# Role of Nicotinamide in Genomic Stability and Skin Cancer Chemoprevention
## 4 NAD+ Status and Skin Aging
### NAD+ and Photo-Aging  
As skin protects the body from environmental insults (e.g., UV radiation, pollutants, xenobiotics, atmospheric oxygen) that induce increases in ROS production, extrinsic aging has a primary role -as well as intrinsic aging- in damaging the tissues. Thus, aged skin can reflect different stages of extrinsic aging, superimposed on intrinsic changes [39]. Acute or repeated sun exposure induces short-term skin damages such as sunburn, characterized by skin erythema. Long-term sunlight exposure to sub-erythemal doses is associated with photo-aging or UV-induced skin cancers [54]. Although keratinocytes are continuously hit by radiations, in aged skin UV-exposure is elevated due to compromised stratum corneum. The concomitant age-related NAD+ deficiency and increased requirements of NAD+ for DNA damage response may contribute to energy stress that generates additional ROS and elevated genomic damage [3]. UV radiation causes several kinds of damage in skin cells (Figure 2): (i) DNA damage; (ii) reduction of DNA repair capacity; (iii) activation of local inflammatory responses; (iv) suppression of cellular immunity [55]. Both types of UV radiation induce DNA damage. UV-B rays (290-320 nm), which account for about 0.5% of solar spectral irradiance reaching the earth, are highly energetic and damage epidermal cells. UV-B radiation induces direct DNA damage by forming cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6-4) pyrimidine photoproducts (6-4 PPs) that are removed primarily by NER system [9; 55]. These DNA lesions, if not effectively repaired, may result in genetic mutations. CPDs give rise to C\(\rightarrow\)T and CC\(\rightarrow\)TT transitional mutations that may alter the function of the p53 gene, which is important as tumor suppressor in skin carcinogenesis [8]. An increase of these transitional mutations has been found in skin tumors of both animal models and human patients [56]. Conversely, UV-A rays (320-400 nm) correspond to 95% of UV radiation at ground level. They are less energetic but have higher penetration properties so that they mainly induce direct dermal alterations through the ROS generation and subsequent oxidative DNA damage. Notably, Nox1 is the major source of UVA-induced ROS in human keratinocytes [9; 55]. UV-induced ATP depletion may hamper DNA repair capacity. Studies performed in mouse models and cultured human keratinocytes demonstrate that UV-B deplete NAD+ making cells more sensitive to DNA damage and prone to tumorigenesis [4]. SIRTs and PARPs play an important role in resistance to photo-damage [57]. Low-dose, sub-erythemal UV-B activate PARP-1 activity, at least partially, via UV-induced oxidative DNA damage [22]. Excessive activation of PARP-1 blocks glycolysis, reduces intracellular energy in keratinocytes, and leads to cell death. Increased activity of PARP-1 depletes the NAD+ pool, leading to reduced activity of SIRTs [4; 5]. Notably, SIRT1 confers protection against UV-B radiation- and ROS-induced skin cell damage [57]. Adequate NAD+ levels are critical for proper DNA repair upon UV exposure. NAD+ deficiency increases skin sensitivity to photo-damage, whereas NAM prevents UV-induced depletion of cellular energy by replenishing the NAD+ pool [3]. NAM is also a PARP inhibitor. Thus, NAM increases intracellular ATP levels by inhibiting the PARP-1 mediated blockade of the glycolytic pathway that, in turn, replenishes NAD+ and ATP reservoirs [58]. Furthermore, NAM enhances repair of UV-induced DNA damage. HaCat cells treated with NAM and then exposed to UV display initial levels of CPD and 8-oxo-dG photolessions similar to untreated cells, indicating that NAM does not reduce or prevent DNA damage induction [59]. Moreover, NAM did not restore the ROS steady-state levels after UV-treatment, and hence does not reduce 8-oxo-dG via direct antioxidant effects [58]. However, an increased amount and rate of DNA excision repair has been found in UV-irradiated NAM-treated cells [59]. NAM enhanced DNA repair also in old mice [4].