What Is NAD⁺ and Why Is It So Important?

Nicotinamide adenine dinucleotide (NAD⁺) is an essential coenzyme involved in cellular metabolism, DNA repair, mitochondrial function, and gene regulation through sirtuin activation. Found in every living cell, NAD⁺ plays a central role in maintaining cellular health and energy production.

However, NAD⁺ levels decline significantly with age, largely due to oxidative stress, inflammation, and circadian rhythm disruption (Covarrubias et al., 2021). This depletion impairs mitochondrial function, increases cellular senescence, and accelerates age-related degeneration. As such, NAD⁺ therapy is emerging as a core strategy in regenerative and aesthetic medicine (Conlon, 2022).

Why NAD⁺ Cannot Enter Cells Directly

Despite its importance, NAD⁺ is too large and polar to cross the plasma membrane unaided. When administered via intravenous (IV) or intramuscular (IM) routes, it does not directly enter cells. Instead, it is rapidly degraded in the extracellular environment by enzymes called ectoenzymes (Zeidler et al., 2022).

Step 1: Extracellular Breakdown by Ectoenzymes

Two key ectoenzymes, CD38 and CD157, catalyse the breakdown of extracellular NAD⁺ into smaller molecules. The primary product of this reaction is nicotinamide (NAM), a form of vitamin B3 that is bioavailable and capable of entering cells.

This enzymatic breakdown enables the body to utilize NAD⁺ precursors for cellular uptake and recycling (Poljšak et al., 2023).

Step 2: The NAD⁺ Salvage Pathway

Once nicotinamide enters the cell, it fuels the salvage pathway, which is the body’s primary and most energy-efficient route for regenerating NAD⁺. This process takes place in almost all cell types and is especially active in metabolically demanding tissues such as muscle, liver, brain, and immune cells (Feng et al., 2025).

Through this pathway, cells can maintain or restore intracellular NAD⁺ levels, powering critical processes like mitochondrial ATP synthesis, DNA repair, and SIRT1-mediated cellular longevity.

Step 3: How Injected NAD⁺ Works

Although NAD⁺ cannot be directly transported into cells, injected or infused NAD⁺ serves as a precursor reservoir adding to a depleted NAD+. Once in circulation, it is enzymatically degraded into NAM and NMN, which are then absorbed by tissues and used to rebuild NAD⁺ internally via the salvage pathway (Zeidler et al., 2022).

This internal regeneration supports:

• Mitochondrial energy metabolism
• Sirtuin (e.g. SIRT1) activation
• Cellular stress resistance
• DNA repair and anti-inflammatory functions
• Enhanced cell performance in tissues like skin, liver, muscle, and brain

Implications for Aesthetic and Regenerative Medicine

NAD⁺ therapy goes beyond energy support, it underpins true cellular rejuvenation. By maintaining mitochondrial efficiency, reducing oxidative damage, and promoting stem cell vitality, NAD⁺ optimisation is becoming a key element in medical aesthetics and anti-aging protocols (Conlon, 2022; Poljšak et al., 2023).

Clinical benefits of NAD⁺-based therapies include:

• Improved skin tone, elasticity, and repair capacity
• Accelerated recovery after aesthetic procedures
• Enhanced metabolic and cognitive performance
• Slowed progression of cellular aging

In Summary

• NAD⁺ cannot cross cell membranes and must be enzymatically broken down into bioavailable precursors like nicotinamide.
• The salvage pathway efficiently converts nicotinamide back into NAD⁺ through enzymes NAMPT and NMNAT.
• Injected NAD⁺ acts as a systemic source of precursors, fuelling intracellular NAD⁺ synthesis.
• Tissues with active salvage pathways benefit most, explaining NAD⁺ therapy’s impact on energy, repair, and rejuvenation.

References (Harvard Style)

Conlon, N.J., 2022. The role of NAD⁺ in regenerative medicine. Plastic and Reconstructive Surgery, 150(4S), pp.58S–65S. Available at: https://journals.lww.com/plasreconsurg/fulltext/2022/10002/the_role_of_nad__in_regenerative_medicine.8.aspx

Covarrubias, A.J., Perrone, R., Grozio, A. and Verdin, E., 2021. NAD⁺ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology, 22(2), pp.119–141. https://doi.org/10.1038/s41580-020-00313-x

Feng, Y., Qiu, H. and Chen, D., 2025. Regulation of stem cell function by NAD⁺. Physiology, 40(5), pp.318–330. https://journals.physiology.org/doi/abs/10.1152/physiol.00052.2024

Poljšak, B., Kovač, V., Špalj, S. and Milisav, I., 2023. The central role of the NAD⁺ molecule in the development of aging and the prevention of chronic age-related diseases: strategies for NAD⁺ modulation. International Journal of Molecular Sciences, 24(3), p.2959. https://www.mdpi.com/1422-0067/24/3/2959

Zeidler, J.D., Hogan, K.A. and Agorrody, G., 2022. The CD38 glycohydrolase and the NAD sink: implications for pathological conditions. American Journal of Physiology - Cell Physiology, 322(3), pp.C452–C467. https://doi.org/10.1152/ajpcell.00451.2021