The Role of DNA Repair in Cellular Aging Process

*Francisco Alejandro Lagunas-Rangel and Rosa María Bermúdez-Cruz* 

### **Abstract**

Aging is defined as the time-dependent decline of functional properties. One common denominator of aging is mitochondrial dysfunction and accumulation of genetic damage throughout life. In fact, the imperfect maintenance of nuclear and mitochondrial DNA likely represents a critical contributor of aging. Each day, the integrity and stability of DNA are challenged by exogenous physical, chemical, or biological agents, as well as by endogenous processes, including DNA replication mistakes, spontaneous hydrolytic reactions, and reactive oxygen species. In this way, DNA repair systems have evolved a complex network that is collectively able of dealing with most of the damages inflicted. However, their efficiency may decrease with age and, therefore, influence the rate of aging. Thus, the purpose of this work is to summarize the recent knowledge in cellular aging process and its link with DNA repair systems, with a particular emphasis on the molecular mechanisms associated.

**Keywords:** DNA damage, DNA repair, BER, NER, MMR, HR, NHEJ

#### **1. Introduction**

 Aging is a complex biological process that results in a progressive loss of physiological integrity. Overall, aging is a consequence of accumulation of cellular damage and is characterized by nine hallmarks: genomic instability, telomere attrition, epigenetic alterations, cellular senescence, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient sensing, stem cell exhaustion, and altered intercellular communication (**Figure 1**) [1]. Although aging may involve damage to various cellular constituents, there is evidence suggesting that DNA constitutes the key target in this process [2]; consequently, genomic instability is the main factor of aging [3–5]. Genome instability has been implicated as a cause of aging since unrepaired DNA damage, DNA mutations, and epimutations accumulate in an age-related manner [3]. In the same way, the notion that multi-system premature aging syndromes are mainly caused by defects in genome maintenance or affect genome function highlights the role of genome integrity in aging [6]. Meanwhile, normal aging is accompanied by telomere shortening with cell division due to the "end-replication problem" and telomere end processing. Currently, there is a wide body of evidence associating reduction in the length of telomeres with failure of cell division and senescence of normal cells, and oxidative stress and inflammation can contribute to the rate of attrition of telomere length [7]. Age-related changes involve alterations in DNA methylation patterns and posttranslational modification of histones such as increased histone H4K16 acetylation [8], H4K20 trimethylation [9], or H3K4 trimethylation [10], as well as decreased H3K9 methylation [11] or H3K27 trimethylation [12]. At the same time, with aging there is also a global heterochromatin loss and redistribution [13], thus affecting the expression of several genes, mainly those involved in DNA repair, cellular proliferation, differentiation, and cell-cycle regulation, and therefore triggering the emergence of other hallmarks of aging [14, 15]. Cellular senescence is a process that has become an important contributor in aging since it imposes a permanent proliferative arrest of cells in response to various stressors such as DNA damage and telomere loss [16]. Furthermore, as cells and organisms age, mitochondria suffer a decline in their integrity and function, tending to diminish the efficacy of the respiratory chain and thus reducing ATP generation, increasing electron leakage and ROS production that can damage DNA, proteins, and lipids, among other important biomolecules [17]. Proteostasis involves mechanisms for correct folding proteins and mechanisms for the degradation of proteins, which act in a coordinated fashion to prevent the accumulation of damaged components and assuring the continuous renewal of intracellular proteins. There is evidence that aging is associated with perturbed proteostasis, thus favoring the development of several diseases [18]. Recent data have shown that anabolic signaling accelerates aging; in agreement with this, caloric-restricted diet decreases nutrient signaling and as a result, a long life span is promoted since DNA repair systems are improved; on the other hand, protein homeostasis decreases ROS production and delays cellular senescence [19]. Decline in the regenerative potential of tissues is one of the most obvious characteristics of aging, where stem cell exhaustion is also important and explained by a decreased cell-cycle activity. Interestingly, this correlates with the accumulation of DNA damage, telomere shortening, and overexpression of cell-cycle inhibitory proteins such as p16INK4a, increasing the relevancy of DNA repair systems [20]. Finally, aging also involves changes at the level of intercellular communication, where neurohormonal signaling tends to be deregulated together with composition of the peri- and extracellular environment

#### **Figure 1.**

*The hallmarks of aging. The figure illustrates nine hallmarks previously described [1] and where age-related changes in DNA repair systems have important roles to promote the development of this phenotype.* 

 and immune system, specially increasing inflammatory reactions and declining immunosurveillance against pathogens and premalignant cells [21]. In this way, our work focuses on describing the molecular bases that associate DNA damage and the cell aging process, with a special emphasis in DNA repair systems.
