# Role of Nicotinamide in Genomic Stability and Skin Cancer Chemoprevention
## 3 Genomic Instability--Hallmark of Aging and Cancer  
Genomic instability refers to an increased tendency of DNA alterations (e.g., point mutation, deletion and insertion, and chromosomal rearrangements) that irreversibly change genomic content and are one of hallmarks of both aging and cancer [8; 10].  
DNA damage is a driver of genome instability. An age-related increase of oxidative stress and/or decline of DNA repair activity could lead to an accumulation of DNA damage. Incorrect DNA repair or incomplete restoration of chromatin after damage repair, induce mutations or epimutations that accumulate with age [10].  
Senescence protects against cancer but causes depletion of stem cell reservoirs and, in the long term, leads to tissue homeostasis decline by SASP that alters the functions of neighboring cells. Age-related deterioration of biological functions, which results in decline of DNA repair capacity and genomic instability, decline of immune system function and chronic inflammation, may contribute to a reduction of the efficacy of senescence response in counteracting tumorigenesis and, in turn, may lead to accumulation of senescent cells in tissues [10; 31]. Studies in mouse models show a causative role of cellular senescence in driving aging in vivo [32; 33].  
Furthermore, the tumor-suppressor function of senescence response may turn into a tumor-promoting mechanism as a consequence of aging. Aged tissues are characterized by the accumulation of both DNA damage and senescent cells, as well as by the presence of SASP-mediated chronic inflammatory status [10]. Cellular senescence is a dynamic and progressive process, and therefore the properties of senescent cells continuously evolve and diversify. The age-related decline of cellular functions can delay the progression of the senescent program and the unstable state of the genome may allow to accumulate additional mutations [34]. Beyond promoting tissue repair and activating immune surveillance, SASP may also promote chronic inflammation, epithelial to mesenchymal transition, tumor immune evasion, angiogenesis or stem cell-like phenotype in malignant cells [30]. Age-related oncogenic stimuli, such as ROS increase and chronic inflammation, might induce damaged senescent cells to re-enter the cell-cycle and progress towards malignant transformation [34]. Notably, senescent cells accumulate in premalignant lesions but are not detectable after progression to malignancy [30; 31; 35]. Thus, malignant cells could derive from damaged cells escaping the senescence program, from cells damaged by neighbouring senescent cells through exacerbated pro-inflammatory secretion, or from senescent cells themselves. Indeed, senescent cells could be considered pre-malignant cells. Recent findings provide evidence regarding this issue: they indicate that the growth arrest of senescent cells can be bypassed upon the inactivation of key tumor suppressor genes, such as p16 INK4a [30; 34; 36]. Therefore, some mutant genotypes, such as inactivation of tumor suppressor genes or oncogene overexpression, selectively favor the growth of cell subclones in a microenvironment suitable for tumor development created by SASP-mediated chronic inflammation.  
Oxidative stress has a key role in epithelial senescence as it is responsible, at least in part, of the DNA damage and genomic instability that induces both p16 INK4a/pRb-mediated cell-cycle arrest and SASP increase. Furthermore, oxidative stress is maintained by positive feedback loop involving SASP itself, p38 MAPK pathway and mitochondrial metabolism. Genome instability due to continuous oxidative damage enables cells to acquire malignant capabilities. Thus, epithelial cell senescence may be a tumor promoting mechanism that generates a reservoir of tumor initiating cells and produces an optimal niche for tumor progression [30; 37]. Accordingly, the most frequent human tumors arise from epithelial cells, and their incidence increases with increasing age [38].  
Thus, aging is a major risk factor of skin tumor development.