NAD in Skin: Therapeutic Approaches for Niacin

Abstract

The maintenance and regulation of cellular NAD(P)(H) content and its influence on cell function involves many metabolic pathways, some of which remain poorly understood. Niacin deficiency in humans, which leads to low NAD status, causes sun sensitivity in skin, indicative of deficiencies in responding to UV damage. Animal models of niacin deficiency demonstrate genomic instability and increased cancer development in sensitive tissues including skin. Cell culture models of niacin deficiency have allowed the identification of NAD-dependent signaling events critical in early skin carcinogenesis. Niacin restriction in immortalized keratinocytes leads to an increased expression and activity of NADPH oxidase resulting in an accumulation of ROS, providing a potential survival mechanism as has been shown to occur in cancer cells. Niacin deficient keratinocytes are more sensitive to photodamage, as both poly(ADP-ribose) polymerases and Sirtuins are inhibited by the unavailability of their substrate, NAD+, leading to unrepaired DNA damage upon photodamage and a subsequent increase in cell death. Furthermore, the identification of the nicotinic acid receptor in human skin keratinocytes provides a further link to niacin's role as a potential skin cancer prevention agent and suggests the nicotinic acid receptor as a potential target for skin cancer prevention agents. The new roles for niacin as a modulator of differentiation and photo-immune suppression and niacin status as a critical resistance factor for UV damaged skin cells are reviewed here.

NAD+ Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus

“…In addition, following DNA damage, NAD + levels can drop low enough that glycolysis and substrate flux to the mitochondria is blocked leading to cell death, despite having an excess of available glucose (Alano et al, 2010; Benavente et al, 2009; Ying et al, 2005; Zhang et al, 2014). This finding highlights the need to understand the mechanisms interconnecting subcellular NAD + pools, as their homeostasis and interaction is essential for the preservation of cell viability and ATP levels.…”

Cellular NAD+Level: A Key Determinant of Mitochondrial Quality and Health

“…1). Cultivation of cells in NAM-free medium causes a reduction in cellular NAD + levels by 90% in 7 days, and 99% in 14 days 46) . These observations reflect that NAD + (physiologically present at approximately 0.3 mM in normal animal cells 47,48) ) is continuously consumed through degradative metabolism, in which classes of NAD + -dependent ADP-ribosyl transferases are major constituents 49) .…”

Pharmacologic Use of Niacin

“…97,98 Physiological niacin supplements will improve skin health in deficient individuals, and pharmacological intakes of niacin could prove to further protect against skin cancer in those with high sun exposure. 99 Topically applied niacin derivatives, which can more efficiently cross the skin barrier, increase epidermal NAD levels, improve skin differentiation, and increase the thickness and barrier functions of the skin. 99 A topical 4% niacinamide gel was successful at reducing acne vulgaris lesions and acne severity in a clinical study.…”

“…99 Topically applied niacin derivatives, which can more efficiently cross the skin barrier, increase epidermal NAD levels, improve skin differentiation, and increase the thickness and barrier functions of the skin. 99 A topical 4% niacinamide gel was successful at reducing acne vulgaris lesions and acne severity in a clinical study. 100 Nicotinamide has been successfully used in combination with other micronutrients in a clinical study evaluating their effects in 198 patients with acne vulgaris and/or acne rosacea.…”