In recent years, neuroinflammation has been accepted as one of the most important factors leading to age-associated cognitive decline, as well as to the establishment of several neurodegenerative diseases (NDD)(Kempuraj et al., 2016; Guzman-Martinez et al, 2019). Neuroinflammation can be generated by multiple causes, but it is known that the glia plays a relevant role in the production and release of proinflammatory molecules (Bernaus et al., 2020). Therefore, we decided to analyze the astroglia participation in this event.

Astrocytes are the most abundant cells in the central nervous system (CNS), and among their multiple functions, they can become activated in response to any alteration in the brain, whether it is an injury, an infection by pathogens, an alteration in the blood-brain barrier, or a disease, which has been described under various names such as reactive gliosis or astrogliosis. However, in response to stressful stimuli, astrocytes are also known to enter into a state called cellular senescence.

Gliosis leads to astrocytes´ morphological, functional, and biochemical modification, and its main characteristics include hypertrophy, a high proliferative rate, the ability to generate the glial scar, and the production of a wide range of cytokines and chemokines that, in addition to favoring inflammation, recruit various cells of the immune system has been described under various names such as reactive gliosis or astrogliosis (Escartin et al., 2021).

Astrogliosis can be considered both beneficial and harmful since it can induce neuronal network regeneration favoring its survival (Diene et al. 2019); but it can also halt axonal regeneration and cell migration, promoting the neuroinflammatory process (Guillamón-Vivancos et al. 2015). Several papers have suggested that astrocytes in gliosis may turn into two main phenotypes A1 and A2. A1 phenotype is associated with neurodegenerative damage and disease, because it generates a neurotoxic response by releasing inflammatory molecules that are potentially damaging to neurons and endothelial cells (Liddelow et al., 2017), and is characterized by increased complement protein C3 and GFAP expression, which are commonly used as markers for gliosis. The A2 phenotype, mainly observed in ischemia, is related to the repair response due to the secretion of trophic factors (Jing et al., 2021, Liddelow et al., 2017), and presents an increase in S100A10 protein expression. Nevertheless, it has recently been discussed that astrogliosis is a general and more complex concept that can encompass various potential phenotypes (not only A1 and A2), which depend on different astrocyte stimuli and responses and should not be confused with the plasticity that healthy astrocytes have, which can also be activated in response to physiological changes in the CNS (Escartin et al., 2021). Thus, for the purposes of this review, no classification will be considered for active astrocytes and they will be referred to only as astrocytes in gliosis.

On the other hand, especially during aging and NDD, it has been proposed that astrocytes may enter a state other than astrogliosis, known as cellular senescence. Cellular senescence is a state in which cells stop proliferating, but remain metabolically active. The stimuli that can induce senescence are varied and range from telomere shortening (replicative senescence), to stress-induced premature senescence, in which the stress can be oxidative stress, loss of proteostostosis, drug exposure, etc. (Rodier and Campisi, 2011, Gorgoulis et al., 2019). Some of the most commonly markers used to assess the senescent state are the activity and presence of the enzyme beta galactosidase (β-Gal), the increase in DNA scars such as gamma H2AX, cell cycle inhibitors such as p16 and p21, or the decrease in lamina B1 (Maciel-Barón et al., 2018a, Gorgoulis et al., 2019). But their most important feature is that senescent cells secrete a large number of cytokines and chemokines, which over time become increasingly proinflammatory and as a whole are called SASP (senescent associated secretory phenotype) (Rodier et al., 2009, Maciel-Barón et al., 2018b, Gorgoulis et al., 2019). The presence of senescent astrocytes has been reported in the brains of patients with neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD)(Bhat et al., 2012; Chinta et al. 2018). Thus, senescent astrocytes also contribute to neuroinflammation (Salas-Venegas et al., 2023).

In response to various stressful stimuli, astrocytes can become either senescent or reactive, affecting CNS function. So, during cognitive decline, dementia, and other NDD, both astrocyte phenotypes most likely coexist in the brain. Nevertheless, there are no studies where the two phenotypes are analyzed simultaneously. Hence, the aim of this systematic review was to investigate the studies performed in different models of astrogliosis and senescent astrocytes, to analyze and compare the secreted cytokines. Our results showed that there are no direct studies comparing the molecules secreted by senescent or activated astrocytes in the same model. Although we did a comparative analysis of the articles found, an accurate contrast of these profiles could not be carried out due to the great heterogeneity of techniques used in these studies. Our systematic review analysis contributes to the understanding of the role of astrocytes in promoting neuroinflammation in age-related diseases and helps to fill the absence of comparative studies of these phenotypes in the aging brain.