The emerging potential of nicotinamide adenine dinucleotide (NAD+) precursors in dermatological health and anti-aging: Elixir of life?

Dear Sir,

Nicotinamide adenine dinucleotide (NAD⁺) therapy has gained significant traction as a sought-after anti-aging treatment, particularly within esthetics and cosmetology. In recent years, increasing attention has been directed toward the potential role of NAD⁺ precursors in dermatological health and skin aging. A quick internet search on NAD⁺ therapy yields an abundance of results touting its near-miraculous effects on skin rejuvenation. However, despite growing public interest, clinical evidence supporting their dermatological efficacy remains limited. In this concise review, we critically evaluate the current scientific literature on NAD⁺ metabolism, precursor supplementation, and their relevance to skin aging and dermatological health. In this correspondence, we synthesize key findings from recent research on NAD⁺ precursors and discuss their implications for health span, longevity, and clinical applications.

Some recent reviews highlight that NAD⁺ plays a central role in metabolic processes, energy production, cellular signaling pathways, DNA repair, and oxidative stress reduction.^[1-4] Its decline with age is linked to a host of pathological conditions, including neurodegenerative diseases, metabolic disorders, and systemic dysfunctions.^[1-3] Recent advancements in dermatological research have brought attention to the role of NAD⁺ precursors in skin health and anti-aging therapies too. Its depletion, a hallmark of aging, is associated with diminished skin resilience, increased photoaging, and impaired wound healing.^[4] Restoring NAD⁺ levels has thus emerged as a promising strategy to combat aging and its associated diseases.

NAD⁺ is synthesized through four main pathways: The kynurenine pathway, converting tryptophan to NAD⁺ while producing neuroprotective or neurotoxic metabolites; the Preiss-Handler Pathway, transforming nicotinic acid (NA) into NAD⁺ through enzymatic steps; the Salvage Pathway, recycling nicotinamide (NAM) into NAD⁺ through enzymes like NAMPT; and the NRH Salvage Pathway, utilizing dihydronicotinamide riboside (NRH) as a precursor.^[1-3]

Key NAD⁺-consuming enzymes include sirtuins, polyADP-ribose polymerases (PARPs), and ADP-ribosyl cyclases (CD38/CD157).^[1,2] While these enzymes regulate essential cellular functions, conditions like aging and injury-induced damage can lead to hyperactivation of enzymes such as PARP and CD38, depleting NAD⁺ and causing harm. Supplementation with NAD precursors – such as NAM, NA, nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR) – can help counteract NAD decline. NMN and NR are particularly promising as they bypass age-related reductions in the NAMPT enzyme, supporting the NAD Salvage Pathway and restoring NAD levels effectively.^[1,3,4]

The therapeutic potential of NAD⁺ across a wide range of nondermatological health conditions. These include metabolic disorders, cardiovascular diseases, neurodegenerative conditions, hepatic diseases, addiction recovery, and age-related disorders. In addition, NAD⁺ therapy has been explored for its role in managing psychological and emotional disorders, highlighting its diverse applications in promoting overall health.

From a dermatological standpoint, upregulation of NAD⁺ may help prevent actinic keratosis and mitigate photoaging by enhancing DNA repair through PARP enzymes.^[3] This mechanism protects against ultraviolet-induced DNA damage and precancerous lesions, while also potentially benefiting conditions like psoriasis, which involve abnormal skin cell division. Various modes of NAD⁺ precursor administration – including oral, intravenous, intramuscular, topical, and localized injectable routes – have been described in translational and early-phase clinical literature [Table 1].

NAD⁺ therapy is offered in various administration methods, each with unique benefits and limitations. Oral supplements are convenient but have low bioavailability, while IV infusions provide rapid, systemic benefits at a high cost and invasiveness.^[1,5,6] Intramuscular injections offer a less invasive alternative with similar advantages but may cause soreness. Intravenous administration of NAD⁺ has been explored in limited clinical and translational settings; however, robust randomized controlled trials evaluating safety and efficacy are currently lacking.^[6,7] Topical applications target localized areas for skin regeneration, though systemic effects are limited.^[2,7,8] Localized injectables, often combined with esthetic procedures, effectively address specific regions but require expertise and remain invasive.

Figure 1 shows proposed mechanisms linking age-related NAD⁺.

Close

Figure 1: Proposed mechanisms linking age-related nicotinamide adenine dinucleotide decline to impaired DNA repair, oxidative stress, mitochondrial dysfunction, and skin aging. NAD+: Nicotinamide adenine dinucleotide

Export to PPT

While NAD⁺ precursors such as NAM, NMN, and NR can increase NAD⁺ levels, concerns remain about unregulated over-the-counter use, inconsistent efficacy, and potential risks, such as neurotoxicity and pro-cancer effects from certain metabolites.^[7] Interest in NAD⁺ precursor supplementation has largely arisen related to cutaneous aging, particularly features such as wrinkles, loss of elasticity, and photoaging, which are linked to age-related declines in cellular energy metabolism, oxidative stress regulation, and DNA repair mechanisms.^[9] This also includes those seeking to improve their overall health and wellness, as NAD⁺ therapy has been shown to have various benefits beyond skin rejuvenation.^[9] Most claims regarding cosmetic rejuvenation and skin anti-aging with NAD⁺ precursors are extrapolated from pre-clinical or systemic studies rather than dermatology-specific clinical trials; thus, these interventions should currently be considered investigational rather than established dermatologic therapies.

NAD⁺ and Boosting Complex Restores (quercetin and enoxolone) proved to be better than NAD⁺ in a study by Kang et al.^[9] Other intravenous therapies offered alongside NAD⁺ therapy (vitamin B complex, vitamin B12, glutathione, magnesium, methionine, inositol, choline, extra NAD⁺,taurine, and zinc) as adjunct micronutrients have been co-administered with NAD⁺ precursors in experimental and wellness settings; however, controlled evidence supporting additive dermatological benefit is lacking.^[8,9]

NR is more studied in humans than NMN but shows limited benefits in improving glucose control, insulin sensitivity, and exercise capacity in healthy older adults. Direct IV NAD⁺ infusion raises NAD⁺ levels effectively and has shown benefits in addiction withdrawal with no significant adverse effects, though it is not FDA-approved. Further research is needed to optimize supplementation strategies, understand long-term effects, and explore combinations with other anti-aging therapies. However, translating these findings into clinical practice requires robust trials to validate their safety and efficacy.

While NAD⁺ precursors play a central role in cellular metabolism, DNA repair, and mitochondrial function, current clinical evidence supporting their dermatological and anti-aging efficacy remains preliminary. Interest in NAD⁺ supplements is growing due to their potential in promoting healthy aging and addressing age-related diseases. Most data derive from pre-clinical models and early-phase human studies, with limited dermatology-specific trials. Therefore, NAD⁺ supplementation should be viewed as a promising yet investigational strategy, warranting further well-designed randomized controlled trials before routine clinical adoption.