NAD+ boosters are substances or interventions designed to increase levels of NAD+ (Nicotinamide Adenine Dinucleotide), a critical coenzyme found in every cell, essential for cellular energy production, metabolism, and repair processes. Boosting NAD+ levels is of significant interest in the fields of health and longevity, as declining levels of NAD+ are associated with aging and various age-related diseases.

Overview of NAD+ Boosters

NAD+ Precursors

NAD+ precursors are compounds that serve as substrates in the biosynthesis of NAD+. They can be converted into NAD+ within the body, thus serving as effective NAD+ boosters.

Nicotinamide Mononucleotide (NMN): A compound that can directly stimulate NAD+ synthesis, playing a crucial role in energy metabolism and cell vitality.
Nicotinamide Riboside (NR): Another precursor that is converted into NMN in the body before participating in the synthesis of NAD+.
Nicotinamide (NAM): A form of vitamin B3, acts as an NAD+ precursor via the NAD+ salvage pathway.

Boosting NAD+ by Inhibiting NAD+ Consumers

NAD+ consumers (NADase) are enzymes that use NAD+ as a substrate, reducing the available NAD+ in the cell. By inhibiting these consumers, more NAD+ remains available for other cellular processes.

Sirtuins: A family of proteins that deacetylate proteins and consume NAD+ in the process. Compounds like resveratrol can activate sirtuins and the subsequent cellular effects can create an environment where cells might maintain or produce NAD+ more efficiently, which could indirectly support NAD+ availability.
PARPs (Poly(ADP-ribose) polymerases): Enzymes involved in DNA repair that also consume NAD+. Inhibiting PARP activity can help maintain NAD+ levels.
CD38: A glycoprotein that uses NAD+; reducing CD38 levels or activity can potentially elevate NAD+ levels.

Other NAD+ Boosting Compounds

Beyond precursors and inhibitors of NAD+ consumers, several other supplements claim to boost NAD+ levels or improve NAD+ metabolism.

Resveratrol: While primarily known as a sirtuin activator, it might also have indirect effects on NAD+ levels and metabolism.
Quercetin: A flavonoid that can inhibit CD38 and may, therefore, increase NAD+ levels indirectly.
Pterostilbene: A polyphenol, similar to resveratrol, purported to have beneficial effects on NAD+ metabolism and sirtuin activation.
Apigenin: A natural compound found in various fruits and vegetables, apigenin is studied for its potential to inhibit CD38 and may, therefore, increase NAD+ levels indirectly.

Interventions to Boost NAD+

Apart from supplements, certain lifestyle and dietary interventions may also support NAD+ levels.

Exercise: Regular physical activity has been shown to increase NAD+ levels, likely due to enhanced energy metabolism and increased demand for ATP.
Caloric Restriction: Reducing calorie intake without malnutrition can elevate NAD+ levels, potentially through the activation of sirtuins and improved metabolic efficiency.
Intermittent Fasting: This dietary approach can also elevate NAD+ levels, likely through mechanisms similar to caloric restriction, such as increased stress resistance and metabolic adaptations.

NAD+ Infusions

NAD+ infusions represent a direct method of increasing NAD+ levels in the body. This intervention involves intravenous administration of NAD+, allowing for higher bioavailability compared to oral supplements.

Effectiveness: NAD+ infusions have been reported to quickly elevate NAD+ levels, potentially offering immediate benefits such as enhanced energy, improved mood, and reduced withdrawal symptoms in addiction treatment.
Uses: This method is utilized primarily in clinical settings and is explored for its potential benefits in addressing conditions like chronic fatigue, addiction, and age-related cognitive decline.
Safety and Accessibility: While generally considered safe when administered under medical supervision, the accessibility, long-term effects, and optimal dosing of NAD+ infusions require further research and standardization.

Comparison

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Booster	Mechanism of Action	Relative Strength	Notes
Nicotinamide Mononucleotide (NMN)	NAD+ Precursor	High	Well-researched, direct precursor to NAD+
NR (Nicotinamide Riboside)	NAD+ Precursor	High	Converted to NMN in the body before participating in NAD+ synthesis
Nicotinamide (NAM)	NAD+ Precursor via the salvage pathway	Medium	More research needed on optimal dosing and long-term effects
Resveratrol	Sirtuin activator; may have indirect effects on NAD+ levels and metabolism	Low to Medium	Effectiveness may be influenced by individual metabolic differences and supplement formulation
Quercetin	Inhibits CD38; may increase NAD+ levels indirectly	Low to Medium	More research needed to quantify the impact on NAD+ levels
Pterostilbene	Similar to resveratrol; purported to have beneficial effects on NAD+ metabolism and sirtuin activation	Low to Medium	Requires more rigorous studies to confirm efficacy
Exercise	Increases NAD+ levels likely due to enhanced energy metabolism and increased demand for ATP	Medium to High	Effectiveness may depend on exercise type, intensity, and individual fitness level
Caloric Restriction	Elevates NAD+ levels potentially through the activation of sirtuins and improved metabolic efficiency	High	Sustained caloric restriction may have compliance challenges
Intermittent Fasting	Elevates NAD+ levels through mechanisms similar to caloric restriction	Medium to High	Impact may vary depending on the specific fasting protocol employed
NAD+ Infusion	Direct intravenous administration of NAD+	High	Rapid elevation of NAD+ levels; primarily used in clinical settings; requires further research on long-term effects and optimal dosing

Conclusion

NAD+ boosters, encompassing NAD+ precursors, inhibitors of NAD+ consuming enzymes, and various other supplements, along with non-supplemental measures like exercise and dietary modifications, offer promising avenues to enhance cellular vitality, metabolism, and potentially, longevity. While the science is evolving, understanding the diverse approaches to boost NAD+ highlights the multifaceted nature of cellular health and provides multiple pathways to explore for maintaining optimal health and combating age-related decline.

Todo

2022, A systems-approach to NAD+ restoration ^[1]
2022, Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies ^[2]

References

↑ Conlon N & Ford D: A systems-approach to NAD+ restoration. Biochem Pharmacol 2022. (PMID 35134387) [PubMed] [DOI] A decline in NAD+ is a feature of ageing and may play a causal role in the process. NAD+ plays a pivotal role in myriad processes important in cellular metabolism and is a cosubstrate for enzymes that play key roles in pathways that modify ageing. Thus, interventions that increase NAD+ may slow aspects of the ageing trajectory and there is great interest in pharmacological NAD+ restoration. Dietary supplementation with NAD+ precursors, particularly nicotinamide riboside, has increased NAD+ levels in several human intervention studies and arguably been the most robust approach to date. However, consistency and reliability of such approaches to increase NAD+, and also impact on markers of efficacy to slow or reverse features of ageing, has been inconsistent. We argue that a major element of this variability may arise from the use of single-target approaches that do not consider the underlying biological complexity leading to NAD+ decline. Thus, a systems approach - targeting multiple key nodes in the NAD+ interactome - is likely to be more efficacious and reliable.
↑ Poljšak B et al.: Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies. Antioxidants (Basel) 2022. (PMID 36139711) [PubMed] [DOI] [Full text] Precursors of nicotinamide adenine dinucleotide (NAD+), modulators of enzymes of the NAD+ biosynthesis pathways and inhibitors of NAD+ consuming enzymes, are the main boosters of NAD+. Increasing public awareness and interest in anti-ageing strategies and health-promoting lifestyles have grown the interest in the use of NAD+ boosters as dietary supplements, both in scientific circles and among the general population. Here, we discuss the current trends in NAD+ precursor usage as well as the uncertainties in dosage, timing, safety, and side effects. There are many unknowns regarding pharmacokinetics and pharmacodynamics, particularly bioavailability, metabolism, and tissue specificity of NAD+ boosters. Given the lack of long-term safety studies, there is a need for more clinical trials to determine the proper dose of NAD+ boosters and treatment duration for aging prevention and as disease therapy. Further research will also need to address the long-term consequences of increased NAD+ and the best approaches and combinations to increase NAD+ levels. The answers to the above questions will contribute to the more efficient and safer use of NAD+ boosters.

[pmid35134387-1] Conlon N & Ford D: A systems-approach to NAD+ restoration. Biochem Pharmacol 2022. (PMID 35134387) [PubMed] [DOI] A decline in NAD+ is a feature of ageing and may play a causal role in the process. NAD+ plays a pivotal role in myriad processes important in cellular metabolism and is a cosubstrate for enzymes that play key roles in pathways that modify ageing. Thus, interventions that increase NAD+ may slow aspects of the ageing trajectory and there is great interest in pharmacological NAD+ restoration. Dietary supplementation with NAD+ precursors, particularly nicotinamide riboside, has increased NAD+ levels in several human intervention studies and arguably been the most robust approach to date. However, consistency and reliability of such approaches to increase NAD+, and also impact on markers of efficacy to slow or reverse features of ageing, has been inconsistent. We argue that a major element of this variability may arise from the use of single-target approaches that do not consider the underlying biological complexity leading to NAD+ decline. Thus, a systems approach - targeting multiple key nodes in the NAD+ interactome - is likely to be more efficacious and reliable.

[pmid36139711-2] Poljšak B et al.: Current Uncertainties and Future Challenges Regarding NAD+ Boosting Strategies. Antioxidants (Basel) 2022. (PMID 36139711) [PubMed] [DOI] [Full text] Precursors of nicotinamide adenine dinucleotide (NAD+), modulators of enzymes of the NAD+ biosynthesis pathways and inhibitors of NAD+ consuming enzymes, are the main boosters of NAD+. Increasing public awareness and interest in anti-ageing strategies and health-promoting lifestyles have grown the interest in the use of NAD+ boosters as dietary supplements, both in scientific circles and among the general population. Here, we discuss the current trends in NAD+ precursor usage as well as the uncertainties in dosage, timing, safety, and side effects. There are many unknowns regarding pharmacokinetics and pharmacodynamics, particularly bioavailability, metabolism, and tissue specificity of NAD+ boosters. Given the lack of long-term safety studies, there is a need for more clinical trials to determine the proper dose of NAD+ boosters and treatment duration for aging prevention and as disease therapy. Further research will also need to address the long-term consequences of increased NAD+ and the best approaches and combinations to increase NAD+ levels. The answers to the above questions will contribute to the more efficient and safer use of NAD+ boosters.

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