Abstract: In recent work, we have shown that cell senescence of mouse fibroblasts in vitro associates with a build-up of cryptic exons in selected mRNAs, whose level is usually controlled by the activity of TAR DNA binding protein of 43 kDa (Tdp-43) (Torres et al., 2022). In vivo, we also found traits of cell senescence in the motor neuron disease model achieved by overexpressing SOD-G93A, the SOD1 gene (harboring a single amino acid substitution of glycine to alanine at codon 93). These mice express an age-related increase in the p21 and p16 mRNA levels, with enhanced protein levels of codified proteins in the cytosol of several cells present in the lumbar spinal cords of the model. Most cells showing increased p16 immunoreactivity were identified as astrocytes and microglia, with neuronal cells relatively spared from this senescence biomarker’s build-up. In addition to increased signs of replicative senescence (increased p16 and p21 expression), these mice also exhibit some characteristics related to senescence-associated secretory profile, such as increased levels of interleukin-6, and interleukin-1a, in a sex-specific manner. We qualify the cellular senescence in this model as atypical, as we were not able to significantly change the motor phenotype by treatment of anti-BCL2-BCLx antagonist, Navitoclax®, whose use has been beneficial in other preclinical models of age-related neurodegenerative diseases, such as Alzheimer’s disease. Of note, reinforcing the complexity of senolytical approaches, in vitro treatments of fibroblasts employing a quercetin-dasatinib® (but not Navitoclax®) combinations were able to abolish the senescence-associated build-up of p16 and p21 (Torres et al., 2022). These results suggest the importance of glial cell senescence in the association between aging and selective neuron demise. Disease-specific reactive astrocytosis secondary to neuron loss and astrocytopathy due to intrinsic alterations of astrocytes occur in neurodegenerative diseases, overlap each other, and, together with astrocyte senescence, contribute to disease-specific astrogliopathy in aging and neurodegenerative diseases with abnormal protein aggregates in old age, including amyotrophic lateral sclerosis (ALS). In addition to the well-known increase in glial fibrillary acidic protein and other proteins in reactive astrocytes, astrocytopathy is evidenced by the deposition of abnormal proteins and could contribute to neuronal loss, either by losing homeostatic support functions or by acting as sources of noxious agents towards neurons (Ferrer, 2017).