Identifying Tipping Points during Healthy Brain Aging through Single-Nucleus Transcriptomic Analysis.

Area of Science:

• Neuroscience
• Systems Biology
• Gerontology

Background:

• Brain aging impacts cognitive and behavioral functions.
• Cellular contributions to age-related brain changes are not fully understood.
• Nonlinear aging patterns exist, but cellular dynamics remain unclear.

Purpose of the Study:

• To analyze cellular and molecular changes during healthy brain aging.
• To identify the tipping point of brain aging at the cellular level.
• To explore the role of different cell types in brain aging fluctuations.

Main Methods:

• Utilized single-cell transcriptomic data from 45 healthy brain samples (ages 29-94).
• Applied nonlinear aging analysis to the cellular level.
• Introduced a dynamic network biomarker to identify tipping points.

Main Results:

• Neuron proportion decreased slightly but remained stable; glial cells significantly increased and showed instability.
• Nonlinear molecular fluctuations peaked at ages 60, 70, and 79.
• Identified 56-60 years as a tipping point for healthy brain aging, with glia mediating the process.

Conclusions:

• Brain aging exhibits nonlinear dynamics at the cellular level.
• Glia are key mediators of the brain's healthy aging tipping point.
• This research offers new strategies for early diagnosis and intervention of neurological aging diseases.