Atlas of Human Cerebellar Aging: Nonlinear Molecular Trajectories Reveal Multidimensional Mechanisms Underlying Cognitive and Motor Function Regulation

Abstract The cerebellum, traditionally recognized for motor coordination, may also contribute to cognitive and emotional regulation, as recent evidence indicates. However, the molecular and structural changes in the human cerebellum during healthy aging remain poorly understood. This study systematically investigated the molecular trajectories and structural alterations in the human cerebellum across the adult lifespan (20-80 years) by integrating cerebella transcriptomic data from 456 non-disease brains and MRI structural neuroimaging data from 264 disease-free subjects. Fuzzy clustering analyses uncovered nonlinear expression trajectories involving synaptic plasticity, metabolic regulation, and protein homeostasis, highlighting multiple critical biological turning points across different age periods. Differential gene expression analyses identified early downregulation of immediate early genes (e.g., FOS, NPAS4, EGR1-3) and sustained activation of stress-response pathways changes that precede observable functional decline. Moreover, we identified an integrated “synaptic plasticity-stress homeostasis” module, where IEGs and heat shock proteins exhibit coordinated regulation whose efficiency progressively declines with age. MRI analyses showed a pronounced acceleration of cerebellar gray matter loss after age 70, with multiple subregions affected, highlighting the nonlinear trajectory of cerebellar structural aging. In combination with the transcriptomic findings, these results indicate that cerebellar aging comprises complex, stage dependent molecular alterations accompanied by gray matter reductions in later decades. This collective evidence advances our understanding of cerebellar aging biology and highlights the synaptic-stress module as a promising molecular axis that may inform future strategies to support cerebellar function in older adults.