Cellular Senescence Drives Brain Aging, Neurodegeneration: A Unified Framework
Background
Aging is the strongest risk factor for neurodegenerative diseases such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Amyotrophic Lateral Sclerosis (ALS), which represent a growing global health burden. While genetic mutations and protein aggregation have long been considered central, emerging evidence highlights aging-related cellular processes as key drivers. Among these, cellular senescence is recognized as a major contributor to neurodegenerative decline, particularly through its role in neuroinflammation, mitochondrial dysfunction, and impaired proteostasis. Current frameworks remain fragmented, often focusing on isolated compartments or pathways, with the interaction between central and peripheral senescence poorly defined.
Study Design
This comprehensive review synthesizes current understanding of cellular senescence in brain aging and neurodegeneration, addressing the fragmentation in existing research. It proposes a unified framework that integrates brain-intrinsic senescence with systemic aging processes across the brain–body axis. The authors critically examine unresolved mechanistic questions and translational limitations, particularly focusing on the interplay between central and peripheral senescence and its implications for disease propagation. The review aims to provide a holistic perspective on how senescent cells contribute to the pathology of major neurodegenerative disorders.
Results
The review establishes cellular senescence as a pivotal contributor to neurodegenerative decline, emphasizing its multifaceted roles in driving neuroinflammation, mitochondrial dysfunction, and impaired proteostasis. It highlights how senescent cells accumulate progressively within the aging brain, affecting endothelial cells, pericytes, astrocytes, and microglia, thereby amplifying cerebrovascular dysfunction. The authors integrate brain-intrinsic senescence with systemic aging processes, underscoring the critical, yet often overlooked, interaction between central and peripheral senescence in disease propagation. > The review proposes a unified framework that bridges fragmented research, offering a comprehensive view of how senescent cells contribute to pathologies in Alzheimer’s Disease (AD), Parkinson’s Disease (PD), and Amyotrophic Lateral Sclerosis (ALS), moving beyond isolated cellular compartments or single molecular pathways.
Key Findings
- Aging is the strongest risk factor for neurodegenerative diseases like Alzheimer’s, Parkinson’s, and ALS.
- Cellular senescence is a major contributor to neurodegenerative decline through neuroinflammation, mitochondrial dysfunction, and impaired proteostasis.
- The review proposes a unified framework integrating brain-intrinsic and systemic cellular senescence across the brain–body axis.
- Interaction between central and peripheral senescence is critical for disease propagation but remains poorly defined.
- Senescent cells accumulate in the aging brain, affecting various cell types and amplifying cerebrovascular dysfunction.
Why It Matters
This review offers a crucial conceptual shift, advocating for a unified understanding of cellular senescence as a systemic process impacting both the brain and body in neurodegeneration. For researchers and clinicians, this integrated framework suggests novel therapeutic avenues targeting both central and peripheral senescent cells, potentially leading to more effective interventions for AD, PD, and ALS. Understanding senescence across the brain-body axis is vital for developing future senolytic or senomorphic strategies. While not a direct protocol, this work informs the design of future preclinical and clinical studies, guiding the development of therapies that address the systemic nature of aging-related neurodegenerative diseases.
neurodegeneration
brain-aging
cellular-senescence
alzheimer's-disease
parkinson's-disease
als