Atlas of human cerebellar aging: nonlinear molecular trajectories reveal multidimensional mechanisms underlying cognitive and motor function regulation.

Fuzzy clustering analyses uncovered nonlinear gene expression trajectories in the aging cerebellum involving synaptic plasticity, metabolic regulation, and protein homeostasis.

• Transcriptomic data were integrated from 456 non-disease brains spanning the adult lifespan (20-80 years).
• Multiple critical biological turning points were identified across different age periods.
• The nonlinear trajectories were distinct from simple linear age-related decline patterns.
• Three major functional categories—synaptic plasticity, metabolic regulation, and protein homeostasis—were represented in the identified trajectories.

Immediate early genes (IEGs) including FOS, NPAS4, EGR1-3 were identified as early downregulated genes in cerebellar aging, preceding observable functional decline.

• Differential gene expression analyses identified early downregulation of these immediate early genes.
• Sustained activation of stress-response pathways was also identified as an early change.
• These molecular changes precede observable functional decline.
• The early downregulation of IEGs was a prominent feature distinguishing early-stage cerebellar aging.

An integrated 'synaptic plasticity-stress homeostasis' module was identified in which immediate early genes and heat shock proteins exhibit coordinated regulation whose efficiency progressively declines with age.

• The module links immediate early genes (e.g., FOS, NPAS4, EGR1-3) with heat shock proteins.
• Coordinated regulation between these two gene groups was detected across the adult lifespan.
• The efficiency of this coordinated regulation progressively declines with age.
• This module was described as a 'promising molecular axis' that may inform future strategies to support cerebellar function in older adults.

MRI analyses showed a pronounced acceleration of cerebellar gray matter loss after age 70, with multiple subregions affected.

• Structural neuroimaging data were obtained from 264 disease-free subjects.
• Gray matter (GM) loss showed a nonlinear trajectory, with acceleration specifically after age 70.
• Multiple cerebellar subregions were affected by the accelerated GM loss.
• The MRI structural findings were consistent with the transcriptomic evidence of stage-dependent molecular alterations.

The study integrated transcriptomic and MRI structural neuroimaging data to characterize cerebellar aging across the full adult lifespan from age 20 to 80.

• Transcriptomic data came from 456 non-disease brains.
• MRI structural neuroimaging data came from 264 disease-free subjects.
• The age range covered was 20-80 years.
• Fuzzy clustering analyses and differential gene expression analyses were among the key methodological approaches used.

The cerebellum, traditionally recognized for motor coordination, also contributes to cognitive and emotional regulation, and its molecular and structural changes during healthy aging were previously poorly understood.

• Recent evidence indicates cerebellar contributions to cognitive and emotional regulation beyond motor coordination.
• The molecular and structural changes in the human cerebellum during healthy aging had remained poorly understood prior to this study.
• The study aimed to systematically investigate molecular trajectories and structural alterations across the adult lifespan.
• The findings were described as advancing 'our understanding of cerebellar aging biology.'