# Astrocyte States in Brain Aging and Neurodegeneration: At the Crossroads of Senescence and Reactivity

## TL;DR

This paper reviews how aging and neurodegeneration affect astrocyte states, highlighting their roles in brain health and disease.

## Contribution

The paper introduces a framework for understanding overlapping astrocyte states in aging and neurodegeneration.

## Key findings

- Aging leads to distinct astrocyte states beyond classical morphology.
- Astrocyte senescence involves altered signaling and impaired neuronal support.
- Reactive and senescence states may coexist or overlap depending on context.

## Abstract

Brain aging involves progressive disruption of tissue homeostasis and susceptibility to neurodegenerative disorders. Within this context, astrocytes are key determinants of region-specific physiology, given their roles in metabolic support, synapse regulation, proteostasis, neuroinflammation, and blood-brain barrier maintenance. Aging is accompanied by broad transcriptional and functional remodeling in astrocytes, leading to the emergence of distinct cellular states that cannot be defined by classical morphological criteria alone. This review discusses how aging modifies astrocyte identities toward reactive and senescence-like states. We summarize core features of astrocyte senescence, including altered secretory signaling, impaired neuronal support, and changes in mitochondrial and proteostatic pathways, while integrating recent single-cell and regionally transcriptomic studies that delineate multiple reactive states associated with aging and pathological contexts. We further address evidence that reactivity and senescence are not mutually exclusive endpoints, but may coexist, arise sequentially, or partially overlap depending on timing, brain region, biological sex, and pathological insults. Finally, we define key open questions and experimental priorities required to establish the temporal and causal relationships among astrocyte states. We argue that resolving these issues is essential for advancing therapeutic strategies that specifically target defined astrocyte phenotypes, rather than nonspecifically suppressing astrocyte activity, in aging and neurodegenerative diseases.