Aging and radiation: bad companions

Abstract

Aging involves a deterioration of cell functions and changes that may predispose the cell to undergo an oncogenic transformation. The carcinogenic risks following radiation exposure rise with age among adults. Increasing inflammatory response, loss of oxidant/antioxidant equilibrium, ongoing telomere attrition, decline in the DNA damage response efficiency, and deleterious nuclear organization are age-related cellular changes that trigger a serious threat to genomic integrity. In this review, we discuss the mechanistic interplay between all these factors, providing an integrated view of how they contribute to the observed age-related increase in radiation sensitivity. As life expectancy increases and so it does the medical intervention, it is important to highlight the benefits of radiation protection in the elderly. Thus, a deep understanding of the mechanistic processes confining the threat of aging-related radiosensitivity is currently of foremost relevance.

Keywords: DNA repair; chromatin organization; nuclear envelope; oxidative stress; radiosensitivity; replicative senescence.

Figure 1

Progressive loss of the pro-oxidant/antioxidant equilibrium with age and the synergic effect that ionizing radiation has on this process. Reactive oxygen species (ROS) production is greater in aging cells in comparison to their young counterparts; in addition, the antioxidant system is also compromised in these cells. This scenario leads to an increase in the oxidative stress. When adding ionizing radiation into this equation, the system becomes oversaturated, resulting in increased amounts of cell damage in aging cells. Red stars represent the ROS and the green triangles the antioxidant systems/enzymes.

Figure 2

Telomere attrition in aging cells. Ionizing radiation induces new DNA double-strand breaks (DSBs), and thus, new opportunities for the uncapped chromosomes undergo unfaithful repair. When aging cells skip replicative senescence, they display a greater number of uncapped chromosomes, which are prone to produce rearrangements. They can undergo end-to-end fusions and DSB-end fusions between different chromosomes. When the two centromeres are pulled in different directions, dicentric chromosome can break, and this breakage results in further fusions followed by other bridges and, again, new breaks will arise. This process is known as the breakage–fusion–bridge cycle (BFB cycles), which leads to broad DNA amplification and progressive terminal deletions. Any of these outcomes lead to a rise in chromosome instability, which, in turn, can initiate or promote a carcinogenic process.

Figure 3

Activation of the DNA damage response (DDR) after DNA double-strand breaks (DSB) induction in young and old cells. The signaling pathway starts with the MRN complex recruitment and continues with ATM phosphorylating H2AX. As represented here, the heterodimer Ku70/80 can also interact directly with the DSB and promote H2AX phosphorylation in DSB-flanking chromatin. The modified histone form (γH2AX) triggers MDC1 and 53BP1 assembly to the DSB and subsequent binding of ubiquitin ligase RNF8 and other chromatin remodeling factors. Proteins from both the nonhomologous end joining (NHEJ) and homologous recombination (HR) pathways are also recruited at the sites of damage to repair the DSB. Aging cells show a decline in the DDR efficiency at different points of this response. These points are represented by numbers (1–4) in the scheme.

Figure 4

Scheme of the age-related defects in nuclear reorganization. The aging process entails changes at the nuclear organization level that may compromise the DNA damage response (DDR) proteins recruitment to the nucleus: accumulation of a premature and dysfunctional prelamin A, untethering of the heterochromatin (HC) domains, and an increased presence of leaking pores. The addition of radiation by means of reactive oxygen species (ROS) production hinders both NPC and lamins function by oxidation.