Genome instability, cancer and aging

Abstract

DNA damage-driven genome instability underlies the diversity of life forms generated by the evolutionary process but is detrimental to the somatic cells of individual organisms. The cellular response to DNA damage can be roughly divided in two parts. First, when damage is severe, programmed cell death may occur or, alternatively, temporary or permanent cell cycle arrest. This protects against cancer but can have negative effects on the long term, e.g., by depleting stem cell reservoirs. Second, damage can be repaired through one or more of the many sophisticated genome maintenance pathways. However, erroneous DNA repair and incomplete restoration of chromatin after damage is resolved, produce mutations and epimutations, respectively, both of which have been shown to accumulate with age. An increased burden of mutations and/or epimutations in aged tissues increases cancer risk and adversely affects gene transcriptional regulation, leading to progressive decline in organ function. Cellular degeneration and uncontrolled cell proliferation are both major hallmarks of aging. Despite the fact that one seems to exclude the other, they both may be driven by a common mechanism. Here, we review age-related changes in the mammalian genome and their possible functional consequences, with special emphasis on genome instability in stem/progenitor cells.

Fig. 1

Of the two major branches of genome maintenance, DNA repair aims to restore the original situation by remwing the lesion, while the complex of DNA-damage signaling pathways assists in these repair activities or initiates cellular responses that kill or terminate mitotic activity of a cell when it is beyond repair.

Fig. 2

Age-related, cell functional divergence as a consequence of stochastic effects. Functional decline is indicated by increasing darkness of shading. Even in a young tissue, the function of highly differentiated cells in an organ or tissue is never maximized. The old tissue is different in the sense that there are many more cells that have suffered functional decline, with some of them dying (†) or eliminated (open space). Others have grown into a hyperplastic or neoplastic lesions (hatched) or have been replaced by fibrosis (not shown).

Fig. 3

Hypothetical relationship between aging, cancer and stem cells (SC). Various endogenous and exogenous factors (e.g., ROS, replication errors, environmental hazards) cause DNA damage, also in stem cells. Among the cellular responses to DNA damage, apoptosis and senescence lead to attrition of stem cell populations, while DNA repair may lead to errors increasing both cancer risk and adversely affect function. Hence, cancer and non-cancer, degenerative dysfunction can both be consequences of stem cells' responses to DNA damage.

Fig. 4

The optimal balance between maintaining the number of stem cells (“quantity”) and eliminating severely damaged stem cells (“quality”) ensures maximal longevity free of cancer and degenerative changes. Shifts towards one or the other extreme will impair longevity by development of degenerative dysfunction due to exhaustion of regenerative capacity or cancer due to accumulation of proliferation competent cells with significant mutation/epimutation load.