at Columbia Mailman School of Public Health and Avshalom Caspi and Terrie Moffitt at Duke University reports a new blood test to measure the pace of biological aging. People with faster aging measured by the blood-test, called “DunedinPoAm”, showed more rapid decline in physical and cognitive functioning and increased risk for chronic disease and mortality.  

PUBLICATION SOURCE: eLife, May 5, 2020. 

FINDINGS: 
•    As we age, our risk for disease rises. These diseases affect many different organ systems in our bodies. This implies that improving health in later life will require interventions that can slow the aging process. Doing so will prevent multiple age-related diseases simultaneously. 
•    Aging is a process of decline in the functioning of many organ systems simultaneously. Our research shows that this process can be measured by a DNA methylation blood test administered at a single time point: DunedinPoAm. 
•    Faster aging measured in midlife adults is associated with the very same symptoms of advanced aging that we see in older adults: Deficits in physical and cognitive functioning, subjective feelings of ill-health, and even looking older to others. 
•    Faster aging measured in older adults is associated with increased risk of developing new chronic disease and also of mortality.  
•    DunedinPoAm compared favorably to other published DNA methylation measures of aging. It captured new information not measured in these alternative algorithms, called “epigenetic clocks” and was often more strongly associated with future health outcomes. 

WHY ARE THESES FINDINGS IMPORTANT: 
•    Breakthroughs in research on aging in worms, flies, and mice are beginning to produce novel therapies to slow human aging. The first clinical trials are being initiated now. 
•    New  treatments aim to prevent multiple age-related diseases at once by slowing down the aging process. But disease prevention will take decades to test. In order to speed up testing the effectiveness of these treatments, measurements of pace of biological aging are needed. 
•    The DunedinPoAm blood test shows proof of concept that such measurements are possible. Intervention trials can administer the blood test at intervention baseline and follow-up to test if the treatment succeeds in slowing the rate of aging. 
•    DunedinPoAm may also be useful in public health surveillance to test how changing environmental conditions or new policies impact population aging. 

SUPPORTING DETAILS: 
A novel approach to measuring aging. The current approach to measuring aging is based on comparing chronologically older people to younger ones. The challenge is that biological differences between older and younger people may reflect more than just aging. For example, people born early in the 20th Century had more exposure to childhood diseases, malnutrition, toxic chemicals like led as compared to those born more recently. In addition, these measurements of aging do not distinguish biological changes that occurred during childhood from those ongoing in adult life. The new measure reported in this study is based on analysis of multi-organ-system change in a cohort of adults all born in the same year. 

We tracked 18 different tests of organ system integrity over 12 years of follow-up in the population-representative Dunedin Study birth cohort, all born in 1972-1973. We measured rate of change in each of these 18 tests over a period of 12 years, from when the cohort was aged 26 until they were aged 38. We then created a composite summarizing change across the 18 indicators, the “Pace of Aging.” In our 2015 PNAS paper reporting this new measure, we showed that the pace of biological aging was already highly variable in young adults free of chronic disease. Moreover, those young adults who were aging faster showed early signs of decline in physical functioning and cognitive integrity. 

In our new analysis, we used a machine-learning technique called “elastic-net regression” to sift through data on more than 400,000 different DNA methylation marks to find the ones that related to the physiological changes captured in Pace of Aging. This analysis identified a set of 46 methylation marks that, together, measured Pace of Aging. We named the algorithm combining information from the 46 marks “DunedinPoAm” for Dunedin (P)ace (o)f (A)ging in (m)ethylation. The average person has a DunedinPoAm value of 1 – indicating 1 year of biological aging per chronological year. In Dunedin Study participants who were all 38 years old, the range of values extend from just above 0.6 (indicating an aging rate nearly 40% slower than the norm) to nearly 1.4 (indicating an aging rate 40% faster than the norm). 
To establish how well the new DunedinPoAm measure worked, we conducted analysis of new data recently collected by the Dunedin Study at age 45 as well as data from the Understanding Society Study, the Normative Aging Study, the E-Risk Longitudinal Twin Study, and the CALERIE randomized trial. 

In the Dunedin Study, we found that DunedinPoAm predicted decline in physical and cognitive functioning and aged appearance as well or better than the original Pace of Aging measure. This gave us confidence that the DNA methylation measure was capturing the same biological process as the organ-system integrity tests. Dunedin Study members with faster DunedinPoAm at age 38 had poorer balance and motor coordination, could do fewer chair stands, and walked and stepped in place more slowly seven years later when they were aged 45, as compared to peers with slower DunedinPoAm. And they also showed more decline fro age 38 to 45. They did not differ in terms of grip strength. Those with faster DunedinPoAm also performed more poorly on cognitive tests of perceptual reasoning, memory, and processing speed, rated their own health as worse, and were rated as looking older by independent raters as compared to peers with slower DunedinPoAm. When we compared cognitive functioning at age 45 to a healthy adolescent baseline, participants with faster DunedinPoAm showed evidence of early cognitive decline. 

In analysis of older men participating in the US Veteran’s Health Administration Normative Aging Study, participants with faster DunedinPoAm showed a 30% increased risk for mortality over follow-up and a 20% increase in risk for developing a new chronic disease. 
DunedinPoAm also revealed differences in aging rates among young people. In the E-Risk Longitudinal Study, 18-year-olds who had grown up in poor families and who were victimized during childhood showed faster DunedinPoAm. Poverty and victimization are both related to shorter healthy lifespan.

We compared DunedinPoAm to three other DNA methylation measures of aging known as epigenetic clocks. DunedinPoAm is qualitatively different from these clocks. The clocks are designed to quantify how much aging has occurred in a person up to the time of measurement. They measure the ‘state’ of aging in a person at point in time. These ‘state’ measures capture aging that has happened over a person’s entire life. DunedinPoAm is different because it measures the ‘rate’ of aging. It measures how fast the process of aging is proceeding in a person in the years leading up to the blood-test. Instead of a clock, it’s more like a speedometer. For this reason, the measure is well-suited to intervention trials where the goal is to test whether a new therapy or a change in behavior can slow down the rate of aging.
In our comparative analysis in the Understanding Society Study, we found that DunedinPoAm overlapped with three epigenetic clocks between 4-9%. Across the different studies included in our analysis, DunedinPoAm was more strongly associated with deficits in physical and cognitive functioning and risk for morbidity and mortality when compared to the epigenetic clocks, although some differences were small. Our analysis suggests that DunedinPoAm can be an important complement to these other measures of aging. It seems to be capturing different aspects of the aging process. 

Among participants in the 2-year CALERIE trial that tested effects of caloric restriction, an intervention known to extend lifespan in animal experiments, DunedinPoAm prediction of the aging rate was disrupted in participants who underwent caloric restriction. 
In addition to intervention trials, DunedinPoAm may be especially valuable to studies that collect data outside of clinical settings and lack blood chemistry, hematology, and other data needed to measure aging-related changes to physiology. 
However, the DunedinPoAm blood test won’t be coming to a doctor’s office near you any time soon. We are showing promising results from our four-step research program. We believe our measure is promising for testing group-level differences in the rate of aging, such as between treatment and control groups in a randomized trial. But more testing is needed to establish whether the DunedinPoAm blood-test can be applied at the individual patient level for personalized wellness or clinical care. 

PARTICIPANTS: The study included data from 5 different research studies: The Dunedin Longitudinal Study tracks the development of a birth cohort of 1,037 children born in 1972-1973 in Dunedin, New Zealand. This birth cohort’s families represent the full range of socioeconomic status and health in the general population. The new study included data from 819 Dunedin Study members who participated in collection of blood DNA methylation data when they were 38 years old. The Understanding Society Study is a longitudinal study of a panel of households in the United Kingdom. The new study included data from 1,175 adults ranging in age from 28-95 years who provided blood DNA methylation data. The Normative Aging Study is a longitudinal study established by the US Department of Veterans Affairs in 1963 including 2,280 male veterans from the greater Boston area. The new study included data from 771 participants who contributed blood DNA methylation data between 1999 and 2013. The E-Risk Longitudinal Study tracks the development of a birth cohort of 2,232 British participants born in 1994-1995. The new study analyzed data from 1,658 participants who provided DNA methylation data when they were 18 years old. The CALERIE Trial is the first-ever randomized controlled trial of long-term (2-year) caloric restriction in healthy, nonobese adults. We analyzed data from 186 participants with blood DNA methylation data from pre-intervention baseline. 

UNIVERSITIES INVOLVED: Columbia Mailman School of Public Health, New York, NY, USA; Duke University, Durham, NC, USA; University of Otago, Dunedin, NZ; Institute of Psychiatry, Kings College London, UK; University of Exeter School of Medicine, UK

MAIN FUNDING SOURCES: The research was supported by US-National Institute on Aging grants AG032282, AG061378, AG054846, US National Institute for Child Health and Development grant HD077482, and UK Medical Research Council grants MR/P005918/1 and G1002190. The Dunedin Multidisciplinary Health and Development Research Unit is supported by the New Zealand Health Research Council Programme Grant (16-604), and the New Zealand Ministry of Business, Innovation and Employment (MBIE). Research also received support from the Jacobs Foundation. 

MEDIA CONTACT: Dan Belsky, Department of Epidemiology and Butler Columbia Aging Center, Columbia Mailman School of Public Health 
Daniel.belsky@columbia.edu (m) +1 919-357-8200 
Experts not involved in this study who may be contacted about this study: Linda Fried, Dean, Mailman School of Public Health (lpfried@columbia.edu , 212-305-9300);  Jamie Justice, Wake Forest School of Medicine (jnjustic@wakehealth.edu)