Harnessing Youthfulness: Enhancing NAD+ Levels with Precursors for Robust Age-Delaying Disease Defense

NAD+ precursors play a critical role in rejuvenating dwindling NAD+ levels due to aging. Supplementation with these precursors can boost physical performance among middle-aged individuals and seniors. As we age, our NAD+ levels dip, leading to a decline in cellular energy production and DNA repair, accelerating aging and heightening the risk of age-related chronic diseases. A marked decrease in NAD+ availability has been detected throughout aging and in numerous age-related diseases.

Studies on animal models hint that elevating NAD+ levels during the aging process can prolong life, regulate aging mechanisms, and even decelerate aging. Enhancing NAD+ levels can positively influence various diseases and conditions, such as metabolic syndrome, type 2 diabetes, insulin sensitivity, cancer, cardiovascular disease, neurodegeneration, kidney function, inflammation reduction, and obesity prevention.

Boosting NAD+ Levels Using Precursor Molecules

NAD+ precursors in mammals include tryptophan, nicotinic acid, nicotinamide, nicotinamide mononucleotide (NMN), and nicotinamide riboside (NR). Our bodies generate and recycle NAD+ through three different pathways: the de novo synthesis pathway from tryptophan, the Preiss-Handler pathway from nicotinic acid or nicotinic acid ribose, and the salvage pathway from nicotinamide mononucleotide, nicotinamide, and nicotinamide riboside.

The salvage pathway is predominantly responsible for NAD+ production from nicotinamide, NR, and NMN, making these molecules the most promising candidates for NAD+ enhancement. Nicotinic acid and tryptophan require additional steps to produce NAD+, which reduces their attractiveness.

Due to the age-related decline of NAD+ levels, efforts to pharmaceutically restore them have been intensifying. These restoration strategies include supplementation with NAD+ precursors such as NR, NMN, and nicotinic acid.

Clinical Trials on NAD+ Precursors

Tryptophan

Found in protein-rich foods like milk, chicken, and nuts, tryptophan is arguably the least effective NAD+ precursor as it requires more biosynthesis steps to become NAD+. A dietary intake of 34 to 86 mg of tryptophan is equivalent to 1 mg of nicotinic acid (niacin).

Niacin

Found in foods like beef, fish, and poultry, niacin demonstrated an increase in blood and muscle NAD+ levels in patients with mitochondrial myopathy, along with strength and performance improvements with a dosage of 1000 mg. While niacin derivatives like acipimox have been used due to niacin’s tendency to cause flushing, they have shown enhanced energy production and mitochondrial function in older type 2 diabetes patients.

Nicotinamide

Found in various meats, legumes, and nuts, nicotinamide was tested for preventing type 1 diabetes in two human trials but failed to show effectiveness. Further research is needed to determine whether nicotinamide alone can combat aging in humans. However, when combined with D-ribose, it improved insulin sensitivity and reduced cortisol levels in middle-aged adults.

Nicotinamide Riboside

NR, like NMN, is a well-studied NAD+ precursor and is found in milk and is available as a supplement. Clinical trials showed that NR increased whole blood and white blood cell NAD+ levels in middle-aged and older adults. However, it did not boost muscle NAD+ levels in older adults, even at high doses.

Despite its inability to raise muscle NAD+ levels, NR reduced blood and heart inflammatory markers, hinting at its potential in lowering chronic inflammation, a major contributor to aging.

Nicotinamide Mononucleotide

NMN is the most direct precursor to NAD+, only one enzymatic step away from forming NAD+. Recent clinical trials revealed NMN's potential in treating age-related deficits. NMN effectively increased blood NAD+ levels in men, improved physical performance, and sleep quality, and even showed potential in preventing type 2 diabetes.

However, not all NMN supplements perform equally. While some brands showed no boost in NAD+ levels or improvement in physical endurance, others demonstrated impressive improvements in physical performance, sleep quality, skin aging, and insulin sensitivity in older adults.

Choosing the Right NAD+ Precursor Supplement

From the research, it seems most NAD+ precursors are safe with minimal side effects for most individuals. However, the long-term effects of these supplements in larger populations are yet to be investigated. Each precursor has been tested for different age-related deficits, making it unclear which ones are better for specific deficits. NR appears to be more effective when combined with other metabolic activators, while NMN seems to exhibit beneficial effects independently.

Conclusion

Enhancing NAD+ levels presents a promising pathway for managing the aging process and delaying age-related diseases. Although research continues to uncover the potential of NAD+ precursors, such as NMN, these findings offer hope for harnessing our biological clocks and improving health span.

References

  1. Imai, Si. The NAD World: A New Systemic Regulatory Network for Metabolism and Aging—Sirt1, Systemic NAD Biosynthesis, and Their Importance. Cell Biochem Biophys 53, 65–74 (2009). https://doi.org/10.1007/s12013-008-9041-4
  2. Poljšak B, Kovač V, Milisav I. Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies. Antioxidants (Basel). 2022 Aug 24;11(9):1637. doi: 10.3390/antiox11091637. PMID: 36139711; PMCID: PMC9495723.
  3. Zhang H, Ryu D, Wu Y, Gariani K, Wang X, Luan P, D’Amico D, Ropelle ER, Lutolf MP, Aebersold R, Schoonjans K, Menzies KJ, Auwerx J. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science. 2016 Jun 17;352(6292):1436-43. doi: 10.1126/science.aaf2693. Epub 2016 Apr 28. PMID: 27127236.
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