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Cellular Senescence Shapes Aging and Brain Function

Neuronal Senescence has a crucial impact on brain aging and neurodegenerative diseases. Senescent Cells have stopped dividing and show changes in gene expression, producing inflammatory molecules or senescence-associated secretory phenotype (SASP). They accumulate DNA damage, exhibit increased ROS, and experience metabolic reprogramming.


Here’s a quick rundown:

Molecular Mechanisms of Senescence:

  • Cyclin-Dependent Kinase Inhibitors: Proteins like p21, p16, and p19 mark senescent neurons, often seen in conditions like Parkinson's.

  • DNA Damage: Markers like γ-H2AX indicate DNA damage and nuclear changes.

  • Reactive Oxygen Species (ROS) and Autophagy: High metabolic demands lead to ROS production. Impaired autophagy triggers senescence.

  • Metabolic Reprogramming: Changes in oxidative phosphorylation and glucose metabolism reprogram neurons, leading to senescence.

Impacts of Senescence:

  • Inflammation: Senescent neurons release inflammatory cytokines, activating nearby cells and causing chronic inflammation.

  • Neurodegenerative Diseases: Found in Alzheimer’s and Parkinson’s, contributing to disease progression.

  • Tissue Dysfunction: Accumulation in older individuals leads to cognitive decline and tissue dysfunction.

  • Compensatory Mechanisms: Initially protective, but long-term senescence causes neurodegeneration and persistent inflammation.

Understanding these processes can help us target therapies to improve brain health and combat age-related neurodegenerative diseases.

Herdy, J.R., J. Mertens, and F.H. Gage, Neuronal senescence may drive brain aging. Science, 2024. 384(6703): p. 1404-1406.

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