Telomere Attrition-Induced Senescence in Human Pluripotent Stem Cell-Derived Astrocytes: Distinct Cellular and Functional Characteristics

Abstract

This study explored the role of telomere attrition in astrocytic senescence by pharmacologically inhibiting telomerase activity in human induced pluripotent stem cell-derived astrocytes. Treatment with the telomerase inhibitor BIBR1532 (BIBR) during differentiation induced hallmark features of senescence, including nuclear lamina abnormalities, enhanced senescence-associated beta-galactosidase activity, increased replication arrest and DNA damage, altered reactive oxygen species homeostasis in mitochondria, accompanied by significant shortening of relative telomere length. Despite these senescence related characteristics, BIBR-treated astrocytes exhibited limited changes in the expression of senescence-associated secretory phenotype-related genes. Moreover, their key functional properties, such as glutamate uptake, synaptic vesicle clearance, mitochondrial membrane potential and morphology remain comparable to those of control astrocytes. These findings suggest that the presence of classical senescence markers does not necessarily lead to functional impairment and that BIBR-induced senescence in astrocytes may represent an early or transitional phase, where classical senescence markers emerge without substantial functional decline. Our results reinforce the notion that while telomere attrition is a major cellular senescence driver, its onset may not be attributed to a single stressor but rather to a complex interplay of cellular stress pathways. This study provides valuable insights into the mechanisms underlying astrocytic senescence and underscores the need for further research on the molecular basis of its occurrence and functional implications.