Molecular and Cellular Mechanisms Driving Aging-Associated Neurodegeneration

Aging is the dominant risk factor for neurodegenerative diseases, yet the mechanistic bridge between cellular aging and neuronal dysfunction remains incompletely defined. Hallmarks of aging—such as genomic instability, loss of proteostasis, mitochondrial decline, chronic inflammation, and senescent cell accumulation—are increasingly recognized as upstream drivers that prime the brain for degeneration and lower its capacity for repair. These processes reshape the neuronal microenvironment, disrupt intercellular homeostasis, impair synaptic resilience, and heighten circuit vulnerability long before overt pathology emerges. Compounding these effects, aging alters glial function, weakens neurovascular integrity, and diminishes metabolic flexibility, collectively accelerating neuronal stress. A unifying framework that explains how these age-dependent changes converge to trigger synaptic failure, protein aggregation, and region-specific neuronal loss is urgently needed to move beyond descriptive pathology toward mechanism-guided interventions and strategies that preserve brain health across the lifespan.

The goal of this Special Issue is to define the core molecular and cellular mechanisms through which the aging process itself initiates and propagates neurodegeneration. We seek to dissect the interplay between fundamental aging hallmarks—such as proteostatic collapse, neuroimmune remodeling, mitochondrial and metabolic dysfunction, DNA damage accumulation, and emerging drivers like neuronal hyperexcitability—that collectively compromise neural integrity. By integrating insights from molecular and cellular neuroscience, systems biology, and glial and vascular biology, this collection has three primary objectives: (i) to elucidate causal pathways that move beyond correlative observations, (ii) to identify shared upstream nodes of dysfunction across neurodegenerative disorders, and (iii) to highlight actionable therapeutic windows that target the biology of aging. Ultimately, this Special Issue aims to shift the research paradigm from a focus on late-stage, disease-specific pathology to the underlying cellular and systemic programs that determine brain resilience, thereby inspiring strategies that promote healthy brain aging.

We invite Original Research Articles, Reviews, and Mini-Reviews focused on mechanisms linking aging to neurodegeneration. Topics of interest include: cellular senescence and SASP signaling; proteostasis and autophagy failure; mitochondrial and metabolic dysfunction; neuroinflammation and glial state transitions; oxidative stress and genomic instability; neuronal hyperexcitability and circuit vulnerability; neurovascular and blood–brain barrier aging; and systemic aging influences on the brain. Studies using iPSC-derived systems, brain organoids, animal models, human tissue, single-cell or spatial omics, imaging, multi-omics integration, or computational network approaches are welcome. Submissions proposing therapeutic concepts—such as senolytics, metabolic reprogramming, neuroprotective strategies, or resilience-based interventions—are particularly encouraged. The aim is to attract diverse, high-impact contributions that define how aging initiates neurodegeneration and how these mechanisms can be targeted to preserve brain function.

Article types and fees

This Issue accepts the following article types, unless otherwise specified in the Issue description:

• Brief Communication
• Commentary
• Mini Review
• Original Research
• Review

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Issue accepts the following article types, unless otherwise specified in the Issue description:

• Brief Communication
• Commentary
• Mini Review
• Original Research
• Review

Keywords: Neurodegeneration, Aging, Cellular Senescence, Mitochondrial Dysfunction, Neuroinflammation, Proteostasis