Centromere inactivation during aging can be rescued in human cells

Aging involves a range of genetic, epigenetic, and physiological alterations. A key characteristic of aged cells is the loss of global heterochromatin, accompanied by a reduction in canonical histone levels. In this study, we track the fate of centromeres during aging in human cells. Our findings reveal that the centromeric histone H3 variant CENP-A is downregulated in aged cells, in a p53-dependent manner. We observe repression of centromeric noncoding transcription through an epigenetic mechanism via recruitment of a lysine-specific demethylase 1 (LSD1/KDM1A) at the centromeric DNA. This suppression results in defective de novo CENP-A loading at aging centromeres. By dual inhibition of p53 and the lysine-specific demethylase 1 in aged cells, we mitigate the reduction in centromeric proteins and centromeric transcripts, leading to the rejuvenation of these cells. These results offer insights into a novel mechanism for centromeric inactivation during aging and provide valuable information on strategies to reactivate it. Overall design: BJ fibroblasts was treated with DMSO/Dox 250nM for 24 hours and then allowed to senesce for 10 days. Total RNA extracted from BJ skin fibroblast cells DMSO and DOX treated. Each sample is given in 2 replicates(Rep). Gene expression analysis to be done untretaed/DMSO vs Dox treated.