Precursor Molecules in NAD⁺ Production
Vitamin B3 is the primary source of NAD⁺ production.
Different forms of B3 are used as supplements to increase NAD⁺ levels .
The forms and derivatives of vitamin B3 used as a source of NAD⁺ are:
Natural Forms:
These are the classic, well-known forms commonly found in nature and in food. * Approved by EFSA .
• Nicotinic acid (NA, niacin) is effective in lowering cholesterol levels and supporting heart health at high doses. These effects are specific to the nicotinic acid form. Very high doses may be required for these effects, and these doses should be taken under medical supervision. The most common side effect is flushing (redness, hot flashes, itching of the face and skin), therefore its use is limited. Very high doses may also cause side effects on the liver.
• Nicotinamide (NAM, niacinamide) is more effective in areas such as energy production, DNA repair, cellular aging processes, and skin health. It penetrates the skin barrier and increases NAD levels in skin cells. Its positive effects on the skin have been proven. It does not experience the side effects seen with nicotinic acid.
Newly Defined Derivatives:
• Nicotinamide Riboside (NR) is found in trace amounts in nature. It provides a more direct and greater effect in raising NAD+ levels, therefore it can be preferred over nicotinamide. It does not produce the side effects seen with nicotinic acid. This form is generally marketed for its potential anti-aging properties. EFSA has also accepted this form as a “Vitamin B3 form” and given it “novel food” approval.
• Nicotinamide Mononucleotide (NMN): Directly participates in NAD⁺ synthesis. However, it is not classified as a form of vitamin B3.*EFSA (European Health Authority) approval is not yet available.
What is NAD⁺ ? What are its functions in the body?
NAD⁺ (Nicotinamide Adenine Dinucleotide) is a critical coenzyme involved in essential biological processes in cells. Because its levels decrease with age, supplementation is thought to slow the effects of aging.
NAD Tasks:
- Intracellular energy production (ATP synthesis)
- DNA repair (via PARP enzymes)
- Sirtuin activation (anti-aging mechanisms)
- Oxidative stress regulation
* EFSA (European Food Safety Authority) is the most authoritative body in the European Union regarding food safety and nutrition. It evaluates health claims for vitamin and mineral supplements based on scientific evidence and determines which claims can be presented to consumers.
In Turkey, the Ministry of Health and the Ministry of Agriculture and Forestry refer to EFSA’s decisions and scientific assessments. Therefore, health claims approved by EFSA are considered valid in Turkey and can be used on product labels.
Vitamin B3 (Niacin) Approved Health Claims
Health claims for vitamin B3 (niacin, nicotinamide, nicotinamide riboside) approved
by organizations such as EFSA and FDA, and also approved in Türkiye:
- It contributes to energy metabolism.
- It contributes to the normal functioning of the nervous system.
- It helps protect the skin and mucous membranes.
- It helps reduce fatigue and exhaustion.
However, it has not been proven that approved health claims will be effective in the absence of deficiencies.
For example, vitamin B3 and its various forms contribute to energy metabolism by
increasing NAD⁺ levels, but may not provide a directly noticeable increase in energy because
energy production is not solely dependent on NAD⁺ levels; mitochondrial function,
oxygen transport, hormone balance, other vitamin and mineral levels, and
lifestyle factors all work together.
Why is the claim that it “stops aging” not verified?
The underlying mechanism of these health claims is the increase in NAD⁺. However, clinical evidence is based on the benefits of vitamin replacement in cases of deficiency. Therefore, supplementation can be effective if there is a niacin deficiency.
But claims such as “stopping aging” or “extending lifespan through sirtuin activation” are not among the approved health claims. Because:
- These claims have not yet been clinically proven, meaning such effects have not been observed in humans when tested, and therefore have not been approved by regulation.
- NAD⁺ decline is part of aging, but it is not the only cause; aging is a much more complex process and cannot be stopped simply by replacing NAD⁺.
- NAD⁺ supplementation can even have a counterproductive effect. When NAD⁺ levels become too high, some NAD⁺-consuming enzymes (e.g., PARP, CD38) can become overactivated. This can increase NAD⁺ consumption, thereby reducing sirtuin activation. So, “too much NAD⁺” may not always be beneficial.
Pathways in NAD⁺ Production
Each form or derivative of B3 (NAM, NR, NMN, NA) follows a different pathway to produce NAD⁺ after entering the cell.
The enzymes used in these pathways and the number of steps they involve differ:
- NA (Nicotinic Acid) → follows a longer path with enzymes such as NAPRT, NMNAT and QPRT.
- NAM (Nicotinamide) is converted to NMN by the NAMPT enzyme, and then NAD⁺ is formed by NMNAT.
- NR (Nicotinamide Riboside) is converted to NMN by the NRK1 enzyme, followed by the formation of NAD⁺.
- NMN (Nicotinamide Mononucleotide) → becomes NAD⁺ directly with NMNAT enzyme (one step)
Capacity of the Precursor Molecule to Enter the Cell
In this case, the shortest pathway in NAD⁺ biosynthesis operates via NMN. This pathway has fewer steps; therefore, enzyme dependence and the risk of loss in intermediate steps are also reduced.
However, the efficiency of NAD⁺ production depends not only on the pathway length but also on the capacity of the precursor molecule used to enter the cell:
Nicotinic acid (NA) cannot cross the cell membrane; it is taken up into the cell via monocarboxylate transporters such as SMCT1 (SLC5A8) and MCT (SLC22A13).
Due to its small and neutral structure, NAM can pass through the cell membrane via passive diffusion without the need for a carrier → this allows for wide tissue access.
Due to its phosphate structure, NMN cannot directly cross the cell membrane. Therefore, in humans, the entry of NMN into the cell is most likely indirect: it is converted to NR (Nicotinamide Riboside ) or NAM (Nicotinamide) in the extracellular environment , and then taken up into the cell.
NR enters the cell via passive transport with ENT1 and ENT2 transporters → it is transporter-dependent but does not require energy. Furthermore, NR does not require the NAMPT enzyme, which decreases with age in NAD⁺ production → this provides an advantage in terms of age-related systemic effects.
Regarding skin cells specifically:
- NAM and NR can pass into epidermal and dermal cells via passive diffusion → in topical applications, they directly support intracellular NAD⁺ production.
- The effect of NMN depends on the level of SLC12A8 transporter in the skin; therefore, the local effect may be limited.
| Input Capacity | Input Capacity | Reason |
| Nicotinamide (NAM) | Very high | Neutral, small, lipophilic; easily passes through by passive diffusion. No carrier required. |
| Nicotinamide Riboside (NR) | High | Actively transported by ENT carriers, moderate lipophilicity, carriers are common. |
| Nicotinic Acid (NA) | Medium | Carrier-dependent (SMCT1, MCT), ionic structure, high expression in some tissues. |
| Nicotinamide Mononucleotide (NMN) | Low-Medium | Due to its phosphate structure, it is charged. Carrier (Slc12a8). Carrier presence is debatable in humans. Possibility of passing through only by converting to NR. |
| NADH | Low | Large and heavily loaded, with limited carrier availability, passage into mitochondria is even more difficult. |
| NAD+ | Very low | It cannot directly cross the cell membrane; carriers are insufficient; it can only be effective through intracellular synthesis . |
Summary and Comparison of Vitamin B3 Forms
NA (Nicotinic Acid)
- Cell entry: SMCT1/MCT transporters
- Pathway length: 3–4 steps (Preiss–Handler)
- NAD⁺ production potential: Medium
- EFSA* approval: ✅ (2010)
- Additional information: Flushing effect; high carrier expression in the intestine, kidney, and liver.
NAM (Nicotinamide)
- Entry into the cell: Passive diffusion
- Pathway length: 2 steps (Salvage pathway)
- NAD⁺ production potential: High
- EFSA* approval: ✅ (2010)
- Additional information: No flushing; NAMPT enzyme may decrease with age.
NR (Nicotinamide Riboside)
- Entry into the cell: ENT transporters
- Pathway length: 2 steps (NRK → NMNAT)
- NAD⁺ production potential: High
- EFSA* approval: ✅ (2019/2020)
- Additional information: No flushing; ENT competition exists but is not clinically significant.
NMN (Nicotinamide Mononucleotide)
- Entry into the cell: Cannot pass directly; indirectly converted to NR/NAM.
- Pathway length: 1 step (NMNAT)
- NAD⁺ production potential: High
- EFSA* approval: ❌ (Not available as of 2025)
- Additional information: The Slc12a8 transporter in humans is controversial; it is being extensively studied in clinical trials.
NAD⁺ (Nicotinamide Adenine Dinucleotide)
- Entry into the cell: Cannot pass directly (large molecule)
- Pathway length: —
- NAD⁺ production potential: Low (oral)
- EFSA* approval: ❌ (Not available as of 2025)
- Additional information: Systemic levels may be increased with IV/IM administration; oral bioavailability is limited.
In conclusion, NAM and NR are prominent B3 derivatives due to both their easy entry into cells and their effectiveness in NAD⁺ production. These forms can also be considered when choosing supplements, as they are the most researched and prominent components
in clinical studies for increasing NAD⁺ levels .