NAD Supplementation for Brain Health in Aging
Recruiting in Palo Alto (17 mi)
Overseen byAndriy Yabluchanskiy, MD, PhD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 4
Recruiting
Sponsor: University of Oklahoma
Must not be taking: NAD enhancers
Disqualifiers: CNS disease, Major psychiatric, others
Prior Safety Data
Trial Summary
What is the purpose of this trial?This trial tests if taking Nicotinamide Riboside (NR), a form of Vitamin B3, can improve brain health and memory in older adults aged 60-85 by boosting a molecule called NAD that helps with energy and cell health. Nicotinamide Riboside (NR) is a precursor to NAD+, which has been identified as a promising treatment strategy for age-related cognitive decline and other conditions.
Will I have to stop taking my current medications?
The trial does not specify if you need to stop taking your current medications, but you cannot take other NAD enhancers like Nicotinamide riboside or nicotinamide mononucleotide within 4 weeks before starting the trial.
What data supports the effectiveness of the treatment Nicotinamide riboside for brain health in aging?
Research shows that Nicotinamide riboside (NR) can increase NAD+ levels, which are important for energy metabolism, and improve brain function in some animal models of neurodegeneration. In humans, NR supplementation has been shown to raise NAD+ levels and modify biomarkers related to neurodegenerative diseases, suggesting potential benefits for brain health.
12345Is NAD supplementation safe for humans?
Nicotinamide riboside (NR), a form of NAD supplementation, has been shown to be generally safe in humans. Studies have found no significant differences in adverse events between NR and placebo groups, and it is recognized as safe for use in foods and dietary supplements. However, high doses of a related compound, nicotinamide, may pose potential risks for long-term use.
24678How does the drug nicotinamide riboside differ from other treatments for brain health in aging?
Nicotinamide riboside is unique because it boosts NAD+ levels, which are important for energy metabolism and brain function, and it has shown potential in improving cognitive function and reducing neurodegenerative markers in aging and Alzheimer's models. Unlike other treatments, it is a precursor to NAD+ and can be taken orally, making it a convenient option for enhancing brain health.
12345Eligibility Criteria
This trial is for people aged 60 to 85 who can read and write in English, have good enough vision and hearing to participate, and can give informed consent. It's not for those with recent severe strokes, major uncontrolled psychiatric conditions, substance abuse issues, active brain diseases or poor kidney function.Inclusion Criteria
I am between 60 and 85 years old.
I can see and hear well enough to undergo tests.
I understand and can agree to the study's procedures and risks.
+1 more
Exclusion Criteria
I haven't taken NAD enhancers like nicotinamide riboside or mononucleotide in the last 4 weeks.
You have a serious mental illness, such as severe depression that is not well controlled with medication, or you have a problem with alcohol or drug abuse.
I have not had a stroke, excluding TIA, in the last 60 days.
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants receive either Nicotinamide Riboside (NR) or placebo daily for 8 weeks to assess effects on neurovascular coupling and endothelial function
8 weeks
Weekly visits for monitoring and assessments
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
2 visits (in-person)
Participant Groups
The study tests if Nicotinamide Riboside (NR), a form of Vitamin B3, improves brain health and memory in older adults. Participants will take NR daily or a placebo without knowing which one they're getting to compare the effects fairly.
2Treatment groups
Experimental Treatment
Placebo Group
Group I: NRExperimental Treatment1 Intervention
Treatment with oral NR (1g/day per os for 8 weeks)
Group II: ControlPlacebo Group1 Intervention
Visually identical placebo (daily, per os, for 8 weeks)
Nicotinamide riboside is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Niagen for:
- Dietary supplement for general health and wellness
🇪🇺 Approved in European Union as Tru Niagen for:
- Dietary supplement for general health and wellness
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of Oklahoma Health Sciences CenterOklahoma City, OK
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Who Is Running the Clinical Trial?
University of OklahomaLead Sponsor
University of PennsylvaniaCollaborator
Elysium HealthIndustry Sponsor
Oklahoma Medical Research FoundationCollaborator
References
Can nicotinamide riboside protect against cognitive impairment? [2021]The present review aims to address the clinical benefits of using nicotinamide riboside, a precursor to the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+) as a therapeutic agent to attenuate age-related cognitive decline.
A randomized placebo-controlled trial of nicotinamide riboside in older adults with mild cognitive impairment. [2023]Nicotinamide riboside (NR) increases blood levels of NAD+, a cofactor central to energy metabolism, and improves brain function in some rodent models of neurodegeneration. We conducted a placebo-controlled randomized pilot study with the primary objective of determining safety of NR in older adults with mild cognitive impairment (MCI). Twenty subjects with MCI were randomized to receive placebo or NR using dose escalation to achieve, and maintain, a final dose of 1 g/day over a 10-week study duration. The primary outcome was post-treatment change from baseline measures of cognition (Montreal Cognitive Assessment, MoCA). Predefined secondary outcomes included post-treatment changes in cerebral blood flow (CBF); blood NAD+ levels; and additional neurocognitive, psychometric, and physical performance tests. DNA methylation was assessed in peripheral blood mononuclear cells (PBMCs) as an exploratory outcome. The target NR dose was safely achieved as evidenced by a 2.6-fold increase in blood NAD+ in the NR group (p
Nicotinamide ribose ameliorates cognitive impairment of aged and Alzheimer's disease model mice. [2022]Nicotinamide adenine dinucleotide (NAD) supplementation to repair the disabled mitochondria is a promising strategy for the treatment of Alzheimer's disease (AD) and other dementia. Nicotinamide ribose (NR) is a safe NAD precursor with high oral bioavailability, and has beneficial effects on aging. Here, we applied NR supplied food (2.5 g/kg food) to APP/PS1 transgenic AD model mice and aged mice for 3 months. Cognitive function, locomotor activity and anxiety level were assessed by standard behavioral tests. The change of body weight, the activation of microglia and astrocytes, the accumulation of Aβ and the level of serum nicotinamide phosphoribosyltransferase (NAMPT) were determined for the evaluation of pathological processes. We found that NR supplementation improved the short-term spatial memory of aged mice, and the contextual fear memory of AD mice. Moreover, NR supplementation inhibited the activation of astrocytes and the elevation of serum NAMPT of aged mice. For AD model mice, NR supplementation inhibited the accumulation of Aβ and the migration of astrocyte to Aβ. In addition, NR supplementation inhibit the body weight gain of aged and APP/PS1 mice. Thus, NR has selective benefits for both AD and aged mice, and the oral uptake of NR can be used to prevent the progression of dementia.
Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin. [2023]Declining nicotinamide adenine dinucleotide (NAD+ ) concentration in the brain during aging contributes to metabolic and cellular dysfunction and is implicated in the pathogenesis of aging-associated neurological disorders. Experimental therapies aimed at boosting brain NAD+ levels normalize several neurodegenerative phenotypes in animal models, motivating their clinical translation. Dietary intake of NAD+ precursors, such as nicotinamide riboside (NR), is a safe and effective avenue for augmenting NAD+ levels in peripheral tissues in humans, yet evidence supporting their ability to raise NAD+ levels in the brain or engage neurodegenerative disease pathways is lacking. Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo-controlled crossover trial (NCT02921659) of oral NR supplementation (500 mg, 2x /day, 6 weeks). We demonstrate that oral NR supplementation increases NAD+ levels in NEVs and decreases NEV levels of Aβ42, pJNK, and pERK1/2 (kinases involved in insulin resistance and neuroinflammatory pathways). In addition, changes in NAD(H) correlated with changes in canonical insulin-Akt signaling proteins and changes in pERK1/2 and pJNK. These findings support the ability of orally administered NR to augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans. Furthermore, NEVs offer a new blood-based window into monitoring the physiologic response of NR in the brain.
Supplementation with NAD+ and Its Precursors to Prevent Cognitive Decline across Disease Contexts. [2022]The preservation of cognitive ability by increasing nicotinamide adenine dinucleotide (NAD+) levels through supplementation with NAD+ precursors has been identified as a promising treatment strategy for a number of conditions; principally, age-related cognitive decline (including Alzheimer's disease and vascular dementia), but also diabetes, stroke, and traumatic brain injury. Candidate factors have included NAD+ itself, its reduced form NADH, nicotinamide (NAM), nicotinamide mononucleotide (NMN), nicotinamide riboside (NR), and niacin (or nicotinic acid). This review summarises the research findings for each source of cognitive impairment for which NAD+ precursor supplementation has been investigated as a therapy. The findings are mostly positive but have been made primarily in animal models, with some reports of null or adverse effects. Given the increasing popularity and availability of these factors as nutritional supplements, further properly controlled clinical research is needed to provide definitive answers regarding this strategy's likely impact on human cognitive health when used to address different sources of impairment.
Safety Assessment of High-Purity, Synthetic Nicotinamide Riboside (NR-E) in a 90-Day Repeated Dose Oral Toxicity Study, With a 28-Day Recovery Arm. [2021]Nicotinamide riboside (NR) is a naturally occurring form of vitamin B3 shown to preferentially elevate the nicotinamide adenine dinucleotide (NAD+) metabolome compared to other vitamin B3 forms (nicotinic acid and nicotinamide). Although daily requirements of vitamin B3 are typically met through the diet, recent studies have shown that additional supplementation with NR may be an effective method to counter the age-related decline in NAD+ levels as NR bypasses the rate-limiting step in NAD+ biosynthesis. Furthermore, pharmaceutical applications of NR for age-related disorders have been proposed. In this study, the safety of a high-purity, nature-identical, synthetic NR (NR-E), manufactured under the guidelines of good manufacturing practices for dietary supplements (21 CFR 111) as well as for drugs (21 CFR 210), was investigated in a 90-day oral toxicity study in Sprague Dawley rats at 300, 500, and 1,200 mg/kg/d. There were no mortality or clinical observations attributable to the test substance at any dose. A small but statistically significant decrease in body weight was observed at day 92 in the 1,200 mg/kg/d NR-treated male rats only. In contrast to a previously published safety assessment using a different synthetic NR (NIAGEN), whose no-observed-adverse-effect-level (NOAEL) was reported to be 300 mg/kg/d, there were no adverse changes in clinical pathology parameters and no notable macroscopic or microscopic findings or treatment-related effects at similar doses. In the current study, the NOAEL for systemic toxicity of NR-E in Sprague-Dawley rats was conservatively determined to be 500 mg/kg/d for males (solely based on body weight) and 1,200 mg/kg/d for females.
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. [2023]Nicotinamide riboside (NR) is a newly discovered nicotinamide adenine dinucleotide (NAD+) precursor vitamin. A crystal form of NR chloride termed NIAGEN is generally recognized as safe (GRAS) for use in foods and the subject of two New Dietary Ingredient Notifications for use in dietary supplements. To evaluate the kinetics and dose-dependency of NR oral availability and safety in overweight, but otherwise healthy men and women, an 8-week randomized, double-blind, placebo-controlled clinical trial was conducted. Consumption of 100, 300 and 1000 mg NR dose-dependently and significantly increased whole blood NAD+ (i.e., 22%, 51% and 142%) and other NAD+ metabolites within 2 weeks. The increases were maintained throughout the remainder of the study. There were no reports of flushing and no significant differences in adverse events between the NR and placebo-treated groups or between groups at different NR doses. NR also did not elevate low density lipoprotein cholesterol or dysregulate 1-carbon metabolism. Together these data support the development of a tolerable upper intake limit for NR based on human data.
Possible Adverse Effects of High-Dose Nicotinamide: Mechanisms and Safety Assessment. [2021]Nicotinamide (NAM) at doses far above those recommended for vitamins is suggested to be effective against a wide spectrum of diseases and conditions, including neurological dysfunctions, depression and other psychological disorders, and inflammatory diseases. Recent increases in public awareness on possible pro-longevity effects of nicotinamide adenine dinucleotide (NAD+) precursors have caused further growth of NAM consumption not only for clinical treatments, but also as a dietary supplement, raising concerns on the safety of its long-term use. However, possible adverse effects and their mechanisms are poorly understood. High-level NAM administration can exert negative effects through multiple routes. For example, NAM by itself inhibits poly(ADP-ribose) polymerases (PARPs), which protect genome integrity. Elevation of the NAD+ pool alters cellular energy metabolism. Meanwhile, high-level NAM alters cellular methyl metabolism and affects methylation of DNA and proteins, leading to changes in cellular transcriptome and proteome. Also, methyl metabolites of NAM, namely methylnicotinamide, are predicted to play roles in certain diseases and conditions. In this review, a collective literature search was performed to provide a comprehensive list of possible adverse effects of NAM and to provide understanding of their underlying mechanisms and assessment of the raised safety concerns. Our review assures safety in current usage level of NAM, but also finds potential risks for epigenetic alterations associated with chronic use of NAM at high doses. It also suggests directions of the future studies to ensure safer application of NAM.