Science of NAD
How are your NAD levels today?
Replenishing NAD levels is more likely to improve your healthspan than your lifespan -- the health of your years rather than the number of years. On the other hand, as one study points out, nicotinamide riboside has lengthened lifespan in every animal that has been tested. But we don't know yet in humans...
ARTICLE: Can NAD Help Me Live Longer?
Here are the studies:
Feb 4, 2023
Heart / Vascular - Aging
NAD+ Homeostasis and NAD+-Consuming Enzymes: Implications for Vascular Health
Although future studies are required to better clarify the potential of targeting NAD+ homeostasis, the strategies based on administering NAD+ precursors or inhibiting NAD+-dependent enzymes seem to be an attractive approach for reducing chronic low-grade inflammation, enhancing mitochondrial biogenesis, and improving oxidative metabolism in vascular cells.
Feb 3, 2023
Aging - Metabolism
International Journal of Molecular Sciences
The Central Role of the NAD+ Molecule in the Development of Aging and the Prevention of Chronic Age-Related Diseases: Strategies for NAD+ Modulation
This article reviews the NAD+ molecule in the development of aging and the prevention of chronic age-related diseases and discusses the strategies of NAD+ modulation for healthy aging and longevity.
Nov 28, 2022
Diabetes - Aging
International Journal of Molecular Sciences
Effects of nicotinamide mononucleotide on older patients with diabetes and impaired physical performance: A prospective, placebo-controlled, double-blind study
In older male patients with diabetes and impaired physical performance, NMN supplementation for 24 weeks was safe, but did not improve grip strength and walking speed.
Oct 26, 2022
A comparative study of metformin and nicotinamide riboside in alleviating tissue aging in rats
Here, we showed that Metformin (MET) and Nicotinamide Riboside (NR) exhibited a geroprotective effect on aged human stem cells and various tissues in aged rats. Both MET and NR repressed systemic inflammation and inhibited aging markers across multiple tissues in aged rats. MET and NR treatment attenuated aging-associated gene expression across tissues, with the most protective effects in adipose and aortic tissues. We found that that both MET and NR alleviated the aging-associated phenotypes, especially systemic inflammation, tissue fibrosis, and aggresome formation in aged rat tissues. We further showed that both MET and NR partially rescued aging Differentially Expressed Genes in several tissues, and the most remarkable effects were found in adipose and aortic tissues
Oct 12, 2022
Aging - Progeria - Bioavailability
Frontiers in Aging
The use of progeroid DNA repair-deficient mice for assessing anti-aging compounds, illustrating the benefits of nicotinamide riboside
Birkisdóttir, María B.
Interestingly, mice supplemented with NA revealed a significant delay in the onset of imbalance, whereas NR supplementation showed a trend towards delaying the median age of onset of tremors. Furthermore, NR significantly extended median lifespan by approximately 25% or 5 weeks, while animals receiving NA lived about as long as control-fed animals.
Oct 11, 2022
Circadian Rhythm - Aging - Heart
American Journal of Physiology - Cell Physiology
Circadian cardiac NAD+ metabolism, from transcriptional regulation to healthy aging
Carpenter, Bryce J.
...Recent studies have expanded on the role of circadian rhythms and the core clock factors that maintain them in the regulation of NAD+ levels in the heart. This has revealed that NAD+ pools and their use are tightly linked to cardiac function, but also heart failure. The convergence of these fields, namely, clock regulation, heart disease, and NAD+ metabolism present a complex network ripe with potential scientific and clinical discoveries, given the growing number of animal models, recently developed technology, and opportunity for safe and accessible precursor supplementation...
Oct 10, 2022
Muscle - Aging - Stem Cells
A randomized placebo-controlled trial of nicotinamide riboside and pterostilbene supplementation in experimental muscle injury in elderly individuals
...The objective of this study was to investigate if supplementation with nicotinamide riboside and pterostilbene (NRPT) promotes skeletal muscle regeneration after muscle injury in elderly individuals by improved recruitment of MuSCs...Daily supplementation with 1,000 mg NR and 200 mg PT is safe but does not improve recruitment of the MuSC pool or other measures of muscle recovery in response to injury or subsequent regeneration in elderly individuals.
Sep 28, 2022
Skin - Aging
Plastic and Reconstructive Surgery
The Role of NAD+ in Regenerative Medicine
Addressing aging at the cellular level is now critically important. Many surgical procedures rely on the healing and regenerative capacity of the skin which is known to decline with age, leading to disappointing results or negative postsurgery outcomes. Improving health and resilience at the cellular level with NAD+ restoration could be harnessed as a way to ensure consistent results and recovery irrespective of patient age. It should also be noted that the efficacy of many nonsurgical aesthetic procedures such as microneedling and laser technologies ultimately rely on the activation of cellular stress pathways to trigger the clearance of damaged cells and stimulate the production of new collagen. Many of these pathways require adequate NAD+ levels for optimal function, meaning NAD+ restoration before treatment could be a strategy to ensure the underlying cells are in an optimal condition to respond to the treatment.
Sep 26, 2022
Aging - Longevity - Sirtuins
Archives of Gerontology and Geriatrics
A Science-Based Review of the World’s Best-Selling Book on Aging
Lifespan, a book by Harvard scientist David Sinclair, has become an influential source of misinformation on longevity, featuring counterfactual claims about longevity genes being conserved between yeast and humans, the existence of supposed activators of these genes, and claimed successful age reversal in mice based on partial reprogramming. The book has popularized a stack of drugs and supplements with significant potential to harm the general public.The reviewer suggests that scientists and physicians emphasize to the general public that aging is known to be a highly polygenic developmental process and that the most important things that people can do to age better are to maintain high physical and mental activity.
Sep 22, 2022
Aging - Longevity - Sirtuins
Sirtuins are Not Conserved Longevity Genes
While sirtuins carry out interesting biochemical reactions and perform important functions for organisms, their degree of regulation is modest compared to most other enzymes that function in the NAD system. In addition, the degree of hype, framing, and nonreproducibility in the sirtuin literature is persistently misleading. Dispassionate analysis of their functions does not support assignment as longevity enzymes or as principal mediators of the effects of NAD repletion.
Sep 20, 2022
Pancreas - Aging
Nicotinamide Riboside Kinase 1 protects against diet and age-induced pancreatic β-cell failure
Disturbances in NAD+ metabolism have been described as a hallmark for multiple metabolic and age-related diseases, including type 2 diabetes. While alterations in pancreatic β-cell function are critical determinants of whole-body glucose homeostasis, the role of NAD+ metabolism in the endocrine pancreas remains poorly explored. Here, we aimed to evaluate the role of nicotinamide riboside (NR) metabolism in maintaining NAD+ levels and pancreatic β-cell function in pathophysiological conditions...
Sep 14, 2022
Heart / Vascular - Aging
Journal of Cardiovascular Aging
Metabolic targets in cardiac aging and rejuvenation
NAD+ repletion can delay several hallmarks of aging and suppress the deterioration of age-related diseases. This suggests a significant potential for the treatment of cardiac diseases in the elderly population with supplementation of NAD+ precursors. Indeed, the dietary intake of NAM could reduce cardiac hypertrophy and diastolic dysfunction in aged mice
Aug 26, 2022
Hearing - Aging
Long-term NAD+ supplementation prevents the progression of age-related hearing loss in mice
Age-related hearing loss (ARHL) is the most common sensory disability associated with human aging. Yet, there are no approved measures for preventing or treating this debilitating condition. With its slow progression, continuous and safe approaches are critical for ARHL treatment. Nicotinamide Riboside (NR), a NAD+ precursor, is well tolerated even for long-term use and is already shown effective in various disease models including Alzheimer’s and Parkinson’s Disease. It has also been beneficial against noise induced hearing loss and in hearing loss associated with premature aging. However, its beneficial impact on ARHL is not known. Using two different wild-type mouse strains, we show that long-term NR administration prevents the progression of ARHL...
Aug 7, 2022
Brain - Aging - Cognitive Decline - Alzheimers - Stroke
Supplementation with NAD+ and Its Precursors to Prevent Cognitive Decline across Disease Contexts
A large body of preclinical research supports the potential effectiveness of NAD+ precursor supplementation for preserving cognitive health across a variety of disease contexts, with the strongest evidence presented for Alzheimer’s disease and other forms of dementia.
May 9, 2022
Heart - Vascular - Circadian Rhythm - Aging
Frontiers in Molecular Medicine
Nicotinamide Riboside Improves Cardiac Function and Prolongs Survival After Disruption of the Cardiomyocyte Clock
Here, we show that supplementation with the NAD+ precursor NR as a dietary supplement improves heart function and extends the lifespan of female mice lacking cardiac REV-ERBs. Thus, boosting NAD+ levels can improve cardiac function in a setting of heart failure caused by disruption of circadian clock factors, providing new insights into the links between the circadian clock, energy metabolism, and cardiac function.
May 1, 2022
Muscle - NMN - Aging
Chronic nicotinamide mononucleotide supplementation elevates blood nicotinamide adenine dinucleotide levels and alters muscle function in healthy older men
NMN oral supplementation at 250 mg/day in healthy older men for 12 weeks was safe and well-tolerated and significantly increased the levels of NAD + and NAD +-related metabolites in whole blood. Furthermore, NMN administration partly improved muscle performance, evaluated using gait speed and grip strength, in healthy older men...NMN did not affect the skeletal muscle mass of participants in our study...Thus, the chronic oral administration of NMN could be a therapeutic strategy for aging-related disorders in humans, such as sarcopenia.
Dec 27, 2021
Aging - NAD Levels
Age-Dependent Decline of NAD +-Universal Truth or Confounded Consensus?
Nicotinamide adenine dinucleotide (NAD+) is an essential molecule involved in various metabolic reactions, acting as an electron donor in the electron transport chain and as a co-factor for NAD+-dependent enzymes. In the early 2000s, reports that NAD+ declines with aging introduced the notion that NAD+ metabolism is globally and progressively impaired with age. Since then, NAD+ became an attractive target for potential pharmacological therapies aiming to increase NAD+ levels to promote vitality and protect against age-related diseases. This review summarizes and discusses a collection of studies that report the levels of NAD+ with aging in different species (i.e., yeast, C. elegans, rat, mouse, monkey, and human), to determine whether the notion that overall NAD+ levels decrease with aging stands true. We find that, despite systematic claims of overall changes in NAD+ levels with aging, the evidence to support such claims is very limited and often restricted to a single tissue or cell type. This is particularly true in humans, where the development of NAD+ levels during aging is still poorly characterized. There is a need for much larger, preferably longitudinal, studies to assess how NAD+ levels develop with aging in various tissues. This will strengthen our conclusions on NAD metabolism during aging and should provide a foundation for better pharmacological targeting of relevant tissues.
Oct 1, 2021
Aging - Metabolism
Mechanisms of Ageing and Development
The balance between NAD+ biosynthesis and consumption in ageing
The progression of some age-related diseases can be halted or reversed by therapeutic augmentation of NAD+ levels. NAD+ metabolism has therefore emerged as a potential target to ameliorate age-related diseases. The present review explores how ageing affects NAD+ metabolism and current approaches to reverse the age-dependent decline of NAD+...As NAD+ is constantly consumed in these reactions, there is a need for continuous NAD+ biosynthesis. Imbalances between these NAD+ consumption and NAD + biosynthesis may result in insufficient NAD+ supply, which has been linked to several diseases, such as neuropathy, autoimmune diseases, and cancer.
Oct 1, 2021
Mechanisms of Aging and Development
Preclinical and clinical evidence of NAD(+) precursors in health, disease, and ageing.
Reiten, Ole Kristian
NAD+ is a fundamental molecule in human life and health as it participates in energy metabolism, cell signalling, mitochondrial homeostasis, and in dictating cell survival or death. Emerging evidence from preclinical and human studies indicates an age-dependent reduction of cellular NAD+, possibly due to reduced synthesis and increased consumption. In preclinical models, NAD+ repletion extends healthspan and / or lifespan and mitigates several conditions, such as premature ageing diseases and neurodegenerative diseases. These findings suggest that NAD+ replenishment through NAD+ precursors has great potential as a therapeutic target for ageing and age-predisposed diseases, such as Alzheimer’s disease. Here, we provide an updated review on the biological activity, safety, and possible side effects of NAD+ precursors in preclinical and clinical studies. Major NAD+ precursors focused on by this review are nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and the new discovered dihydronicotinamide riboside (NRH). In summary, NAD+ precursors have an exciting therapeutic potential for ageing, metabolic and neurodegenerative diseases.
Sep 21, 2021
Aging - Brain - Ataxia - Stem Cells - Bone Marrow - Inflammation
NAD+ augmentation with nicotinamide riboside improves lymphoid potential of Atm−/− and old mice HSCs
Our data suggest that NR administration in compromised hematopoietic systems (NAD+ depleted system) drives cell-intrinsic changes of the HSC compartment together with an overall reduction in circulating inflammatory cytokines. However, once the aged system has been exposed to NR, the effects of removing the supplementation may have undesirable consequences. Thus, once a deficient system is exposed to NAD+ supplementation, to maintain the benefits we have demonstrated, the regimen may need to be sustained long-term...Our results showed significant alterations in lineage commitment of HSCs after NR treatment, with enhanced lymphoid potential. This correlated with changes in inflammatory cytokines and transcriptional alterations of the HSCs. While transplantation of aged NR-treated HSCs reproduced the enhanced lymphoid output seen in the transcriptional profiles, the changes in potential are not sustained after NR withdrawal in the aged mice, and the rebound phenotype appear to exacerbate aging phenotypes. Our results highlight the importance of the duration of NR exposure and the timing of initial exposure to derive robust, balanced lineage outputs from HSCs.
Aug 22, 2021
Aging - Metabolism
Age-related NAD+ decline
Our results suggested that oral administration of [combined metabolic activator cocktail including nicotinamide riboside] for 84 days has a considerable effect on cognitive function in AD patients..
Aug 4, 2021
Precursor comparisons for the upregulation of nicotinamide adenine dinucleotide. Novel approaches for better aging
Nicotinamide adenine dinucleotide (NAD) is a coenzyme found in every human cell and regulates a number of systems across multiple cellular compartments and tissue types via an endogenous and exogenous influence. NAD levels are demonstrated to decline with age and therefore measures to counteract the waning of NAD have been devised. A number of NAD precursor candidates such as nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), the reduced form of nicotinamide mononucleotide (NMNH), nicotinic acid (NA) nicotinamide (NAM), and dihydronicotinamide riboside (DNR) increase NAD levels in vitro and in vivo. This discussion will focus on the precursors NR, NMN, NMNH, and DNR in the upregulation of NAD...Bioavailability and potency of NR, NMNH, NMN, and DNR is also examined on the light of the most recent literature.
May 11, 2021
Bone Marrow - Stem Cells - Aging
Nicotinamide riboside attenuates age-associated metabolic and functional changes in hematopoietic stem cells
With age, hematopoietic stem cells (HSC) undergo changes in function, including reduced regenerative potential and loss of quiescence, which is accompanied by a significant expansion of the stem cell pool that can lead to haematological disorders. Elevated metabolic activity has been implicated in driving the HSC ageing phenotype. Here we show that nicotinamide riboside (NR), a form of vitamin B3, restores youthful metabolic capacity by modifying mitochondrial function in multiple ways including reduced expression of nuclear encoded metabolic pathway genes, damping of mitochondrial stress and a decrease in mitochondrial mass and network-size. Metabolic restoration is dependent on continuous NR supplementation and accompanied by a shift of the aged transcriptome towards the young HSC state, more youthful bone marrow cellular composition and an improved regenerative capacity in a transplant setting. Consequently, NR administration could support healthy ageing by re-establishing a more youthful hematopoietic system.
Apr 1, 2021
Bone - Osteoporosis - Aging
Aging and Mechanisms of Disease
A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging
Age-related osteoporosis is caused by a deficit in osteoblasts, the cells that secrete bone matrix. The number of osteoblast progenitors also declines with age associated with increased markers of cell senescence...We found decreased levels of NAD+ in osteoblast progenitor cultures from old mice, associated with increased acetylation of FoxO1 and markers of cell senescence. The NAD+ precursor nicotinamide riboside (NR) abrogated FoxO1 and β-catenin acetylation and several marker of cellular senescence, and increased the osteoblastogenic capacity of cells from old mice. Consistent with these effects, NR administration to C57BL/6 mice counteracted the loss of bone mass with aging. Attenuation of NAD+ levels in osteoprogenitor cultures from young mice inhibited osteoblastogenesis in a FoxO-dependent manner. In addition, mice with decreased NAD+ in cells of the osteoblast lineage lost bone mass at a young age. Together, these findings suggest that the decrease in bone formation with old age is due, at least in part, to a decrease in NAD+ and dysregulated Sirt1/FoxO/β-catenin pathway in osteoblast progenitors. NAD+ repletion, therefore, represents a rational therapeutic approach to skeletal involution
Mar 31, 2021
17-a-estradiol late in life extends lifespan in aging UM-HET3 male mice; nicotinamide riboside and three other drugs do not affect lifespan in either sex
Harrison, David E.
Despite some data suggesting that nicotinamide riboside would be effective, neither it nor the other three increased lifespans significantly at the doses tested.
Jan 19, 2021
Muscle - Aging
NAD+ boosting reduces age-associated amyloidosis and restores mitochondrial homeostasis in muscle
Aging is characterized by loss of proteostasis and mitochondrial homeostasis. Here, we provide bioinformatic evidence of dysregulation of mitochondrial and proteostasis pathways in muscle aging and diseases...Treatment of either aged N2 worms, a nematode model of amyloid-beta muscle proteotoxicity, human aged myotubes, or old mice with the NAD+ boosters nicotinamide riboside (NR) and olaparib (AZD) increases mitochondrial function and muscle homeostasis while attenuating amyloid accumulation. Hence, our data reveal that age-related amyloidosis is a contributing factor to mitochondrial dysfunction and that both are features of the aging muscle that can be ameliorated by NAD+ metabolism-enhancing approaches, warranting further clinical studies.
Nov 16, 2020
Inflammation - Aging
Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages
Covarrubias, Anthony J.
These results link the accumulation of senescent cells with age to the age-related NAD decline…Our study demonstrates that increased expression of CD38 in macrophages is an important source of increased NADase activity during ageing.
Nov 2, 2020
Re‐equilibration of imbalanced NAD metabolism ameliorates the impact of telomere dysfunction
Short telomeres are a principal defining feature of telomere biology disorders, such as dyskeratosis congenita (DC), for which there are no effective treatments. Here, we report that primary fibroblasts from DC patients and late generation telomerase knockout mice display lower nicotinamide adenine dinucleotide (NAD) levels, and an imbalance in the NAD metabolome that includes elevated CD38 NADase and reduced poly(ADP-ribose) polymerase and SIRT1 activities, respectively, affecting many associated biological pathways. Supplementation with the NAD precursor, nicotinamide riboside, and CD38 inhibition improved NAD homeostasis, thereby alleviating telomere damage, defective mitochondrial biosynthesis and clearance, cell growth retardation, and cellular senescence of DC fibroblasts. These findings reveal a direct, underlying role of NAD dysregulation when telomeres are short and underscore its relevance to the pathophysiology and interventions of human telomere-driven diseases.
Jun 1, 2020
Metabolism - Aging
Age-related NAD+ decline
...Here, we discuss the state of the evidence for an age-related decline in NAD+, along with potential mechanistic explanations, including increased consumption or decreased synthesis of NAD+ and changes in the composition of cells or tissues with age...