Science

More About The DunedinPACE Study

And Its Development

Dunedin: a small city located in the South Island of New Zealand and home to the Dunedin School of Medicine at the University of Otago.

PACE: the pace of aging measure.

The Dunedin Multidisciplinary Health and Development Study is a detailed study of human health, development, and behavior. The Dunedin Study has followed the lives of 1037 babies born between April 1, 1972, and March 31, 1973, at Queen Mary Maternity Hospital, Dunedin, New Zealand, since their birth. The study is now in its fifth decade and has produced a considerable amount of data that shapes what we know about the pace at which humans age. [1] This algorithm was created by looking at over 1,000 individuals’ data at 173 CpG sites.

The Dunedin Study

The Dunedin cohort is one of the most remarkable resources for studying human biology. This is not the biggest nor the longest longitudinal study conducted, but it is special because it has a very high retention rate of participants. With 95% of the original cohort remaining in the study since its launch, the Dunedin cohort is THE MOST closely examined group on earth. To put in perspective a good retention rate for longitudinal studies is between 60 to 80 percent of the original cohort population. [11]

Previous studies have attempted to measure the pace of aging by analyzing DNA methylation differences between people of different chronological ages. However, the “limitation of this approach is that individuals born in different years have grown up under different historical conditions, with a possibility of more exposure to childhood diseases, tobacco smoke, airborne lead, and less exposure to antibiotics and other medications, as well as lower quality nutrition — all of which affect DNA methylation. An alternative approach is to study individuals who were all born the same year, and find methylation patterns that differentiate those who have been aging biologically faster or slower than their same-age peers.” [3] The Dunedin study focuses on a one-year age cohort makes it more effective at tracking its participants, which contributes to the low number of extraneous variability in the results.

Following the one-year birth cohort, the repeated measures of data were collected via blood when the study members were 26, 32, 38, and 45 years old to quantify their rates of biological aging. The gathered data represents a personal rate of multi-organ system decline over a dozen years which determines the algorithm for pace of aging.

Four-Step Approach

The researchers took a four-step approach toward developing a blood DNA methylation metric that represents individual variation in the pace of biological aging.

Step 1

In the initial step, the Dunedin researchers collected a blood panel of 18 and organ-system-function biomarkers at three successive waves of the Dunedin Study. By using repeated measures of data the study members were aged 26, 32, 38, and 45 years old. They calculated the rate of change in each biomarker and how each individual’s rate of change differed from the cohort’s norm. Then they combined the individual’s 18 personal rates of change across the panel of biomarkers to compute a composite for each study member, which is how they determine the pace of aging. [7]

Step 2

In the second step they validated the pace of aging from known criteria. Members of the studys cohort who had faster paces of aging performed more poorly on tests of physical function, by showing signs of cognitive decline on a panel of dementia-relevant neuropsychological tests from an early-life baseline for the individuals. These individuals were also rated, using an impartial system, as looking older based on their facial photographs. They also reported themselves to be in worse health.

They also found that a faster pace of aging is associated with early-life factors important for aging: familial longevity, low childhood social class, and adverse childhood experiences. [6] Notably, the pace of aging was not well-correlated with published epigenetic clocks, which were designed to measure how old a person is rather than how fast they are biologically aging. [5]

Step 3

In step three, they refined the pace of aging into a measurement that is obtained from a single blood sample. Here we focused on blood DNA methylation as an accessible molecular measurement that is sensitive to changes in physiology occurring in multiple organ systems.

Researchers used the data from a previous study published by the same authors (Belsky et al., 2018b) to apply an algorithm that captured the DNA methylation patterns linked with variation among individuals in their pace of aging. This algorithm is what they termed “DunedinPACE.”

Step 4

Step four is the validation step of the algorithm. They validated it in five ways

Fifth, to ascertain the potential usefulness of DunedinPACE as a measure for trials of geroprotector treatments, the algorithm was applied to DNA methylation data from a randomized trial of caloric restriction, CALERIE [Ravussin et al., 2015]. Earlier we reported from this trial that the intervention (two years of prescribed 25% caloric restriction) slowed the rate of biological aging as measured by a blood-chemistry biological-age composite measure [Belsky et al., 2018a]. Here, using newly generated methylation data from blood drawn at the CALERIE baseline assessment, it was tested if (a) DunedinPACE from blood drawn before caloric restriction could predict the future rate of biological aging of participants during the two-year trial, and (b) if this prediction was disrupted in participants who underwent caloric restriction, but not among control participants. Promising results from this four-step research program was reported, while appreciating that additional measurement development will be needed to support the applied use of DunedinPACE.

Dunedin Longitudinal Study

The above chart shows the Dunedin Longitudinal Study. Dunedin researchers collected a blood panel of 19 markers (shown above) and organ-system-function biomarkers at four successive waves of the Dunedin Study. By using repeated measures of data the study members were aged 26, 32, 38, and 45 years old.

They calculated the rate of change in each biomarker and how each individual’s rate of change differed from the cohort’s norm. Then they combined the individual’s 18 personal rates of change across the panel of biomarkers to compute a composite for each study member, which is how they determine the pace of aging.

Science

More About The DunedinPACE Study

And Its Development

The Dunedin Study

Four-Step Approach

Step 1

Step 2

Step 3

Step 4

Step 1

Step 2

Step 3

Step 4

Dunedin Longitudinal Study

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