A team led by the Buck Institute and collaborators from IHU HealthAge and INSERM created the IC Clock, an epigenetic aging biomarker that quantifies intrinsic capacity. It leverages DNA methylation data from the INSPIRE-T cohort and validates performance using the Framingham Heart Study to forecast mortality and functional decline.
Key points
The IC Clock uses DNA methylation signatures from blood or saliva to assess six intrinsic capacity domains.
Model training utilized the INSPIRE-T cohort (ages 20–102) with four-year follow-up data, covering physical, cognitive and lifestyle measures.
Validation against the Framingham Heart Study cohort demonstrates superior mortality prediction compared to first- and second-generation aging clocks.
Why it matters:
By focusing on functional aging rather than chronological age, the IC Clock offers a clinically actionable biomarker to inform interventions that enhance healthy longevity.
Q&A
What is the IC Clock?
How does DNA methylation measure aging?
What is intrinsic capacity (IC)?
Why validate on the Framingham Heart Study?
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Academy
Epigenetic Clocks
Definition and Purpose: Epigenetic clocks are predictive models that estimate biological age or functional health by analyzing DNA methylation patterns—chemical modifications to DNA that regulate gene activity without changing genetic code. These clocks correlate specific methylation changes at genomic sites with clinical or functional outcomes, offering insights into an individual’s aging trajectory.
How DNA Methylation Works: DNA methylation occurs when methyl groups attach to cytosine bases at CpG sites (regions where a cytosine nucleotide is followed by a guanine nucleotide). Methylation can silence gene expression or modulate transcription. Environmental factors, lifestyle, and disease can alter methylation patterns, making them sensitive markers of physiological state.
Major Epigenetic Clock Types:
- Chronological Clocks predict calendar age (e.g., Horvath Clock).
- Phenotypic or Functional Clocks estimate disease risk or functional capacity (e.g., DNAm PhenoAge).
- Intrinsic Capacity Clocks focus on composite functional metrics like mobility, cognition, and mental health.
Intrinsic Capacity (IC) Concept: Intrinsic capacity is a holistic measure of an individual’s combined physical and mental abilities, including mobility, cognition, mental health, vision, hearing, and nutritional status. It shifts focus from disease treatment to maintaining functional resilience throughout life.
The IC Clock Methodology:
- Data Collection: Longitudinal cohorts collect blood or saliva samples alongside performance tests (e.g., gait speed, memory tests).
- Methylation Profiling: High-throughput arrays or sequencing quantify methylation at hundreds of thousands of CpG sites.
- Machine Learning: Algorithms select CpG sites most correlated with intrinsic capacity metrics and train regression models.
- Validation: Independent cohorts (e.g., Framingham Heart Study) assess accuracy in predicting functional decline and mortality.
Applications in Longevity Science:
- Screening individuals at risk of rapid functional decline.
- Monitoring intervention effects (diet, exercise, therapies).
- Guiding personalized geroprotective strategies to extend healthspan.
Advantages Over Traditional Biomarkers:
- Non-invasive sampling via blood or saliva.
- Integrates multiple health domains into one score.
- Predicts mortality and decline more precisely than chronological age alone.
Future Directions: Developing dried-blood spot assays for broader accessibility, integrating multi-omic data (proteomics, metabolomics), and expanding to diverse populations will enhance epigenetic clock utility in global aging research.
