Age and gender effects on DNA strand break repair in peripheral blood mononuclear cells

Abstract

Summary Exogenous and endogenous damage to DNA is constantly challenging the stability of our genome. This DNA damage increase the frequency of errors in DNA replication, thus causing point mutations or chromosomal rearrangements and has been implicated in aging, cancer, and neurodegenerative diseases. Therefore, efficient DNA repair is vital for the maintenance of genome stability. The general notion has been that DNA repair capacity decreases with age although there are conflicting results. Here, we focused on potential age-associated changes in DNA damage response and the capacities of repairing DNA single-strand breaks (SSBs) and double-strand breaks (DSBs) in human peripheral blood mononuclear cells (PBMCs). Of these lesions, DSBs are the least frequent but the most dangerous for cells. We have measured the level of endogenous SSBs, SSB repair capacity, γ-H2AX response, and DSB repair capacity in a study population consisting of 216 individuals from a population-based sample of twins aged 40– 77 years. Age in this range did not seem to have any effect on the SSB parameters. However, γ-H2AX response and DSB repair capacity decreased with increasing age, although the associations did not reach statistical significance after adjustment for batch effect across multiple experiments. No gender differences were observed for any of the parameters analyzed. Our findings suggest that in PBMCs, the repair of SSBs is maintained until old age, whereas the response to and the repair of DSBs decrease.

Selenoprotein H Suppresses Cellular Senescence through Genome Maintenance and Redox Regulation

“…Accumulation of ROS (63,64) and reduction of antioxidant capacity, DNA repair efficacy and selenoprotein expression (65)(66)(67)(68)(69)(70)(71)(72) have been linked to cellular and organismal aging. However, damage accumulation early in life can also contribute to or accelerate cellular senescence, as DNA breaks and ATM pathway activation are prominent and there are 3-fold more viable clones when SelH shRNA MRC-5 cells are maintained in 3% O 2 than in 20% O 2 incubators (data not shown) as early as two passages after clonal selection.…”

Effects of age on the frequency of micronuclei and degenerative nuclear abnormalities

“…Studies suggest that this process is associated with an increase in genomic instability due to the reduced capacity to repair damaged DNA. 1,2 It has been reported that, in old age, biomarkers of genomic instability, such as micronuclei (MN), are more common in the peripheral lymphocytes 3,4 and exfoliated epithelial cells. 5,6 The accumulation of DNA damage is a significant event in the aging of cells.…”

Impaired DNA double-strand break repair contributes to the age-associated rise of genomic instability in humans

“…Using different analysis approaches, several studies have demonstrated that aging is often associated with the accumulation of DNA DSBs in various organs and tissues in mammals such as mice and humans. [7][8][9][10][11] Moreover, a recent study provides direct evidence that an induction of DNA DSBs in genomes causes aging in mouse livers. 12 However, why DNA DSBs accumulate with age remains an open question.…”

“…A number of studies indicate that it may be a consequence of a progressing imbalance between DNA damage and the efficiency of the molecular machinery that catalyzes DNA repair. 7,9,11 Two major pathways, nonhomologous end joining (NHEJ) and homologous recombination (HR) evolved to repair DNA DSBs. NHEJ is further divided into two sub-pathways: the classical NHEJ pathway (c-NHEJ)-in which the major participating factors include DNA-PKcs, Ku70/Ku80 heterodimers, Artemis, XRCC4, XLF and DNA Lig4-and the alternative NHEJ pathway (alt-NHEJ), comprised of the repair factors, PARP1 and DNA Lig3.…”