Longitudinal analysis in PPMI shows accelerated epigenetic aging in blood associates with worsening tremor phenotypes in Parkinson's disease—particularly in men—while associations with gait, rigidity, and bradykinesia are weaker or absent.

This supports blood-based epigenetic clocks as candidate biomarkers for monitoring tremor progression and for patient stratification in trials, providing translational value despite limited direct mechanistic or therapeutic targets.

Motor decline is a hallmark of Parkinson's disease (PD) and biological aging, yet the specific relationship between systemic biological aging and neuromotor function remains under-characterized. This study leveraged longitudinal phenotypic and whole-blood DNA methylation data from the Parkinson's Progression Markers Initiative (PPMI) to evaluate associations between seven epigenetic aging measures, spanning first-generation, second-generation (risk-optimized), rate-based, and next-generation deep-learning clocks, and motor impairment. Motor function was assessed using the Movement Disorder Society-sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). While cross-sectional analyses yielded limited evidence, longitudinal repeated-measures analyses revealed robust associations between accelerated epigenetic aging and worsening postural and kinetic tremor phenotypes. Associations with gait, rigidity, and bradykinesia were largely non-significant or inversely related in the overall sample. Sex-stratified analyses revealed sexual dimorphism, with males exhibiting a broad, multi-clock phenotype (involving Horvath, PhenoAge, and GrimAge), where accelerated aging was associated with worsening tremor, gait, and rigidity. In contrast, females showed restricted associations, primarily linking the Hannum clock to tremor and global staging. These findings suggest that systemic biological aging is more strongly associated with longitudinal progression of tremor-related phenotypes than with rigidity or bradykinesia, although mechanistic interpretations regarding specific neural circuits remain hypothesis-generating. Accordingly, accelerated epigenetic aging is robustly associated with longitudinal tremor progression in this cohort, particularly in men, suggesting these metrics may serve as valuable biomarkers for monitoring progression and risk stratification in tremor-dominant phenotypes.