Oxidative stress induces chromosomal instability through replication stress in fibroblasts from aged mice

Chromosomal aneuploidy has been associated with aging. However, whether and how chromosomal instability (CIN), a condition frequently seen in cancer cells in which chromosome missegregation occurs at a high rate, is associated with aging is not fully understood. Here, we found that primary fibroblasts isolated from aged mice (24 months old) exhibit an increased level of chromosome missegregation and micronucleation compared with that from young mice (2 months old), concomitant with an increased rate of aneuploid cells, suggesting the emergence of CIN. Reactive oxygen species were increased in fibroblasts from aged mice, which was accompanied with mitochondrial functional decline, indicating that they are under oxidative stress. Intriguingly, antioxidant treatments reduced chromosome missegregation and micronucleation rates in cells from aged mice, suggesting a link between oxidative stress and CIN. As a cause of CIN, we found that cells from aged mice are under replication stress, which was ameliorated by antioxidant treatments. Microtubule stabilization is a potential cause of CIN promoted by replication stress. Our data demonstrate the emergence of CIN with age, and suggest an unprecedented link between oxidative stress and CIN in aging.

Automated summary

Chromosomal instability (CIN), characterized by chromosome missegregation and micronucleation, emerges in fibroblasts from aged mice, along with an increased rate of aneuploid cells. This CIN is associated with oxidative stress, as indicated by increased reactive oxygen species and mitochondrial functional decline. Antioxidant treatments reduce CIN by alleviating replication stress and potentially stabilizing microtubules.