NAD+ and Cardiovascular Health: New Research for Aging Hearts

by Goldman Labs Team

Key Takeaways

NAD+ plays a crucial role in heart health, but levels decline significantly with age, contributing to cardiovascular disease progression. Here are the essential insights from current research:

• NAD+ levels drop by 50% by middle age, with the heart being particularly vulnerable due to its high energy demands and reliance on mitochondrial function for cardiac output.

• Age-related NAD+ decline drives heart aging through decreased ATP synthesis, increased oxidative stress, and mitochondrial dysfunction, ultimately leading to heart failure and reduced cardiac function.

• Common cardiovascular risk factors like obesity, hypertension, and diabetes all deplete NAD+ levels through inflammatory pathways and metabolic disruption, creating a vicious cycle of cardiac deterioration.

• NAD+ precursor supplementation shows promising clinical results including 6-9 mmHg blood pressure reductions, improved ejection fraction in heart failure patients, and enhanced vascular function.

• Early human trials demonstrate safety and tolerability of NAD+ precursors like NR and NMN at doses up to 2,000mg daily, though larger long-term studies are needed to establish optimal therapeutic protocols.

The research suggests NAD+ restoration may represent a novel therapeutic approach for aging hearts, offering hope for preventing and treating cardiovascular disease through metabolic intervention rather than traditional symptom management alone.

NAD+ cardiovascular health research reveals a concerning pattern: NAD+ pools decline with normal aging, obesity, and hypertension, all major risk factors for cardiovascular disease9. NAD+ deficiency serves as the main driver of heart aging. This results in decreased energy synthesis and may lead to heart failure23. Recent studies demonstrate that NAD+ replenishment extends healthspan and reduces blood pressure in preclinical models while avoiding metabolic syndrome9. This piece is about how NAD functions in heart health and how aging affects cardiac NAD+ levels. It also reviews current clinical evidence for NAD+ supplementation in cardiovascular conditions.

Understanding NAD+ and Its Role in Heart Function

What NAD+ Does in Your Body

Nicotinamide adenine dinucleotide acts as a central metabolite in cellular operations. NAD+ interacts with over 500 enzymes and participates in nearly every vital aspect of cell biology24. The molecule operates in two capacities: as a coenzyme for redox reactions and as a substrate for various NAD+-dependent enzymes.

As a coenzyme, NAD+ shuttles electrons between its oxidized (NAD+) and reduced (NADH) forms during oxidation-reduction reactions. This electron transfer captures or liberates cellular energy in the form of ATP9. The conversion happens during metabolic processes like glycolysis, the tricarboxylic acid cycle, fatty acid oxidation and oxidative phosphorylation in mitochondria25.

NAD+ also acts as a substrate for multiple enzyme families beyond energy metabolism. Sirtuins consume NAD+ while performing protein deacylation reactions that regulate gene expression and metabolic adaptation9. Poly(ADP-ribose) polymerases (PARPs) use NAD+ for DNA repair functions4. NAD+ glycohydrolases like CD38 and CD157 degrade NAD+ during cell signaling processes4. NAD+ influences DNA repair, chromatin remodeling, cellular senescence, immune cell function, inflammation control and stress responses through these activities45.

Why the Heart Needs NAD+

The heart ranks among the organs with the highest NAD+ levels, alongside the kidney and liver24. This elevated concentration reflects the cardiac muscle's extraordinary energy demands. Cardiomyocytes accumulate NAD+ mostly within their mitochondria, where the bulk of cellular oxidation-reduction reactions occur9. Cardiac mitochondrial NAD+ constitutes up to 70% of the whole cellular NAD+ pool25. Some estimates suggest over 80% of cellular NAD+ in cardiomyocytes resides in mitochondria26.

This mitochondrial enrichment stems from the high density of mitochondria within cardiomyocytes and the heart's substantial energy requirements26. Mitochondria produce adenosine triphosphate by coupling bioenergetic reactions, and their performance remains essential to maintain cardiac output25. Mitochondrial dysfunction represents a hallmark of heart disease progression25.

NAD+ also regulates mitochondrial calcium signaling and the production of reactive oxygen species25. Mitochondrial sirtuins play a major role in regulating mitochondrial energetics and ROS production under homeostatic conditions25. NAD+ pools are compartmentalized subcellularly, with concentrations that vary across the cytosol, nucleus and mitochondria25. Mitochondrial NAD+ homeostasis regulates mitochondrial function and cellular health, though the precise mechanisms controlling this balance remain not fully understood25.

NAD+ Biosynthesis Pathways

Mammalian cells generate NAD+ through two distinct routes: the de novo pathway and the salvage pathway24. The de novo pathway blends NAD+ from the amino acid tryptophan through the kynurenine metabolic pathway or from nicotinic acid via the Preiss-Handler pathway45. The liver handles de novo synthesis, but most extrahepatic organs, including the heart, lack the necessary enzymes for this process924.

The heart relies almost entirely on the salvage pathway. Researchers found that 99.3% of NAD+ in the heart generates through this route249. The salvage pathway recycles nicotinamide, a byproduct of NAD+ consumption reactions, back into NAD+4. Nicotinamide phosphoribosyltransferase (NAMPT) acts as the rate-limiting enzyme and converts nicotinamide into the intermediate product nicotinamide mononucleotide (NMN)249.

NMN then converts into NAD+ through NMN adenylyltransferases (NMNAT1-3) in the final step24. Nicotinamide riboside (NR) enters cells and converts to NMN via NR kinases (NRK1/2) as an alternative245. Both NMN and NR preserve the pyridine ring structure and bypass the need for NAMPT to convert back to NAD+24.

NAMPT appears to be the sole rate-limiting enzyme for NAD+ biosynthesis expressed in the healthy heart under physiological conditions9. Nicotinamide serves as the source of cardiac NAD+ under normal conditions, in part because nicotinamide is the most abundant NAD+ precursor in circulation at 2000 nmol/L compared to just 7 nmol/L for NR9. Visit our detailed guide on NAD+ and mitochondria for more information on how NAD+ functions at the cellular level.

How Aging Affects NAD+ Levels in the Heart

Diagram illustrating changes in mitochondrial dynamics affecting the aging heart's function and structure.

NAD+ Decline with Age

NAD+ concentrations inside cells decline with age in tissues of all types and species, humans included9. NAD+ levels drop to approximately half of youthful concentrations in both mice and humans by middle age. This comes with corresponding losses in sirtuin and PARP activity27. The decline in cardiac tissue varies between species and studies substantially, reporting anywhere from 0% to 65% reduction in 2-year-old rodents9.

Research comparing female Wistar rats of different ages found reduced NAD+ in the heart of 24-month-old rats compared to younger controls at 3 and 12 months28. This reduction occurred alongside an increase in NADH across tissues. The NAD+/NADH ratio skewed in the oldest group28. Multiple studies documented decreased NAD+ in liver, spleen, adipose tissue and skeletal muscle from mice between 5 and 32 months of age28. Wild-type mice at 32 months expressed about half the NAD+ of young mice27.

Factors Contributing to NAD+ Depletion

Steady-state NAD+ concentration declines either through progressive decay in biosynthesis or increased activity of degradation enzymes. Both mechanisms may combine9. A growing body of evidence implicates CD38 as a major culprit in age-related NAD+ decline in mammals9. CD38-deficient aged mice show increased NAD+ content in tissues of various types, while specific CD38 inhibitors reverse age-related degradation and improve cardiac function in aged mice9.

CD38 protein levels increased in multiple tissues during aging, along with corresponding increases in enzymatic activity27. SIRT1 and PARP1 levels did not change. CD38 expresses predominantly in immune cells and shows unique cellular localization with its catalytic site toward extracellular space, degrading circulating NMN in vivo9. Senescent cells accumulate and secrete proinflammatory cytokines that raise tissue CD38 levels progressively. This promotes age-associated diminution of NAD+ and NMN9. Senescent cells induce inflammation and begin a cycle that guides to NAD+ depletion, which activates more senescent cells subsequently29.

Downregulation of NAMPT has been implicated in age-related NAD+ decline across multiple tissues. Whether this occurs in the heart remains unknown9. Chronic inflammation damages metabolic tissues like fat, skeletal muscle and liver, where inflammatory cytokines decrease NAMPT levels30.

PARPs consume NAD+ to repair age-related DNA damage in aging tissues reportedly9. Postmitotic cardiomyocytes face accumulating metabolic and oxidative damage throughout their lifetimes, given their limited regenerative capacity. This causes DNA damage and PARP activation that reduces NAD+ concentration9. Heart failure tissue biopsies show increased reactive oxygen species and free radicals that raise PARP1 expression and activity, degrading NAD+ substrate31.

Effect on Cardiac Function

NAD+ deficiency serves as the main driver of heart aging and results in decreased energy synthesis23. The aging heart demonstrates thinning of the ventricular wall and enlargement of cardiac chamber diameter. Heart failure develops as the process continues23. Functional decline has low ejection fraction, reduced shortening fraction and increased left ventricular diameter, causing dilated cardiomyopathy and insufficient blood supply23.

Decreased ATP synthesis represents a major cause and inducer of heart failure in aging organisms23. Metabolic abnormality is the first thing to think over in NAD+-deficiency-induced aging, with low aerobic energy supply and high glycolysis levels driving tissue aging23. The reduction in mitochondrial NAD+ preservation may induce cardiomyocyte senescence, and this is a big deal. It manifests as decreased adaptability to adverse changes such as high glucose, hypoxia, drug stress or ischemia-reperfusion injury23.

Oxidative stress injury remains a common feature in cardiac aging32. DNA damage represents a key aging factor associated with aging-induced inflammatory response commonly32. Exogenous NAD+ supplementation or overexpression of NAMPT or NMN adenylyltransferase restores cellular NAD+ levels and prevents cardiac myocyte death in vitro9. Late-in-life dietary nicotinamide intake delays cardiac aging hallmarks in C57BL/6 mice. This has reduced cardiac hypertrophy and diastolic dysfunction9. Visit our guide on NAD+ and longevity to learn more about how NAD+ influences aging processes.

NAD+ and Common Cardiovascular Risk Factors

Cardiovascular risk factors include unhealthy diet, lack of exercise, obesity, smoking, mental stress, alcohol, high blood pressure, sugar, and cholesterol.

Cardiovascular risk factors cluster together in patients often. They share common metabolic disturbances that affect NAD+ homeostasis. Obesity, hypertension and diabetes represent three interconnected conditions where NAD+ dysregulation plays a central role in disease progression.

NAD+ in Obesity and Metabolic Health

Multiple mechanisms drive NAD+ decline in obesity, with subclinical inflammation playing a key role. The inflammatory state associated with obesity downregulates NAMPT expression and reduces NAD+ salvage pathway activity in tissues of all types8. Mice with adipocyte-specific NAMPT deletion develop severe multi-organ insulin resistance. The heart shows a 50% reduction in insulin-induced glucose uptake, which NMN supplementation can reverse9.

High-fat diet models demonstrate that PARP depletion boosts NAD+ levels and increases SIRT1 activity. Mitochondrial function improves as well8. CD38 deficiency protects mouse hearts from high-fat diet-induced oxidative stress by activating the SIRT3/FOXO3-mediated antioxidative stress pathway9. Chronic inflammation affects systemic metabolic processes through intricate crosstalk between immune cells and metabolism. Persistent low-grade inflammation links causally to age-dependent NAD+ decrease8.

NAD+ precursor supplementation produces measurable metabolic benefits. Intraperitoneal NMN injection stimulates NAD+ biosynthesis and reinstates blood glucose control in obese wild-type mice9. Chronic NAM supplementation in aged mice fed high-fat diets induces marked reduction in inflammation and ameliorates healthspan8. If you're interested in NAD+ supplementation options, visit our guide on the best NAD+ supplements.

NAD+ in Hypertension

Hypertensive patients exhibit depleted NAD+ levels compared to healthy controls. Research with 102 participants found NAD+ levels decreased by 44% in peripheral blood mononuclear cells from hypertensive patients33. Aortic tissue from hypertensive patients showed NAD+ reductions of 47.7%33. These decreases relate negatively with blood pressure elevation and associate with impaired vascular function as measured by flow-mediated dilation and pulse wave velocity33.

Clinical intervention studies demonstrate therapeutic potential for NAD+ restoration in hypertension. A trial administering NMN supplement for 6 weeks to hypertensive patients produced a 43% increase in NAD+ levels. Systolic blood pressure reduced by 6.11 mmHg and diastolic blood pressure reduced by 3.56 mmHg33. Flow-mediated dilation improved by 0.6%, while pulse wave velocity decreased by 116.66 cm/s33. A detailed meta-analysis of 29 studies with 8,664 participants confirmed substantial reductions in systolic blood pressure (2.54 mmHg) and diastolic blood pressure (2.15 mmHg) with NAD+ precursor supplementation10.

Endothelial CD38 activation drives NAD+ degradation in hypertension. Macrophage-derived IL-1β production activates the JAK1/STAT1 signaling pathway in endothelial cells and contributes to CD38 overexpression. This accelerates NAD+ breakdown33.

NAD+ in Diabetes

Diabetes disrupts cardiac NAD+ redox balance and promotes protein hyperacetylation. Mitochondrial dysfunction follows. Hyperglycemia associates with decreased NAD+/NADH ratio in diabetic organs11. Mouse models with mitochondrial complex I deficiency show exacerbated cardiac dysfunction when challenged with diabetic stress. The dysfunction is characterized by increased superoxide dismutase 2 acetylation, oxidative stress and impaired energetics11. NAMPT overexpression normalizes NAD+/NADH ratio and reverses these pathogenic mechanisms in diabetic hearts11.

NAD+ administration substantially improves cardiac outcomes in diabetic mice with myocardial infarction. Cardiac function improved compared to non-diabetic mice. NAD+ reduced cardiac injury area and facilitated angiogenesis in infarction zones1. NAD+ promotes M2 macrophage polarization and regulates VEGF alternative splicing. This generates pro-angiogenic VEGF165 while inhibiting anti-angiogenic VEGF165b1.

NAD+ Research in Specific Heart Conditions

Specific cardiac conditions show distinct patterns of NAD+ dysregulation. Targeted research reveals therapeutic opportunities in multiple disease states.

Ischemic Heart Disease and Heart Attacks

Cardiac NAD+ levels decline faster when ischemia-reperfusion injury occurs. Depletion becomes detectable as early as 15 minutes after I/R in mice12. Experimental models show myocardial NAD+ deficiency in both ischemic and nonischemic cardiac regions9. Cardiomyocytes move to glycolysis for ATP production when ischemia sets in. This requires recycling of glycolysis-produced NADH through the malate-aspartate shuttle to maintain glycolytic activity13.

Genetic studies explain how NAD+ provides protection. CD38-deficient mice preserve their NAD+ pool and resist myocardial ischemia and I/R injuries9. Mice with cardiomyocyte-specific NAMPT overexpression show protection from cardiac decline in NAD+ and ATP pools. They also have reduced myocardial infarction in vivo9. NAMPT downregulates at protein and mRNA levels in response to ischemia or I/R9.

NAD+ precursor supplementation produces substantial cardioprotection. Mice treated with NR exhibit higher ejection fraction and smaller infarct size after I/R9. Intraperitoneal NMN injection to aged rats preserves the NAD+/NADH ratio. This leads to smaller infarct size, preserved cardiac function, intact mitochondrial membrane potential, and reduced reactive oxygen species levels9. A swine model showed that intravenous NAD+ injection before reperfusion reduced myocardial necrosis, fibrosis and inflammation by a lot while promoting recovery of cardiac function9.

A clinical trial in 180 adults with ischemic cardiomyopathy showed that NAD+ treatment improved left ventricular ejection fraction to 45.44% compared to 42.44% in placebo at 1 month14. The 6-month composite event rate appeared lower in the NAD+ group at 14.6% versus 24.7% in placebo14.

Heart Failure with Preserved Ejection Fraction

HFpEF represents an especially difficult cardiac condition where NAD+ cardiovascular health research shows promise. Patients with HFpEF exhibit cardiac NAD+ deficit associated with diastolic dysfunction15. Mouse models combining metabolic and mechanical stressors summarize key HFpEF features. These include left ventricular hypertrophy, diastolic dysfunction, oxidative stress and fibrosis6.

Nicotinamide riboside supplementation over 8 weeks improved diastolic function, left ventricular hypertrophy, exercise capacity and pulmonary congestion despite ongoing stress6. NR-mediated NAD+ repletion reversed VLCAD hyperacetylation without correcting overall bulk mitochondrial protein acetylation6. Nicotinamide improved cardiomyocyte passive stiffness and calcium-dependent relaxation through deacetylation of titin and SERCA2a via a SIRT1-dependent mechanism15.

Arrhythmias and Electrical Problems

NAD+ modulates cardiac sodium channel Nav1.5 function through multiple pathways. A reduced NAD+/NADH ratio alters Nav1.5 expression and conductance through NADH-dependent protein kinase C activation9. NAD+ administration to isolated mouse hearts with Nav1.5 haploinsufficiency reduces ventricular tachycardia risk9. Human failing heart studies show that NAD+ application increases conduction velocity at multiple pacing cycle lengths12.

Dilated Cardiomyopathy

DCM associates with reduced NAMPT expression alongside NMRK2 upregulation9. Researchers observed a 30% loss in NAD+ levels in murine failing hearts of DCM models. This came with decreased NAMPT expression7. The NMRK2 enzyme increased 40-fold in DCM models compared to 4-fold in pressure overload models7. This shift also appeared in human failing heart biopsies compared to non-failing controls7. NR supplementation stabilized myocardial NAD+ levels and attenuated heart failure development more effectively in DCM than in pressure overload models7. Visit our guide on NAD+ and mitochondria to learn more about how NAD+ supports cellular energy production in these conditions.

NAD+ Precursors: Types and How They Work

Chemical structure diagram of NAD+ molecule showing its components and phosphate groups.

Several NAD+ precursor molecules can lift tissue NAD+ concentrations. Each follows distinct metabolic routes with varying efficiency profiles.

Nicotinamide (NAM)

Scientists found nicotinamide alongside niacin in the late 1930s. It became the preferred form for nutritional supplementation because it avoids the flushing reaction that niacin intake causes2. NAM supports NAD+ synthesis through the salvage pathway. A two-step process recycles nicotinamide back into NAD+2. Circulating NAM accounts for 95% of liver release and serves as the main NAD+ source for peripheral tissues5.

High doses of nicotinamide inhibit sirtuins though. This family of NAD+-dependent enzymes is involved in cellular metabolism, DNA repair and stress response2. A recent human trial found that NAM supplementation at 0.5 grams daily for 14 days did not increase whole-blood NAD+ levels by a lot16.

Nicotinamide Riboside (NR)

Scientists first found nicotinamide riboside in the 1940s. It gained recognition as an effective NAD+ precursor in 20042. NR belongs to the vitamin B3 family and appears naturally in milk. You would need to consume approximately 87 gallons to get a typical 300 milligram supplement dose2. NR causes no flushing unlike niacin. It does not inhibit sirtuin activity unlike nicotinamide2.

NR enters cells through equilibrative nucleoside transporters. It converts to NMN via NR kinases before final conversion to NAD+54. Human studies demonstrate dose-dependent NAD+ increases. Taking 1 gram daily produces approximately 2-fold elevation in whole-blood NAD+ after 14 days16. NR has shown benefits in arterial function and oxidative stress reduction for cardiovascular applications, as I wrote in our piece on NAD+ and longevity.

Nicotinamide Mononucleotide (NMN)

NMN represents an intermediate molecule formed during nicotinamide and NR conversion to NAD+. It is not a vitamin B3 form2. Research suggested that extracellular NMN required conversion to NR before cellular entry4. Recent work found SLC12A8 as a specific NMN transporter that is highly expressed in small intestine4.

Human trials using 1 gram daily NMN supplementation achieved similar 2-fold increases in whole-blood NAD+ as NR after 14 days16.

Comparing Different NAD+ Precursors

Both NR and NMN lift whole-blood NAD+ concentrations by a lot compared to placebo. The concentration differences are 49.4 micromolar and 43.1 micromolar respectively16. NAM showed no effect by contrast16. The gut microbiome metabolizes both NR and NMN. It converts them to nicotinic acid through bacterial hydrolysis and deamidation16.

Clinical Evidence: NAD+ Supplementation in Humans

Diagram showing decreased NAD+ synthesis pathways linked to aging, metabolic, cardiovascular, and neurodegenerative diseases, with benefits of NAD+ supplementation.

Safety and Tolerability Studies

Clinical trials confirm NAD+ precursors demonstrate favorable safety profiles in human subjects. The FDA granted NR "Generally Recognized as Safe" status. Health Canada, EFSA, and Australia's Therapeutic Goods Administration approved it as well17. Doses up to 2,000 mg daily for periods extending to 20 weeks produced no serious adverse events18. A systematic review of 10 studies with 489 participants found supplementation well tolerated. Minor side effects included muscle pain, fatigue, and headaches19. Compliance rates exceeded 95% across multiple trials2018.

Effects on Blood Pressure and Vascular Health

NR supplementation at 1,000 mg daily for 6 weeks tended to lower systolic blood pressure by 3.9 mmHg in middle-aged adults21. Subjects with elevated baseline blood pressure experienced systolic reductions of 9 mmHg21. Carotid-femoral pulse wave velocity showed trends toward reduction, which indicates improved arterial stiffness2122.

Results in Heart Failure Patients

A randomized trial of 180 adults with ischemic cardiomyopathy receiving intravenous NAD+ showed substantially improved left ventricular ejection fraction at 1 month (45.44% vs 42.44%, p=0.024)14. The 6-month composite event rate appeared lower at 14.6% versus 24.7% in placebo14. Oral NR at 2 g daily for 12 weeks doubled whole blood NAD+ levels in HFrEF patients. This correlated with improved mitochondrial respiration and decreased inflammatory markers20.

Current Limitations and Future Research Needs

Current evidence relies on small participant numbers and short treatment periods despite encouraging results143. The safety dose, therapeutic window, and optimal treatment duration remain undetermined17. Larger multicenter trials with clinical endpoints are warranted1417.

Conclusion

NAD+ cardiovascular health research demonstrates compelling connections between declining NAD+ levels and heart disease progression. The heart's high energy demands make it especially vulnerable to age-related NAD+ depletion, which contributes to metabolic dysfunction, oxidative stress, and cardiovascular complications.

Emerging evidence from preclinical and early clinical studies suggests NAD+ precursor supplementation may offer benefits for heart health, especially in conditions like hypertension, heart failure, and ischemic injury. Current safety data appears positive. However, the field just needs larger, longer-term trials to establish optimal dosing strategies and confirm clinical effectiveness. Those interested in learning about NAD+ and longevity or NAD+ supplementation options should consult healthcare providers first.

FAQs

Q1. How does NAD+ support heart function? NAD+ serves as a critical coenzyme for energy production in heart cells, particularly within mitochondria where up to 70-80% of cardiac NAD+ is concentrated. It facilitates electron transfer during metabolic processes that generate ATP, the energy currency cells need to function. Additionally, NAD+ acts as a substrate for enzymes involved in DNA repair, gene expression regulation, and stress response—all essential for maintaining healthy cardiac function.

Q2. Why do NAD+ levels decrease as we age? NAD+ levels decline with age due to several factors. The enzyme CD38, which breaks down NAD+, increases in activity as we get older, particularly due to inflammation and accumulating senescent cells. Additionally, the enzyme NAMPT, which helps produce NAD+, may decrease with age in some tissues. DNA damage from oxidative stress also activates PARP enzymes that consume NAD+ for repair processes, further depleting cellular stores.

Q3. Can NAD+ supplementation help with high blood pressure? Clinical studies show promising results for NAD+ precursors in managing hypertension. Research found that NMN supplementation for 6 weeks increased NAD+ levels by 43% and reduced systolic blood pressure by approximately 6 mmHg and diastolic pressure by 3.5 mmHg. A meta-analysis of multiple studies confirmed significant blood pressure reductions with NAD+ precursor supplementation, along with improvements in vascular function markers.

Q4. What's the difference between NMN and NR supplements? Both NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside) are NAD+ precursors that effectively raise NAD+ levels in the body. NR enters cells through specific transporters and converts to NMN before becoming NAD+, while NMN may enter cells directly through the SLC12A8 transporter. Human studies show both compounds produce similar increases in blood NAD+ levels when taken at 1 gram daily, roughly doubling NAD+ concentrations after two weeks.

Q5. Are NAD+ supplements safe for long-term use? Current clinical evidence indicates NAD+ precursors have favorable safety profiles. NR has received "Generally Recognized as Safe" status from the FDA, and studies using doses up to 2,000 mg daily for up to 20 weeks reported no serious adverse events. Minor side effects like muscle pain, fatigue, or headaches occurred infrequently. However, optimal long-term dosing and extended safety data from larger trials are still needed to fully establish safety parameters.

References

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