Astrocytes in Brain Aging and Neurodegeneration: Cellular Mechanisms and Interventional Strategies

Aging is characterized by progressive changes in the physiology of brain cells, which may contribute to cognitive decline, ultimately leading to dementia and impaired quality of life. The increase in senescent cells, including glial cells in the brain, is a general feature of normal aging and has been associated with age-related pathologies. Although recent evidence suggests that astrocytes undergo senescence in these conditions, little is known about the molecular, and cellular mechanisms underlying this event. This mini review, prepared as part of the special issue Neurochemistry in Latin America, provides a focused overview of astrocyte dysfunction in physiological aging and neurodegenerative conditions, integrating findings from the field alongside recent contributions from our group. We discuss how astrocyte aging contributes to cognitive decline and highlight emerging evidence on how targeting astrocytes, both genetically and pharmacologically, may rescue cognitive decline associated with aging and neurodegenerative diseases. Astrocytes produce several molecules that control synapse formation and function, which are decreased in the aging brain and in Alzheimer's disease models. In this context, recent studies indicate that astrocytes undergo significant molecular and functional remodeling during aging. Notably, astrocyte senescence has been associated with loss of lamin-B1, nuclear alterations, impaired synaptogenic and neuritogenic capacity, altered glutamate metabolism, and mitochondrial dysfunction, all of which may contribute to reduced neuronal support and circuit integrity. In parallel, recent advances have shown that astrocyte responses during aging also include diverse reactive states that vary according to brain region, microenvironment, and disease stage. Importantly, senescence-associated and reactive features are not mutually exclusive and may coexist or interact, further contributing to synaptic dysfunction and increased vulnerability to neurodegeneration. Finally, we discuss emerging therapeutic strategies aimed at modulating astrocyte function, including targeting astrocyte-derived synaptogenic factors and metabolic pathways, as potential approaches to mitigate cognitive decline. Together, current evidence indicates that astrocyte dysfunction in aging reflects a complex and dynamic spectrum of cellular states that play a central role in brain vulnerability and represent promising targets for intervention in aging and neurodegenerative diseases.