DNAm PhenoAge: An Epigenetic Biomarker of Aging for Lifespan and Healthspan
Publication: Levine ME, et al. Aging. 2018;10(4):573–591.
Study overview
Biological aging varies between individuals and is not always reflected by chronological age. In this study, Levine and colleagues developed DNAm PhenoAge, an epigenetic biomarker designed to capture biological aging and its relationship with lifespan, healthspan, and age-related diseases.
Unlike earlier epigenetic clocks that primarily estimate chronological age, DNAm PhenoAge was developed using clinical biomarkers associated with mortality risk and physiological health.
Study methodology
The researchers developed and validated DNAm PhenoAge using a multi-step approach:
- Clinical phenotypic age: A composite measure was developed using nine clinical biomarkers and chronological age, based on data from 9,926 adults in NHANES III.
- Epigenetic age estimation: DNA methylation data from the InCHIANTI study were used to identify 513 CpG sites that predict clinical phenotypic age.
- Independent validation: DNAm PhenoAge was evaluated across five independent samples comprising 9,164 participants to assess its associations with mortality, disease risk, and physical functioning.
- Biological investigation: The researchers examined associations with gene expression, immune cell composition, and molecular pathways involved in aging.
Key findings
1. Association with mortality and lifespan
- Each one-year increase in DNAm PhenoAge was associated with a 4.5% higher hazard of all-cause mortality, independent of chronological age (HR = 1.045).
- Individuals in the highest 5% of epigenetic aging had an estimated mortality hazard approximately 2.58 times higher than those in the lowest 5%.
- DNAm PhenoAge outperformed earlier Horvath and Hannum epigenetic clocks in predicting mortality in the study's comparative analyses.
2. Relationship with healthspan and age-related diseases
Higher DNAm PhenoAge was associated with:
- Greater numbers of coexisting chronic conditions.
- Lower likelihood of being disease-free.
- Reduced physical functioning.
- Increased coronary heart disease risk.
- Alzheimer's disease-related neuropathology, including amyloid accumulation and neurofibrillary tangles in postmortem brain tissue.
These findings suggest that DNAm PhenoAge captures aspects of biological aging associated with multiple health outcomes.
3. Biological mechanisms of aging
Higher age-adjusted DNAm PhenoAge was associated with several biological processes linked to aging:
- Increased activation of inflammatory and interferon-related pathways.
- Changes in immune cell populations consistent with immunosenescence.
- Reduced expression of pathways involved in protein synthesis and DNA damage recognition and repair.
These findings provide insights into the molecular processes associated with accelerated epigenetic aging.
4. Associations with lifestyle and metabolic health
The study also identified relationships between DNAm PhenoAge and lifestyle or metabolic characteristics:
- Lower epigenetic age: Associated with greater physical activity, higher educational attainment, and higher circulating carotenoid levels.
- Higher epigenetic age: Associated with smoking, elevated inflammatory markers, higher glucose and insulin levels, and increased body mass index.
These observational findings do not establish that lifestyle modifications directly change epigenetic age.
Clinical and scientific relevance
The study highlights the potential of DNA methylation-based biomarkers to provide information about biological aging beyond chronological age.
DNAm PhenoAge may be particularly valuable in research investigating aging mechanisms, disease susceptibility, and differences in healthspan.
However, DNAm PhenoAge is not established as a replacement for conventional clinical biomarkers or as a standalone diagnostic tool. Further research is required to determine its clinical utility and whether changes in DNAm PhenoAge reflect responses to interventions.
Conclusion
DNAm PhenoAge represents an important advancement in epigenetic aging research. By incorporating clinical measures associated with physiological aging, it demonstrated strong associations with mortality, age-related disease, and functional health.
The findings support the potential of epigenetic biomarkers to improve our understanding of biological aging and its relationship with healthspan and lifespan.
Read the full publication
Explore the complete study to learn more about the development and validation of DNAm PhenoAge, the detailed statistical findings, and the biological pathways associated with epigenetic aging.
This summary is intended for healthcare professional education and does not replace the original scientific publication or clinical guidance.
Levine et al. This is an openaccess article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
