What is the clinical significance and interpretation of the DunedinPACE (epigenetic clock) in assessing biological age and associated health risks in adults?

DunedinPACE: A Next-Generation Epigenetic Clock for Measuring Biological Aging

DunedinPACE is a DNA methylation biomarker that measures the pace of biological aging rather than static biological age, showing superior clinical utility for predicting morbidity, mortality, and organ system decline compared to traditional epigenetic clocks. 1

What Makes DunedinPACE Different

DunedinPACE represents a fundamental shift in how epigenetic clocks assess aging. Unlike earlier clocks (Horvath, Hannum) that estimate biological age at a single timepoint, DunedinPACE quantifies the rate at which aging is occurring—essentially measuring how fast someone is aging rather than how old they are biologically. 1

The clock was developed by tracking 19 organ-system integrity markers across four timepoints over two decades in the Dunedin Study birth cohort, then distilling this longitudinal pace of decline into a single blood test using DNA methylation patterns. 1 This methodology makes it uniquely suited for detecting changes in aging trajectories in response to interventions. 1

Clinical Performance and Validation

Mortality and Morbidity Prediction

DunedinPACE demonstrates effect sizes comparable to GrimAge (one of the strongest mortality predictors) while adding incremental predictive value beyond GrimAge for incident morbidity, disability, and mortality. 1 This means using both clocks together provides better risk stratification than either alone.

The clock has been validated across multiple age ranges and populations:

• In midlife adults (age 45): Associated with lower total brain volume, reduced hippocampal volume, greater white matter microlesions, and thinner cortex 2
• In older adults (mean age 63-75): Consistently predicted brain structural decline across the Framingham Heart Study and Alzheimer's Disease Neuroimaging Initiative cohorts 2
• In Asian populations: Reflected Taiwanese diabetes (p=5.4E-6), hypertriglyceridemia (p=1.1E-5), low HDL-C (p=4.0E-5), and obesity better than other epigenetic age acceleration measures 3

Specific Disease Associations

DunedinPACE shows particularly strong associations with:

• Metabolic dysfunction: Diabetes, dyslipidemia, and high triglyceride-to-HDL-C ratio 3
• Neurological decline: Brain atrophy, cognitive dysfunction, and incident dementia 2
• Cardiovascular outcomes: Predictive of cardiovascular disease risk 4
• Early-life adversity effects: Indicates faster aging in young adults with childhood adversity 1

Technical Advantages

DunedinPACE was specifically optimized to exclude DNA methylation probes with low test-retest reliability, resulting in superior measurement stability compared to earlier clocks. 1 This makes it more suitable for:

• Monitoring aging trajectories over time
• Evaluating geroprotective interventions
• Serial measurements in clinical trials 1

The biomarker can be measured from peripheral blood samples and remains stable in stored biological samples, making it practical for clinical implementation. 5

Clinical Interpretation Framework

When interpreting DunedinPACE results:

1. Values >1.0 indicate faster-than-average pace of aging (accelerated biological decline)
2. Values <1.0 indicate slower-than-average pace of aging (decelerated biological decline)
3. Values around 1.0 indicate average pace of aging for chronological age 1

The American Geriatrics Society emphasizes that no single biomarker represents exhaustive assessment of biological aging; DunedinPACE should be combined with clinical history, geriatric assessments, and potentially other biomarkers (particularly inflammatory markers like IL-6) for comprehensive evaluation. 5

Comparison to Other Epigenetic Clocks

Across multiple validation studies, DunedinPACE and GrimAge consistently show the strongest and most robust associations with health outcomes, outperforming Horvath, Hannum, and PhenoAge clocks. 2 However, each clock captures different aspects of aging:

• Horvath/Hannum: Primarily track chronological age with some biological age signal 6
• PhenoAge/GrimAge: Predict mortality and age-related phenotypes 4
• DunedinPACE: Uniquely measures rate of aging, making it optimal for intervention studies 1

Current Limitations and Cautions

The National Institute on Aging states that further research is needed before routine clinical implementation, particularly in determining when knowledge of biological aging pace would change treatment decisions. 5 Key limitations include:

• Most validation data comes from European and Hispanic ancestry populations, though emerging evidence supports validity in Asian populations 3
• Individual-level prediction remains imperfect; population-level associations are stronger 6
• Different aging mechanisms may operate on different timescales, and DunedinPACE may not capture all simultaneously 5
• Cost and accessibility currently limit widespread clinical use 6

Practical Applications

DunedinPACE is most clinically useful for:

• Risk stratification in preventive medicine programs, identifying individuals with accelerated aging who may benefit from intensive lifestyle or pharmacological interventions 4
• Monitoring intervention efficacy in longevity clinics, anti-aging programs, and geroprotective drug trials 4
• Research settings evaluating the biological impact of exposures, treatments, or lifestyle modifications 1

The European Society of Clinical Gerontology suggests combining DunedinPACE with clinical assessments and other biomarkers for the most comprehensive evaluation of biological aging status. 5