What tests are used to determine biologic age?

Biological Age Testing: Evidence-Based Recommendations

DNA methylation-based epigenetic clocks are the most validated and accurate tests currently available for determining biological age, with the strongest evidence supporting their use over other biomarkers. 1

Primary Recommended Tests

Epigenetic Clocks (First-Line)

• DNA methylation profiles represent the gold standard for biological age assessment, demonstrating high correlation with chronological age and robust prediction of mortality, functional decline, frailty, and brain aging. 1
• Epigenetic age exceeding chronological age by 3+ years independently predicts cancer mortality and overall mortality across multiple disease states. 2, 1
• These tests are practical for clinical implementation as they remain stable in stored biological samples and can be assessed from peripheral blood. 1
• Specific validated epigenetic clocks include PhenoAge and GrimAge indices, which show the strongest predictive validity for mortality, disability, and dementia. 3

Inflammatory Markers (Readily Available)

• Interleukin-6 (IL-6) is the only biomarker with both cross-sectional and longitudinal validation as a predictor of multimorbidity, mobility loss, and disability. 2, 1
• All hallmarks of aging directly or indirectly cause inflammatory states, making inflammation a central pillar of biological aging assessment. 2, 1
• C-reactive protein (CRP) is readily available in clinical laboratories and can be measured serially to track persistent elevations beyond acute illness. 2

Mitochondrial Function Measures

• Mitochondrial function testing is ready for implementation based on multiple epidemiological studies demonstrating associations with aging outcomes. 1

Secondary Tests with Emerging Evidence

p16INK4a Expression

• This cellular senescence marker shows dramatic changes after physiological stress, with breast cancer chemotherapy causing biological aging equivalent to 14-17 years within 12 months. 2, 1
• Currently measured in research laboratories but not yet available in clinical labs; implementation awaits standardization. 2
• High-throughput methods for measuring senescence in T lymphocytes, skin, and intramuscular fat are becoming available. 1

Telomere Length

• Telomere length tracks modestly with chronological age and predicts overall mortality, but results have been inconsistent for other aging outcomes. 2
• Technical measurement aspects are evolving, and telomere length alone provides only a rough estimate of aging rate. 4
• Telomere length is most useful when combined with other biomarkers rather than used in isolation. 5, 4

Composite Assessment Approach

Multi-Biomarker Integration

• No single measure represents an exhaustive assessment of biological aging; aggregate measures leveraging multiple biomarkers are needed. 1
• The Pace of Aging composite index captures organ function and reserve across multiple systems. 2
• Combining DNA methylation with inflammatory markers, mitochondrial function, and clinical assessments provides the most comprehensive evaluation. 1

Clinical Geriatric Assessment (For Ages 65+)

• Geriatric assessments covering multiple aging domains are feasible, require less than 30 minutes to administer, and are recommended for treatment decisions in older adults. 2
• These assessments capture aging-related processes including muscle mass loss, mobility limitations, chronic disease accumulation, and activities of daily living impairment. 2

Critical Implementation Considerations

Practical Limitations

• Blood-based tests are preferred over tissue biopsies for practical implementation, ideally performed quickly and at low cost. 2
• DNA methylation testing remains relatively expensive but has good predictive and concurrent validity. 2
• Different manifestations of biological aging may occur on different time schedules, with some mechanisms preceding others. 1

Clinical Decision-Making Gaps

• Further research is needed to determine when knowledge of biological age would change treatment decisions in routine clinical practice. 1
• Longitudinal validation is required to demonstrate that accelerated biological aging parallels accelerated deterioration in phenotypic and functional dimensions. 2

Common Pitfalls to Avoid

• Do not rely on telomere length alone—it provides insufficient predictive accuracy as a standalone marker. 4
• Avoid interpreting inflammatory markers during acute illness or active cancer treatment, as these confound biological aging assessment. 2
• Do not assume different biological age tests measure the same aspects of aging—they show low agreement and may capture distinct aging processes. 6

Algorithmic Testing Strategy

For routine clinical assessment:

1. Order DNA methylation-based epigenetic clock testing as the primary biological age marker 1
2. Add IL-6 measurement for multimorbidity and functional decline prediction 2, 1
3. Include CRP for readily available inflammatory status 2
4. Consider adding mitochondrial function testing when available 1

For comprehensive research or specialized assessment:

• Combine epigenetic clocks with telomere length, p16INK4a expression (when available), and composite indices 1
• Integrate with geriatric assessment tools for patients ≥65 years 2