The versatile and multifacetic role of astrocytes in response to ketogenic interventions

Ketone therapies refer to metabolic interventions aimed to elevate circulating levels of ketone bodies (KB), either through direct supplementation or stimulating endogenous production via medium-chain fatty acids intake, ketogenic diets, caloric restriction, intermittent fasting, or exercise. These strategies have gained attention as potential treatments for neurodegenerative diseases by preserving neuronal function, improving metabolic efficiency, and enhancing cellular resilience to stress. KB are taken up and metabolized by various brain cell types-including neurons, astrocytes, oligodendroglia and microglia-under basal and pathological conditions. However, their cell-type-specific effects remain incompletely understood. Notably, although astrocytes play a key role in supporting neuronal metabolism and can both produce and utilize KB, research has focused predominantly on neuronal responses, leaving the impact of ketotherapeutics on astrocytes relatively unexplored. This review aims to compile and discuss current evidence concerning astrocytes responses to both exogenous and endogenous ketotherapeutic strategies. Although still limited, available studies reveal that astrocytes undergo dynamic changes in response to these interventions, including morphological remodeling, calcium signaling modulation, transcriptional and metabolic reprogramming, regulation of transporters, and neurotransmitter uptake-a crucial process for synaptic function. Astrocytes appear to actively contribute to the neuroprotective and pro-cognitive effects of ketone therapies, particularly in the context of aging and disease. However, significant gaps still remain, concerning the stage when ketone therapy should be initiated, the underlying mechanisms, regional specificity, and long-term consequences. Future research focused on astrocyte heterogeneity, activation of intracellular pathways, and metabolic and transcriptional reprogramming will enable the translational potential of astrocyte-targeted ketone therapies for neurological disorders.