# Role of Nicotinamide in Genomic Stability and Skin Cancer Chemoprevention
## 4 NAD+ Status and Skin Aging
### NAD+ and Chronological Skin Aging  
Chronological or intrinsic skin aging results from the passage of time and is mainly influenced by genetic factors and metabolic processes. Indeed, specific skin aging signs, such as mitochondrial dysfunction, genomic instability, cellular senescence, and the breakdown of the extracellular matrix (ECM) are a consequence of dysfunctional oxidative processes [39]. Chronologically aged skin is characterized by epidermal atrophy that mainly affects the stratum spinosum and is due to lower epidermal turnover rates [40]. The loss of stem cell function can result, in part, from genomic instability and senescence. As the levels of NAD+ [41] and BER activity [42] decrease with epidermal aging, the DNA integrity can be compromised. Accordingly, an accumulation of 8-oxo-dG has been observed in aged primary keratinocytes. Notably, 8-oxo-dG accumulation displays a positive linear relationship with the expression of the skin aging biomarker p16 INK4a and stem cell depletion [42]. Furthermore, NAD+ depletion also increases NOX-mediated ROS production that can be counteracted by NAM administration [14]. Figure 2: Nicotinamide (NAM) and genomic stability. The increase of reactive oxygen species (ROS) and the decrease of DNA repair capacity characterize skin aging and result in oxidative DNA damage with high levels of 8-oxo-dG lesions. Reduced NAD+ biosynthesis and/or NAD+ consumption induce cellular energy depletion that lead to decreased DNA repair activity and PARP-1 inhibition. Both NAD+ depletion and DNA damage can induce cell senescence or apoptosis. Senescent cell accumulation in the tissue is associated with chronic inflammation. UV radiation causes in the skin direct and indirect damages to DNA including cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6–4) pyrimidine photoproducts (6–4 PPs) and 8-oxo-dG lesions. UV rays also induce cellular energy depletion by increasing PARP-1 activity, activation of inflammatory responses and suppression of cellular immunity. NAM is a precursor of NAD+. Replenishment of the NAD+ pool increases adenosine triphosphate (ATP) production, counteracts the inflammatory responses and the suppression of immunity. Furthermore, the ATP increase enhances DNA repair mechanisms maintaining genomic stability. Therefore, NAM protects the skin from DNA damage and may have beneficial effects against skin aging and tumor development. The inhibition of NAM conversion to NAD+ in primary human keratinocytes reduces the rates of glycolysis and OXPHOS, and induces cell senescence indicating an instrumental role of NAD+ status in the balance of epidermal proliferation/differentiation [43]. Indeed, NAM administration prevents the differentiation of keratinocytes and enhances their clonogenicity and proliferation [43]. Alteration to the oxidative and energy metabolism has a causative role also in NER disorders. Xeroderma pigmentosum (XP) is caused by deficiency of specific NER enzymes (XPA-XPG) and is characterized by premature aging and high skin cancer incidence. The XPC enzyme has a protective role against oxidative DNA damage [44; 45]. XPC silencing in normal human keratinocytes induces the activation of NOX that lead to redox unbalance and mitochondrial dysfunction [45; 46]. NOX1 activation in XPC-deficient cells triggers premature skin aging and neoplastic transformation of keratinocytes. Inhibition of NOX1 activity rescues premature skin aging signs in young _Xpc-1_ mice [45]. Aged dermal fibroblasts display reduced NADPH/NADP+ redox ratio and collagen secretion compared to those from young donors. NAM administration induces a significant increase of collagen biosynthesis with significant positive effects in counteracting skin aging and photodamage [47]. An age-related NAD+ decrease could be due to decreased biosynthesis and/or increased NAD+ consumption. The biosynthetic enzyme NAMPT expression decreases in several tissues during aging, thus leading to NAD+ deficiency, reduced Sirt1 activity and, in turn, to cell senescence [5].