Mounting evidence suggests that DNA damage plays a central role in aging. Multiple tiers of defense have evolved to reduce the accumulation of DNA damage, including reducing damaging molecules, repairing DNA damage, and inducing senescence or apoptosis in response to persistent DNA damage. Mutations in or failure of these pathways can lead to accelerated or premature aging and age-related decline in vital organs, supporting the hypothesis that maintaining a pristine genome is paramount for human health. Understanding how we cope with DNA damage could inform on the aging process and further on how deficient DNA maintenance manifests in age-related phenotypes. This knowledge may lead to the development of novel interventions promoting healthspan.
From Increased DNA Damage to AgingMultiple endogenous and exogenous molecules can chemically modify our DNA. To deal with these stressors, cells have developed ways to reduce the production of, or eliminate, endogenous damaging molecules before damage occurs (Box 1), to repair damage once it occurs, or to eliminate cells that have accumulated too much damage (Figure 1). These three tiers of defense are the focus of this review. The most well-described mechanism to reduce toxic molecules is antioxidant removal of reactive oxygen species (ROS) before they can react with other molecules such as DNA, proteins, or lipids. In addition, oxidized lipids and proteins can react and form toxic adducts with DNA [1,2]. Nonenzymatic antioxidants such as glutathione and vitamin C and E as well as antioxidant enzymes such as superoxide dismutase, catalase, and peroxidases attempt to counter these reactive molecules and could protect the genome. If this first tier of defense fails, repair enzymes coordinate the processes that attempt to reverse the damage and return the DNA to its undamaged (functional) state. These highly conserved repair mechanisms can be classified into the following pathways: direct reversal, base excision repair, nucleotide excision repair, double-strand break repair, and interstrand crosslink repair (Box 2).The association between DNA damage and aging is well established with extensive data from humans and animal models showing increased markers of genome instability with age [3,4]. One possible reason for an age-associated increase in DNA damage is that DNA repair capacity may decrease with age [5][6][7][8]. Markers of DNA damage have been observed in age-associated diseases such as dementias, cardiovascular disease, and cancer, suggesting that genome instability could be a causal factor in these pathologies [9][10][11]. A compelling piece of evidence for a causal role of DNA damage is the observation that some patients with inherited defects in DNA repair proteins show features of premature or accelerated aging (Figure 2) [12,13]. Importantly, defects in different pathways lead to aging features in different tissues. For example, individuals with Cockayne syndrome and ataxia-telangiectasia display features of premature neurological aging [14,15], while Werner syndr...
