NAD+: a review of the current state of research on mitochondrial metabolism

NAD+ (nicotinamide adenine dinucleotide) is a central coenzyme of cellular metabolism. Its intracellular concentration decreases with age in multiple tissues, which has positioned NAD+ and its precursors as subjects of intensive research in the biology of aging.

Main biochemical functions

1. Redox cofactor. NAD+/NADH is the main redox pair of glycolysis, β-oxidation and the Krebs cycle.
2. Substrate of sirtuins (SIRT1-7). Sirtuins are NAD+-dependent deacetylases that regulate the stress response, metabolism and chromatin repair.
3. Substrate of PARP1. A key polymerase in DNA damage repair. Under extensive damage, PARP1 consumes large amounts of NAD+.
4. Substrate of CD38 and CD73. Ectoenzymes that consume NAD+ in immune signaling.

The decline of NAD+ with age

Multiple studies have documented a 30–50% reduction in tissue NAD+ between young adults and older adults. Proposed causes include: increased CD38 activity, greater consumption by PARP1 due to accumulated DNA damage, and reduced de novo synthesis from tryptophan.

Replenishment pathways

There are four commonly investigated NAD+ precursors:

• Nicotinamide (NAM). Classic pathway; requires conversion to NMN and then to NAD+.
• Nicotinic acid (niacin). The Preiss-Handler pathway, known since the 1950s.
• Nicotinamide riboside (NR). Intensively investigated since 2007.
• Nicotinamide mononucleotide (NMN). One step closer to NAD+ than NR; its bioavailability is debated.

Direct administration of NAD+

Direct administration of NAD+ is a subject of recent research. The hypothesis is that it bypasses the enzymatic bottleneck of the precursors. In animal models, the following has been observed:

• Restoration of tissue NAD+ after intraperitoneal administration.
• Improvement of mitochondrial markers in aged skeletal muscle.
• Increased SIRT1 activity measured by acetylation levels of p53 and FOXO.

Important: the literature on exogenous NAD+ administration in humans is still limited and long-term clinical effects have not been established.

Observable markers in research

In preclinical studies, the following are typically monitored:

1. NAD+/NADH ratio in tissue (LC-MS).
2. SIRT1 activity (acetylation of substrates).
3. Mitochondrial biogenesis (PGC-1α, mitochondrial mass by TEM).
4. Oxidative capacity (oxygen consumption in isolated mitochondria).
5. Cellular senescence markers (p16, p21, SA-β-gal).

Conclusion

NAD+ is one of the few compounds whose relevance in cellular aging has a solid mechanistic basis. Translational research is in its early phases, but the weight of the preclinical evidence justifies the attention it receives.

🔬 Updated on March 4, 2026 · Reviewed by the NeoPeptidos team · Content for research purposes (RUO).