PMCID: PMC10721522

PMID: 37619764

The Safety and Antiaging Effects of Nicotinamide

Mononucleotide in Human Clinical Trials: an Update
Qin Song,1,† Xiaofeng Zhou,2,† Kexin Xu,3 Sishi Liu,3 Xinqiang Zhu,4,∗∗ and Jun Yang3,5,∗

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Abstract

The importance of nicotinamide adenine dinucleotide (NAD+) in human

physiology is well recognized. As the NAD+ concentration in human skin,
blood, liver, muscle, and brain are thought to decrease with age, finding
ways to increase NAD+ status could possibly influence the aging process
and associated metabolic sequelae. Nicotinamide mononucleotide (NMN)
is a precursor for NAD+ biosynthesis, and in vitro/in vivo studies have
demonstrated that NMN supplementation increases NAD+ concentration
and could mitigate aging-related disorders such as oxidative stress, DNA
damage, neurodegeneration, and inflammatory responses. The
promotion of NMN as an antiaging health supplement has gained
popularity due to such findings; however, since most studies evaluating
the effects of NMN have been conducted in cell or animal models, a
concern remains regarding the safety and physiological effects of NMN
supplementation in the human population. Nonetheless, a dozen human
clinical trials with NMN supplementation are currently underway. This
review summarizes the current progress of these trials and
NMN/NAD+ biology to clarify the potential effects of NMN
supplementation and to shed light on future study directions.

Keywords: nicotinamide adenine dinucleotide, nicotinamide

mononucleotide, antiaging, clinical trial

Statement of Significance

This article integrates the safety and antiaging effects of NMN in

preclinical animal studies and human clinical trials, particularly human
clinical trials, to clarify the potential benefits of NMN supplementation as
well as to shed light on future study directions.
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Introduction

With the decline in the birth rate and extension of life expectancy, the
composition of the global population is changing dramatically; in
particular, the proportion of citizens over 60 y of age is growing rapidly.
For example, in 2019, the global population over 60 was one billion; by
2050, it is expected to reach 2.1 billion, accounting for one-fifth of the
world’s population [1]. Aging is a major risk factor for many chronic
human diseases; in addition, the incidence of many age-related diseases
such as hypertension, atherosclerosis, diabetes mellitus, cancer,
Alzheimer’s disease, as well as many other cardiovascular and
cerebrovascular diseases have risen drastically, leading to a heavy global
socioeconomic and medical burden
[[2], [3], [4], [5], [6], [7], [8], [9], [10]]. This phenomenon, combined with
the human longing for better health and longer lifespan, has created a
huge demand for antiaging (the preventative approach to improve late-
life health) products. Among various antiaging healthcare products, as an
antiaging product, nicotinamide mononucleotide (NMN) has attracted
great attention in North America, Europe, and China over the past
decade. NMN is used as a dietary supplement and is widely applied in
cosmetic products. The global market for NMN was valued at US $252.7
million in 2020 and is expected to reach US $385.7 million by the end of
2027 [11].

However, on 10 November, 2022, the US Food and Drug Administration

(FDA) declared that β-NMN is prohibited as a health supplement. Metro
International Biotech LLC had synthesized a proprietary form of β-NMN
called MIB-626 that is being developed as a novel drug. Based on the
“Federal Food, Drug & Cosmetic Act,” FDA concluded that “NMN was
authorized for investigation as a new drug (before being lawfully
marketed in supplements) and was the subject of substantial clinical
investigations that were instituted and made public.” This finding had
the effect of excluding NMN as a dietary supplement. This raised
concerns among NMN manufacturers as well as consumers, leading the
Natural Products Association and Alliance for Natural Health USA to file a
citizen petition with the FDA regarding NMN, and a public hearing was
requested in the US Congress to clarify the agency’s position regarding
the use of NMN in dietary supplements. How these events will impact
NMN’s future consumer market remains to be seen.

NMN is a main precursor of nicotinamide adenine dinucleotide (NAD+),

an essential coenzyme for vital cellular physiological activities such as
metabolism, cell death, aging, DNA repair, gene expression, and
neuroinflammation [[12], [13], [14], [15], [16], [17], [18], [19], [20]].
About a century ago, the link between NAD+ and health were first
established by Conrad Elvehjem, who discovered that pellagra
(characterized by dementia, dermatitis, and diarrhea) was caused by a
dietary deficiency of niacin (NAD+ precursor) in 1937 [21]. As it turns
out, NAD+, coupled with its reduced form NADH, are key to cellular
metabolic processes of all living life forms and have to be maintained in a
proper ratio (referred to as the NAD+ status). To prevent pellagra, the
daily requirement for NAD+ synthesis can be achieved by dietary
consumption of tryptophan (TRP) or niacin from food. Later on,
NAD+ depletion is reported to be closely related to aging and several age-
related diseases, including various metabolic diseases and cognitive
decline [22]. Additionally, studies have shown that NAD+ concentrations
(in liver and white adipose tissue) decrease under disturbed nutrient
conditions [22]. For instance, a high fat or high sugar diet can cause
energy overload, ultimately culminating in reduced NAD+/NADH ratio (in
liver) and decreased NAD+ concentrations (in C2C12 myotubes) [23,24].
Also, such diets can lead to increase in blood sugar, insulin levels, and
reactive oxygen species formation, which triggers oxidative damage and
postprandial oxidative stress [25]. Therefore, it seems that the
maintenance of normal NAD+ status is important for health, and
approaches that can regulate NAD+ status, such as nutritional
intervention, might be a strategy against aging and metabolic diseases. In
fact, it has been shown that caloric restriction increases
NAD+ bioavailability by activating the expression of NAMPT
(nicotinamide phosphoribosyltransferase, which transforms
nicotinamide [NAM] to NAD+ in the NAD+ salvage pathway) [26], whereas
it lowers NADH levels and activates sirtuins to extend the life span of
yeast [27,28]. Recently, studies have shown that administration of
NAD+ precursors such as NMN and nicotinamide riboside (NR), which are
also present in natural foods, e.g., cow milk, meat, and vegetables, can
increase NAD+ concentrations in human blood and tissue [29,30],
indicating that modulating NAD+ metabolism can be a practical target for
nutritional intervention. However, it should be kept in mind that
although this review discusses NAD+ status and concentrations, the
terminologies and interpretations are nuanced and complex because 1)
there is no consensus standard as to “high” compared with “adequate”
compared with “low” NAD+ levels with respect to concentrations that
impact cell-specific pathways; and 2) concentrations may differ by tissue,
across species, and even within subcellular pools. Therefore, in many
studies, NAD+ concentrations were measured in blood or tissue, and such
measurements may or may not be an indicator of NAD+ status. The only
validated surrogate biomarker for NAD+ status is urinary markers of
NAD+ metabolism, such as methylated NAM, which is predictive of
pellagra. In contrast, whether blood and/or tissue NAD+ concentrations
are predictive of disease risk or susceptibility is not yet established (see
below). Similarly, whether repletion of blood or tissue NAD+ through
NMN (or other precursor) supplementation directly modifies the risk of
disease, dysfunction, or toxicity in the general population is still to be
established. Nonetheless, as an emerging antiaging product in recent
years, the impressive results from cell and animal studies
[[31], [32], [33], [34]] and those from clinical trials [35,36] are
accelerating the market’s growth for NMN supplements. In animal
studies, accumulating evidence proved that NMN supplementation could
restore NAD+ concentrations (in liver, white adipose tissue, skeletal
muscle, and primary islets) [24,37] and thus delay the aging process and
prevent age-associated diseases. However, clear evidence for antiaging
effects (the effects of using preventative approaches to improve late-life
health) of NMN on the human body is still scarce. Hence, this review
focuses on the research that has assessed NMN’s safety and antiaging
effects in human clinical trials.
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The Important Role of NAD+ in Aging

NAD exists in 2 forms, the oxidized (NAD+) and reduced (NADH) forms, in
which NAD+ accepts a hydride ion to become NADH. The conversion
process is crucial for the central carbon metabolism as NAD+ serves as a
coenzyme for redox reactions, making it a vital component of energy
metabolism [16,30,[38], [39], [40]]; in addition, it is an essential cofactor
for nonredox enzymes such as sirtuins and poly(adenosine diphosphate-
ribose) polymerases (PARPs) [12,22,41]. It is also critical for maintaining
tissue and metabolic homeostasis for healthy aging. There have been
extensive reviews of the relationship between NAD+ and the 9 aging
hallmarks, namely genomic instability [[42], [43], [44], [45]], telomere
attrition [46], epigenetic alterations [47], loss of proteostasis [44,
[48], [49], [50]], deregulated nutrient sensing [[51], [52], [53]],
mitochondrial dysfunction [54,55], cellular senescence [55,56], stem cell
exhaustion [[57], [58], [59], [60]], and altered intercellular
communication [[60], [61], [62], [63]]. Aging is accompanied by a
gradual decline of NAD+ concentration across multiple human tissues,
including skin, blood, liver, muscle, and brain
[[64], [65], [66], [67], [68], [69], [70]]. For instance, the average
NAD+ concentration in human skin tissues is several times lower in
adults than in newborn babies [66]. Two magnetic resonance imaging-
based studies revealed that NAD+ concentrations in the human brain
declined 10% to 25% from young adulthood to old age [69,70]. Many
factors, including DNA damage, chronic inflammation, oxidative stress
[31], and increased NAD+-consuming enzyme activities [71], have also
been shown to accelerate NAD+ degradation. Lowering the
concentrations of NAD+ in cell or tissue results in decreased energy
production within mitochondria, which contributes to the development
of aging and a range of age-related disorders, including atherosclerosis,
arthritis, hypertension, cognitive decline, diabetes, and cancer [22,
[72], [73], [74], [75], [76], [77], [78]].

NAD+-dependent mechanisms in aging have been summarized by

Covarrubias et al. [22] and McReynolds et al. [79] as follows: 1)
Metabolic dysfunction. The relationship between NAD+ and metabolism
has been known for almost a century. Changing or disrupting metabolic
status caused by factors such as a high-fat diet, postpartum weight loss,
and disruption of the circadian rhythm can lead to lower
NAD+ concentrations (in the liver and white adipose tissue), thus
reducing the activity of sirtuins and other NAD+-dependent cellular
processes; 2) Inflammation. Numerous studies have showcased the
regulatory function of NAD+ and NAD+-consuming enzymes in the biology
of macrophages, T cells, and B cells. With aging being a known factor and
a significant catalyst for numerous diseases, heightened expression of
proinflammatory cytokines can cause increased inflammation, leading to
tissue and DNA damage and further activation of major NAD+-consuming
enzymes, such as CD38 and PARPs, resulting in a hastened decline of
NAD+ in macrophages; 3) Senescence. The senescence-associated
secretory phenotype (SASP) of aging cells depends on the
NAD+ concentration in senescent cells. In addition, CD38 levels are
increased in aging tissues, which could at least partially explain the age-
related decrease in liver NAD+ concentration; 4) Neurodegeneration,
which is linked to a decline in NAD+ concentrations in the brain, is closely
associated with aging and various neurodegenerative disorders. Axonal
degeneration, a forerunner to many neuronal diseases associated with
aging, is identified by swift NAD+ depletion, which is attributed to a
reduction in the NAD+ biosynthetic enzyme nicotinamide
mononucleotide adenylyltransferase 2 (NMNAT2). Furthermore, the
NAD+-consuming enzyme SARM1 is activated by axonal injury and
mediates axonal degeneration by promoting NAD+ degradation.
Therefore, strategies to increase NAD+ are of great interest in antiaging
and longevity studies. Indeed, preclinical studies of NMN intervention in
mouse models have shown that increasing NAD+ concentration could
prevent and treat age-related diseases by improving tissue and organ
function, reducing inflammation, enhancing immune and reproductive
function, increasing physiological benefits, and protecting cognitive
function (Table 1). These benefits may work together to improve health
and perhaps increase lifespan. Several potential strategies are available
to boost NAD+ concentrations (in blood, myocardial cell, adipose tissue,
liver, brain, or U2OS cells), including lifestyle changes (such as exercise
[105,106], diet and caloric restriction [107,108], and enhancing
circadian rhythm [109,110]), use of small-molecule inhibitors or
activators to boost NAD+ biosynthesis [72,
[111], [112], [113], [114], [115], [116]],and supplementation with
NAD+ precursors (primarily NMN, NR, and NAM) (Figure 1) [22].
Supplementation with NAD+ precursors and activation of
NAD+ biosynthetic enzymes/inhibition of NAD+ degradation have
produced health benefits in mouse models. However, only NAD+ [117]
and NAD+ precursors (NA, NMN, NR, and NAM) are being explored in
humans [29,[118], [119], [120], [121], [122]].

TABLE 1
Preclinical studies (after 2015) in mouse models using NAD+ boosting strategies (NMN
intervention)

Model NMN dose Potential health benefits References

Restored nuclear entry of Sirt2 and
Intraperitoneal
C57BL/6, G3 Terc−/−, rejuvenated aged oligodendrocyte
injection: 10
SIRT2−/−, Sirt2flox/flox and progenitor cells; [80]
mg/kg body
NG2-CreERT34 mice Enhanced new myelin generation in
weight
aged central nervous system
Improved stress resistance against
acetaminophen-induced liver
Intraperitoneal injury, restored Nrf2-mediated
C57BL/6 wild-type
injection: 500 adaptive homeostasis;
mice and Sirt3-deficient [81]
mg/kg body Restored liver redox homeostasis
mouse
weight via the Sirt3–Nrf2 axis and
protected aged liver from oxidative
stress-induced injury
Oral
Aged 4 wk male administration: Increased brain NAD+ levels in
[82]
C57BL/6J mice 400 mg/kg body mice after 45 min oral intervention
weight
Middle cerebral artery Intraperitoneal NMN accumulated earlier than [83]
occlusion mouse injection: 300 NAD in the brain, reduced cerebral
and 2000 mg/kg infarction at 24 h post-middle
body weight cerebral artery occlusion;
Protected from acute ischemic
Model NMN dose Potential health benefits References
stroke injury
Modulated GABA and glutamate
production by increasing
Intraperitoneal
GABAA receptor α2 and glutamic
injection: 300,
Aged 5–6 wk male acid decarboxylase 65/67
400 and 500 [84]
Kunming mice expression;
mg/kg body
Enhanced immune system by
weight
boosting nitric oxide secretion and
IL-1β expression
Oral
Significantly increased body and
STZ-induced diabetic administration:
testis weight and number of sperm [85]
C57BL/6J mice 500 mg/kg body
in STZ-induced diabetic mice
weight
Improved the intestinal structural
and functional decline; the potential
mechanism was boosting the
Intraperitoneal
Aged (16 mo) male NAD+ pool and activating the
injection: 500 [34]
C57BL/6J mice SIRT3/6-mediated signaling
mg/L
pathway with regard to antioxidant,
anti-inflammatory, and barrier
function
Oral Prevented lung physiological
administration: decline and pulmonary fibrosis;
C57BL/6 mice [33]
500 mg/kg body Improved respiratory system
weight function
Blocked UVB-induced
photodamage in mice, maintaining
Intraperitoneal normal structure and amount of
Aged 7 wk female ICR injection: 250 collagen fibers, normal thickness of
[86]
mice mg/kg body epidermis and dermis, reducing the
weight production of mast cells, and
maintaining complete organized
skin structure
Increased NAD+ levels, SIRT1
Intraperitoneal protein expression, and heme
Aged (7–10 wk) injection: 250 oxygenase-1 expression;
[87]
C57BL/6 mice and 500 mg/kg Exerted neuroprotective effects on
body weight photoreceptors after retinal
detachment and oxidative injury
ICR mice Intraperitoneal Improved the quality of oocytes [88]
injection: 200 from naturally aged mice by
mg/kg body recovering NAD+ levels;
Model NMN dose Potential health benefits References
Increased ovulation of aged oocytes
but also enhanced their meiotic
competency and fertilization ability
weight by maintaining the normal
spindle/chromosome structure and
the dynamics of the cortical granule
component ovastacin
Intraperitoneal
Protected vascular system by
Aged 3 and 24 mo male injection: 500
changing miRNA expression [89]
C57BL/6J mice mg/kg body
profile
weight
Restored youthful expression levels
Intraperitoneal
in 204 genes;
Aged 3 and 24 mo male injection: 500
Promoted SIRT1 activation in the [90]
C57BL/6 mice mg/kg body
neurovascular unit;
weight
Protected neurovascular function;
Alleviated Al-induced bone injuries
by decreasing bone loss, suppressed
Intraperitoneal oxidative stress as well as inhibited
Aged 3 wk male injection: 20 thioredoxin-interacting protein-
[91]
Sprague Dawley rat mg/kg body NOD-like receptor pyrin domain
weight containing 3 inflammasome
pathway and proinflammatory
cytokine production
Reversed aging-induced learning
Intraperitoneal and memory impairment;
Aged (24 and 3 mo) injection: 100 Improved mitochondrial function in
[92]
male Wistar rats mg/kg body the brains of aged animals;
weight Reduced apoptosis in the brains of
aged animals
Oral
Increased endurance;
Aged (18 mo) administration:
Improved blood flow in elderly [32]
C57BL/6J mice 400 mg/kg body
mice by increasing capillary density
weight
Reversed aging-induced
cerebrovascular endothelial
Intraperitoneal
dysfunction;
Aged (24 mo) C57BL/6 injection: 500
Restored NAD+ and mitochondrial [93]
male mice mg/kg body
energetics and reduced mtROS;
weight
Improved cognitive performance in
NMN treated aged mice
Male Long-Evans rats Oral Reduced lactic acidosis and serum [94]
Model NMN dose Potential health benefits References
IL-6 levels, increased NAD+ levels,
and prevented mitochondrial
dysfunction in both liver and
administration:
(decompensated kidney;
400 mg/kg body
hemorrhagic model) Mitigated inflammation, improved
weight
cellular metabolism, and promoted
survival following hemorrhagic
shock
Aged (6 mo old) Subcutaneous Reduced inflammatory responses,
APP(swe)/PS1(DE9) double injection: 100 synaptic loss, amyloid plaque
[53]
transgenic (Alzheimer mg/kg body burden and β-amyloid production
disease model) mice weight for 28 d by inhibition of JNK activation
Intraperitoneal Decreased mortality, brain
Middle cerebral artery injection: 300 infarction, edema, apoptosis, and
[95]
occlusion CD1 mice mg/kg body hemorrhage via protecting blood–
weight brain-barrier integrity
Reduced brain edema, brain cell
death, oxidative stress,
Intraperitoneal neuroinflammation, intercellular
Collagenase-induced
injection: 300 adhesion molecule-1 expression,
intracerebral [96]
mg/kg body microglia activation and neutrophil
hemorrhage CD1 mice
weight infiltration in brain hemorrhagic
area by suppressing
neuroinflammation/oxidative stress
Improved cardiac functions,
Male cardiac-specific
Intraperitoneal reduced energy waste and improved
FXN-knockout mice
injection: 500 energy utilization in FXN-knockout
and male SIRT3- [97]
mg/kg body mice but not in
knockout/FKN-
weight SIRT3-knockout/FKN-knockout
knockout mice
mice
Preserved mitochondrial
Intraperitoneal
ultrastructure, reduced ROS, and
Cardiac-specific injection: 500
prevented cell death in the heart;
deficiency of Klf4 mg/kg body [98]
Protected the mutant mice from
C57BL/6J mice weight for 3 or 5
pressure overload-induced heart
d
failure
Oral Restored SIRT1 activity and
Aged (26–28 mo) administration: reversed age-related arterial
[99]
C57BI/6 male mice 300 mg/kg body dysfunction by decreasing
weight oxidative stress
C57BL/6N male mice Oral Suppressed body weight gain; [100]
administration: Improved eye function, healthy
Model NMN dose Potential health benefits References
plasma lipid profile, insulin
sensitivity, physical activity, energy
metabolism, and other
100 and 300
physiopathologies;
mg/kg body
Enhanced mitonuclear protein
weight
imbalance and mitochondrial
oxidative metabolism in skeletal
muscles
Increased liver citrate synthase
Intraperitoneal
activity and triglyceride
High-fat diet-fed aged injection: 500
accumulation; [101]
C57BL6/J female mice mg/kg body
Improved glucose tolerance,
weight
NAD+ levels of muscle and liver
Transverse aortic Intraperitoneal
Improved mitochondrial function
constriction-stressed injection: 500
and protected mice from heart [102]
mice, male conditional mg/kg body
failure
knockout mice weight
Oral Dramatically ameliorated the
administration: hippocampal CA1 injury and
Aged 3 mo osteoporotic 31.25, 62.5, 125, significantly improved neurological
[103]
male C57BL/6 mice 250 and 500 outcome;
mg/kg body Prevented the increase in PAR
weight formation and NAD+ catabolism
Intraperitoneal Improved cognitive function and
Male Wistar rats
injection: 500 energy metabolism, ameliorated
(Alzheimer disease [55]
mg/kg body neuron survival, reduced ROS
model)
weight accumulation
Subcutaneous Decreased brain APP levels and
APP(swe)/PS1(DE9) double
injection: 100 increases brain mitochondrial
transgenic (Alzheimer [104]
mg/kg body function;
disease model) mice
weight Reversed cognitive deficits
Open in a separate window

Al, aluminum; APP, amyloid precursor protein; FKN, fractalkine; FXN, frataxin; GABA, γ-
aminobutyric acid; IL, interleukin miRNA, microRNA; mtROS, mitochondrial reactive
oxygen species; NAD, nicotinamide adenine dinucleotide; NMN, nicotinamide
mononucleotide; NOD, nucleotide-binding oligomerization domain; Nrf, nuclear factor
erythroid 2-related factor; PAR, poly-ADP-ribose; ROS, reactive oxygen species; SIRT,
sirtuin; STZ, streptozotocin; UVB, ultraviolet B;
FIGURE 1
+ +
The changes of NAD levels during aging (a), the approaches to restore NAD levels (b), and
+
the health benefits of restoring NAD levels by NMN supplementation (c). NAD,
nicotinamide adenine dinucleotide; NMN, nicotinamide mononucleotide.
Numerous studies have validated that alterations in NAD+ homeostasis
can adversely impact the normal functions of cells. Nevertheless, a
precise definition of the association between NAD+ homeostasis and
human health outcomes remains necessary. Recently, Zapata et al. [123]
reviewed the relationship between NAD+ homeostasis and human health
outcomes. They highlighted that NAD+ depletion could lead to various
pathological phenotypes, including rare inherited defects, Leber
congenital amaurosis, severe neonatal encephalopathy, and pellagra
[123]. Primary NAD+ deficiencies result from impaired biosynthesis, such
as when deleterious variants of NAD+-related genes are mutated. In
contrast, the secondary deficiencies may be caused by other factors
affecting NAD+ homeostasis, such as increased NAD+ consumption or a
dietary deficiency of NAD+ precursors [123]. Furthermore, several recent
epidemiological studies have attempted to define the relationship
between NAD+ concentrations (in blood, sperm, and skeletal muscle) and
disease. Tran et al. [124] evaluated skeletal muscle NAD+ and NADH
concentrations in asymptomatic middle-aged people with HIV, revealing
that decreased NAD+ concentrations in skeletal muscle are related to
increased physiological weakness and coinfection with the virus. Yang
et al. [125] analyzed the relationship between blood
NAD+ concentrations and anemia in 727 female participants from the
Jidong community in China. Blood samples were collected from the large
antecubital veins after overnight fasting. NAD+ concentrations in blood
were then stratified into 4 categories: Q1 (<27.6 μmol), Q2 (27.6–31.0
μmol), Q3 (31.0–34.5 μmol), and Q4 (≥34.5 μmol). The study findings
indicated that an increased concentration of blood NAD+ was strongly
linked to a decreased occurrence of anemia among women, specifically
microcytic and normocytic anemia [125]. Bai et al. [126] found that
sperm NAD+ concentration was independent of age and negatively
correlated with sperm quality in males, indicating that NAD+ has a unique
role in spermatogenesis. Xiao et al. [127] analyzed the metabolomics and
cytokine/chemokine profiling in serum samples from 17 healthy
controls and 20 mild and 44 severe COVID-19 patients and observed that
NAD+ concentrations decreased with the increase in the severity of
COVID-19. However, such observations remain correlational and do not
prove the relationship between NAD+ and diseases. Furthermore, it
remains to be determined how much NAD+ is required for normal tissue
function and the threshold level to trigger pathophysiological changes in
different tissues.

NAD+ Biosynthesis and NAD+ Precursors

NAD+ can be synthesized from diverse dietary sources, including TRP,

nicotinic acid (NA), NR, and NAM. The NAD+ biosynthesis pathways
include the de novo synthesis pathway, Preiss-Handler pathway, and
salvage pathway [12], as illustrated in Figure 2. In the de novo synthesis
pathway, TRP goes through a series of reactions in 8 steps to generate
NAD+. TRP, as an NAD+ precursor, is first converted to quinolinic acid
(QA) through a 5-step enzymatic reaction and then to nicotinic acid
mononucleotide (NAMN) under the action of quinolinic acid
phosphoribosyl transferase (QPRT). In addition, QA can also enter the
tricarboxylic acid cycle. QPRT is the most critical rate-limiting enzyme in
the de novo synthesis pathway. The enzyme catalyzes the reaction step
in an ATP-dependent manner that requires the participation of Mg2+ and
5-phosphoribosyl-1-pyrophosphate (PRPP). Finally, NAMN enters the
Preiss-Handler pathway.
FIGURE 2
+
NAD levels are maintained by 3 independent pathways. The salvage pathway is the major
+
source of NAD . 3-HAA, 3-hydroxyanthranilic acid; ACMS, 2-amino-3-carboxymuconate-6-
semialdehyde; cADPR, cyclic ADP-ribose; IDO, indoleamine 2,3-dioxygenase; L-kin, L-
kinurenine; NAAD, nicotinic acid adenine dinucleotide; NAD, nicotinamide adenine
+
dinucleotide; NADS, NAD synthase; NAM; nicotinamide; NAMN, nicotinic acid
mononucleotide; NAMPT, nicotinamide phosphoribosyltransferase; NAPRT, nicotinic acid
phosphoribosyltransferase; NMNAT, nicotinamide mononucleotide adenylyltransferase;
NRK, nicotinamide riboside kinase; PARP, poly(adenosine diphosphate-ribose)
polymerase; PRPP, 5-phosphoribosyl-1-pyrophosphate; TDO, tryptophan 2,3-dioxygenase.

In the Preiss-Handler pathway, NA is catalyzed by nicotinic acid

phosphoribosyl transferase to generate NAMN. Subsequently, NAMN is
catalyzed by NMNAT to generate nicotinic acid adenine dinucleotide
(NAAD). Afterward, NAAD is converted to NAD+ under NAD+ synthetase.

Among the 3 pathways, the de novo biosynthetic pathway is the most

indirect mechanism contributing to system-wide NAD+, with most
NAD+ coming from the NAM salvage pathway [64,128]. In the salvage
pathway, NAM, as an NAD+ precursor, comes from diverse dietary
sources and by-products of NAD+-consuming enzymes such as NAD+-
dependent protein deacetylase (sirtuin), PARP, and CD38. First, NAM is
catalyzed by NAMPT to generate NMN, and then NMN is catalyzed by
NMNAT to generate NAD+. As a precursor of NAD+, NR can generate
NAD+ under the action of nicotinamide riboside kinases in the salvage
pathway.

The metabolic pathways of NAD+ precursors can facilitate their

conversion into NAD+ within the human body. Yiasemides et al. [129]
reported that oral administration of 500 mg NAM for 1 h significantly
increased human blood NAD+ concentration 1.3-fold and significantly
reduced UV immunosuppression in the skin. Oral administration of 1000
mg/d NR for 1, 3 and 6 wk significantly increased NAD+ concentration
2.7-fold [130] in peripheral blood mononuclear cells (PBMCs) of a 52-y-
old healthy participant, 2.3-fold [131] in the whole blood of older
participants (average age of 75), and 1.7-fold [120] in PBMCs of healthy
participants (55–79 y). In addition, the concentration of
NAD+ metabolites significantly increased in the blood, skeletal muscle,
and urine [120,130,131]. Other NR human clinical trials also showed that
NR could significantly increase the concentrations of NAD+ by about 1- to
2-fold [[132], [133], [134], [135], [136], [137]] and NAD+ metabolites in
the blood [134,[137], [138], [139]]. Oral administration of 250 mg/d
NMN for 4, 8, and 12 wk also significantly increased baseline
NAD+ concentration 2.5-fold, 2-fold, and 1.7-fold, respectively, in the
whole blood of healthy participants, simultaneously raising
NAD+ metabolite concentrations in the whole blood and skeletal muscle
of healthy participants [140]. No significant changes in the baseline
concentrations of NAD+ and its metabolites in whole human blood were
observed even after 16 wk of treatment with the same dose of NMN
[140]. Furthermore, Igarashi et al. [141] found that oral administration
of 250 mg/d NMN for 12 wk significantly increased baseline
NAD+ concentration by 2.57-fold in whole blood. NAD+ metabolite
concentrations in the whole blood of healthy participants and muscle
strength and performance were also significantly improved [141]. Oral
administration of 250 mg/d NMN for 10 wk could significantly increase
the baseline NAD+ concentration in PBMCs of prediabetic women and
increase muscle insulin sensitivity but not the NAD+ concentration in
skeletal muscle [36]. Similarly, in NR human clinical trials,
NAD+ concentrations also were not increased in skeletal muscle
[131,139,142]. These details are summarized in Supplementary Table 1,
which shows the effects of different NAD+ precursors on NAD+ and its
metabolites in human clinical trials [35,36,119,120,122,
[129], [130], [131], [132], [133], [134], [135], [136], [137], [138], [139], [
140], [141], [142], [143], [144]). The above human clinical trials
confirmed that these NAD+ precursors could improve NAD+ status in the
blood; however, the bioavailability, quantitative metabolomics, or
pharmacokinetics of NA, NAM, NR, and NMN have yet to be
systematically compared. Recently, a clinical trial (NCT05517122)
entitled “Effect of oral NAD+ precursors (NAM, NR, NMN) administration
on blood NAD+ concentration in healthy adults” was launched, and its
results are pending.

Most of the preclinical models and clinical studies published to date

demonstrate NAD+ precursor supplementation as a means of remedying
tissue dysfunction linked to severely compromised NAD+ metabolism.
However, whether maintenance of normal NAD+ status through diet or
NAD+ precursor supplementation can delay age-related functional
decline and reduce risk of disease in the general population remains to
be clearly established. Several NMN clinical trials were conducted on
healthy volunteers, and the results showed that NMN increased aerobic
capacity during exercise training [145], improved muscle strength and
performance during the 30-second chair stand test and walking speed
[141], decreased blood pressure, pulse pressure, and blood glucose
[146], and increased the telomere length of PBMCs [147]. On the whole,
it is simply too early to state with confidence whether
NAD+ supplementation will delay age-related functional decline and
reduce the risk of disease in the general population because longer-term
studies with large populations have not been performed.

The primary precursors for NAD+ are NA, NAM, NR, and NMN. NA acts
like a vitamin in preventing pellagra and is a widely used drug for
dyslipidemia treatment. Its pharmacological effect involves inhibiting
adipose tissue lipolysis, leading to a reduction in free fatty acid
concentration and its transport to the liver [148]. Compared with other
precursors, the side effects of NA are well known. The most common
adverse effects of NA include flushing, rash, hyperglycemia,
hyperuricemia, and gastrointestinal disorders. Additional side effects of
NA have also been reported, including a small reduction in both platelet
count and prolongation of prothrombin time, rhabdomyolysis, and other
dermopathies [148]. NAM is a water-soluble compound found in meat,
fish, mushrooms, grains, nuts, and legumes [149]. Besides treating
pellagra, NAM has a potential for clinical use in the prevention and
treatment of various diseases, such as rosacea, acne [149], and
hyperphosphatemia [150]. Furthermore, NAM has been tested for the
treatment of diabetes. The European NAM diabetes intervention test
allowed children to receive 5 to 3000 mg NAM daily for 5 y. No
significant difference in the incidence rate of adverse events was found
between the NAM and placebo groups [151]. Supplementing 1 g of NAM
daily is a safe and effective way to improve the metabolic abnormalities
and quality of life in diabetes patients with nonalcoholic fatty liver
disease [152]. Compared to NA, NAM has shown far greater tolerability
in humans, and its tolerance dose can be almost up to 3 g/d in adults
[149]. Nonetheless, certain side effects exist, including epigenetic
changes, impeded bioenergetics and gastrointestinal disturbance
(nausea, vomiting, diarrhea) for NAM [149,153]. Moreover, NAM has
shorter retention in rats’ bodies than NMN [154]. On the other hand,
existing human clinical trials have not shown any side effects of NR and
NMN. While the pharmacokinetics and metabolic mechanisms of NR and
NMN are still being investigated, it is important to note that not all cells
have the ability to convert all NAD+ precursors to NAD+ [155]. The fates of
NAD+ precursors appear to depend on the tissue distribution and
expression levels of NAD+ biosynthetic enzymes, nucleosidase, and
presumptive transporters for each specific precursor. Furthermore,
these precursors are differentially utilized in tissues and organs
[155,156]. To identify the potential mechanisms for the physiological
and side effects of each precursor, it is necessary to comprehend the
distinct features of the metabolism of every NAD+ precursor.

Interestingly, as a fact that existed in the antiaging market before the

FDA ban was executed, NMN was the dominating product in the
antiaging consumer market. For example, a search on Amazon.com for
‘NMN’ returned 6 pages (each page contains 60 listings) of various
brands of NMN products; after excluding some duplicated or inaccurate
listings, the total number is still close to 300. In contrast, a search for
‘NA’ showed around 40 brands, ‘NAM’ with ∼20 and ‘NR’ with only 4
brands (search conducted on 26 January, 2023). Theoretically, both NR
and NMN can increase NAD+ concentrations, making them equally
competitive in the consumer market. However, from a biochemist’s
perspective, NR holds an edge over NMN because cells cannot directly
absorb NMN, and NMN must be converted to NR before entering cells.
Thus, this market anomaly may be attributed to the fact that NMN is a
more direct precursor in the biosynthesis pathway of NAD+ when viewed
from a layman’s standpoint (Figure 2). This illusion, probably further
fanned by the manufacturers, is responsible for the hyped demands and
sales of NMN to consumers that causes more people to be exposed to
NMN compared to other NAD+ precursors. Consequently, NMN should
receive more attention for its effects and safety issues. For more
information about NR, NAM, and NA, we refer the readers to several
reviews dealing with this topic [29,155,157,158]. In this review, we only
focus on NMN.

NMN as NAD+ Precursor

Since NAD+ cannot be absorbed orally or pass through the cell

membrane, elevating NAD+ concentrations can be accomplished by
supplementing the diet with its precursors, which include TRP, NA, NAM,
NR, and NMN. To prevent pellagra resulting from a lack of tryptophan,
NA and NAM dietary supplements have been employed. Nonetheless, due
to their potential side effects, such as flushing and inhibiting PARPs and
sirtuins, both NA and NAM should be used with caution [159]. Therefore,
NMN and NR have gained priority as agents to raise NAD+ concentrations.
As explained above, compared with NR, NMN is a more direct precursor
of NAD+. Unfortunately, all the dietary precursors of NAD+, including TRP,
NA, NR, and NAM, are imported directly into the cells and can produce
NAD+, except NMN. Although studies have shown that NMN can increase
NAD+ concentrations in rodents and humans, how NMN is absorbed by
cells and tissue is still controversial and needs to be better understood.
Two mechanisms have been proposed to explain NMN uptake in cells or
tissues. One is that the cell can directly absorb NMN through a specific
transporter, Slc12a8, a cell membrane transporter in the aged mouse
ileum [160]. However, this observation had some challenges [161,162].
Furthermore, it is necessary to verify the expression profile of Slc12a8 in
the human gastrointestinal tract. Another more widely accepted
mechanism entails the dephosphorylation of extracellular NMN into NR
by ectonucleotidases (e.g., CD73) prior to its cellular absorption
[[162], [163], [164], [165]]. After NR enters the cell through equilibrative
nucleoside transporters (ENT1, ENT2, and ENT4), it is phosphorylated
by NRK1 and NRK2 to generate NMN [162,163,166,167]. This
mechanism is also supported by the results of Kim et al. [167], who
showed via isotope-labeled NMN that most orally ingested NMN was
converted to NR in intestinal tissue. The study suggested that the NMN
uptake bypasses direct transport and is first dephosphorylated to NR to
promote intestinal absorption [168].

NMN is a bioactive nucleotide with a molecular weight of 334.22 g/mol

and has α and β configurations, with the β configuration showing better
bioactivity. It has good water solubility, and its solution is acidic. In the
human body, NMN can be found in placental tissue, blood, urine, and
other bodily fluids [100] and is mainly distributed in the nucleus,
mitochondria, and cytoplasm of cells [169]. NMN occurs naturally in an
assortment of vegetables, fruits, and meats, such as cabbage, tomato,
mushroom, soybean, pear, orange, cherry, shrimp, scallops, beef, and
salmon. The concentration of NMN varies across these food items,
ranging from 0.035 to 1.88 mg/100 g in vegetables, 0.021 to 1.6 mg/100
g in fruits, and 0.029 to 0.51 mg/100 g in aquatic products [100,167].
The most studied NAD+ precursors in humans are NA and NAM,
collectively termed niacin and/or vitamin B3. The most fundamental use
of NAM and NA is to protect against pellagra, which can develop from
TRP deficiency [29,167,170]. Dietary TRP is also classified as a niacin
equivalent, and 60 mg of TRP is considered the equivalent of 1 mg of
niacin [170]. The recommended daily allowance (RDA) of NA is 16 and
14 mgNE/d for adult men and women, respectively [170]. However, an
excessive human oral dose of NAM and NA can cause side effects,
including vasodilation (30–100 mg/d NA) [171], headache, hypotension,
liver toxicity [172,173], glucose intolerance [174], epigenetic changes,
impeded bioenergetics, potential carcinogenesis, blurred vision (1.5 g/d
NA) [175], and gastrointestinal tract disturbances (nausea, vomiting,
diarrhea) (3 g/d NAM) [174,176]. NR is found in trace amounts in cow’s
milk [177] and has beneficial effects in multiple conditions in rodents
and humans. Clinical studies have demonstrated the safety of NR, with
oral doses ranging from 100 to 2000 mg/d in human trials, as displayed
in Supplementary Table 1. It should be noted, however, that
overconsumption of any substance can lead to toxicity. So far, existing
human clinical trials have not shown any side effects of NR and NMN
(Table 2 and Supplementary Table 1). Neither NMN nor NR has an
established official RDA.
TABLE 2
The safety and antiaging effects of NMN in human clinical trials

Registration Dose & Locati Referen

Design Indicators Outcome
number duration on ces
UMIN0000213 Nonblinded Oral Clinical ↑NMN Japan [35]
09 , administrat parameters, metabolites
nonrandomi ion: 100, ophthalmic (2Py and
zed, non– 250 or 500 parameters, 4Py) in
placebo- mg for 5 h sleep quality plasma and
controlled score, serum bilirubin
study; 10 parameters, levels;
healthy men NMN ↓creatinine,
aged 40–60 metabolites chloride, and
y levels in glucose
plasma levels within
the normal
ranges in
serum;
No
significant
changes in
ophthalmic
examination
and sleep
quality
score;
Single oral
administrati
on of NMN
up to 500
mg is safe
and well-
tolerated in
healthy men
without
causing any
significant
deleterious
Registration Dose & Locati Referen
Design Indicators Outcome
number duration on ces
effects
↑NAD+ and
NAMN
Adverse levels but
events, not NMN;
clinical Pulse rate is
parameters, strongly
Double- blood and correlated
blind, urine with the
randomized biochemical increase in
Oral
, placebo- parameters, NAD+ level;
administrat
jRCTs0412000 controlled body No obvious
ion: 250 Japan [140]
34 study; 30 composition, adverse
mg daily
healthy skeletal effects, and
for 12 wk
volunteers muscle mass, no
aged 20–65 bone mineral significant
y mass, NAD+, changes in
and amino other
acid indicators;
metabolome Oral
of blood administrati
on of NMN
is safe
1000 mg
once or
Double-
twice daily
blind,
regimens
block- Oral
were safe
randomized administrat NMN, NAD+,
and
, placebo- ion: 1000 and
associated Ameri
/ controlled mg once NAD+ metabo [122]
with ca
study; 32 daily or lome in blood
substantial
overweight twice daily and urine
dose-related
or obese for 14 d
increases in
adults aged
blood NAD
55–80 y
levels and its
metabolome
NCT03151239 Double- Oral NMN ↑ NAD+ and Ameri [36]
blind, administrat metabolites NMN ca
randomized ion: 250 and NAD+ in metabolites
, placebo- mg daily plasma, in plasma;
controlled for 10 wk PBMCs, and ↑ NMN
study; 25 skeletal metabolites
Registration Dose & Locati Referen
Design Indicators Outcome
number duration on ces
muscle; body
composition
and basal
in skeletal
metabolic
postmenopa muscle but
variables;
usal and not NMN;
skeletal
prediabetic ↑muscle
muscle insulin
women insulin
sensitivity and
aged 55–75 sensitivity,
signaling;
y insulin
skeletal
signaling
muscle global
transcriptome
profile
↑aerobic
capacity,
Double- enhanced
blind, O2 utilization
randomized of skeletal
Oral
, placebo- muscle;
administrat Body
controlled ↑VT in a
ion: 300, composition
ChiCTR20000 study; 48 dose-
600 or and China [145]
35138 healthy dependent
1200 mg cardiopulmon
recreational manner;
daily for 6 ary function
ly trained No obvious
wk
runners adverse
aged 27–50 symptoms
y and
abnormal
ECG
↑NAD+ and
Clinical
NAD+ metab
characteristics
Double- olite levels
, blood and
blind, in blood,
urine
randomized Oral improved
biochemical
, placebo- administrat muscle
UMIN0000363 parameters,
controlled ion: 250 strength and Japan [141]
21 body
study; 42 mg daily performance
composition,
healthy old for 12 wk , and no
skeletal
men aged obvious
muscle mass,
≥65 y adverse
segmental
effects were
lean
observed
UMIN0000380 Double- Oral body NMN intake Japan [118]
Registration Dose & Locati Referen
Design Indicators Outcome
number duration on ces
composition, in the
blind, muscle mass, afternoon is
randomized bone mass, more
, placebo- sleep quality, effective in
administrat
controlled fatigue, improving
ion: 250
97 study; 108 physical lower limb
mg daily
overweight performances function and
for 12 wk
or obese reducing
adults aged drowsiness
≥65 y in older
adults
↑ telomere
Nonblinded
length of
,
PBMC,
nonrandomi Oral
which may
zed, non– administrat
The telomere be the
placebo- ion: 300
NCT04228640 length of the potential China [147]
controlled mg daily
PBMC molecular
study; 8 for 30–90
mechanisms
healthy men d
of NMN for
aged 45–60
extending
y
lifespan
NCT04228640 Double- Oral Blood cellular ↑NAD+/ China [146]
blind, administrat NAD+/NADH NADH
block- ion: 300 concentration levels in the
randomized mg in serum, six serum, SF-
, placebo- NMN/d for minutes 36 score,
controlled 60 d walking minute
study; 66 endurance walking
healthy test, blood endurance,
participants pressure, and HOMA-
aged 40–65 pulse IR index;
y pressure, SF- ↓blood
36 pressure,
questionnaire, pulse
adverse pressure,
events; blood and blood
biochemical glucose;
parameters, All test data
HOMA-IR did not have
any
statistically
significant
Registration Dose & Locati Referen
Design Indicators Outcome
number duration on ces
changes.
However,
the increase
in
NAD+/NAD
H levels in
serum and
the
improvemen
t in overall
health and
walking
endurance
were
clinically
significant
Did not
cause
changes
Double- exceeding
blind, physiologica
Safety
randomized Oral l variations
evaluation of
, placebo- administrat (including
NMN oral
UMIN0000430 controlled ion: 1250 anthropomet
administration Japan [178]
84 study; 31 mg ry,
in healthy
healthy NMN/d for hematologic
adult men and
participants 4 wk al,
women
aged 20–65 biochemical,
y urine, and
body
composition
)
Open in a separate window

2Py, N-methyl-2-pyridine-5-carboxamide; 4Py, N-methyl-4-pyridone-5-carboxamide; ECG,

electrocardiogram; HOMA-IR, Homeostatic Model Assessment for Insulin Resistance; NAD,
nicotinamide adenine dinucleotide; NAMN, nicotinic acid mononucleotide; NMN,
nicotinamide mononucleotide; PBMC, peripheral blood mononuclear cell; SF-36, 36-Item
Short Form Survey; VT, ventilatory threshold.
There is speculation that the human body can obtain NMN from daily
food sources to support physiological function and NAD+ biosynthesis
[100]. The amount of NMN obtained from food is likely ≤2 mg/d
[36,100,179]. However, NAD+ concentration is reduced with age in
human blood. Yang et al. [180] reported that the whole blood
NAD+ concentration decreased gradually with aging in healthy men.
Clement et al. [65] quantified changes in the NAD+ metabolome in plasma
collected from healthy human subjects; their data showed NAD+ was
significantly and negatively correlated with age from 20 to 87 y
(correlation coefficient = −0.93). Hence, it is essential to supply NMN
from nondietary sources to sustain proper NAD+ status. In human clinical
trials with NMN, oral doses ranged from 100 mg/d to 2000 mg/d, with
250 mg/d being the most common dosage employed
[35,36,118,140,141]. As a dietary supplement for antiaging and
longevity, the dose of NMN available ranges from 50 to 500 mg per
capsule in commercial products (data from Amazon.com and Ebay.com).
Some consumers take 2 150-mg capsules daily [36]. The dose of NR
available ranges from 100 to 2000 mg per softgel in commercial
products (data from Amazon.com and Ebay.com). According to the
dietary standards from the European Food Safety Authority, the
tolerable upper intake level (UL) for NA is 10 mg/d, and the UL for NAM
is 900 mg/d in adults [181]. The UL for niacin (including NA, NAM, and
derivatives that exhibit the biological activity of NAM) is 35 mg/d (US
National Academies of Science) [179]. Although there is currently no
established UL for NR and NMN intake, based on molar equivalency, 900
mg of NAM equals 7.37 mmol, while 7.37 mmol of NR or 7.37 mmol of
NMN equals 1889 mg and 2463 mg, respectively. Nevertheless, the safety
of these higher doses cannot be determined without further toxicological
studies and clinical trials involving larger cohorts. Establishing
recommended safe levels for long-term administration is crucial. Still,
compared with the RDA of vitamin B3, the supplemental dose of NMN is
very high. Pellagra prevention is a different endpoint compared to
optimizing NAD+ status to extend health span and reduce age-related
dysfunction and disease. RDA is a minimum intake standard established
to prevent a deficiency disease, so a direct comparison between them
may not make much sense. However, NMN should be supplemented
within a safe dose, at least below the UL.

A recent trend entails combining NMN with other antiaging agents.

Compared to NMN alone, NMN combined with resveratrol and
ginsenoside Rh2 and Rg3 showed better performance in increasing
NAD+ concentrations in the heart and skeletal muscle of mice [182]. NMN
has even been considered as an adjuvant to combat the COVID-19
pandemic; a study entitled “Study to evaluate the effect of NMN as an
adjuvant to the standard of care on fatigue associated with COVID-19
infection” is currently in progress, and the results are of interest
(NCT05175768).

There are several synthesis methods to obtain high-purity NMN

[[183], [184], [185]], including chemical synthesis, microbial
fermentation, and enzymatic synthesis. Chemical synthesis utilizes
substrates such as 1,3,5-tri-O-benzoyl-β-D-ribofuranose, 1,2,3,5-tetra-O-
acetyl-D-ribose, nicotinamide, ethyl nicotinate, and adenosine
monophosphate. NMN is synthesized through Vorbruggen glycosylation,
ketalization, phosphorylation, and ammonolysis
[[186], [187], [188], [189]]. The disadvantages of this method include
high cost, producing uncontrollable chiral by-products, multiple-step
reactions, low yield, low purity, and the use of a large number of organic
solvents, causing serious environmental damage [185,190]. On the other
hand, biosynthesis is a relatively green and environment-friendly
preparation method because it does not contain any organic solvent
residue. Recently, several approaches have attempted to produce NMN
in Escherichia coli but with low productivity and lack of practicality due
to unintelligent mass transfer [183,191,192]. As for bioenzyme-catalyzed
synthesis, it generally uses nicotinamide and phosphoribosyl
pyrophosphate as substrates to generate NMN under the catalysis of
nicotinamide phosphoribosyltransferase [190]. The phosphate group in
NMN is primarily derived from energy-rich molecules like ATP or PRPP.
However, the expensive cost of these precursors in the market results in
a higher production cost for NMN [190]. Li et al. [185] designed an in
vitro synthetic enzymatic biosystem to improve productivity further and
reduce the production cost in one pot to produce NMN from low-cost
starch and NAM. In a recent clinical trial, MetroBiotech, a Boston-based
company, disclosed that its drug MIB-626 is a microcrystalline unique
polymorph β-NMN formulation [122].

Although NMN has demonstrated antiaging properties in both cellular

and animal models, there is a pressing need for additional clinical trials
to determine its safety and efficacy in humans. Given its status as a top-
selling antiaging product in recent years, human clinical trials on NMN
have generated considerable interest. To date, 10 human clinical trials
have been published (Table 2), with an additional 13 completed but
unpublished trials and 11 ongoing trials (see Supplementary Table 2).
Go to:

Human Clinical Trials with NMN Supplementation

Safety assessment

For the past few years, researchers have started to assess the safety and
effects of NMN supplementation in humans to determine whether the
effects observed in cells and animal models can be translated to humans.
Thus far, we have identified 10 published human clinical trials, although
more studies have yet to be published. The first clinical trial that
assessed the safety of NMN in humans came from the Keio University
School of Medicine (UMIN000021309) in 2016 [35]. To investigate the
safety of NMN, a short-term study was conducted on 10 healthy men.
During each visit, after overnight fasting, the participants orally
consumed NMN capsules containing 100, 250, or 500 mg of NMN at
09:00. They were then monitored for 5 h at rest and were only allowed
to drink water freely. The results of the study showed that the
concentration of NMN metabolites (N-methyl-2-pyridine-5-carboxamide
[2Py] and N-methyl-4-pyridone-5-carboxamide [4Py]) in human plasma
increased as a result of NMN consumption, but there were no significant
clinical symptoms, harmful effects, or changes in heart rate, blood
pressure, oxygen saturation, or body temperature. The single oral
administration of NMN up to 500 mg was safe and well-tolerated by the
participants. Seven other studies conducted human clinical trials with
the same NMN oral doses (250 mg once daily for 6 or 12 wk) or different
doses (300, 600, and 1200 mg once daily for 6 wk; 300 mg once daily for
60 d) [36,118,140,141,[145], [146], [147]]. The highest NMN oral dose
administered was 1000 mg twice daily for 14 d by Harvard Medical
School [122]. The findings of these studies suggest that the
administration of NMN orally is safe and has good tolerance. A recent
investigation examined the safety of NMN in oral form (1250 mg/d for 4
wk) in 31 healthy individuals aged 20 to 65 and conducted an Ames test.
The results revealed that NMN is a nonmutagenic substance that is safe
and well-tolerated [178]. However, most selected participants were
older individuals (age ≥55 y), and only 2 trials recruited middle-aged
people (age <40 y) as partial participants, one from Guangzhou Sport
University in China [145] and the other from the University of Toyama in
Japan [140]. Nonetheless, it is believed that antiaging interventions
should be initiated at a comparatively younger and healthier age than at
a very old age, which will last longer. Therefore, there is a need for
further investigation and determination of the safety and dietary
reference intake of NMN in different age groups for long-term oral
administration. Additionally, the number of participants in the human
clinical trials conducted so far is limited. Eight studies included a range
of 8 to 66 participants, which is primarily at the phase I clinical trial
level. The University of Tsukuba in Japan conducted the most extensive
trial with 108 older individuals as participants, utilizing a rigorous
double-blind, randomized, placebo-controlled study method, which
barely reached the level of a phase II clinical trial. In addition, 2 of these
clinical trials evaluated the safety of oral NMN and the change of
NAD+ and its metabolite concentrations in blood. Okabe et al. [140]
reported that the concentrations of NAD+ and NAMN were significantly
increased in whole blood after NMN intervention, but the levels of NMN,
NAAD, NR, nicotinic acid nucleoside (NAR), NAM, NA, and N-methyl
nicotinamide (MNAM) remained unchanged; however, the pulse rate
exhibited a strong positive correlation with the increase of
NAD+ concentration in blood. Although the exact reason is unclear, the
association of pulse rate with energy consumption might be a direction
for further investigation [140]. Pencina et al. [122] found that a higher
dose of NMN was associated with a more pronounced increase in NMN
and NAD+ concentration in the blood and the concentration of
NAD+ metabolites (NAM and 2Py) in the urine. Three of the clinical trials
included in the studies mentioned above evaluated both the safety of oral
NMN and its potential antiaging effects, as well as the changes of NAD+ or
its metabolite concentrations in blood, PBMCs, plasma, skeletal muscle,
or urine.

Whether NMN is approved for marketing as a drug or dietary

supplement, its safety for human consumption is always the most
important issue. Although no clear side effects have been reported in
existing human clinical trials, few studies have reported the possible
toxic effects of NMN. For instance, Di Stefano et al. [193,194] reported a
prodegenerative effect on axons after NMN supplementation in a
chemotherapy-induced peripheral neuropathy mouse model. In addition,
they revealed NMN-synthesizing enzyme as an important new
therapeutic target in axonopathies. Nacarelli et al. [195] also found that
NMN supplementation could enhance the proinflammatory SASP in
oncogene-induced senescence cells and promote pancreatic ductal
adenocarcinoma progression in a mouse model driven by oncogenic
Kras. Moreover, a cell-permeant mimetic of NMN activated SARM1 to
produce cyclic ADP-ribose and induced nonapoptotic cell death [196].
However, due to NMN’s limited toxicological data, future studies should
focus more on this direction.

Antiaging effect assessment

Sleep

Sleep quality is an important indicator of the health effects of any

supplement. The first NMN human clinical trial assessed the sleep quality
in 10 healthy Japanese men (age 40–60 y) via the Pittsburgh sleep
quality index. It detected the levels of NMN and NAD+ metabolites (2Py
and 4Py) in plasma. During the study, the researchers administered NMN
(250 mg) or a placebo once a day for 6 or 12 wk to 20 healthy old men
(age ≥65 y) and monitored their physiological muscle motility and blood
NAD+ concentrations. The results showed a significant dose-dependent
increase in NAD+ metabolites, but unfortunately, NMN was not detectable
in the plasma samples. Moreover, there were no significant changes in
the sleep quality score before and after NMN administration [35]. Owing
to the poor sleep quality of older people, fatigue often occurs among
them and more frequently in the afternoon. Therefore, sleep quality and
fatigue in a lot of overweight or obese older people (age ≥ 65 y) were
assessed via the Pittsburgh sleep quality index, self-reported sleep diary,
and questionnaire [118]. The participants were divided into 2 groups:
one took 250 mg NMN or placebo daily for 12 wk in the morning (after
waking up until 12:00) and the other took 250 mg NMN or placebo daily
for 12 wk in the afternoon (from 18:00 until bedtime). The results
revealed no significant differences in sleep quality and fatigue tests
before and after the intervention. However, the effect sizes of sleep
quality and fatigue in the afternoon intervention group were larger than
in the morning intervention group. Similar results were also found in the
placebo-controlled group, in which the effect sizes in the afternoon
placebo group were better than those in the morning placebo group
[118]. The time-of-the-day-dependent manner of NMN intervention may
be related to the circadian clock of NAD+ biosynthesis. Nakahata et al.
[197] and Ramsey et al. [198] reported that NAD+ concentration (in
serum-entrained mouse embryo fibroblasts and mouse liver) was the
lowest between 12:00 to 20:00 every day, and CLOCK-SIRT1 and NAMPT
regulated the circadian clock of NAD+ biosynthesis in mice.
Physical activity

Endurance exercise increases aerobic capacity by improving

mitochondrial function, vascular endothelium function, and capillary
muscle density [199]. In addition, NMN has also been reported to
improve mitochondrial function in various metabolic organs (such as
skeletal muscle), vascular endothelium function, neoangiogenesis,
capillary density, blood flow, and soluble oxygen levels in rodents
[22,23,148,174]. Igarashi et al. [141] investigated the effects of NMN
intervention on the physical activity of older individuals. They observed
the physiological muscle motility and blood NAD+ concentrations in 20
healthy older men (age ≥65 y), and NMN (250 mg) or placebo was
administered once a day for 6 or 12 wk [141]. The NMN intervention did
not have an impact on insulin sensitivity, skeletal muscle, and visceral fat
mass. However, it was found to significantly improve gait speed, left grip
strength, and the frequency of the 30-s chair-stand test [141]. Oral NMN
supplementation effectively increased NMN and NAD+ concentrations in
blood, and an increase in NR level was also observed, indicating that
NMN might be converted into NR by CD73 [141]. It should be noted that
oral NMN also significantly increased the level of NAMN and NAR, which
was not a route for converting NMN to NAD+ [141]. The increase of
NAD+ concentration in blood may lead to the deamidation of NMN and,
ultimately, the formation of NAM; besides, the deamidation of NMN by
intestinal microflora may be another mechanism [141]. In summary,
Igarashi’s research demonstrated that NMN was an efficient
NAD+ booster for preventing aging-related muscle dysfunctions in
humans [141]. Kim et al. [118] evaluated the effect of oral NMN on
physical performance in older individuals, including grip strength, 5-
times sit-to-stand (5-STS), timed up and go, and a 5-m habitual walk. The
5-STS test results for all groups postintervention showed significant
improvement compared to those before the intervention. The effect size
of the NMN intervention in the afternoon (d = 0.72) was larger than that
of the morning intervention (d = 0.40). No significant improvement was
observed in other test items. Overall, these findings suggest the potential
of NMN to improve physical performance in older adults.

The effects of NMN intervention on the physical activity of middle-aged

people were investigated by the Department of Sports Medicine,
Guangzhou Sport University, China [145] and Effepharm (Shanghai) Co.,
Ltd, China [146]. Liao et al. [145] conducted a double-blind, randomized,
placebo-controlled human clinical trial, which included 48 young and
middle-aged recreationally trained runners (aged 27–50 y). The
participants underwent randomization into 4 groups, with each group
receiving either 300 mg, 600 mg, 1200 mg NMN or a placebo orally for 6
wk. Concurrently, all participants performed aerobic exercise, including
running and cycling, with 40- to 60-min training sessions 5 to 6 times
each week while taking the NMN orally [145]. In addition,
cardiopulmonary exercise testing was performed to assess the aerobic
capacity of the runners; NMN intervention significantly increased oxygen
consumption in ventilatory threshold 1 (VT1) and improved energy
consumption in VT1 and VT2. These results indicate that physical
training combined with oral NMN administration could be a new
strategy to improve athletes’ performance [145]. Huang et al. [146]
conducted a 6-min walking endurance test for older people (age 40–65
y) after NMN intervention (300 mg/d for 60 d). On day 30 of the
treatment, the NMN intervention and placebo groups exhibited a 4.3%
and 3.9% increase in walking endurance, respectively. When the same
treatment was continued for up to 60 d, the NMN intervention group
showed a further rise of 6.5%, whereas the placebo group showed no
additional increase, remaining at 3.9%. Although the difference between
the NMN and placebo intervention groups was not statistically
significant in the 6-min walking endurance test, it was evident that the
NMN intervention group showed sustained improvement in walking
endurance from 30 to 60 d of treatment [146].
Nervous system-related

Irie et al. [35] assessed ophthalmic parameters, including visual acuity,

functional visual acuity, intraocular pressure measurement, and
meniscometry. The results showed no significant changes in ophthalmic
parameters before and after NMN administration. In addition, Igarashi
et al. [141] conducted a hearing test and a relatively simple cognitive
function test. Furthermore, the right auditory ability of older men
significantly improved, and the authors hypothesized that the underlying
mechanism could be similar to that observed in mice, where NMN
supplementation activates the SIRT3 protein and regulates the
reduced/oxidized glutathione ratio in the mitochondria [141,200,201].
However, no effect was observed in overall cognitive function in the
mini-mental state examination Japanese and the Japanese version of the
Montreal cognitive assessment [141].
Diabetes

Diabetes is a leading cause of blindness, amputations, heart disease,

kidney failure, and premature death. So far, there is no effective method
to cure diabetes. A study led by Yoshino et al. [36] showed that NMN
could increase muscle insulin sensitivity, insulin signaling, and
remodeling in women with prediabetes who are overweight or obese. A
total of 25 postmenopausal women with prediabetes were randomly
assigned to either the placebo group (n = 12, 250 mg/d) or the oral NMN
group (n = 13, 250 mg/d) for 10 wk. The study assessed the following
indicators: 1) NMN metabolites and NAD+ concentrations in plasma,
PBMCs and skeletal muscle; 2) body composition and basal metabolic
indexes; 3) the impact of NMN on skeletal muscle insulin sensitivity and
signaling; and 4) the effects of NMN on the skeletal muscle global
transcriptome profile [36]. Surprisingly, after NMN intervention,
participants’ insulin sensitivity was improved by 25 ± 7% [36].
Interestingly, it was also found that a series of downstream signals of the
insulin pathway, including the phosphorylation of AKT at Ser473 and
Thr308, was triggered and the expression of platelet-derived growth
factor (PDGF) receptor β and other muscle remodeling-associated genes
were upregulated. Since the PDGF signaling pathway has been reported
to enhance insulin-stimulated AKT phosphorylation and glucose
transport in skeletal muscle and multiple cell types in previous studies
[202,203], this provided a possible explanation for the effect of NMN in
enhancing muscle insulin sensitivity. In addition, NAD+ concentrations
did not change in skeletal muscle but increased significantly in PBMCs,
and the NAD+ metabolites (2Py and 4Py) significantly increased both in
PBMCs and skeletal muscle [36]. A sex difference was observed in the
effect of NMN on glucose tolerance in diabetic mice and female mice
were more sensitive than male mice [24]. Although the cause of sex
difference is still unclear, the results showed that NMN treatment could
improve impaired glucose tolerance by improving insulin sensitivity or
insulin secretion [24]. Moreover, the effect of sex differences on glucose
tolerance also needs to be further verified in human clinical trials.
Telomere

Telomere shortening is an important biomarker for aging [204]. NMN

has been reported to maintain telomere length in the liver of mouse
[205]. In another study, Niu et al. [147] examined the changes in
telomere length in 8 middle-aged men (aged 45–60 y) before and after
oral administration of 300 mg/d NMN. They discovered that NMN
supplementation resulted in a nearly doubled telomere length in PBMCs
within 90 d, indicating a potential antiaging effect. The underlying
mechanism of NMN on elongating telomere length may be associated
with the increased NAD+ concentration in liver [24,205], stabilizing
telomere and preventing tissue damage and fibrosis in a partially sirtuin-
1-dependent manner [205].

Completed but Unpublished and Ongoing Clinical Trials

We also identified completed but unpublished clinical trials and ongoing
clinical trials from clinicaltrials.gov (https://www.clinicaltrials.gov/),
WHO International Clinical Trials Registry Platform
(https://trialsearch.who.int), and UMIN-CTR Search Clinical Trials
(https://center6.umin.ac.jp/cgi-open-bin/ctr_e/index.cgi?function=02).
Furthermore, 13 completed but unpublished clinical trials and 11
ongoing clinical trials were identified (Supplementary Table 2). The
objectives of these trials encompassed the following aspects: 1) assessing
the safety and metabolic kinetics of NMN nutrition intervention in
healthy adults (18–70 y); 2) investigating the effects of NMN nutrition
intervention on various diseases (including diabetes, chronic disease,
hypertension, polycystic ovary syndrome, and premature ovarian
failure); 3) observing the antiaging effects of NMN nutrition intervention
on the skin (including fine lines and wrinkles, eye bags, dark circles, skin
texture, moisture, puffiness, and brightness); 4) studying changes in
various hormonal levels and aging markers, male fertility indicators,
cardiovascular and metabolic functions, and physical activity; 5)
comparing the impact of NMN and other NAD+ precursors on blood
NAD+ metabolome. Although each clinical trial must be registered in a
publicly accessible database, there is no obligation to publish the results.
This is unfortunate, as results from completed but unpublished clinical
trials would provide useful information for scrutinizing NMN nutrition
intervention’s safety and antiaging effects. Thus, it is strongly
recommended that the results of any reasonable clinical trial should be
published, and this should be the responsibility of the researchers and
the funding sources, including the food and pharmaceutical industries.
Go to:

Conclusions and Challenges

Existing human clinical trials suggest that oral NMN administration is

generally safe, and although only a limited number of indicators were
studied, the results suggest that NMN has potential as an antiaging agent.
However, there are still obstacles that need to be addressed before NMN-
containing products can be confidently marketed.

 1.

Longer, larger and better-designed human trials are needed to

investigate NMN administration’s safe dosage, tolerance and
frequency.

Humans usually take supplements for a long time and sometimes for
most of their lifespan. Thus, the long-term safety issue should be
addressed about NMN supplementation. Also, a larger/more diverse
population should be examined, as certain adverse effects could only be
observed in a very small number of people. Furthermore, it remains to
be seen whether the beneficial effects of NMN were only limited to a
specific group or the general population. For instance, NMN
supplementation increased skeletal muscle insulin signaling, insulin
sensitivity, and muscle remodeling in postmenopausal women with
prediabetes, how about other populations? Finally, better-controlled
clinical trials will avoid biased results.
  2.

More comprehensive studies are needed to elucidate the beneficial

effects of NMN and underlying mechanisms fully. In addition,
mechanistic toxicological studies are also warranted.

In the existing human clinical trials, very limited indicators were

examined; in particular, nutritionally relevant endpoints were absent.
For example, whether NMN supplementation could improve the
absorption of nutrients, whether and how NMN affects the activity of the
various metabolic enzymes; and as a hot research area in recent years,
whether NMN has any influence on the gut microbiota and whether gut
microbiota mediates the function of NMN. Such topics are all worthy of
further investigation. Thus, omics techniques (such as the evaluation of
transcriptome, proteome, and metabolome) should be used to establish
the toxicology, beneficial effects and safety dose ranges of NMN in
humans, including different age groups, health status and sex. Also, even
though NAD+ and NAD+ metabolites can be detected in the blood after
oral NMN administration, the biological effects may differ in different
tissues and organs. Thus, the biological effects on different tissues and
organs should be considered in future studies. More importantly, a better
understanding of the molecular mechanism of the action of NMN is a
prerequisite for its human applications, which will help to avoid
unwanted side effects.

 3.

Some fundamental issues regarding NAD+ and NMN must be

carefully addressed. Different ethnic groups, age groups, gender
groups and dietary pattern groups may have different ‘normal’
NAD+ concentrations. Without a clear definition of the ‘normal’
concentration, many results from different studies may not be
applied to other populations. Thus, a large-scale baseline
 measurement of NAD+ and NADome in multiple age groups and
regions is necessary to establish the ‘golden standard.’
Furthermore, many questions remained to be answered, e.g.,
whether and to what extent blood and tissue NAD+ concentration
should be considered as biomarker of status; the need for
population-based studies to determine whether blood and tissue
concentrations can be considered surrogates for dysfunction or
risk for chronic disease; and how NMN (or other precursors)
supplementation may impact these. Also, large epidemiological
studies need to show a clear relationship between NAD+ ‘deficiency’
and age-associated health outcomes. As noted before, there were
currently few such studies, and without a clear association, the
potential of NMN, or other NAD+ precursors, is greatly undermined.

Finally, an important issue to consider is the excessive hype surrounding

NMN in the market. For example, some have touted NMN as a solution to
skin aging, and while a recent study showed promising results in mice,
further research is needed before conclusions can be drawn about its
effectiveness in humans [33]. Another study showed that NMN reduced
melanogenesis in aged melanocytes by downregulating the signaling of
melanogenesis-associated receptors [206]. Nevertheless, there have yet
to be any results obtained from those human clinical trials examining the
skin antiaging effect by either oral or external NMN intervention.
Furthermore, it is well known that NMN cannot pass through the skin
barrier directly due to its high water solubility. However, many NMN
skin care products, including essence, facial mask, moisturizing water,
and sunscreen, are widely sold. Thus, there is an urgent need to conduct
appropriate clinical trials to determine the effects and safety of NMN
supplements in different aspects so that their potential benefits can be
realized in more people.
Go to:
Acknowledgments
We are grateful to the anonymous Reviewers and the Editors for
providing many helpful comments and suggestions that greatly
improved the quality of this manuscript, which we directly or indirectly
incorporated into the text.
Go to:

Footnotes

Appendix A
Supplementary data to this article can be found online
at https://doi.org/10.1016/j.advnut.2023.08.008.

Go to:

Author contributions

The authors’ responsibilities were as follows—QS, XFZ, XQZ, JY:

conceptualization; QS: drafting the manuscript; QS, SSL: making figures;
QS, XFZ: providing tables, XFZ, XQZ, JY: review of the manuscript; and all
authors: read and approved the final manuscript.

Go to:

Conflicts of interest

The authors report no conflicts of interest.

Go to:

Funding
This work was supported in part by grants from the National Natural
Science Foundation of China (Nos. 31971138, 32270186 and 62202136),
Zhejiang Provincial Natural Science Foundation (LZ19H260001 and
LQY20F030001), and Health Commission of Zhejiang Province (No.
2022506699).

Go to:

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1:
Click here to view.(36K, docx)Multimedia component 1
Go to:

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