A MODERN, NUTRIENT-BASED DEFENSE AGAINST …

A MODERN, NUTRIENT-BASED DEFENSE AGAINST INFLAMMATION AND AGING

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Table of Contents

A Lifestyle of Chronic Inflammation

When Short-Term Protection Becomes A Chronic Burden

Managing Inflammation for Immune Health

NAD+ Status and Inflammation

Nicotinamide Riboside (NR) Supplementation Boosts NAD+ Levels and Attenuates Inflammation

NR and the Body Function Synergistically to Help Your Clients and Patients

Adding Health to Years®

References

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A Lifestyle of Chronic Inflammation

Whether you are working with clients to optimize physical performance or regain control of health, you will inevitably be discussing the impacts of diet and lifestyle choices on health outcomes and performance. Published evidence suggests managing inflammation is integral to optimizing health, supporting immune function, and recovering from physical activity [1]. Underlying chronic inflammation appears to be a consistent factor in age-associated functional decline, even in relatively healthy individuals [2]. This article will discuss inflammation at the cellular level and how nicotinamide adenine dinucleotide (NAD+) and its vitamin B3 precursors play a role in managing inflammation.

When Short-term Protection Becomes a Chronic Burden

Research has demonstrated environmental and lifestyle factors such as poor diet, lack of exercise, and sleep deprivation can contribute to states of chronic underlying inflammation [3] known today as metaflammation and inflammaging. Inflammaging is defined as the long-term result of the chronic physiological stimulation of the innate immune system occurring later in life. Changes occur in numerous organ systems, such as the brain, gut, liver, kidney, adipose tissue, and muscle, which are driven by the seven pillars of aging (adaptation to stress, epigenetics, inflammation, macromolecular damage, metabolism, proteostasis, stem cells, and regeneration) [3].

“Metaflammation” is the metabolic inflammation accompanying metabolic diseases. This form of inflammation is thought to be caused by low nutrition density and overnutrition from excessive intake of highly refined carbohydrates, saturated and trans fat, and high sodium, and has similar characteristics to inflammaging. In both forms of chronic inflammation, the gut microbiota plays a role due to its function in the regulation of inflammatory factors, contribution to circadian rhythms, and crosstalk with other organs and systems [4].

Managing Inflammation for Immune Health Inflammation is the body’s natural protective response to harmful stimuli, including infection and injury. Therefore, it is important to keep in mind the goal is not to eradicate all inflammation, but to help clients support a healthy immune response, which helps mitigate chronic inflammation and support the body as it moves into recovery and repair.

Acute inflammation is the initial response to harm. Chemical signals are released by the infected or injured tissue causing white blood cells to rush to the site to begin the healing process. Uncontrolled inflammation may cause harm, as in the case of allergies, including food allergies, when the immune system is hypersensitive to harmless stimuli. More recently, inflammation has been studied for its role as a risk factor for a variety of chronic illnesses ranging from obesity to cardiovascular disease and cancer [5].

Inflammaging describes the association between chronic low-grade inflammation and age-associated dysfunction [6, 7] and is marked by an increased influx of proinflammatory immune cells, elevated IL-6 and tumor necrosis factor (TNF) cytokine levels, and

"NAD+ converts everything you eat into everything you are."

Charles Brenner, PhD, discoverer of the vitamin activity of NR, Alfred E Mann Family Foundation Chair of Diabetes & Cancer Metabolism at City of Hope



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activation of nucleotide oligomerization domain (NOD), leucine-rich repeat (LRR), and pyrin domain-containing protein 3 (NLRP3) inflammasome (a protein responding to cellular signals and can initiate an inflammatory form of cell death [6, 8]. Inflammaging is thought to contribute to the development of many age-associated disorders, including diabetes, cardiovascular disease, Alzheimer’s and other neurodegenerative diseases, and certain cancers [4, 6, 9].

Understanding the inflammatory process in the disease can help identify lifestyle choices that may promote or mitigate the body’s inflammatory state. Some lifestyle factors include consuming common nutrients recognized for their role in inflammation, such as omega-3 fatty acids, curcumin, and astaxanthin.

NAD+ Status and Inflammation

NAD+ is an essential molecule in all living cells and functions as a coenzyme in oxidation-reduction (redox) reactions. Intracellular NAD+ pools must be maintained to support critical cellular and metabolic processes, including ATP production and DNA repair. Research suggests NAD+ depletion is linked to innate immune dysfunction and modulation of NAD+ levels, indicating that NAD+ levels may have a critical impact on the function of immune cells [11, 12]. NAD+ supports cellular functions by serving as a co-substrate for several classes of proteins involved in the inflammatory response: CD38 glycohydrolases, polyADP ribose polymerase (PARP), and sirtuins (SIRT) [13-16]. Expression of these NAD+ consuming enzymes are activated during various types of metabolic stress such as poor diet, excess sun exposure, and a sedentary lifestyle [17-20][13-16][17-20]. These enzymes break down NAD+ into its component parts, using it as a source of ADP-ribose during inflammatory macrophage activation, which leads to NAD+ depletion.

"At the cellular level, the innate immune system is activated by infection and commits NAD+ to

self-defense. Early phase clinical work with Niagen shows that NR has anti-inflammatory activity in people."

Research suggests NAD+ depletion is linked to innate immune dysfunction and modulation of NAD+ levels may have a critical impact on the function of immune cells.

New preclinical science suggests an essential and ubiquitous coenzyme, nicotinamide adenine dinucleotide (NAD+) also plays a role in the inflammatory response. Given chronic inflammation accompanies many conditions, it is difficult to determine the extent to which inflammation is a cause vs. a manifestation of disease. The depletion of NAD+ is hypothesized to be both a source of inflammaging [10] and a contributing factor to poorly-controlled immune responses, including response to viral exposure, such as coronaviruses.

Immune stress due to viral exposure and other pathogens represents a challenge to our cells. Immediately upon infection, our cells’ defense mechanism is activated and upregulates NAD-dependent enzymes, primarily PARPs and SIRTs, to defend the cell. One function of SIRTs is to act as inflammatory sensors and regulators in immune cells, and an increase in SIRT activity results in a reduction of proinflammatory cytokines [21].

When PARPs and SIRTs are upregulated, NAD+ is depleted, making it less available for energy production, resulting in a decline in cellular health [10]. Therefore, maintaining a sufficient supply of NAD+ becomes critical.



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Nicotinamide Riboside (NR) Supplementation Boosts NAD+ Levels and Attenuates Inflammation

Methods such as routine fasting and regular, moderate exercise can increase the natural production of NAD+, but results vary, and these may not be viable options for everyone. While several supplements exist on the market, not all have been equally studied and safety validated. Nicotinamide Riboside (NR) helps replenish NAD+ levels and helps counter the effects of physiological and metabolic stressors [12, 17, 18, 22].

FIGURE 1. EFFECT OF DAILY NIAGEN® SUPPLEMENTATION ON NAD+ LEVELS

NR is also one of the most bioavailable of the NAD+ precursors [23]. Bioavailability is vital in determining whether the host cell is capable of blocking or feeding the infectious process, which ultimately determines whether the pathogen will thrive or be cleared within the host. NR supplementation is clinically proven to elevate NAD+ levels. Boosting NAD+ levels with a precursor such as NR may help to sustain the innate immune response. Heer et al. [24] showed NR was most effective at reducing viral replication in two different coronavirus-infected cell lines.

These studies outline how boosting NAD+ may be beneficial in supporting the innate immune system and managing inflammation. Trammel et. al. showed NR supplementation (up to 1000 mg/day) increased levels of NAD+ by 2.7-fold in peripheral blood mononuclear cells (PBMC) at eight hours post-ingestion [23].

Since its publication, additional research has shown this boost in NAD+ is accompanied by anti-inflammatory action. Oral NR administration for 5-9 days enhanced PBMC respiration and reduced gene expression of NLRP3 and inflammatory cytokines (IL-1b, IL-6, and IL-18) in four heart failure patients [25]. And in a placebo-controlled, randomized, double-blind, crossover trial of NR supplementation of 1g/day for 21 days in aged men, NR reduced levels of circulating inflammatory cytokines IL-6, IL-5, IL-2, and TNF-α [26].

NR and the Body Function Synergistically to Help Your Clients and Patients

We have learned environmental and lifestyle factors can lead to what has been termed as “inflammaging” and “metaflammation”. This chronic inflammaging taxes the immune system and can lead to age-associated disorders. NAD+ depletion is associated with increased inflammation. Of the NAD+ precursors, studies have shown NR is bioavailable and clinically proven to significantly elevate NAD+ levels by 51% at the 300 mg/day dose and 142% at 1000 mg/day within two weeks [27].

Increased NAD+ has been shown to have positive outcomes on inflammatory markers and supporting the immune system [25, 26]. Many individuals may be overwhelmed with lifestyle changes to help manage chronic inflammation. While dietary changes are likely needed to help manage inflammation, it may not be feasible for everyone or it may not be enough to impact positive change. Boosting NAD+ levels with NAD+ precursors such as NR in addition to lifestyle modification may be necessary to help combat inflammation at the cellular level and support health.



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ADDING HEALTH TO YEARS®

TRU NIAGEN® PRO is made with patented NIAGEN® nicot inamide r iboside, manufactured by ChromaDex Corp., a science-based integrated nutraceut ical company devoted to improving the way people age.

ChromaDex scient ists partner with leading univers i t ies and research inst i tut ions worldwide to discover, develop and create solut ions to del iver the fu l l potent ia l of NAD+ and i ts impact on human health.

TRU NIAGEN® PRO is backed with clinical and scientific research and sold exclusively by healthcare practitioners.

To learn more about TRU NIAGEN® PRO products,

visit: practitioner.truniagen.comV1.0

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References

1. Buonocore, D., et al., Anti-inflammatory Dietary Interventions and Supplements to Improve Performance during Athletic Training. J Am Coll Nutr, 2015. 34 Suppl 1: p. 62-7.

2. Singh, T. and A.B. Newman, Inflammatory markers in population studies of aging. Ageing Res Rev, 2011. 10(3): p. 319-29.

3. Furman, D., et al., Chronic inflammation in the etiology of disease across the life span. Nat Med, 2019. 25(12): p. 1822-1832.

4. Franceschi, C., et al., Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol, 2018. 14(10): p. 576-590.

5. Hotamisligil, G.S., Inflammation and metabolic disorders. Nature, 2006. 444(7121): p. 860-7.

6. Franceschi, C. and J. Campisi, Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci, 2014. 69 Suppl 1: p. S4-9.

7. Franceschi, C., et al., Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci, 2000. 908: p. 244-54.

8. Latz, E. and P. Duewell, NLRP3 inflammasome activation in inflammaging. Semin Immunol, 2018.

9. Pawelec, G., D. Goldeck, and E. Derhovanessian, Inflammation, ageing and chronic disease. Curr Opin Immunol, 2014. 29: p. 23-8.

10. Schultz, M., et al., NAD+ DEPLETION AS A CAUSE OF INFLAMMAGING. Innovation in Aging, 2018. 2(suppl_1): p. 746-746.

11. Minhas, P.S., et al., Macrophage de novo NAD(+) synthesis specifies immune function in aging and inflammation. Nat Immunol, 2018.

12. Mesquita, I., et al., Exploring NAD+ metabolism in host-pathogen interactions. Cell Mol Life Sci, 2016. 73(6): p. 1225-36.

13. Kim, M.Y., et al., NAD+-Dependent Modulation of Chromatin Structure and Transcription by Nucleosome Binding Properties of PARP-1. Cell, 2004. 119(6): p. 803-814.

14. Zocchi, E., et al., A single protein immunologically identified as CD38 displays NAD+ glycohydrolase, ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase activities at the outer surface of human erythrocytes. Biochemical and Biophysical Research Communications, 1993. 196(3): p. 1459-1465.

15. Imai, S., et al., Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature, 2000. 403(6771): p. 795-800.

16. Frye, R.A., Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochemical and Biophysical Research Communications, 1999. 260(1): p. 273-279.

17. Altay, O., et al., Combined metabolic cofactor supplementation accelerates recovery in mild-to-moderate COVID-19. MedRxiv, 2020.

18. Seyssel, K., et al., Regulation of energy metabolism and mitochondrial function in skeletal muscle during lipid overfeeding in healthy men. J Clin Endocrinol Metab, 2014. 99(7): p. E1254-62.

19. Costford, S.R., et al., Skeletal muscle NAMPT is induced by exercise in humans. Am J Physiol Endocrinol Metab, 2010. 298(1): p. E117-26.

20. Yiasemides, E., et al., Oral nicotinamide protects against ultraviolet radiation-induced immunosuppression in humans. Carcinogenesis, 2009. 30(1): p. 101-5.

21. Wang, X., et al., Sirtuins and Immuno-Metabolism of Sepsis. Int J Mol Sci, 2018. 19(9).

22. Covarrubias, A.J., et al., Senescent cells promote tissue NAD(+) decline during ageing via the activation of CD38(+) macrophages. Nat Metab, 2020. 2(11): p. 1265-1283.

23. Trammell, S.A., et al., Nicotinamide riboside is uniquely and orally bioavailable in mice and humans. Nat Commun, 2016. 7: p. 12948.

24. Heer, C.D., et al., Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity. J Biol Chem, 2020.

25. Zhou, B., et al., Boosting NAD Level Suppresses Inflammatory Activation of PBMC in Heart Failure. The Journal of Clinical Investigation, 2020.

26. Elhassan, Y.S., et al., Nicotinamide Riboside Augments the Aged Human Skeletal Muscle NAD(+) Metabolome and Induces Transcriptomic and Anti-inflammatory Signatures. Cell Rep, 2019. 28(7): p. 1717-1728 e6.

27. Conze, D., C. Brenner, and C.L. Kruger, Safety and Metabolism of Long-term Administration of NIAGEN (Nicotinamide Riboside Chloride) in a Randomized, Double-Blind, Placebo-controlled Clinical Trial of Healthy Overweight Adults. Sci Rep, 2019. 9(1): p. 9772.

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A MODERN, NUTRIENT-BASED DEFENSE AGAINST …