Epigenetic clocks are biochemical tests that measure biological age by analyzing DNA methylation (DNAm) patterns—chemical modifications to the genome that regulate gene expression without altering the DNA sequence. Unlike chronological age, which tracks time, biological age serves as a proxy for physiological integrity, predicting morbidity and mortality risks.

Generations of Clocks Epigenetic clocks have evolved through different "generations":

• First-Generation (e.g., Horvath, Hannum): Trained to predict chronological age. They are useful for general age estimation but less sensitive to health status.

• Second-Generation (e.g., PhenoAge, GrimAge): Trained on physiological biomarkers and mortality data. These clocks outperform their predecessors in predicting life expectancy, cardiovascular health, and age-related disease.

• Third-Generation (e.g., DunedinPACE): Measures the pace of aging rather than a static age, capturing the rate of physiological decline.

Development and Critical Transitions The "ticking" of the epigenetic clock begins early. In children, biological age acceleration is often a marker of developmental maturity, correlating with increased height, BMI, and fat mass, but also with adverse factors like childhood stress and pollution. Life transitions represent critical windows of epigenomic plasticity. Puberty and menopause are associated with accelerated biological aging, potentially increasing susceptibility to later disease. Similarly, pregnancy induces a significant acceleration in biological age (up to 5.3 years), though evidence suggests this effect may reverse postpartum.

Lifestyle Modifiers Lifestyle choices significantly influence the rate of epigenetic aging:

• Accelerators: Obesity, metabolic syndrome, smoking, chronic stress, and sleep disordered breathing are linked to faster biological aging.

• Decelerators: Higher educational attainment, regular physical activity, and diets rich in fish, poultry, fruit, and vegetables (specifically carotenoids) associate with slower aging. One-carbon metabolism (involving B vitamins like folate and choline) is crucial for maintaining the epigenome and brain health.

Tissue Specificity Aging is not uniform across the body. General clocks often fail to accurately measure age in specific tissues, particularly skeletal muscle. Specialized clocks, such as MEAT (Muscle Epigenetic Age Test), have been developed to track muscle-specific aging, which is characterized by distinct molecular changes like sarcopenia and fiber atrophy.

Limitations Despite their promise in research, current epigenetic clocks lack the precision, reliability, and clear biological interpretation required for individual clinical diagnosis. Technical noise and short-term biological fluctuations limit their use as personal health biomarkers