Creative Touch Permanent Makeup and Aesthetics

Nicotinamide adenine dinucleotide exists in every living cell in oxidised (NAD⁺) and reduced (NADH) forms. In skin biology, its significance extends well beyond energy metabolism. NAD⁺ is the obligate cosubstrate for the sirtuin deacetylases – particularly SIRT1 – which regulate circadian clock amplitude in dermal and epidermal cells, suppress NF-κB-driven inflammation in fibroblasts, and gate the DNA repair response to UV exposure. It is also the substrate consumed by PARP1 during photodamage repair. Because both sirtuins and PARP1 draw from the same cellular NAD⁺ pool, chronic UV accumulation, metabolic stress, or age-related CD38 upregulation can deplete this pool to a degree that impairs clock precision and repair capacity simultaneously. The skin consequence is not a single failure but a coordinated decline: blurred circadian repair timing, reduced fibroblast function, and attenuated UV damage response occurring together.

What NAD⁺ Is – and Why the Standard Description Understates It

NAD⁺ is a dinucleotide coenzyme built from nicotinamide and adenine, found in every living cell as an interconvertible pair: the oxidised form (NAD⁺) and the reduced form (NADH). The ratio between them – the NAD⁺/NADH ratio – reflects the cellular redox state and determines which metabolic and signalling processes can operate.

The conventional description of NAD⁺ as an energy carrier is accurate but incomplete. In skin biology, the more consequential roles are non-redox: NAD⁺ is the obligate cosubstrate for two enzyme classes whose activity is directly gated by its availability – the sirtuins (class III deacetylases, notably SIRT1, SIRT3, and SIRT6) and the poly(ADP-ribose) polymerases (PARPs, notably PARP1). Unlike conventional cofactors that are recycled, these enzymes consume NAD⁺ as a reactant, releasing nicotinamide as a byproduct. The skin cannot compensate for NAD⁺ depletion by working harder at the enzyme level – the reactions cannot proceed without the substrate.

How Skin Cells Synthesise NAD⁺

Two routes maintain cellular NAD⁺:

The de novo pathway builds NAD⁺ from tryptophan via the kynurenine pathway – a metabolically expensive route that supplements rather than sustains the primary supply.

The salvage pathway is the dominant route. It recycles the nicotinamide released when sirtuins and PARPs consume NAD⁺, converting it back to new NAD⁺ via NAMPT (nicotinamide phosphoribosyltransferase). NAMPT produces NMN (nicotinamide mononucleotide), which NMNAT enzymes then convert to NAD⁺. This salvage cycle is the route through which dietary nicotinamide – niacinamide – enters the system as a precursor.

The rate-limiting enzyme, NAMPT, is itself under direct clock control: BMAL1 and CLOCK drive NAMPT gene expression as part of the circadian transcription cycle. Ramsey et al. demonstrated that this creates a self-amplifying feedback loop – the clock drives NAMPT expression, NAMPT produces NAD⁺, NAD⁺ activates SIRT1, and SIRT1 deacetylates BMAL1 to maintain oscillation amplitude, which sustains NAMPT transcription in the next cycle. [pmc.ncbi.nlm.nih.gov/articles/PMC6501775/] When the loop is disrupted at any point – whether by clock amplitude loss, metabolic NADH accumulation, or absolute pool depletion – the deficit compounds through the entire cycle.

Why NAD⁺ Declines With Age: Two Converging Mechanisms

The conventional explanation for age-related NAD⁺ decline focuses on falling NAMPT activity – reduced synthesis throughput. More recent evidence has substantially revised this picture. A 2025 review concluded that increased consumption, rather than impaired synthesis, is the dominant mechanism in older tissue. ^[6]

CD38 upregulation. CD38 is a glycohydrolase whose primary biochemical function is consuming NAD⁺ as its substrate. It is expressed in immune cells, including the macrophages and T-cells that accumulate in inflamed and senescent tissue. CD38 expression increases significantly with age in adipose tissue and skin-resident immune populations, and the inflammatory environment of photoaged dermis – with its elevated senescent fibroblast burden – sustains CD38 activity chronically. This creates a self-reinforcing cycle: tissue ageing depletes NAD⁺ through CD38 upregulation, and NAD⁺ depletion impairs the sirtuin-mediated mechanisms that would otherwise limit senescence and inflammation. ^[6]

PARP1 hyperactivation from cumulative UV damage. Every UV photon that damages keratinocyte DNA activates PARP1 to initiate base excision repair. In young skin with an intact NAD⁺ pool, this is a routine metabolic event. As cumulative UV damage accumulates over decades and the repair backlog grows, PARP1 maintains a constitutively elevated activity state that draws continuously on the NAD⁺ pool. ^[4] Because sirtuins draw from the same pool, chronic PARP1 activation operates as a direct competitive drag on clock function: photoaged skin faces a forced allocation between DNA repair (PARP1) and circadian precision (SIRT1), both competing for the same depleted substrate.

The metabolic contribution: ratio suppression. A third mechanism operates through the NAD⁺/NADH ratio rather than absolute pool depletion. The metabolic impasse generated by simultaneous high-glucose and high-fat substrate delivery – the Randle Cycle mechanism described in the Metabolic Chronodisruption entity – produces NADH accumulation that suppresses the ratio. This reduces the functional availability of NAD⁺ for signalling enzymes without consuming the total pool. Where this ratio suppression is sustained by consistent dietary patterns, it operates as a background clock amplitude suppressor independently of the CD38 and PARP1 mechanisms – and can operate in skin that is not significantly photoaged or chronologically aged.

NAD⁺-Dependent Enzymes in Skin

The practical significance of NAD⁺ availability is most clearly understood through what stops working when the pool is depleted:

SIRT1’s role is developed in full in the Sirtuins entity. The point for NAD⁺ biology is this: SIRT1 cannot be “activated” by any ingredient strategy that bypasses NAD⁺ availability. The early framing of resveratrol as a direct SIRT1 activator has been substantially revised – the activation observed in initial assays used a fluorescent substrate artefact. Current evidence indicates that any pro-sirtuin effect from resveratrol operates through indirect metabolic mechanisms, principally AMPK-mediated NAMPT upregulation. The functional route to sirtuin activation is NAD⁺ precursor sufficiency, not direct enzyme stimulation. ^[1]

Precursors: The Restoration Hierarchy

Three nicotinamide-family precursors can raise cellular NAD⁺. Their evidence quality differs substantially and this distinction matters for clinical communication.

Nicotinamide (niacinamide). Nicotinamide enters the salvage pathway directly as the NAMPT substrate, making it the most efficient dietary precursor route. Topical niacinamide has demonstrated measurable downstream SASP gene suppression – including MMP-12, MMP-1, and CXCL9 downregulation across 20 ageing-related genes – in aged human dermal fibroblasts in vivo in a 2024 Scientific Reports study using a topical niacinamide and hyaluronic acid formula. The authors attributed the senomorphic effect to niacinamide’s established NAD⁺/sirtuin biology, though NAD⁺ levels were not directly measured in this study. ^[2] Oral nicotinamide at therapeutic dose reduces non-melanoma skin cancer risk in field cancerisation, an effect attributed to restoration of NAD⁺-dependent DNA repair capacity. This is the most extensively evidenced precursor strategy for skin. Clinical evidence for topical and oral application is covered in the Niacinamide entity.

NMN (nicotinamide mononucleotide). NMN enters one step downstream of NAMPT, bypassing the rate-limiting step. Pihl et al. (Photochem Photobiol Sci., 2025) confirmed that oral NMN raises tissue NAD⁺ in both skin and liver in humans. ^[5] Whether this elevation translates to the specific skin outcomes – clock amplitude restoration, UV repair capacity, fibroblast function – predicted by the NAD⁺ mechanism has not yet been confirmed in skin-endpoint RCTs. The evidence position: NMN demonstrably raises tissue NAD⁺; skin-specific outcome data is preclinical.

NR (nicotinamide riboside). Converts to NMN and follows the same pathway. The human evidence profile is substantially equivalent to NMN – demonstrated NAD⁺ elevation in accessible tissue, skin-specific outcomes primarily preclinical.

Clinical Pearl: For clients enquiring about NAD⁺ supplementation, nicotinamide is the evidence-first recommendation – cheap, stable, well-absorbed, with decades of safety data and the strongest skin-specific outcome evidence. NMN and NR are biologically coherent options whose mechanistic rationale for bypassing the NAMPT bottleneck is sound, but their additional cost is not yet justified by skin-specific human outcome data at the level that nicotinamide achieves.

CD38 Inhibition: Addressing the Consumption Side

Since accelerated consumption rather than impaired synthesis is now understood to be the primary age-related driver of NAD⁺ depletion, strategies that reduce consumption rate represent a mechanistically distinct complement to precursor supplementation. Kang et al. (Cells, 2024) combined topical NAD⁺ with quercetin and enoxolone as CD38 expression inhibitors, demonstrating significantly greater sirtuin activation and fibroblast replicative lifespan extension than NAD⁺ supplementation alone. ^[3] This positions quercetin – already present in the aesthetics conversation for anti-inflammatory and antioxidant properties – as having a mechanistically distinct additional role: prolonging the half-life of NAD⁺ in the cell rather than increasing its supply. The evidence is from a single study and warrants characterisation as an emerging finding rather than an established recommendation.