Niacin: James B. Kirkland, Mirella L. Meyer-Ficca

CHAPTER THREE
Niacin
James B. Kirkland*, Mirella L. Meyer-Ficca†,1
*Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
†
Utah State University, Logan, UT, United States
1
Corresponding author: e-mail address: mirella.meyer@usu.edu
Contents
1. Introduction 84
2. Role of Dietary Niacin in Disease Origin and Progression 84
2.1 Historic Niacin-Deficiency Syndrome: Pellagra 84
2.2 Current Risks and Causes of Niacin Deficiency and Pellagra 86
2.3 Niacin and Vitamin B3, Assessment of Niacin Status, and Recommended
Daily Allowance 88
2.4 Niacin Food Sources 91
2.5 Risk Factors Predisposing to Niacin Deficiency 91
3. NAD Metabolism 93
3.1 NAD Synthesis 93
3.2 NAD Recycling 97
3.3 NADPH Synthesis 97
3.4 NAD and NADP Utilization 97
3.5 NAD as Substrate 105
3.6 Turnover of PAR and MAR Modifications 117
4. NAD: Relevance to Health and Disease 118
4.1 NAD Decline During Aging and Age-Related Disorders 119
4.2 DNA Damage Accumulation 121
4.3 Cell Death/Cancer 122
4.4 Mitochondrial Dysfunction 122
4.5 Neurological Disorders 124
4.6 Skin Health and Skin Cancer Prevention 127
4.7 Cardiovascular Disorders and Niacin in Clinical Trials 128
5. Summary 132
References 132
Abstract
Nicotinic acid and nicotinamide, collectively referred to as niacin, are nutritional precur-
sors of the bioactive molecules nicotinamide adenine dinucleotide (NAD) and nicotin-
amide adenine dinucleotide phosphate (NADP). NAD and NADP are important
cofactors for most cellular redox reactions, and as such are essential to maintain cellular
metabolism and respiration. NAD also serves as a cosubstrate for a large number of ADP-
ribosylation enzymes with varied functions. Among the NAD-consuming enzymes
Advances in Food and Nutrition Research, Volume 83 # 2018 Elsevier Inc. 83

ISSN 1043-4526 All rights reserved.
https://doi.org/10.1016/bs.afnr.2017.11.003
84 James B. Kirkland and Mirella L. Meyer-Ficca
identified to date are important genetic and epigenetic regulators, e.g., poly(ADP-
ribose)polymerases and sirtuins. There is rapidly growing knowledge of the close
connection between dietary niacin intake, NAD(P) availability, and the activity of
NAD(P)-dependent epigenetic regulator enzymes. It points to an exciting role of dietary
niacin intake as a central regulator of physiological processes, e.g., maintenance of
genetic stability, and of epigenetic control mechanisms modulating metabolism and
aging. Insight into the role of niacin and various NAD-related diseases ranging from
cancer, aging, and metabolic diseases to cardiovascular problems has shifted our view
of niacin as a vitamin to current views that explore its potential as a therapeutic.
1. INTRODUCTION
Niacin (nicotinic acid or vitamin B3) is a functional group present in
the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide
adenine dinucleotide phosphate (NADP), which are essential for oxidative
processes. Niacin was first identified in 1937 as the dietary factor that
prevented black tongue disease in dogs, the animal model for pellagra
(Koehn & Elvehjem, 1937). Pellagra is a dietary-deficiency disease whose
study facilitated the identification of niacin as the pellagra-preventing factor,
the discovery of niacin as the essential vitamin required for adequate NAD
synthesis in humans, and the identification of multiple roles of coenzyme
NAD(P) in metabolism.
2. ROLE OF DIETARY NIACIN IN DISEASE ORIGIN AND

PROGRESSION
2.1 Historic Niacin-Deficiency Syndrome: Pellagra
The disease pellagra was first described in 1763 by the Spanish physician
Casal, soon after maize (corn) became a major part of the European diet.
In 1771, Francesco Frapolli, an Italian physician, coined the term
“pellagra” (literally: sour or rough skin) to describe the crusty and inflamed
skin characteristic in human patients suffering from dietary niacin wasting
deficiency.
In 1870, frequent pellagra outbreaks among poor populations in
southern and central Europe had followed the introduction of maize.
At the end of the 19th and the beginning of the 20th centuries, pellagra
reached epidemic proportions among the population of the southern
United States and became the most severe deficiency disease in the history
of the United States, with more than 120,000 deaths by the 1920s
Niacin 85
(Etheridge, 1972; Rajakumar, 2000). Joseph Goldberger, working for the

United States Public Health Service in the 1920s, discovered that milk
and meat could provide a pellagra-preventing (PdP) factor, which was
absent in corn.
In 1937, Koehn and Elvehjem used liver extracts to isolate the dietary
PdP factor that prevented black tongue disease in a dog model of pellagra
and subsequently identified it as nicotinic acid (Elvehjem, Madden,
Strong, & Woolley, 1937; Koehn & Elvehjem, 1937). This discovery laid
the foundation for more studies that confirmed lack of nicotinic acid as
the underlying cause of pellagra in humans, and the rapid implementation
of nicotinic acid and nicotinamide supplementation as the efficient
treatment.
It was initially puzzling that Latin American populations had been spared
from pellagra, despite using corn as their main staple food for centuries. This
riddle was solved when differences in the traditional food processing
methods were discovered. Traditional Latin American food processing prac-
tices involved presoaking corn in alkaline “lime-water” prior to cooking,
which released the niacin from binding to glycoproteins, increasing its
bioavailability.
In 1942, the US government mandated a niacin enrichment program for
flour, and similar programs in other developed countries have diminished
the occurrence of clinical pellagra to sporadic cases associated with malnu-
trition (e.g., neglect, abuse, or anorexia nervosa), alcoholism, iatrogenic sit-
uations (e.g., cancer treatments), malabsorption, and prolonged diarrhea.
In the 1960s and 1970s, pellagra still was considered a public health con-
cern in developing African and Asian countries, where seasonally between
15% and 50% of the population presented with skin manifestations of pel-
lagra (Aykroyd, 1971; Barrett-Connor, 1967; Gopalan, 2009). Pellagra out-
breaks still occur frequently among refugee populations, where they
continue to be of ongoing concern.
Pellagra became known as the disease of the “4 D’s,” referring to three
commonly seen components (diarrhea, dermatitis, and dementia) of the syn-
drome culminating in death (the 4th D) (Hegyi, Schwartz, & Hegyi, 2004).
The first D, diarrhea, the gastrointestinal presentation of pellagra, results
from intestinal inflammation, when the normally metabolically active and
rapidly dividing mucosal tissue is affected. Patients appear nauseous and have
poor appetite and abdominal pain. Anorexia and malabsorptive diarrhea
exacerbate a state of malnutrition.
The second D, dermatitis, refers to extensive skin lesions. After an initial
erythematous phase resembling sunburn with blisters, the skin becomes
thickened and hyperpigmented when dermatitis progresses. Typical for

pellagra is a symmetrical and bilateral distribution of affected regions in
sun-exposed skin, e.g., dorsal parts of hands, feet, cheeks, forehead, and
sun-exposed regions of the neck, sometimes referred to as “Casal’s necklace.”
The third D refers to frequently observed neurological symptoms, e.g.,
muscle weakness, and the frequent deterioration of mental health observed
in pellagra patients, progressing from lethargy, apathy, and depression to
anxiety and irritability. While these symptoms are not surprising during
severe malnutrition, many patients with pellagrous dementia experience
visual and auditory hallucinations and display paranoid and aggressive behav-
iors, which can disappear within hours of niacin supplementation,
suggesting impairment of brain signaling rather than structural degeneration.
The final D, death, indicates the high mortality rate observed in severe
pellagra cases when depletion of the niacin-based coenzyme NAD prevents
maintenance of vital body functions.
2.2 Current Risks and Causes of Niacin Deficiency and Pellagra

In addition to a diet deficient in niacin or its precursor tryptophan, the com-
mon causes of pellagra, other mechanisms can contribute to suboptimal nia-
cin status. Primary causes of pellagra include dependence on a corn-based
diet, or general malnutrition (associated with poverty, neglect, abuse, and
famine, as well as anorexia nervosa) (Jagielska, Tomaszewicz-Libudzic, &
Brzozowska, 2007). Some secondary causes include chronic alcoholism
(Nogueira, Duarte, Magina, & Azevedo, 2009) and general malabsorptive
states such as prolonged diarrhea. Alcohol-associated pellagra cases continue
to be reported in countries with niacin fortification (Li et al., 2016; Terada,
Kinoshita, Taguchi, & Tokuda, 2015). In scientific and medical reports of
pellagra cases, alcoholism is the most frequently identified etiology (35%)
compared to medications (56%), inadequate intake and malabsorption
(16% and 13%, respectively), metabolic disorders (8%), and infrequent
unknown etiologies (Goudarzi et al., 2016). When diarrhea sets in as part
of the progression of pellagra, it tends to cause a vicious cycle of worsening
niacin status.
In addition, other secondary factors induce pellagra-like symptoms and
contribute to impaired NAD synthesis:
2 Diets rich in leucine, like those based on Sorghum, can lead to pellagra
due to altered tryptophan metabolism in the presence of excessive leu-
cine (Beretich, 2005; Gopalan, 1969, 2009).
Niacin 87
2 Hartnup disease is an autosomal recessive mutation in the gene for the

neutral amino acid transporter SLC6A19, leading to depletion of tryp-
tophan and increased susceptibility for development of pellagra (Br€ oer,
Cavanaugh, & Rasko, 2005; Kraut & Sachs, 2005; Nozaki et al., 2001).
Administration of niacin reverts the pellagra symptoms and highlights
tryptophan’s importance as complementary NAD precursor.
2 Carcinoid tumors can cause secondary tryptophan degradation due to
excessive serotonin production. As tryptophan is a precursor for both,
NAD and serotonin synthesis, an increased tryptophan demand via an
increase in serotonin synthesis depletes tryptophan that is available for
NAD synthesis resulting in niacin deficiency and occasional pellagra-like
symptoms (Bouma et al., 2016; Shah et al., 2005).
2 Infections with human immunodeficiency virus (HIV) have been asso-
ciated with decreased plasma tryptophan levels and a pellagra-like state
that responded to nicotinamide supplementation (Murray, Langan, &
MacGregor, 2001).
2 Additional diseases, e.g., liver cirrhosis, diabetes mellitus, and prolonged
fevers, have been associated with niacin deficiency and pellagra.
2 Increasing age correlates with dropping NAD+ levels (Braidy et al.,
2011). Because nicotinamide and NAD+ levels are currently moving
to the limelight as players determining longevity (Li, Chong, &
Maiese, 2006; Verdin, 2015), current research aims to augment intracel-
lular NAD+ to prevent aging-associated disorders and decline
(Srivastava, 2016).
2 Women have about twice the risk of niacin deficiency compared to men
(Miller, 1978). A study of sex-specific effects of tryptophan to niacin
conversion in rats found a sex hormone-dependent decrease in the effi-
ciency of tryptophan to niacin and NAD synthesis in females. This sex-
specific difference puts women, and in particular pregnant females, at an
increased risk for niacin deficiency and pellagra (Shibata & Toda, 1997).
Indeed, a recent human study measured blood vitamin concentrations in
pregnant women during the trimester of pregnancy. The women were
healthy and eating a good diet supplemented with vitamins. Despite
hypervitaminemic levels of folate, biotin, pantothene, and riboflavin,
blood levels of vitamin A, niacin, thiamine, and vitamin B12 were defi-
cient. The niacin hypovitaminemia was especially pronounced. A high
percentage of pregnant women were deficient already in the first trimes-
ter, and this deficiency worsened in the later trimesters (Baker,
DeAngelis, Holland, Gittens-Williams, & Barrett, 2002).
2.3 Niacin and Vitamin B3, Assessment of Niacin Status, and

Recommended Daily Allowance
2.3.1 Vitamin B3 Structures
Pellagra is the manifestation of a deficiency in NAD. Molecules that serve as
dietary precursors for NAD, other than tryptophan, constitute the vitamin
B3 family. Fig. 1 gives an overview of currently known vitamin B3 mole-
cules. The first identified “pellagra-preventing factor,” i.e., vitamin B3, was
nicotinic acid or pyridine-3-carboxylic acid, subsequently referred to as nia-
cin (nicotinic acid vitamin), and this is the main source of B3 found in plant-
based foods. Nicotinamide or pyridine-3-carboxamide, sometime called
niacinamide, also serves as nutritional NAD precursor and prevents pellagra
through a similar, albeit not completely identical pathway. Nicotinamide is
formed by the cleavage of NAD+ and is the main circulating form of B3 in
blood. Despite this original distinction in nomenclature between niacin and
niacinamide, today the term niacin often indiscriminately refers to both, nic-
otinic acid or nicotinamide, or a combination of both. In 2004, Bieganowsi
and Brenner discovered that nicotinamide ribose, a molecule present, e.g., in
milk, can similarly be converted to NAD and thus classifies as the newest
discovered member of the vitamin B3 family (Bieganowski &
Brenner, 2004).
2.3.2 Measurement of Niacin Status

Since the availability of dietary niacin in humans is directly reflected by
NAD content in the body, biochemical determination of blood or tissue
NAD is utilized as a measure of niacin status (Jacobson & Jacobson, 1997;
Shah et al., 2005). A study determining blood NAD content in a metabolic
ward demonstrated that the NAD content in red blood cells can be used as a
marker for niacin status in humans. Blood NAD content directly mirrored
low niacin diet or niacin supplementation in the form of either decreased or
increased blood NAD levels (Fu, Swendseid, Jacob, & McKee, 1989;
Jackson, Rawling, Roebuck, & Kirkland, 1995; Jacobson, Shieh, &
Huang, 1999). Since blood NADP content remains relatively stable even
with a niacin poor diet that causes NAD to drop (Tang, Sham, Hui, &
Kirkland, 2008), the ratio of NAD to NADP (called niacin number) is some-
times used as a measure of niacin status. Interestingly, even in developed
countries with niacin-fortified flour, blood niacin numbers vary to a surpris-
ing degree, and 15%–20% of the population were found niacin deficient
(Jacobson, 1993).
Alternatively, quantification of urinary metabolites, i.e.,
N-methylnicotinamide and 2-pyridone, can be measured to determine
Niacin 89
H H
N
O
O O
+
N
H H
O N
O
H H O
N N
O O H
Nicotinic acid Nicotinamide H
niacin “niacinamide”
Nicotinamide riboside
+ PRPP, ATP
+P
RP
P
AT
P
,A
2
TP
+
,Q
H N
Nicotinamide adenine N
dinucleotide (NAD+) N
H N
N
H N O H
O
O
+
N O O O H
O
O P H
O
HO O P O
O O−
H
Fig. 1 Vitamin B3 molecules (nicotinic acid, nicotinamide, and nicotinamide riboside)

are dietary precursors that support the formation of nicotinamide adenine dinucleotide
(NAD). Cofactors for the synthesis of NAD from the respective precursor are indicated as
follows: ATP, adenosine triphosphate; PRPP, 5-phosphoribosyl-ribose-1-pyrophosphate;
Q, glutamate.
recent dietary niacin intake and niacin status at an individual and population
level, with the caveat that 2-pyridone more likely indicates adequate protein
intake than niacin status.
2.3.3 Dietary Need and Recommended Daily Intake

Dietary need for NAD synthesis is usually expressed as of “niacin”
requirements, i.e., the direct precursors for NAD synthesis taken up as vita-
min B3 molecules. A small percentage of NAD is generated from the
essential amino acid tryptophan via the de novo NAD synthesis. The effi-
ciency of the tryptophan to NAD metabolism is estimated to require
60 mg tryptophan for the generation of 1 mg niacin, so that a 60 mg trypto-
phan intake counts as 1 niacin equivalent (NE) (Horwitt, Harper, &
Henderson, 1981).
In the United States, the Food and Drug Administration regulates vita-
mins as “dietary supplements” and requires vitamin manufacturers to follow
current GMP regulations. To prevent and correct dietary insufficiencies in
certain food products, most flour and grain products produced as “enriched
products” must contain specified levels of thiamin, niacin, riboflavin, iron,
and folic acids. According to 21 CFR137.165 (fda.gov; revised as of April 1,
2016), each pound of flour must contain 24 mg of niacin.
The recommended daily allowance (RDA) is the amount of nutrient
or vitamin that is enough to meet the nutrient requirements of nearly all
(97%–98%) healthy people. RDA for niacin in adults is 16 mg/day of NE
for men and 14 mg of NE for women according to the FOA/WHO, status
1996 (see Table 1). For children, these values are adjusted to age groups and
gradually increase from 6 NEs daily in toddlers to 12 in teenagers, until they
reach the adult requirements. Recent studies estimate the median daily
intake of preformed dietary niacin in the United States to be 28 mg for
men and 18 mg for women. In Canada, median daily intake was approxi-
mately 41 mg in men and 28 mg in women (Institute of Medicine, 1998).
Chronic high oral doses of nicotinic acid can induce hepatotoxicity and der-
matological problems in the form of skin flushing, so that the US Food and
Nutrition Board has recommended a 35 mg tolerable upper limit (UL) for
daily intake (Institute of Medicine, 1998).
2.3.4 Factors That Influence Dietary Niacin Requirement

One important factor influencing the dietary niacin requirements is the bio-
availability of the niacin that is present in available food. In mature cereal
grains, the majority of niacin is bound and only about 30% is bioavailable.
Beans and liver are among the foods that contain niacin in the free form. As
mentioned, tryptophan as an NAD precursor in humans is thought to be
converted to NAD at an efficiency of 60:1 to 70:1 (Horwitt et al., 1981).
This conversion rate has been found to vary widely (30%) between individ-
uals and tends to increase with increased tryptophan consumption, likely
because more tryptophan is available for conversion to NAD once trypto-
phan demand for protein synthesis is met (Patterson, Brown, Linkswiler, &
Harper, 1980). Factors that reduce this conversion efficiency increase the
Niacin 91
Table 1 Recommended Dietary Allowance (RDA) of Niacin Intake for Humans at

Different Point in the Life Span
Group Age (Years) Recommended Intake (NE/Day)
Infants (AI) 0–0.5 2
0.5–1 4
Children (RDA) 1–3 6
4–8 8
9–13 12
Adolescents and adults (RDA)
Males >14 16
Females >14 14
Pregnant 18
Lactating 17
AI, adequate intake, recommendation when there is not enough evidence to develop an RDA; NE, nia-
cin equivalent, defined as mg niacin + 1/60 mg tryptophan; RDA, recommended daily allowance, aver-
age daily level of intake that is thought enough to meet the nutrient requirements of nearly all (97%–98%)
healthy people.
USDA Agricultural Research Services, Dietary Reference Intakes, Information Retrieved on April 7,
2017.
requirement for niacin. Examples in addition to low tryptophan intake are

carcinoid syndrome, in which increased serotonin synthesis depletes trypto-
phan, and Hartnup disease, which is characterized by deficient tryptophan
uptake, and long-term treatment with the drug Isoniazid, which interferes
indirectly with the tryptophan to NAD pathway.
2.4 Niacin Food Sources

Plants, bacteria, and yeast produce niacin and nicotinamide. From there, the
vitamin molecules are maintained in the food chain. Niacin content varies in
different food sources (see Table 2), and various food groups are suitable
sources for dietary niacin. Fish, meat, milk, peanuts, and enriched flour
products are good niacin sources for human consumption.
2.5 Risk Factors Predisposing to Niacin Deficiency

The major risk factor for niacin deficiency is the ongoing consumption of a
diet that relies mostly on nonfortified refined grains and grain products, as
well as a diet with little variety that is low in animal or dairy products
and legumes. Maize- or Sorghum-based diets are examples of such diets
Table 2 Preformed Niacin Content in Food

Food Niacin Content (Values in mg per 100 g or 100 mL)
Meats and Fish Fish (tuna, skipjack) 12–19
Fish (salmon, mahimahi, swordfish) 7–9
Poultry (chicken, turkey) 9–12
Pork 6–11
Beef and veal 7–9
Game meat, bison 7–11
Dairy and Eggs Milk (liquid, whole—nonfat) 0.09–0.1
Milk (dry, nonfat) 0.7–1
Yoghurt (various kinds) 0.1–0.2
Ice cream (various kinds) 0.07–1.5
Cheese 0.03–1.2
Egg 0.075–0.2
Grains, Cereals, ready to eat 0.2–90
Cereals
Rice, uncooked 5
Pasta and noodles, enriched, dry 6–8.4
Flour (wheat, barley, rice, buckwheat, white, 6–7.5
enriched)
Cornmeal (enriched) 4.9–5.2
Corn flour, cornmeal, corn grain 2.6–3.6
Vegetables Mushrooms 3–14
Tomato products (canned, paste) 0.9–3
Beans 2–3
Corn 1.1–1.8
Potatoes 1.3–1.9
Mustard greens, spinach, cabbage, cauliflower 0.2–0.3
Yeast extract spread 128
Legumes Peanuts (raw and roasted nuts, butter) 12–15
Soy products (beans, meal, flour, sauce) 1–3.2
Soymilk 0.2
Beans (kidney, garbanzo, mung, black, adzuki, lima) 0.4–0.7
Niacin 93
Table 2 Preformed Niacin Content in Food—cont’d

Food Niacin Content (Values in mg per 100 g or 100 mL)
Nuts Almonds (raw, roasted, butter, paste) 1.4–3.7
Cashew (raw and roasted nuts, butter) 1–1.7
Coconut (milk, meat, cream) 0.3–0.9
Sunflower seed kernels (dried, roasted, butter) 4–8
Sesame seeds (meal, flour, paste, butter) 4.5–13.4
Fruit Physalis (groundcherries, fresh poha) 2.8
Avocados (raw) 1.9
Oranges 0.4
Strawberries 0.4
Apples 0.08
Baked goods Leavening agents (active dried yeast) 40.2
Bagels 1.8–4.6
Bread 2–6
Waffles 2–7
USDA Agricultural Research Services, Food Composition Database (version from March 29, 2017).
low in bioavailable niacin. Sorghum (millet, jowar) contains suitable amounts

of tryptophan, but excessive amounts of leucine in Sorghum interfere with
utilization of tryptophan for niacin synthesis.
Certain population groups are at risk for niacin deficiency even in the
context of supplemented food products, i.e., secondary niacin deficiency.
This is usually due to either increased niacin demand with increased meta-
bolic NAD consumption, e.g., as seen in elderly people and pregnant
women, or cancer patients undergoing treatments that induced DNA dam-
age, such as radiation therapy or exposure to DNA-damaging drugs.
3. NAD METABOLISM
3.1 NAD Synthesis
NAD can be synthesized from nicotinic acid (NA), nicotinamide (NAM),
nicotinamide riboside (NR) (all members of the vitamin B3 molecule
group), and tryptophan.
NAD is synthesized from NA by the Preiss–Handler pathway. It comprises
three individual metabolic conversions (Fig. 2). In a first step, NA is
Vitamin B3 Tryptophan
O
O
Nicotinamide Nicotinamide Nicotinic acid N N
H
H H
“Niacinamide” Riboside Niacin H
O
H N H
O TDO
O IDO1/IDO2
H O
N +
N H
H H
O N H O
N O
N
H O
H
O O H O N-Formyl-
O HNH H
kynurenine
NAMPT1 NRK1 NAPRT1 AFMID

NAD used as substrate for enzymatic reactions,
NRK2 Phosphoribosyl
Phosphoribosyl KMO
pyrophosphate pyrophosphate
ATP
KYNU
PPi PPi
NAD salvage pathway
PPi
HAAO
H
O O
O
O ACMSD
N H
HH H
ACMS
Acetyl CoA
Phospho- O
CO2
H ribosyl pyro- Nonenzymatic,
O N +
H
O
H phosphate spontaneous
Nicotinamide –
O
O
PPi H
O P O H
O
mononucleotide O
O
O
N+
H +
O
(NMN) H
O N
O
–
O
Nicotinic acid QPRT N
H
O P O
H O
O
H mononucleotide Quinolinic
O O O
(NAMN) H acid
ATP ATP
NMNAT1–3 NMNAT1–3 PPi
PPi
H N
Nicotinamide adenosine N
H N
dinucleotide (NAD+) N
H
N
N
H N
O N
O
H
N O
N
H NADS H
O
O O
O
N+ O O H
O O
+
O H O–
N
O
O
O Glutamate Glutamine P
O
H
H O P O
O
O P
O
H + AMP + ATP O O
H O P O H
O
+ PPi
O O–
H
Nicotinic acid adenine dinucleotide
(NAAD)
Fig. 2 NAD synthesis pathways present in mammals. Blue arrows illustrate the Preiss–
Handler pathway of NAD synthesis from the nicotinic acid conversion, and the NAD sal-
vage pathway comprises NAD synthesis from nicotinamide (green arrows). NAD from
tryptophan occurs via the de novo synthesis pathway (brown arrows). Abbreviations:
ACMSD, ACMS decarboxylase [EC:4.1.1.45]; ACMS, alpha-amino-beta-carboxy-
muconate-semialdehyde; AFMID, N-formylkynurenine formamidase [EC:3.5.1.9]; HAAO,
3-hydroxyanthranilate 3,4-dioxygenase [EC:1.13.11.6]; IDO1, indoleamine 2,3-
dioxygenase 1 [EC:1.13.11.52]; IDO2, indoleamine 2,3-dioxygenase 2 [EC:1.13.11.52];
KMO, kynurenine 3-monooxygenase [EC:1.14.13.9]; KYNU, kynureninase [EC:3.7.1.3];
NAAD, nicotinic acid adenine dinucleotide; NAD, nicotinamide adenine dinucleotide;
NADS, NAD synthetase [EC:6.3.5.1]; NAMN, nicotinic acid mononucleotide; NAMPT, nic-
otinamide phosphoribosyl transferase [EC:2.4.2.12]; NAPRT, nicotinic acid phospho-
ribosyl transferase [EC:6.3.4.21]; NMN, nicotinamide mononucleotide; NMNAT,
nicotinamide mononucleotide adenylyltransferase [EC:2.7.7.1 2.7.7.18]; NR, nicotin-
amide riboside; NRK1, NR kinase 1 [EC:2.7.1.22 2.7.1.173]; NRK2, NR kinase 2
[EC:2.7.1.22 2.7.1.173]; QPRT, quinolinate phosphoribosyl transferase [EC:2.4.2.19];
TDO, tryptophan 2,3-dioxygenase [EC:1.13.11.11].
Niacin 95
converted to nicotinic acid mononucleotide (NAMN) by the enzyme nic-

otinic acid phosphoribosyl transferase (NAPT, encoded for by the gene
NPT1) and use of 5-phosphate-α-D-ribose 1-diphosphate as cosubstrate.
NAMN is then converted to nicotinic acid adenine dinucleotide
(NAAD) by the enzyme NMNAT (nicotinamide mononucleotide
adenylyltransferase) using ATP as cosubstrate. Three isoforms of NMNAT
enzymes with distinct subcellular localizations have been described in
humans, which permits differentially regulated subcellular NAD concentra-
tions (Emanuelli et al., 2001; Raffaelli et al., 2002; Zhang et al., 2003). As a
final step toward NAD synthesis, the NA moiety is amidated by the enzyme
NADS (NAD synthetase), which transfers an amino group from glutamine
and simultaneously forms glutamate in an ATP-consuming step.
The synthesis of NAD from nicotinamide follows the salvage pathway.
The name reflects the role of this pathway in the reutilization of nicotin-
amide released by ADP-ribosylases and NAD glycohydrolases in the body.
The enzyme nicotinamide phosphoribosyl transferase (NAMPT) performs
the initial step from nicotinamide to nicotinamide mononucleotide
(NMN). This step is rate limiting for local NAD synthesis, and NAMPT
activity is considered an important regulator of several downstream
NAD-consuming enzymes, e.g., sirtuins (Revollo, Grimm, & Imai, 2004,
2007). Making more NAD available is presumed to be the mechanism by
which NAMPT overexpression delays senescence in human cells (van der
Veer et al., 2007). Additional relevance for NAMPT comes from observa-
tions that the expression of NAMPT is regulated by the circadian rhythm
machinery. This makes it a direct mediator between circadian rhythms
and NAD salvage pathway (Nakahata, Sahar, Astarita, Kaluzova, &
Sassone-Corsi, 2009; Ramsey et al., 2009). The final step toward NAD syn-
thesis is performed by the NMNAT enzymes that condense the adenylyl
moiety to NMN in a manner comparable to the NAMN to NAD step dis-
cussed earlier.
The third molecule of the vitamin B3 group, nicotinamide riboside,
comprises the phosphorylation of NR by the enzyme NR kinase (NRK)
to form NMN, which subsequently serves as a substrate for NAD synthesis
via NMNAT adenylyl transfer, as discussed. Two isoforms for NRK have
been described (NRK1 and NRK2), and this pathway appears to be highly
conserved between species, e.g., it was found in yeast and humans (Belenky
et al., 2007; Bieganowski & Brenner, 2004).
An additional important pathway of NAD synthesis involves the
conversion of tryptophan to NAD via the de novo NAD synthesis pathway
(right section in Fig. 2). This pathway involves seven biochemical reactions
in the kynurenine pathway, which transforms tryptophan to NAMN. NAMN
is transformed to NAAD and finally to NAD by NMNAT/NADS activities,
using the identical metabolic transformation that synthesizes NAD from the
NAMN generated by the NA metabolisms in the Preiss–Handler pathway.
The first, and rate-limiting step, of the de novo synthesis pathway
involves the conversions of tryptophan to n-formylkynurenine. This step
can be catalyzed by each of three enzymes: indoleamine 2,3-dioxygenase
1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), or tryptophan 2,3-
dioxygenase (TDO). These three enzymes have partially overlapping
expression patterns and potentially distinct functions (Ball, Jusof,
Bakmiwewa, Hunt, & Yuasa, 2014). TDO is the major enzyme relevant
for de novo synthesis in liver, while IDOs have highest activity in lung, small
intestine, and placenta (Kudo & Boyd, 2000; Yamazaki, Kuroiwa,
Takikawa, & Kido, 1985).
The four subsequent enzymatic reactions result in the formation of
alpha-amino-beta-carboxy-muconate-semialdehyde (ACMS). ACMS has
two distinct fates that influence niacin status; either it is decarboxylated
by the enzyme ACMS decarboxylase to alpha-amino-muconate-
semialdehyde (AMS), or it undergoes spontaneous enzyme-independent
cyclization and forms quinolinic acid. Quinolinic acid subsequently serves
as a precursor for NAD synthesis. AMS on the other hand serves as a sub-
strate for a pathway, leading to the formation of acetyl CoA. The efficiency
of NAD synthesis from tryptophan therefore hinges on the accumulation of
ACMS. High activity of ACMSD can enzymatically deplete this interme-
diate from the NAD-directed pathway and prevent efficient tryptophan
to NAD conversion, while low levels of ACMSD activity allow enough
ACMS accumulation to form quinolinic acid (Fukuwatari, Sugimoto, &
Shibata, 2002; Fukuwatari, Ohta, Kimtjra, Sasaki, & Shibata, 2004).
Quinolinate phosphoribosyl transferase (QPRT) condenses quinolinic acid
with 5-phospho-alpha-D-ribose 1-diphosphate to form NA mononucleo-
tide (NAMN), which is further metabolized to NAAD by NMNAT and
subsequently to NAD by NADS, as described for the NA to NAD pathway
earlier. QPRT represents the second rate-limiting step in the tryptophan
to NAD de novo synthesis pathway. It is expressed primarily in liver, kidney,
and brain (Magni et al., 2004; Rongvaux, Andris, Van Gool, & Leo,
2003). Deficiencies of QPRT activity are associated with neurological
problems, e.g., epilepsy and Huntington’s disease, likely reflecting the
neurotoxic properties of quinolinic acid (Feldblum et al., 1988; Foster,
Whetsell, Bird, & Schwarcz, 1985).
Niacin 97
3.2 NAD Recycling

Due to the continuous activity of NAD+-consuming enzymes, e.g.,
poly(ADP-ribose)polymerases (PARPs), sirtuins, and CD38, there is an
ongoing loss of NAD+ which is enzymatically cleaved usually with produc-
tion of nicotinamide as a reaction by-product. Simple dietary niacin intake
could not sustainably compensate for this NAD+ loss. Instead, nicotinamide
has to be efficiently recycled to NAD+. This is achieved by the consecutive
enzymatic activity of nicotinamide phosphoribosyltransferase (NAMPT)
and nicotinamide mononucleotide adenylyltransferase (NMNAT1–3), as
illustrated in Fig. 2 (green arrows, salvage pathway). The importance of this
pathway becomes clear when considering that levels of NAMPT in cells had
a larger effect on achievable NAD+ levels than concentrations of nicotin-
amide, as was demonstrated in cell culture models in which NAD+ levels
correlated with modulated expression of NAMPT (Yang et al., 2007).
3.3 NADPH Synthesis

NADH can be converted to NADPH phosphate (NADP) by the enzymatic
activity of NADH 20 -phosphotransferase or NADH kinase, which transfers a
phosphate group from ATP to NADH. NADPH is essential for many
reductive biosynthetic reactions in cells, e.g., fatty acid, steroid, and nucle-
otide synthesis, as outlined later.
During cellular metabolism, NADPH is regenerated from NADP via
several pathways, including the pentose phosphate pathway (aka hexose
monophosphate shunt), reductive reactions that reduce cytoplasmic oxalo-
acetate to pyruvate in the so-called pyruvate/malate cycle via the malic
enzyme, and NADP+-specific forms of isocitrate dehydrogenase (IDH)
and aldehyde dehydrogenase (ADLH) (Pollak, D€ olle, & Ziegler, 2007).
3.4 NAD and NADP Utilization

Enzymes utilizing NAD and NADP fall into several distinct categories (see
Fig. 3). The first category of enzymes utilize NAD[H] and the phosphory-
lated form NADP[H] as cofactors for cellular reduction and oxidation (redox)
reactions, in which NAD and NADP oscillate between the oxidized forms
(NAD+ and NADP+) and the reduced forms (NAD(H) and NADP(H)).
While the ratio of oxidized to reduced forms depends on the metabolic reac-
tion involved, the total amount of NAD or NADP is not affected.
The second group of NAD+-dependent enzymes represents a category
of enzymes that utilized only the oxidized form, i.e., NAD+, as a substrate in
reactions that require ADP-ribose moieties (see Fig. 3, red arrows). Such
Purine
receptors
– Neurotransmitter
NADH
NADP+/NADPH
Redox reactions
- Cellular metabolism
Nicotinamide - Protection from
oxidative damage
adenosine dinucleotide
O
(NAD+)
O- NH2
+
O P O N
O
Recycling O
OH OH NH2
(NAMPT, N N
NMNAT) O P O N N
O- O
OH OH
Nicotinamide CD38,
“niacinamide” CD157
O MARTs Sirtuins
PARPs
NH2
N
– Inflammation – Longevity – Genomic stability
– Metabolic control – Longevity
(via calcium – Mitochondrial function – Epigenetics
signaling)
(via PTM control in (via DNA repair,
chromatin and chromatin and
transcriptional factors) transcription)
Fig. 3 NAD as essential cofactor for a wide variety of cellular processes. NAD is an essen-
tial enzymatic cofactor for most biochemical reactions in cellular metabolism processes
and is required to regenerate glutathione necessary to prevent and minimize cellular
damage due to naturally occurring reactive oxygen species (black circles, right upper cor-
ner). Additionally, NAD serves as a neurotransmitter, when it binds to and activates
purine receptors (black arrows, left upper corner). Three enzyme groups use NAD as
an enzymatic cosubstrate. The groups comprise MARTs, PARPs, and sirtuins (red arrows,
bottom part of diagram). Activity of these enzymes leads to a cleavage of NAD, which
causes loss of available NAD and the production of nicotinamide as a reaction
by-product. Increasing concentration of nicotinamide has inhibitory effects on PARPs
and sirtuins and reduces their activity (indicated by gray blocking arrows). Nicotinamide
is used as a substrate for NAD regeneration through activity of NAMPT and NMNAT in
the NAD salvage pathway (green arrow). Abbreviations: MART, mono(ADP-ribose)
transferase; NAMPT, nicotinamide phosphoribosyl transferase; NMNAT, nicotinamide
mononucleotide adenylyltransferase; PARP, poly(ADP-ribose)polymerase.
Niacin 99
reactions require enzymatic cleavage of NAD+ and therefore result in a

change of total NAD+ amounts that are available for all cellular reactions.
Enzyme families in this category comprise PARP enzymes (PARPs, also
known as ADP-ribose transferases (ARTDs)), sirtuins (members of the class
III NAD-dependent histone deacetylases, HDACs), NAD+-dependent
ADP cyclases CD38 and CD157, and indoleamine 2,3-dioxygenases
(IDOs).
The most recently discovered third function of NAD+ is as a ligand to a
small group of purine receptors, e.g., P2Y1 and P2Y11. Regulated NAD+
release occurs in neurosecretory cells, vascular and visceral smooth muscles,
urinary bladder, large intestine, as well as the brain (Breen, Smyth,
Yamboliev, & Mutafova-Yambolieva, 2006; Durnin et al., 2012;
Mutafova-Yambolieva, 2012; Mutafova-Yambolieva et al., 2007; Smyth,
Bobalova, Mendoza, Lew, & Mutafova-Yambolieva, 2004; Yamboliev,
Smyth, Durnin, Dai, & Mutafova-Yambolieva, 2009). NAD+-responsive
receptors are present on colonic cells, nucleated blood cells such as mono-
cytes, and endothelial cells of arteries, where NAD+ neurotransmitter-like
actions at purine receptors alter vascular tone.
3.4.1 Redox Reactions

NAD+ and NADP+ are indispensable cofactors in over 400 enzymatic redox
reactions central to most metabolic processes (https://www.cmescribe.com/
vitamin-dependent-gene-databases/) (Penberthy & Kirkland, 2012). The
following section provides a general and abbreviated overview highlighting
some of the most important biochemical processes that rely on sufficient
NAD and NADP availability, and hence indirectly on sufficient dietary nia-
cin consumption.
The redox couple NAD+/NADH [designated NAD(H) from here on]
primarily promotes oxidative and catabolic reaction, while NADP+/
NADPH [designated NADP(H)] most often drives reductive and anabolic
reactions. This difference is due to the wide difference in redox potentials
between those two redox couples. Under normal cellular conditions, most
of the molecules of the NAD(H) redox couple are present in the form of
oxidized NAD+, while most molecules in the NADP(H) redox couple
occur in the reduced form NADPH.
The oxidized NAD+ is necessary mostly for catabolism, e.g., in the
breakdown of glucose to pyruvate via glycolysis and the formation of acetyl
coenzyme A and subsequently complete catabolism in the Krebs cycle,
which generates NADH reduction equivalents that drive energy production
via the respiratory chain in the mitochondria. In addition, NAD+ reduction

to NADH facilitates β-oxidation of fatty acids in the mitochondria. The
overview illustrates some select NAD+-dependent enzymes and their
specific enzymatic functions in diverse catabolic processes are shown in
Fig. 3. NAD+-dependent steps are central to energy production from
glucose via glycolysis, Krebs cycle, and anaerobic oxidation (steps 1–3 in
Fig. 4). Enzymes mediating central oxidative steps, such as glyceraldehyde
3-phosphate dehydrogenase, pyruvate dehydrogenase, IDH, and lactate
dehydrogenase, all require NAD+ as coenzyme. Various enzymes required
for β-oxidation of fatty acid processes during lipolysis also require NAD+ as a
cofactor, e.g., L-3-hydroxyacyl coenzyme A dehydrogenase and short-
chain hydroxyacyl coenzyme A dehydrogenase (step 4 in Fig. 4). Energy
generation via amino acid catabolism similarly is mediated by enzymes that
require NAD+ as a cofactor to catalyze oxidations steps, e.g., glutamate
dehydrogenase, branched chain a-ketoacid dehydrogenase, etc. (step 5 in
Fig. 4). This overview is far from being complete and is merely intended
to illustrate how central NAD+ is to most biochemical processes in the cells.
Both NAD+ and NADH/H+ are cofactors for some anabolic processes,
as illustrated in Fig. 5. If glucose levels are insufficient, cells can synthesis
glucose via gluconeogenesis. In this process, the enzymatic equilibrium of
three enzymes in the glycolysis pathway is reverted to allow them to utilize
the reductive energy of NADH/H+ to facilitate the synthesis of glucose
molecules starting from substrates such as lactate, pyruvate, and acetyl coen-
zyme A that have been generated by degradation of either amino acids or
fatty acids. Common enzymes with such a reversible enzymatic equilibrium
are lactate dehydrogenase, malate dehydrogenase, and glyceraldehyde
3-phosphate dehydrogenase (see step 1 in Fig. 5). NADH/H+ cofactors also
facilitate the synthesis of fat via the synthesis of glycerol 3-phosphate (step 2
in Fig. 5) and are required for the synthesis of dihydrotestosterone from
testosterone as a cofactor for the 5-α-reductase enzyme that mediates this
last conversion (step 3 in Fig. 5).
NADPH, the reduced form of NADP+, is an essential cofactor for many
anabolic biochemical processes, e.g., the synthesis of fatty acids and choles-
terol (see Fig. 6). It also required to support the reductive processes necessary
in cytochrome P450-mediated functionalization reactions, glutathione/fatty
acid hydroperoxidases, and thioredoxin defense against reactive oxygen
stress, and as a substrate for immune response-associated oxidative defense
reactions (Pollak et al., 2007).
During fatty acid synthesis, two molecules of NADPH are required for
each acetyl group that is added and reduced during lipogenesis. Enzymes that
Niacin 101
Fig. 4 Overview of biochemical redox reactions in catabolic processes that utilize NAD+
as a cofactor. This list shows important catabolic processes that lead to reduction of
NAD+ to NADH/H+. The general pathway name is indicated next to the numbers. Spe-
cific reactions occurring during the indicated general process are shown by name of
reaction intermediated (in black); enzymes that catabolize the reaction are indicated
in blue; relevant amino acid examples are indicated in green. Abbreviations: AA, amino
acid; CoA, coenzyme A.
are active in the process of fatty acid synthesis and require NADPH as a
coenzyme include β-ketoacyl ACP reductase and enoyl ACP reductase (step
1 in Fig. 6). In liver cells, the availability of NADPH therefore depends on
the activity of ongoing fatty acid synthesis processes.
Fig. 5 Overview of biochemical redox reactions in anabolic processes that utilize NADH
or NAD+ as a cofactor. This list shows important anabolic processes that are associated
with either the reduction of NADH/H+ to NAD+ (steps 1–3) or the reduction of NAD+ to
NADH/H+ (step 4). The general pathway name is indicated next to the numbers. Specific
reactions occurring during the indicated general process are shown by name of reaction
intermediated (in black); enzymes that catabolize the reaction are indicated in blue.
Cholesterol synthesis is a complex biochemical synthesis process that

requires consumption of NAD+ as well as NADPH. Early in this process,
the enzyme 3-hydroxy-3-methylglutaryl CoA reductase requires NADPH
as a cofactor to synthesize mevalonate from 3-hydroxy-methylglutaryl CoA.
Mevalonate is one of the basic building blocks for cholesterol synthesis. Sev-
eral pharmacological substances that prevent this enzymatic step are admin-
istered to human patients as cholesterol-lowering drugs, e.g., lovastatin,
atorvastatin, and simvastatin. Interestingly, combinations of such drugs with
niacin are used to treat dyslipidemia. Later sections of this chapter will
review this in more detail. In a similar fashion, the enzyme squalene
synthase, which catalyzes the step from farnesyl pyrophosphate to squalene,
requires NADPH. It is inhibited by the drug squalestatin. Several biochem-
ical pathways can be used to synthesis cholesterol and all require NADPH as
a cofactor for the respective enzymes (see step 2 in Fig. 6).
Niacin 103
Fig. 6 Overview of biochemical redox reactions in anabolic processes that utilize

NADPH as a cofactor. This list shows some important anabolic processes that are asso-
ciated with either the reduction of NADPH/H+ to NADP+. The general pathway name is
indicated next to the numbers. Specific reactions occurring during the indicated general
process are shown by name of reaction intermediated (in black); enzymes that catab-
olize the reaction are indicated in blue.
Further important biochemical processes that require NAD+ and

NADPH as redox cofactors are various synthesis reactions that originate
from cholesterol: the synthesis of bile acids is initiated by conversion of
cholesterol to 7-α-hydroxycholesterol by 7-α-hydroxylase under the
consumption of NADPH and O2 (step 3 in Fig. 6). Cholesterol also is the

basic building block for the generation of steroid hormones.
High levels of NADPH are present in red blood cell due to the fact that
red blood cells lack mitochondria, and therefore have to rely on the pentose
phosphate pathway for their energy metabolism. The resulting abundance of
NADPH supplies these cells with the important cofactor that allows ongoing
activity of glutathione reductase, which allows glutathione/fatty acid
hydroperoxidase enzymes to reduce oxidative damage within the iron
and oxygen-rich environment of red blood cells.
NAD(H) and NADP(H) also play a central role in the metabolism of eth-
anol and other alcohols. Ethanol is popular as a mood-altering compound
that is consumed mostly as wine, beer, and spirits. Small quantities of alcohol
intake have been associated with health benefits, while consumption of large
ethanol quantities causes severe physiological complications, i.e., liver cir-
rhosis, alcoholic fatty liver disease (AFLD), and hypoglycemia (Gaziano &
Manson, 1996). Through a series of consecutive enzymatic oxidation reac-
tions, ethanol is converted to acetaldehyde and finally to acetate. The initial
metabolic step, the conversion of ethanol to acetaldehyde, can be catalyzed
by either the enzyme alcohol dehydrogenase with production of NADH or
enzymes of the microsomal ethanol-oxidizing system, i.e., cytochrome
P450 complex enzymes, with consumption of O2 and NADPH/H+, and
leakage of superoxide. Higher ethanol doses, and chronic exposure, will
force more ethanol through the P450 route, leading to greater risk of hepatic
injury. Also, detoxification of the resulting acetaldehyde to acetate requires
the enzymatic activity of ADLH with NAD+ as the enzymatic cofactor.
Chronic ethanol consumption has been associated with a decrease in blood
NAD+ levels, and since the accumulation of acetaldehyde is associated with
the unpleasant consequences often experiences with alcohol consumption
“hangover,” supplemental niacin intake is thought to help with more effi-
cient ethanol metabolism. If ethanol consumption occurs to a degree at
which ethanol metabolism leads to markedly decreased NAD+ and increased
NADH/H+ levels, the enzymatic equilibrium in NAD-dependent enzymes
is shifted. Such a shift in NAD to NADH ratio results in a shift of the lactate
dehydrogenase product equilibrium from pyruvate to lactate, which results
in inhibited gluconeogenesis, and consequently can cause hypoglycemia.
A similar shift from α-ketoglutarate to isocitrate is observed for IDH, and
from oxaloacetate to malate for malate dehydrogenase. Together with a
direct NADH concentration-dependent inhibition of the enzyme
α-ketoglutarate dehydrogenase, this results in an inhibition of energy
Niacin 105
production via the Krebs cycle in the liver tissues that are detoxifying the
consumed ethanol.
Both NAD(H) and NADP(H) are essential to maintain the cellular respi-
ratory chain within all cells. Within cells, NAD and NADP are present at
higher concentrations in the mitochondria than the rest of the cell. This
compartmentalization explains why mitochondria-rich tissues, e.g., heart,
contain more NAD than tissues with fewer mitochondria, e.g., liver.
Absolute tissue content of NADP(H) and NAD(H) varies widely. Liver
contains about double the amounts of NAD(H) than NADP(H)
(800 nmol/g fresh rat liver tissue weight compared to 420 nmol/g tissue
weight), while skeletal muscle contains closer to 30 times more NAD(H)
than NADP(H) (590 nmol/g NAD(H) and 30 nmol/g NADP(H)).
Taken together, the role of NAD in redox metabolism relies heavily on
the ratio of oxides to reduced molecules, i.e., how many of the NAD(H)
molecules are present as NAD+ vs NADH/H+, since this ratio can cause
a significant shift in the product equilibrium of enzymatic reaction. This
can be seen, e.g., for lactate dehydrogenase, which produces mostly lactate,
if there is excessive NADH, while the presence of excessive oxidized NAD+
allows for the predominant formation of pyruvate. The ratio of NAD+ and
NADH/H+ is influenced (and influences) not only by the activity of a single
or few enzyme(s), but is the result of the sum of cellular metabolic processes
(glycolysis, citric acid cycle, fatty acid synthesis, mitochondrial respiratory
chain, etc.). The redox state of NAD(H) therefore reflects a complex read-
out of ongoing biochemical energy metabolism in a given cell type and sit-
uation, making NAD(H) an ideal candidate indicator molecule to monitor
cellular metabolism, due to its capability to integrate information regarding
nutritional quality, overall energy intake, and energy expenditure.
3.5 NAD as Substrate

Supporting the notion that NAD(H) can function as an indicator of the
cellular metabolic environment is the fact that NAD+ is the substrate for
enzymatic reactions that permit modulation of cellular epigenetic informa-
tion. NAD+, the oxidized form of NAD(H), is the form whose cellular
concentration varies most significantly and whose concentration most
closely reflects metabolic situations such as insufficient dietary niacin intake,
malnutrition, or excessive exercise. NAD+ levels fluctuate not only with
nutritional intake and exercise but also with circadian cues (Nakahata
et al., 2009). The close relationship between NAD+ availability and energy
metabolism has resulted in studies testing if increased muscular NAD+ syn-

thesis could promote oxidative phosphorylation, and prompted thoughts of
modulating the NAD+ pool for therapeutic purposes, e.g., using NAD+
supplementation to improve energy metabolism in sporting performance
(Cantó, Menzies, & Auwerx, 2015; Frederick et al., 2015).
At the same time, activity of the NAD+-consuming enzymes will
directly control NAD+ concentrations and therefore directly change meta-
bolic processes in response to external exposures and situation that activate
these NAD-consuming enzymes. Several families of enzymes continuously
consume NAD+. As mentioned earlier, the NAD+-consuming enzyme
families comprise sirtuins, PARPs, ADP cyclases, and IDO. The degree
of NAD+ consumption is dependent on several factors, e.g., the presence
of external DNA-damaging agents. The enzymatic activity of the major
PARP enzyme, the nuclear enzyme PARP1, is strongly activated in
enzymes that bind to DNA strand breaks. Activation of PARP1 induces
enzymatic cleavage of NAD and utilization of the ADP-ribose moiety to
form poly(ADP-ribose) (PAR). The degree of enzymatic activation corre-
sponds to the degree of DNA damage. Moderate levels of PAR formation
facilitate efficient DNA repair and prevent cell cycle progression to prolif-
eration of abnormal cells that could lead to carcinogenesis (Masutani &
Fujimori, 2013; Masutani, Nakagama, & Sugimura, 2003). Exposure to
severe DNA damage will lead to PARP1 hyperactivation. This results in
dramatically increased cellular NAD+ consumption, and to a lethal degree
of cellular NAD+ depletion. Taken together, cellular NAD+ concentration
varies directly as a consequence of exposure to any kind of external DNA-
damaging conditions, e.g., radiation or exposure to alkylating agents
(Burkle & Virag, 2013; Fouquerel & Sobol, 2014; Kupper, van Gool, &
Burkle, 1995; Masutani et al., 2000; Meyer, Muller, Beneke, Kupper, &
Burkle, 2000; Schreiber et al., 1995; Van Gool et al., 1997). Reduced
NAD+ availability will not only change cellular metabolic processes but
can also result in altered gene expression, DNA repair, apoptosis, cell death,
or carcinogenesis. This example illustrates the close interdependence of cel-
lular levels of NAD+ not only on metabolic processes and the nutritional
situation but also on additional environmental conditions, e.g., to any kind
of exposure, that modulate the activities of individual NAD+-consuming
enzymes.
3.5.1 ADP-Ribosyl Cyclases

The NADase/ADP-ribosyl cyclase enzyme CD38 and its homolog CD157
use NAD+ and NADP+ to generate cyclic ADP-ribose (Aarhus, Graeff,
Niacin 107
Dickey, Walseth, & Lee, 1995; Ferrero, Lo Buono, Horenstein, Funaro, &
Malavasi, 2014; Guse & Lee, 2008). Both enzymes are highly expressed in
neutrophil cells and endothelial cells where they participate in immune
response-associated signal transduction. Thus, they were long regarded as
an immune cell “activation marker.” This view has evolved significantly
in the last years to CD38 as a multifunctional molecule (Quarona et al.,
2013). The synthesized cyclic ADP-ribose functions as a signaling molecule
that triggers an intracellular signaling cascade and results in Ca2+ elevation,
likely by activating receptors in the endoplasmic/sarcoplasmic reticulum
(Pollak et al., 2007). Immunocytes deficient in CD38 display a defect in
migration to inflammatory sites and render mice with such a defect more
susceptible to infections (Partida-Sánchez et al., 2001; Partida-Sanchez
et al., 2007; Schuber & Lund, 2004). Interestingly, CD38-deficient mice
retain higher NAD+ levels and are protected against obesity and metabolic
syndrome (Barbosa et al., 2007), potentially through changes in NAD+
levels, which then alter other enzymes, like the sirtuins (Escande et al.,
2013). CD38 was recently identified as a major factor contributing to the
so far enigmatic observation that NAD+ levels steadily decline with age
in a nutrition-independent fashion, and that this decline causes mitochon-
drial dysfunction (Camacho-Pereira et al., 2016; Schultz & Sinclair, 2016).
CD38/157-induced cyclic ADP-ribose and calcium release are also
involved in controlling oxytocin secretion and thus play a regulatory role
in social behaviors. In addition to support from animal models, a human sur-
vey has shown that expression levels and polymorphisms in these genes have
been associated with the Autism Quotient of individuals. These observations
provide some mechanistic insight to the appearance of dementia in pella-
grins, and the rapid disappearance of psychoses following niacin supplemen-
tation (Chong et al., 2017).
3.5.2 Poly(ADP-Ribose) Polymerases (PARPs) or ADP-Ribose

Transferases (ATRDs)
PAR formation, using NAD+ as a substrate, has been known for more
than 50 years. Chambon and colleagues first observed NAD+ depletion
and PAR formation upon DNA damage (Chambon, Weill, & Mandel,
1963). Most of the initial studies focused on the most prevalent and most
active PAR-forming enzyme, PARP1, whose central role in DNA repair
and the maintenance of genomic stability shaped the general and prevailing
assessment of poly(ADP-ribosyl)ation as the “guardian angel of the genome”
(Chatterjee, Berger, & Berger, 1999; Jeggo, 1998). Subsequent studies rev-
ealed the existence of additional proteins with structural homology to PARP
(Johansson, 1999), and eventually of a large protein family of related

enzymes (Ame, Spenlehauer, & de Murcia, 2004; Meyer, Meyer-Ficca,
Jacobson, & Jacobson, 2004; Meyer-Ficca, Meyer, & Jacobson, 2005).
So far, 17 enzymes have been identified as members of the human PARP
superfamily, and our knowledge on the evolutionary origins, protein
domains, and cellular functions of these proteins grows continually
(Aravind, Zhang, de Souza, Anand, & Iyer, 2015; Gupte, Liu, & Kraus,
2017; Kraus, 2015; Perina et al., 2014; Poltronieri & Miwa, 2016).
In general, members of the PARP superfamily generate ADP-ribose
posttranslational modification at specific sites in target proteins. Among
the members of the PARP family, only some enzymes turned out to be true
PARPs. This means that they cleave the glycosylic bond between nicotin-
amide and ribose in NAD+, release nicotinamide, attach the liberated
ADP-ribose unit to a given target protein, and in subsequent steps
keep adding more ADP-ribose units to the initially attached ADP-ribose,
thereby generating polymers of (ADP-ribose) (PAR) as posttranslational
modifications. Fig. 7A illustrates the chemical structure of PAR molecules
(Meyer-Ficca et al., 2005). Detailed structural analyses demonstrated
that PAR can comprise hundreds of ADP-ribose units, either as linear or
as branched molecules (Alvarez-Gonzalez & Jacobson, 1987; Juarez-
Salinas, Levi, Jacobson, & Jacobson, 1982; Kiehlbauch, Aboul-Ela,
Jacobson, Ringer, & Jacobson, 1993; Miwa et al., 1981; Miwa, Saikawa,
Yamaizumi, Nishimura, & Sugimura, 1979; Miwa & Sugimura, 1984).
In the majority of PARP family members, the enzymatic activity is lim-
ited to the initial first step, i.e., cleaving NAD+, releasing nicotinamide, and
attaching one single ADP-ribose unit to the given target protein. Since the
subsequent addition of several units does not occur and only mono(ADP-
ribose) (MAR) is attached to the target protein, these enzymes have to be
classified as functional mono(ADP-ribose)transferases (MARTs). The pres-
ence of an HYE amino acid motif in the catalytic center was identified as
required, but not sufficient for PAR formation, as it is present in all four
enzymes with true PARP activity, i.e., PARP1, PARP2, PARP5a, and
PARP5b (better known as tankyrase 1 or TNKS1 and tankyrase 2 or
TNKS2). Several in vitro and in vivo studies ascertained that other members
of the PARP family either exhibited mono(ADP-ribosyl)transferase activity
(PARP 3, 4, 6–12, 14–16) or no activity could yet be demonstrated exper-
imentally (PARP13) (Karlberg et al., 2015; Meyer-Ficca et al., 2015; Vyas
et al., 2014; Yang et al., 2017). The discrepancies between common names
and enzymatic properties led to an effort aiming to change the nomenclature
from PARPs to “ADP-ribosyl transferases” in order to prevent the obvious
Niacin 109
A B
O
OH OH
Poly(ADP-ribose) + DNA damage –DNA damage
CH2 CH2 C O (PAR)
O
O (ADP-ribose)n
O P O
Target protein NH2
O
(e.g. PARP1 N N
O P O
itself)
O O N N
HO O OH OH
O
PAR
O
O P O
NH2
O
O P O N N
PARG O O N N
(ADP-ribose)n–x H2O +
HO O OH
+ ADP-ribose O
HO HO O O
Nuclei
O P O
O O NH2
O
O P O N N
NH2 O P O
O
O O N N
N N
O P O
N N O HO OH
O
HO OH
C Nicotinamide O
O O
NH2
Salvage pathway, PAR as PTM
+
NAD regeneration N
NH2
PARP-1
Enzymatic (inactive) N
N
O
activity
NH2 N
+ O O N
NH2
NAD N O P O P O
N
O
+ OH OH
O O N
N N OH O OH
O P O P O OH
O
OH OH
PARP-1 1⬙ 2⬘
OH O OH
OH OH (activated) PARG
Free PAR
PARP-1
DNA strand
breaks Free ADPR NH2
N
N
O O N
N
O P O P O
O
OH OH
OH O
OH OH
OH OH
Fig. 7 Poly(ADP-ribosyl)ation by PARP1. (A) The chemical structure of a poly(ADP-

ribose) molecule with a single branch point is shown. Glycosylic bonds that can be
cleaved by poly(ADP-ribose)glycohydrolase (PARG, indicated in red) are indicated by
red arrows. (B) HeLa cells treated with 500 μM MNNG as DNA-damaging agent
accumulation amounts of PAR that can easily be stained with PAR-specific
antibodies (visible as red fluorescence signals in the left top panel), while PAR
levels in untreated cells cannot be visualized clearly (right top panel). Bottom panel:
Blue, DAPI-stained nuclei for the cells seen in the top panels. (C) Poly(ADP-ribose) is
rapidly synthesized upon PARP1 activation. PAR automodification of PARP1
temporarily inactivates the enzyme until PAR is degraded by PARG activity and PARP1
is liberated in the not automodified form. Abbreviations: DAPI, 2-(4-amidinophenyl)-1H-
indole-6-carboxamidine; MNNG, N-methyl-N0 -nitro-N-nitrosoguanidine.
discrepancy between the term “PARP” as the common name for most
members of the PARP superfamily that are limited to MART activity
(Hottiger, Hassa, Luscher, Schuler, & Koch-Nolte, 2010). A low general
acceptance of this novel nomenclature has led to the simultaneous
occurrence of several names for the same enzyme in the current scientific
literature.
In PARP1, the most active and best-studied PARP, enzymatic activity
is rapidly activated upon detection of and binding to DNA strand breaks.
Activated PARP1 uses NAD to form large and branched PAR molecules,
attached to various target proteins, including PARP1 itself, where it tempo-
rarily inactivates enzymatic activity (see Fig. 7C). The effects of PAR are
normally short-lived due to rapid degradation by poly(ADP-ribose)
glycohydrolase (PARG). Treatment of culture cells with DNA-damaging
agents leads to a rapid increase in PAR that can be detected using
specific antibodies, e.g., in Fig. 7B, where nuclear PAR is visible as red
signals in the top-left panel, while untreated control cells have no visible
signals.
The degree of enzymatic activity of PARP1 after activation by DNA
breaks directly reflects the degree of DNA damage that is present. The
synthesized PAR temporarily blocks cell cycle progression in order to allow
sufficient DNA repair and to prevent proliferation of damaged or mutated
cells. Extensive DNA damage leads to hyperactivation of PARP1, which
causes severe NAD+ depletion and results in cell death. This process has long
been regarded as a cancer prevention mechanism that allows for elimination
of severely damaged, potentially malignant cells. In line with this concept are
studies that show that Parp1-deficient mice are more sensitive to radiation
exposure and display increased genomic instability upon gamma radiation
and exposure to DNA-damaging drugs and have an increased predisposition
to develop tumors (Trucco et al., 1999; Wang et al., 1995). At the same
time, preventing PARP1 hyperactivation with its associated NAD+ loss
and spike in PAR formation either in genetic knock out model, or pharma-
cologically with PARP inhibitors protects from cell death after inflamma-
tory processes or ischemia–reperfusion injuries [reviewed by Herceg and
Wang (2001) and Shall and de Murcia (2000)]. These varied functions of
PARylation have led to ongoing interest in the development and clinical
use of PARP inhibitors for cancer treatment, as well as spiked interest in
exploring the benefit of PARP inhibition in nononcological diseases
(Berger et al., 2017; Lord & Ashworth, 2017; Rajawat, Shukla, &
Mishra, 2017).
Research over the last years has broadly expanded our understanding of
cellular functions of ADP-ribosylation beyond these accepted roles in DNA
repair.
Niacin 111
It has grown from primarily being regarded as mechanism safeguarding

genetic information via facilitation of DNA repair to the emerging view of
ADP-ribosylation as a versatile posttranslational modification that is associ-
ated with many key biological processes. In addition to its undisputed major
role in DNA repair, ADP-ribosylation facilitates and regulates DNA repli-
cation, cell division, transcription and signal transduction, cellular responses
to stress, infections, and aging (Palazzo, Mikoč, & Ahel, 2017). This is
achieved through modulation of a wide array of protein/protein interactions
and through control of transcription and epigenetic information encoded in
the specific DNA/protein interactions in chromatin.
Table 3 briefly illustrates major functions identified to date for individual
enzymes in the PARP superfamily.
3.5.3 Sirtuins
One other group of enzymes that consume NAD+ by enzymatic cleavage
are sirtuins. These are members of the class III NAD-dependent HDACs.
Sirtuins moved to the limelight of scientific interest by the discovery of their
central role mediating life span extension in situations of caloric intake
restriction (Anderson, Bitterman, Wood, Medvedik, & Sinclair, 2003;
Cohen et al., 2004; Howitz et al., 2003). To date, they have remained at
the center of ongoing scientific interest as pharmacological targets with a
potential to slow down or ameliorate the aging process (Grabowska,
Sikora, & Bielak-Zmijewska, 2017; Pan & Finkel, 2017).
Mammals possess seven ubiquitously expressed sirtuin homologs,
Sirt1–7. The common feature of sirtuins as class III HDACs is that they con-
sume NAD+ to be catalytically active (see Fig. 8). Consequently, changes of
NAD+ availability as well as the NAD+/NADH ratio directly regulate their
activity, which makes them excellent sensors for both cellular energy status
and redox status (Michan & Sinclair, 2007).
As HDACs, one of their major sirtuin function is the enzymatic
deacetylation of lysine residues on target proteins, and SIRT1–SIRT3,
SIRT5, and SIRT6 indeed preferentially act as deacetylases (see Fig. 8,
top section). The reaction is a two-step process that consumes NAD+:
sirtuins cleave the nicotinamide moiety of an NAD+ molecule, which
releases the ADP-ribose moiety. In a subsequent step, the acetyl or acyl
group of the target protein is then transferred from directly to this
ADP-ribose, resulting in a deacetylated target protein and the formation
of 200 -O-acetyl-ADP-ribose (Tanner, Landry, Sternglanz, & Denu, 2000).
Table 3 The PARP Enzyme Superfamily

Enzymatic
PARP Synonyms Product Currently Known Predominant Function
DNA repair (multiple pathways),
transcriptional regulation, chromatin
1 ARTD1 PAR
structure regulation, cell death control,
inflammation
2 ARTD2 PAR DNA repair, transcriptional regulation,
chromatin structure regulation
3 ARTD3 MAR Transcriptional regulation
ARTD4, vault
4 MAR
PARP
ARTD5, Telomere length regulation, stress signal
5a PAR
tankyrase 1 transduction
ARTD6, Telomere length regulation, protein
5b PAR
tankyrase 2 degradation
6 ARTD17 MAR
ARTD14,
7 MAR TCDD-mediated toxicity, cell division
tiPARP
8 ARTD16 MAR Nuclear membrane integrity
9 ARTD9, BAL1 MAR Cell migration, cytoskeleton
10 ARTD10 MAR Signal transduction
11 ARTD11 MAR Nuclear membrane integrity
ARTD12,
12 MAR Cytoplasmic stress response
ZC3HDC1
ARTD13,
13 ZC3HAV1, Unknown miRNA-mediated gene silencing
ZAP
Cell migration, cytoskeleton, signal
14 ARTD8, BAL2 MAR
Transduction
15 ARTD7, BAL3 MAR Cytoplasmic stress response
16 ARTD15 MAR Unfolded protein response
Overview of current nomenclature, known enzymatic activity, and primary function.
The remaining sirtuins, SIRT4 and SIRT6, preferentially utilize NAD+ to

transfer ADP-ribose units to target proteins, an enzymatic property that
SIRT2 and SIRT3 execute in addition to their deacetylase properties. In
this reaction, the sirtuin enzyme cleaves NAD, releases the nicotinamide
Niacin 113
- Acetyllysine - Lysine
Acetylated N
Deacetylated
O
protein protein N
N
O O N
O
O
O P O P O
Deacetylation O O
(SIRT1, SIRT2, SIRT3, O O O O N
N
SIRT5, SIRT6) O O N
NH
N
H
O O 2’-O-Acetyl-ADP-ribose N
OH
O
+
H
O
O
NAD+ Salvage pathway

O
N H Nicotinamide
(NAMPT, MNMAT)
–O
O
P
H
O
O
N
P
O
O
H
N-H
N
HO
N
O
H
ADP-ribosylation
(SIRT2, SIRT3, SIRT4, SIRT6)
N
N
N
+ N
N
H H O
O
Protein Protein O
H
H O
O
H O
O O P
H O
O P O
O HH O
O
Fig. 8 Sirtuin-mediated activities. Sirtuins SIRT1, 2, 3, 5, and 6 utilize NAD+ to remove

posttranslational acetylation marks from target proteins, producing O-acetyl-ADP-
ribose and nicotinamide (top). Activities of SIRT4 and SIRT5 are limited to transfer of
ADP-ribose moieties to target proteins (bottom).
moiety, and enzymatically transfers the liberated ADP-ribose moiety to tar-

get proteins (see Fig. 8, bottom section). Functionally SIRT2, SIRT3,
SIRT4, and SIRT6 thus are MARTs.
As an overall consequence of collective sirtuin activity, epigenetic infor-
mation is changed, e.g., not only in the form of altered chromatin structure
following histone deacetylation but also in the form of direct changes of
transcription factor activities.
Among the sirtuin target proteins are transcription factors, e.g., FOXO1,
PGC-1α, and HIF-1α, i.e., factors that regulate oxidative metabolism, anti-
oxidant defense, and gene expression in the mitochondria both directly and
indirectly. Consequently, reduced sirtuin activity, e.g., as expected in
situations of NAD+ paucity, will reduce the cell’s ability to perform oxida-
tive metabolism in the mitochondria (Imai & Guarente, 2016). The presence
of multiple sirtuin proteins, each with specific subcellular locations and tar-
get protein preferences, allow sirtuin activity to influence a variety of cellular
processes in the organisms, e.g., myogenesis, gluconeogenesis and insulin
secretion, adipogenesis, DNA repair, development, and senescence (Jiang,
Liu, Chen, Yan, & Zheng, 2017; Michan & Sinclair, 2007; van de Ven,
Santos, & Haigis, 2017; Vazquez, Thackray, & Serrano, 2017).
Sirtuins are functionally connected to NAD+ on several levels. Sirtuins
directly depend on NAD+ availability to be enzymatically active. Their
activity increases with rising NAD+ concentrations, while increasing levels
of NADH and nicotinamide directly inhibits sirtuin enzymatic activity. This
regulation allows sirtuins to directly sense and respond to cellular NAD+
concentrations and cellular redox status. At the same time, sirtuins compete
with other NAD+-consuming enzymes for available NAD+. PARP1 is
among the enzymes that have a high capacity for NAD+ utilization and
can deplete cellular NAD+ to levels that change the activity of sirtuins. Gen-
erally, tissue concentrations of NAD+ exceed the levels that sirtuins need for
activity. It still is conceivable that subcellular NAD+ concentrations in the
organelles vary and are in ranges that limit sirtuin activity; it is also possible
that DNA damage-induced activation of PARP1 depletes NAD+ to a
degree where it actively curbs sirtuin activity. On the other hand, sirtuin
activity directly downregulates PARP1 activity via deacetylation, pointing
to a complex situation where PARP1 and sirtuins compete for NAD+
resources.
A third link between sirtuins and NAD+ is provided by the reported con-
nection between sirtuins, the circadian transcription factors CLOCK/
BMAL1, and their regulator effect on expression of NAMPT, the enzyme
that is central for mammalian NAD+ synthesis in the NAD salvage pathway.
Together these factors form a circadian feedback loop that allows for the cir-
cadian oscillation of NAD+ directly connected to the activity of sirtuins
SIRT1 and SIRT6 (Asher et al., 2008; Belden & Dunlap, 2008;
Kritikou, 2008; Nakahata et al., 2008, 2009). An interesting extension of
the NAD+/circadian rhythm connection is the finding that liver PARP1
activity also oscillates in a daily manner and that is regulated by feeding
(Asher et al., 2010; Kumar & Takahashi, 2010; Peek et al., 2013;
Schuldt, 2010).
Collectively, there is a broad interplay of nutrition, metabolism, and cir-
cadian rhythm control, with NAD+ as a central player connecting dietary
Niacin 115
intake information with the individual facets of the transcription machinery

(Asher & Sassone-Corsi, 2015).
This close connection between NAD+ and sirtuin activity is seen as a
central component of the life span extending properties that sirtuins like, e.g.,
Sir2 (the yeast homolog to the human SIRT1) and SIRT1, exert. Mutations
that result in a loss of a functional NAD+ biosynthesis pathway cause signif-
icantly decreasing life span (Lin et al., 2002; Smith et al., 2000). A decrease in
NAD+ occurs also naturally during aging (Braidy et al., 2011; Massudi et al.,
2012), potentially exacerbating age-related health decline. Interestingly,
yeast with mutations in SIR2 orthologs that allow higher enzymatic activity
in an NAD-depleted environment was recently identified, raising the ques-
tion if polymorphisms in sirtuin genes that allow efficient enzymatic activity
in the presence of low NAD+ concentration have an evolutionary advantage
(Ondracek, Frappier, Ringel, Wolberger, & Guarente, 2017).
In conclusion, the collective activities of NAD+-dependent enzymes
(poly- and mono(ADP-ribosyl)transferases, ADP-ribosyl cyclases, and
sirtuins) provide mechanisms that integrate cellular signaling and with the
regulation of chromatin structure and epigenetic control, allowing for a spa-
tiotemporal fine-tuning of transcription and gene expression to adjust for
changed environmental conditions (see Fig. 9).
3.5.4 Indoleamine 2,3-Dioxygenase

Among the enzymes that potentially control NAD+ concentrations is IDO,
the enzyme mediating the initial and rate-limiting first step of the
kynurenine pathway. TDO and IDO activity controls the entry of the nor-
mally limiting essential amino acid tryptophan into the kynurenine pathway,
which results in decreased plasma tryptophan and increased NAD+. In con-
trast to mostly hepatic expression of TDO, IDO is expressed in various
tissues, e.g., neurological tissues, where it is subject to extensive regulation.
IDO activity can be activated by proinflammatory cytokines, e.g., inter-
feron gamma, IL-6, and nitric oxide. Immune responses like HIV/AIDS as
well as cancers and autoimmune disease can cause IDO overactivation and
consequently result in depletion of plasma tryptophan and increased concen-
trations of neurotoxic metabolites like quinolinic acid (Brown et al., 1991).
This was recently demonstrated in HIV/AIDS patient in low-income Afri-
can populations (Bipath, Levay, & Viljoen, 2015). Similarly, patients with
flaky dermatitis displayed metabolic changes, e.g., increased kynurenine/
tryptophan ratio and lowered tryptophan, which are consistent with
increased IDO activity (Maltos et al., 2015). In astroglia, metabolic, and
Fig. 9 NAD availability regulates ADP-ribosylation and sirtuin-mediated epigenetic

changes. External factors, e.g., composition and quantity of food, metabolic parameters,
such as body condition, exercise, and caloric intake, as well as direct exposures to DNA
stressors (certain DNA-damaging toxicants, radiation, etc.) control the activity of the
sirtuins and ADP-ribose-transferase, two powerful epigenetic regulators. ADP-
ribosylation and sirtuin-dependent processes regulate the chromatin structure in a
large variety of ways, e.g., histone PTM modifications of histones and transcription fac-
tors, heterochromatin condensation, transcriptional regulation, and DNA repair and rep-
lication. Change in chromatin structure results in adjusted gene expression, which in
turn results in an overall adjustment of the physiological situation by controlling many
cellular processes, e.g., metabolism, cellular differentiation, and DNA damage response.
The extent of the enzymatic ADP-ribosylation and sirtuin response directly depends on
availably NAD+ levels (green arrows), allowing for a direct readout and integration of
complex nutritional and external factors into epigenetic gene expression control. At
the same time, the consumption of NAD+ in these processes changes NAD+ levels (dark
green arrows). The sum of the adjusted overall cellular responses, e.g., gene expression
response, will directly adjust cellular metabolism which in turn influences energy
metabolism and NAD+ oxidation status (light green arrow).
Niacin 117
neurotropic support cells, activation of IDO by the proinflammatory factor

IFN-gamma resulted in increased neurotoxic metabolites, but at the same
time maintained NAD levels via de novo synthesis by the kynurenine
pathway, which supports the hypothesis that one role of increased IDO
activity during inflammation is to maintain NAD+ levels (Grant &
Kapoor, 2003).
Local IDO upregulation causes cellular tryptophan starvation in certain
immune cells (e.g., T cells). This is required for the induction of immune
tolerance, as it is required to prevent fetal rejection during pregnancy, but
occurs similarly in autoimmune diseases and constitutes an immune-
suppressive mechanism that regulates the tumor microenvironment
(Muller & Prendergast, 2007; Munn & Mellor, 2016; Penberthy, 2007).
Induction of IDO and resulting immune suppression is also beneficial for
the suppression of graft-vs-host diseases and may have the therapeutic poten-
tial in a clinical setting (Jasperson et al., 2009). Inflammation induces IDO
activity and results in tryptophan depletion. Inflammation simultaneously
increases the production of iNOS-peroxynitrate activation of PARP activ-
ity, which results in chronic NAD+ depletion and persistent TNF-alpha
synthesis.
In addition to the connection to immune diseases, abnormal IDO reg-
ulation has been associated with cancer and neurological disorders and neu-
rodegenerative diseases, likely also via accumulation of neurotoxic
metabolites and depletion of neuroprotective tryptophan and NAD+
(Badawy, 2017). Increased tryptophan degradation via overactivation of
the kynurenine pathways has recently also been associated with cardiovas-
cular disease (Song, Ramprasath, Wang, & Zou, 2017).
In conclusion, the control of IDO activity by the immune system allows
for a local metabolic adjustment of innate and adaptive responses to inflam-
matory and immunological signals on a cellular and systemic level (Munn &
Mellor, 2013) and is associated with a control of NAD+ levels.
3.6 Turnover of PAR and MAR Modifications

Synthesis of PAR by PARPs, e.g., after exposure to DNA damage, leads to a
rapid and significant loss of cellular NAD+. Sirtuin activity, either as
deacetylation or as mono(ADP-ribosyl)ation (MAR), is a cause for
NAD+ loss in a similar manner. Both reactions release nicotinamide as a
reaction by-product, which will contribute to the NAD+ regeneration
via the NAD+ salvage pathway as described earlier (see Figs. 2, 3, 7, and 8).
The additional moieties of NAD+, the ADP-ribose subunit that was

transferred to acceptor proteins during the enzymatic NAD+ cleavage reac-
tion, can undergo a similar regeneration. This regeneration is mediated by
enzymatic activities of PARG and ADP-ribosyl hydrolase-3 (ARH3), two
enzymes that cleave the linkage between ADP-ribose and the acceptor
proteins.
3.6.1 Poly(ADP-Ribose)Glycohydrolase
PARG releases PAR polymers and degrades the polymer into individual
ADP-ribose moieties by cleaving the O-glycosidic bond of the PAR chains.
Through alternative splicing, a single PARG gene gives rise to several
PARG protein isoforms of different sizes. Importantly, the different subcel-
lular localization allows PARG to degrade PAR molecules present in
different parts of the cell (Cortes et al., 2004; Koh et al., 2004; Meyer,
Meyer-Ficca, Whatcott, Jacobson, & Jacobson, 2007; Meyer-Ficca,
Meyer, Coyle, Jacobson, & Jacobson, 2004; Winstall et al., 1999). The
terminal ADP-ribose unit at the receptor glutamate amino acid residue in
a PAR-modified target protein can be removed by MACROD1 and MAC-
ROD2 proteins, and by TARG1/C6ord130 (Chen et al., 2011; Sharifi
et al., 2013). Deficiency of TARG1 is associated with neurological defects
comparable to the cytotoxic effects observed with neuronal PAR accumu-
lation (Andrabi et al., 2006; Sharifi et al., 2013; Yu et al., 2006). This empha-
sizes how important turnover and recycling of PAR and MAR signals are
for cellular functions.
3.6.2 ADP-Ribosyl Hydrolases (ARH1 and ARH3)

The ADP-ribosyl hydrolase family of enzymes consists of several
members. Of interest in this context are ARH1 and ARH3. ARH1 releases
the ADP-ribose subunit from proteins with mono-ADP-ribosylated argi-
nines, while ARH3 releases ADP-ribose moieties from PAR as well as from
O-acetyl-ADP-ribose, the by-product of sirtuin-mediated protein
deacetylation (Kasamatsu et al., 2011; Mashimo, Kato, & Moss, 2013, 2014).
4. NAD: RELEVANCE TO HEALTH AND DISEASE

Impaired niacin status can decrease total NAD(H), decrease NAD+,
shift the cellular NAD+ to NADH ratio, and change the ratios between
NAD(H) and NADP(H) pools. The ratios are likely important to health,
recalling that a shift toward reduced NADH occurs during aging.
Niacin 119
Furthermore, the shifted ratio also affects enzymatic reactions pertinent to

cellular metabolism. It changes the cells’ preference for oxidative phosphor-
ylation toward glycolysis, a process often observed in cancer cells. This
decreases pyruvate production and results in a net increased lactate forma-
tion. This increased glucose uptake and glucose to lactate fermentation is
known as the Warburg effect. The Warburg effect occurs even in the
presence of completely functional mitochondria and is known to promote
cellular growth and rapid proliferation, i.e., promoting tumorigenic prop-
erties (Liberti & Locasale, 2016).
Furthermore, the reduced NAD+ directly affects a large number of
NAD+-dependent signaling pathways discussed earlier (MARTs, PARPs,
sirtuins, ADP-ribose cyclases). Those pathways are involved in a large array
of biological processes, e.g., control of energy metabolism and mitochon-
drial functions, calcium homeostasis, control of exposure oxidative stress
(antioxidation mechanisms and generation of oxidative stress), control of
signaling and gene regulation pathways, immunological functions, aging,
and cell death (Ying, 2008). A common feature of the NAD+-dependent
pathways is the release of nicotinamide as a reaction by-product that can
be recycled to NAD (Opitz & Heiland, 2015).
In summary, disturbance of the NAD homeostasis and recycling
processes may potentiate an array of disorders that range from metabolic
syndrome, to cancer, neurological diseases, and age-associated decline.
The following section briefly illustrated some recent findings regarding
the connection between niacin, NAD, and clinical problems.
4.1 NAD Decline During Aging and Age-Related Disorders

Aging is a complex process caused by the interplay of many pathophysiolog-
ical processes. Two current theories on aging see either DNA damage
accumulation or mitochondrial deficiencies due to DNA damage following
nuclear to mitochondrial signaling as major contributors to aging. Both
processes are dependent on cellular NAD+ availability. Availability and
redox status of available NAD directly link DNA-damage repair with
mitochondrial function and nuclear to mitochondria signaling, indicating
the central role the adequate availability of niacin plays as a dietary precursor
of NAD for aging-related pathophysiology.
For many years, a connection has been proposed between NAD+ levels
and the link between aging and altered metabolism. This led to the term
“NAD world” as a relevant term in aging and with the view of NAD as
a metabolic oscillator that regulates aging and metabolism (Imai, 2009a,

2009b, 2010, 2011; Imai & Guarente, 2014, 2016; Rehan, Laszki-
Szcza˛chor, Sobieszcza nska, & Polak-Jonkisz, 2014).
A significant and steady decline of NAD+ levels has been observed with
increasing aging in various species (Braidy et al., 2011; Camacho-Pereira
et al., 2016; Massudi et al., 2012; Schultz & Sinclair, 2016). In rats, a signif-
icant decline in tissue NAD and a shift in NAD+ to NADH ratio were
observed with aging, concomitantly with an increase in lipid peroxidation
and DNA damage as well as a decline in antioxidant capacity (Braidy et al.,
2011). A similar strong negative correlation between age and tissue NAD
content was observed in humans, with similarly increased lipid oxidation
and PARP activity (Massudi et al., 2012). Factors that contribute to this
age-associated NAD+ loss include increased activity of NAD+-consuming
enzymes, e.g., PARPs, CD38, and sirtuins (Jasper, 2013; Mouchiroud
et al., 2013; Schmeisser et al., 2013). Reducing NAD+ levels in worms
resulted in reduced life span, while pharmacological or genetic restoration
to normal NAD+ levels restored longevity and avoided age-associated met-
abolic decline (Mouchiroud et al., 2013).
Increased PARP activity in this context is thought to be a response to the
age-associated accumulation of DNA damage, and at the same time one of
the contributing factors responsible for the increased NAD+ catabolism seen
in aging. Furthermore, a recent study implicated an age-related increase in
the activity of the NAD-consuming enzyme CD38 with this age-associated
drop in NAD+ and mitochondrial dysfunction that was at least partially
dependent on a pathway regulated by SIRT3 (Camacho-Pereira et al.,
2016). This finding provided new clues to the long-known but puzzling
observation that NAD+ declines with age, independent of nutritional niacin
intake (Schultz & Sinclair, 2016). Keeping NAD+ levels up via a knockout
of CD38 protected from NAD+ decline and increased SIRT3 activity. Con-
sequently, improved mitochondrial function and increased glucose toler-
ance prevented aging-associated defects (Chini, Tarragó, & Chini, 2016).
Reduced NAD+ availability, in turn, prevents optimal sirtuin activity,
which is central to preventing age-associated changes in metabolic processes
and mitochondrial dysfunction (van de Ven et al., 2017). A simplified
scheme (Fig. 10) illustrates the vicious cycle of aging-related NAD decline,
and the exacerbating effects on cellular senescence, DNA damage, and met-
abolic dysfunction.
In model organisms, supplementation of NAD+ precursors, e.g., nico-
tinamide ribose, could increase net NAD+ synthesis and increase life span
Niacin 121
Fig. 10 Vicious cycle of age-dependent NAD+ loss. Aging (as cellular senescence) is
associated with exposure to increasing DNA damage and oxidative stress. Cellular
defense mechanisms against such stressors, e.g., PARPs and sirtuins, utilize NAD+.
Increased NAD+ use decreases NAD+ availability, which in turn increases aging-related
dysfunctions and promotes cellular senescence.
even in the absence of caloric restriction (Belenky et al., 2007). There are
current efforts to translate the growing knowledge about the correlation
between aging and declining blood NAD+ into clinical efforts to augment
intracellular NAD to prevent aging-associated disorders and decline
(Srivastava, 2016).
4.2 DNA Damage Accumulation

Aging is associated with an increase in basal DNA damage and increased rate
of mutations and cell death. PARP1 enzyme activation as a first response to
external DNA damage can facilitate DNA repair and, in the case of DNA
damage overwhelming the cellular repair capacity, induce apoptotic cell
death. This process requires utilization and cleavage of significant amounts
of NAD+ and therefore is indirectly dependent on nicotinamide as the die-
tary precursor for NAD+ in humans (for a recent review, see Surjana,
Halliday, & Damian, 2010). A moderate degree of cell damage can be
managed by the PARP1 systems while consuming a tolerable portion of
the cellular NAD+. Exposure to severe genotoxic stress in contrast causes
irreversible depletion of the cellular NAD+ content and results in cell
death (Schraufstatter, Hinshaw, Hyslop, Spragg, & Cochrane, 1986).
Supplementing NA to cultured human mononuclear blood cells improved
their genomic integrity after X-irradiation, as measured by increased viabil-
ity and reduced micronuclei formation. Supplemented cells also maintained
higher cellular NAD+ levels, produced more PAR, and maintained higher
SIRT1 activity (Weidele, Beneke, & B€ urkle, 2017; Weidele, Kunzmann,
Schmitz, Beneke, & B€ urkle, 2010). An increase of intrinsic maximal PARP
activity correlates with the maximum life span observed on a species level
(Grube & B€ urkle, 1992). This indicates that species’ higher capability to effi-
ciently recognize and repair DNA damage has a beneficial effect to prevent
damage by the increased ROS insults that occur with aging.
4.3 Cell Death/Cancer

Genotoxic stress causes a rapid and oftentimes dramatic depletion of NAD+
from the nucleus and the cytoplasm, which triggers or at least contributes to
cell death. An increased mitochondrial NAD+ level can rescue cells from cell
death mediated by NAD+ depletion (Yang et al., 2007). This indicates that
mitochondrial NAD+ is a major determinant of apoptosis and presents the
intriguing possibility that boosting mitochondrial NAD via adequate diet
can determine organ health and disease.
Many of these protective pathways are dysregulated in cancer cells,
which makes NAD+ pathways intriguing targets for cancer therapeutics.
NAD+ depletion reduces energy synthesized by citric acid cycle activity
and oxidative phosphorylation and instead promotes Warburg-like metab-
olism focused on glycolysis. Recently studies have explored the effect of
well-known cancer therapeutics in combination with pharmacological
depletion of NAD+ levels. In many cases, there is a synergistic effect on can-
cer cell cytotoxicity. The combinations predispose cancer cells to oxidative
damage by disrupting their antioxidant defense system, increase cell death by
preventing DNA repair, and shift cell signaling pathways (e.g., SIRT1 and
p53) to a cytotoxic route (Kennedy et al., 2016).
4.4 Mitochondrial Dysfunction

4.4.1 Direct Connection Between Niacin, NAD, and Mitochondrial
Function
The correlation between aging and NAD+ levels and functionality are of
interest for mitochondrial health. The ratio of available NAD+ to NADH
regulates the activity of enzymes central to glycolysis, TCA cycle, fatty
acid oxidation, and fatty acid synthesis, i.e., pathways essential to cellular
metabolism. Aging and insufficient dietary niacin intake cause reduced
NAD+ availability and a shift toward more NADH that in turn leads to
reduced oxidative phosphorylation and impaired mitochondrial respiration,
while benefitting glucose consumption and Warburg effect.
Niacin 123
The reduced availability of NAD+ prevents optimal activity of the mito-

chondrial sirtuins (Sirt3–5). Sirt3–5 dependency on NAD+ allows them to
act as metabolic sensors that sense the metabolic state of the cell and translate
this info into mitochondrial regulation. Activity of the mitochondrial
sirtuins has been implicated in protection against age-related neuropathies,
insulin resistance, and cardiopathologies (van de Ven et al., 2017).
PARPs, the other major group of NAD+-consuming enzymes, also have
been identified as modulators of mitochondrial activity (Bai, Nagy, Fodor,
Liaudet, & Pacher, 2015). PARP hyperactivation causes a rapid loss of
mitochondrial potential and decreases mitochondrial oxygen consumption,
in particular upon ischemia–reperfusion injuries (Klaidman et al., 2003;
Módis et al., 2012). It can result in uncoupling of the electron transport chain
as well as superoxide production (Fang & Bohr, 2017; Fang et al., 2014).
Those observations have led to the suggestion of using PARP inhibitors
therapeutically to prevent cell death in ischemia–reperfusion scenarios, such
as myocardial infarction and stroke.
Examples of mitochondrial-related disease associated include glaucoma.
A recent study found an age-related decrease in retinal NAD+ levels
that makes neurons vulnerable to disease-related insults. Increased NAD+
content via oral administration or through gene therapy driving local
NAD+ production prevented glaucomas in 93% of eyes in the tested rodent
model (Williams et al., 2017).
4.4.2 Indirect Connection Between Niacin, NAD, and Mitochondrial

Function
Repletion of NAD+ can increase life span and—most importantly—health
span in animal models with defects in DNA repair response associated
with genetic aging disorders (such as, ATM/ataxia telangiectasia mutated,
XPA/xeroderma pigmentosum group A, CS/Cockayne syndrome). This
is thought to occur via the restoration of a defective mitophagy, the selective
clearance of defective mitochondria, as well as possible activation of general
autophagic proteins and through improved DNA repair (Croteau, Fang,
Nilsen, & Bohr, 2017; Fang & Bohr, 2017). One of the cellular problems
caused by these genetic defects is a loss of intracellular NAD+ that results
from persistent PARP1 activation due to increased DNA damage in the
mitochondria. This decreased NAD+ availability in turn causes other
NAD+-dependent enzymes, e.g., sirtuins, to suffer a loss of activity
(Croteau et al., 2017). SIRT1 is a multifunctional protein deacetylase whose
proper activity is central to longevity, metabolism, cellular senescence,
genome maintenance, DNA repair, and inflammation. Hampering SIRT1

activity by restricting or making the rate limiting coenzyme NAD+
unavailable therefore leads to defects in mitochondrial homeostasis, to
increased production of reactive oxygen species, decreased DNA repair
capability and results in reduced cell survival.
4.5 Neurological Disorders

4.5.1 Age-Related Neurodegeneration
Although pellagrins with dementia display remarkable and rapid improve-
ment with niacin supplementation, suggesting a defect in cell signaling,
some brain pathologies are also observed with chronic pellagra. In the
aging brain, CNS decline underlies the progressive loss of cognitive, social,
and physical abilities that occur with aging. In this context, declining
sirtuin activity likely contributes to the aging process, opening up potential
opportunities for treating or preventing these age-associated dysfunctions
(Satoh, Imai, & Guarente, 2017).
Memory formation and circadian rhythms are closely intertwined, and
disruption of circadian rhythms, as it occurs, e.g., during aging, seems to
contribute to the age-associated memory loss. The close connection
between epigenetic changes, e.g., DNA methylation and sirtuin 1 activity,
and both memory formation and circadian rhythm, has given rise to the
concept that epigenetic changes in these processes contribute to the
age-associated cognitive decline (Deibel, Zelinski, Keeley, Kovalchuk, &
McDonald, 2015; Mazucanti et al., 2015).
Neurodegeneration in aging is often associated with mitochondrial
dysfunction. Recent studies have been able to link such mitochondrial-
associated neurodegeneration in animal models of several progeriatric
genetic diseases, e.g., CS and xeroderma pigmentosum group A (XPA) to
a decreased availability of mitochondrial NAD+ (Fang et al., 2014;
Scheibye-Knudsen et al., 2014).
4.5.2 Parkinson’s Disease

Parkinson’s disease (PD) is characterized by degeneration of neurons in
the substantia nigra of the brain stem, which leads to tremors associated with
insufficient dopamine synthesis. The complex etiology of the disease is not
completely understood, but includes genetic and environmental factors.
Dopamine is synthesized from tyrosine through several enzymatic steps that
among others requires NADH as a coenzyme.
Niacin 125
A direct link between dietary niacin intake, niacin index, and PD

progression was recently described by Wakade and Chong (2014) and
Wakade, Chong, Bradley, Thomas, and Morgan (2014). In PD patients,
low blood levels of NAD correlated with high expression levels of NA
receptor GPR109A PD patients compared to age-matched control individ-
uals. Dietary niacin supplementation normalized NAD levels and GPR109A
expression to levels seen in healthy control individuals and ameliorated
motor and cognitive functions in the PD patient (Wakade, Chong,
Bradley, & Morgan, 2015).
Recent genome-wide association studies have identified several poly-
morphic gene loci associated with altered risks or age of onset for PD
(Bandres-Ciga et al., 2016; Davis et al., 2016). Among the commonly found
genes is ACMSD, an enzyme central in the tryptophan to NAD+ metabolic
pathway that links PD risk to NAD metabolism, albeit though currently
unknown mechanistic details.
Familial forms of PD are associated with a gene mutation of PINK1 that
results in mitochondrial impairment, and subsequent neurodegeneration
due to mitochondrial deterioration. The mitochondrial disruption is associ-
ated with alteration of the NAD+ redox state and a reduction in NAD+
metabolites. Dietary supplementation with nicotinamide as well as genetic
suppression of PARP activity was able to prevent mitochondrial dysfunction
in an animal model of this pink1 mutation-associated form of PD and could
prevent neurodegeneration (Lehmann, Loh, & Martins, 2017).
Similar beneficial effects of exogenous niacin supplementation had
previously been observed in a human cellular PD model, in which niacin
supplementation protected from exogenously induced mitochondrial
defects and oxidative damage (Jia et al., 2008). In a transgenic Drosophila
PD model, Jia et al. (2008) found that niacin supplementation facilitated
improved motor function. Taken together, it appears that mitochondrial
dysfunction caused by NAD deficiency is becoming apparent as one of
the many factors contributing to the pathogenesis of PD, and that a potential
benefit of dietary niacin supplementation warrants further studies of this
treatment option.
4.5.3 Multiple Sclerosis

Multiple sclerosis (MS) is a disease characterized by progressive neu-
rodegeneration associated with inflammation. Current treatment options
target inflammation, but appear unable to prevent the neurodegeneration
that underlies the progressiveness of the disease. Mitochondrial dysfunction,

associated with reduced NAD+ levels and potentially caused by
inflammation-associated oxidative stress, was found to contribute to the
neurodegeneration seen in MS (reviewed by Nimmagadda et al., 2017).
Neuroprotective effects preventing axon degeneration were observed in
neurons with increased activity of NMNAT, i.e., enzymes that increased
NAD+ and preserved ATP production and mitochondrial function in
those neurons (Araki, Sasaki, & Milbrandt, 2004; Park et al., 2013;
Yahata, Yuasa, & Araki, 2009), and in animal models overexpressing
SIRT1 (Nimmagadda et al., 2013). Both pathways point toward a central
role of NAD+ depletion in the pathogenesis of the MS-associated neu-
rodegeneration and indicate that pharmacological interventions designed
to increase the intracellular NAD+ content, e.g., via dietary niacin
supplementation, should be studied in the context of clinical applications.
4.5.4 Schizophrenia
While the pathophysiology underlying most schizophrenia cases is not well
understood, a recent study observed that chronically ill schizophrenia
patients had a significant reduction in NAD+/NADH ratio compared to
a matched healthy control group (Kim et al., 2017). The study provides evi-
dence that schizophrenia is linked to redox imbalance in the brain, pointing
toward a role of niacin intake and resulting NAD+ in schizophrenia etiology.
Additionally, full expression of pellagrous dementia is similar to schizophre-
nia, suggesting that some of the underlying changes in calcium signaling in
the niacin-deficient brain may be similar to schizophrenia, although schizo-
phrenia patients, on the whole, do not improve with niacin supplementation
(Prousky, Millman, & Kirkland, 2011).
4.5.5 Memory Loss

Ataxia telangiectasia (AT) in humans is associated with progressive neu-
rodegeneration. Treatments that replenished intracellular NAD+ in AT ani-
mal models (mouse and worms) improved neuromuscular function, delayed
memory loss, and extended the life span of the test animals. Mechanistically,
the intervention prevented DNA damage accumulation and mitochondrial
dysfunction, and at the same time stimulated neuronal DNA repair and
improved mitochondrial quality, pointing toward a therapeutic potential
of NAD-stabilizing treatment to prevent memory loss and neu-
rodegeneration (Fang et al., 2016).
Niacin 127
4.6 Skin Health and Skin Cancer Prevention

Severe niacin deficiency, as seen in clinical pellagra, is characterized by ery-
thematous rashes in sun-exposed areas, hyperkeratosis, and dermal fibrosis.
NAD+ restoration via niacin supplementation allows the skin to recover.
NAD deficiency in human keratinocytes causes reduced growth rates,
increases rates of apoptotic cell death, and leads to formation of reactive oxy-
gen species and increased rates of DNA damage (Benavente, Schnell, &
Jacobson, 2012). In addition, niacin restriction caused photosensitization
in skin cell lines, as illustrated by increased amounts of DNA damage, a
reduction in DNA damage-induced PAR formation, and alterations of
sirtuin expression levels (Benavente et al., 2012).
Skin cells are also prone to exhibit epidermal differentiation defects
following chronic UV skin exposure. This effect could largely be averted
by administration of pharmacological doses of a topically available NA deriv-
ative (Jacobson et al., 2007). A potential underlying mechanism for this
protective effect of niacin might be altered cell signal mediated by stimula-
tion of the NA-responsive G-protein-coupled receptors GPR109A and
GPR109B. Expression pattern analyses demonstrate the presence of func-
tional receptors in normal human primary and immortalized keratinocytes,
while squamous cell carcinoma (SCC) cells only have nearly nonfunctional
receptors available (Bermudez et al., 2011).
Using a mouse animal model, Gensler, Williams, Huang, and Jacobson
(1999) showed that nutritive administration of nicotinamide could
inhibit photocarcinogene. Conversely, mild niacin deficiency in a different
mouse study demonstrated an increased incidence of skin cancers after
UV-B treatment, indicating that already mild niacin deficiency similar to
what is frequently seen in humans might be sufficient to increase the skin
cancer risk. In clinical settings and human treatments, benefits of niacin
application for skin growth and differentiation have long been demonstra-
ted in the form of improved wound healing, treatment of psoriasis with
6-aminonicotinamide, smoothed skin surface structure, and reduced light
damage in skin cells (Gehring, 2004). In line with these findings, another
recent large-scale clinical trial on the protective role of oral nicotinamide
against skin cancer recurrence found that niacin intake was associated with
a reduced risk of SCC (Park et al., 2017). The same study demonstrated a
marginally positive association between niacin intake and the risk of basal
cell carcinoma and, in men only, with melanoma formation. Overall,
Park et al. (2017) concluded that niacin intake might be of potential benefit
with respect to development of SCC, but likely not for prevention of BCC
or melanoma.
4.7 Cardiovascular Disorders and Niacin in Clinical Trials

In pharmacological doses, niacin intake can reduce myocardial infarction,
atherosclerosis, and stroke. The majority of these beneficial effects are
thought to be mediated by changes of lipoprotein composition. The ability
of pharmacological niacin intake to lower blood lipids, and to increase high-
density lipoprotein (HDL) cholesterol, i.e., the “good” cholesterol, has long
been recognized. Niacin was the first hypolipidemic drug that significantly
reduced cardiovascular clinical events and mortality in patients with cardio-
vascular disease. For current reviews on function and the use of niacin, see la
Paz et al. (2016) and Zeman et al. (2016).
Niacin in cultured human aortic cells increased levels of NADH and
reduced glutathione, which caused a reduction of reactive oxygen species
synthesis, low-density lipoprotein oxidation, and synthesis of TNF-alpha
and TNF-alpha-associated monocyte adhesion. This study thus indicated
that therapeutic niacin administration inhibits vascular inflammation, an
independent protective effect on the cardiovascular system that functions
in addition to niacin’s antiatherosclerotic effects on lipoprotein composition
(Ganji, Qin, Zhang, Kamanna, & Kashyap, 2009).
Early clinical studies consistently demonstrated that pharmacological
doses of niacin, either as monotherapy or in combination with bile acid
and cholesterol-sequestering drugs such as colestipol, significantly reduced
serum cholesterol and triglyceride levels and improved clinical outcomes:
3-year mortality rate in survivors of myocardial infarction was significantly
reduced, the frequency of coronary lesion was reduced, and atherosclerosis
regressed and coronary status improved (Blankenhorn et al., 1987; Brown
et al., 1990; Carlson, Danielson, Ekberg, Klintemar, & Rosenhamer,
1977; Carlson & Rosenhamer, 1988; Kane, 1990).
The Coronary Drug Project, a niacin monotherapy trial intended to
evaluate the frequency of recurrent myocardial infarction over a 6-year
interval and the associated 15-year total mortality, found significantly
reduced infarct and mortality rates in niacin monotherapy patients
(Canner, Furberg, & McGovern, 2006).
Increased levels of low-density lipoprotein cholesterol (LDL-C) and
lower-than-average levels of high-density lipoprotein cholesterol (HDL-
C) in patients with dyslipidemia were found to be independent risk factors
Niacin 129
for CVD (Barr, Russ, & Eder, 1951; Gordon, Castelli, Hjortland, Kannel, &
Dawber, 1977). This has led to the so-called HDL hypothesis that high
HDL protects from arteriosclerosis, and simultaneous correction of the
LDL-C to HDL-C ratio together with a general reduction of blood lipids
may provide reduced CV morbidity and mortality (reviewed, e.g., in
Vergeer, Holleboom, Kastelein, & Kuivenhoven, 2010). Niacin (nicotinic
acid) intake increases blood HDL-C levels and reduces LDL-C levels. While
the underlying mechanism for increased HDL-C is not yet completely
understood, increased production of apolipoprotein A-1 (ApoA-1) and
ATP-binding cassette subfamily A member 1 (ABCA1) contributes to the
effect (Lamon-Fava et al., 2008; Pang et al., 2014; Rubic, Trottmann, &
Lorenz, 2004; Wu & Zhao, 2009).
The unique property of niacin to correct the HDL-C:LDL-C ratio has
generated interest in the potential for combined niacin–statin therapies to
reduce blood lipid levels by statins and correct HDL-C:LDL-C ratios by
niacin in dyslipidemic patients. A study comparing safety and effectiveness
of combination formulations of extended release niacin with either a statin
or a bile acid sequestrant showed that both, niacin alone and its combination
preparations, effectively reduced LDL-C and triglycerides and increased
HDL-C (Guyton et al., 1998). The combination of niacin with statin
appeared to be most effective. Further trials (including HATS,
ARBITER-2, ARBITER-3, ARBITER-6, Oxford Niaspan Study,
AVANT, and COMPELL) corroborated that treatment with niacin in
combination with statins effectively reduced LDL-C levels and increased
HDL-C levels. In these trials, significantly reduced thickening of the carotid
intima media, a surrogate marker for atherosclerosis, and reduced stenosis
progression were also observed (Brown et al., 2001; deGoma et al., 2015;
Lee et al., 2009; McKenney et al., 2007; Taylor, 2004; Taylor, Lee, &
Sullenberger, 2006; Taylor et al., 2009). In a clinical trial called the “NIA
Plaque study,” patients with statin therapy-adjusted LDL-C blood levels
were supplemented with niacin or placebo. While the addition of niacin
to the statin therapy increased HDL-C levels, the reduction in internal
carotid artery wall volume was comparable in both treatment groups. This
indicates that it may be sufficient to control LDL-C levels in order to reduce
atherosclerosis independent of HDL-C levels (Sibley et al., 2013).
Further clinical trials addressed the growing concern that the predictive
value of surrogate measurements, e.g., arterial wall thickness, as indicators
for the risk of actual CVD events may be limited. This would mean that
reduction of blood lipids and prevention of atherosclerosis by supplementing
niacin in a statin treatment regimen might not necessarily translate into

improved clinical outcomes (Hochholzer, Berg, & Giugliano, 2011).
Two trials (AIM HIGH and HPS2-THRIVE) therefore tested whether
supplementing a statin therapy with niacin is able to reduce the risk of
CV events in patients with atherogenic dyslipidemia below the levels
achieved by statins alone or not (The AIM-HIGH Investigators, 2011b,
2011c). Despite significantly reduced triglyceride and increased HDL-C
levels, the incidence of cardiovascular incidents (stroke, nonfatal myocardial
infarction, ischemic stroke, acute coronary syndrome, etc.) appeared not to
be reduced by adding niacin to the statin therapy during a 36-month follow-
up period (The AIM-HIGH Investigators, 2011a; The HPS2-THRIVE
Collaborative Group, 2014). Niacin augmentation was associated with
significantly increased rates of certain serious adverse events, leading to early
termination of one study (Anderson et al., 2014; Lloyd-Jones, 2014; The
HPS2-THRIVE Collaborative Group, 2014). Skin-related adverse effects,
diabetic complications and new onset diabetes, infections, gastrointestinal
and musculoskeletal problems, heart failure, and a 9% increased risk of death
were all observed. There is also a growing concern that there is no true causal
relationship between low HDL-C and cardiovascular risk, and that low
HDL-C levels should be considered a risk marker instead of a risk factor
(Voight et al., 2012). If this is the case, additional niacin treatment to correct
HDL-C levels cannot be expected to yield clinical benefit (Lloyd-
Jones, 2014).
Reports of other clinical trials utilizing such combination therapies
conclude that niacin could be safely added to statin or combined statin/
cholesterol sequestrator regimens, but recommend monitoring of blood
glucose levels as an indicator of intermittent occurrence of transient diabetes
in patients on niacin (Fazio et al., 2010; Guyton et al., 2012).
The increased incidence of diabetes in patients in the niacin-
supplemented groups raised the question if the benefit of niacin therapy
depended on metabolic status of patients. While the niacin-mediated cor-
rection of plasma lipid levels occurs regardless of the presence of metabolic
syndrome or diabetes mellitus (Ooi et al., 2015), evidence is accumulating
from primary studies and meta-analyses that niacin treatment can indeed
induce hepatic insulin resistance and increase the risk of developing diabetes
(Blond et al., 2014; Goldie et al., 2015).
Vasodilation resulting in skin flushing and itching is a well-known side
effect of niacin intake that often leads to increased dropout rates in niacin
treatment clinical trial groups and to reduced patient compliance.
Niacin 131
A clinical trial focusing on safety and tolerability of prolonged-release

niacin found that a daily dose of 2000 mg over a period of 15 weeks
did not lead to significant hepatotoxicity or muscular adverse effects, but
to high incidence of skin flushing (>40% of patients), and a related rate
of 10% of patient that withdrew from the study (NAUTILUS study,
Vogt, Kassner, Hostalek, Peiter, & Steinhagen-Thiessen, 2006; Vogt,
Kassner, Hostalek, Steinhagen-Thiessen, & NAUTILUS Study Group,
2006). Coadministration of a selective prostaglandin D2 receptor subtype
1 antagonist, laropiprant, was shown to reduce the niacin-induced vasodi-
lation (Lai et al., 2007), to safely attenuate skin flushing and to improve
patient compliance (Hussein & Nicholls, 2010). In addition, niacin/
laropiprant combination therapy improves lipid levels across a range of
patient types, irrespective of sex, race, age, statin use, and presence of
coronary heart disease, including type 2 diabetes mellitus patients
irrespective of glycemic control (Bays et al., 2015, 2012; Bays, Shah,
Dong, McCrary Sisk, & Maccubbin, 2011).
The current therapeutic role of niacin for dyslipidemia treatment remains
unclear. The perceived negative outcome of the clinical trials that failed to
show a potential for niacin to further improve on clinical benefits of statin
treatments led to a slight decrease in current niacin therapy for improved
cardiovascular health (Bittner et al., 2015). The patients in those trials were
already treated to optimal low LDL-C levels with statins, and niacin favor-
ably changed HDL-C and triglyceride levels. Niacin therefore could be used
as adjuvant therapy to reduce atherogenic lipoprotein burden in patients that
cannot reach their target HDL-C and LDL-C values, or that have contra-
indications for taking statins or bile-acid sequestrants (Boden, Sidhu, &
Toth, 2014; Lloyd-Jones, 2014). There is also growing evidence that the
low HDL-C might not be a causal risk factor for cardiovascular disease,
but rather a marker of high risk for cardiovascular disease (often associated
with metabolic syndrome and insulin resistance) (Voight et al., 2012), in
which case pharmacologically increasing HDL-C could not be expected
to yield any clinical benefit. Current reevaluations of the AIM-HIGH
and the HPS2-THRIVE clinical trial showed that the perceived negative
outcome might not be justified due to several methodological flaws in
the studies. The reevaluation indicates that some of the beneficial
antiatherosclerotic effects of niacin supplementation can be due to niacin
supplementation boosting antioxidative and antiinflammatory mechanisms
(Zeman et al., 2016). It should be emphasized that these studies are using
doses in the range of 1–3 g/day of nicotinic acid, and these side effects are
unlikely in studies supplementing 100 mg/day of nicotinamide or nicotin-

amide riboside, for example.
5. SUMMARY
The central role dietary niacin plays for cellular NAD levels and, thus
for most metabolic processes, is directly reflected in the variety and large
number of clinical problems associated with a suboptimal niacin status
and emphasizes how important the maintenance of a good niacin status is
for overall health. Niacin has a long and successful history as a safe vitamin
supplement, which makes it a promising candidate for therapeutic interven-
tions to ameliorate or treat many of the clinical problems described earlier,
and furthermore might prove beneficial in the prevention of health decline
associated with aging.
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CHAPTER THREE

Advances in Food and Nutrition Research, Volume 83 # 2018 Elsevier Inc. 83

2. ROLE OF DIETARY NIACIN IN DISEASE ORIGIN AND

(Etheridge, 1972; Rajakumar, 2000). Joseph Goldberger, working for the

thickened and hyperpigmented when dermatitis progresses. Typical for

2.2 Current Risks and Causes of Niacin Deficiency and Pellagra

2 Hartnup disease is an autosomal recessive mutation in the gene for the

2.3 Niacin and Vitamin B3, Assessment of Niacin Status, and

2.3.2 Measurement of Niacin Status

Fig. 1 Vitamin B3 molecules (nicotinic acid, nicotinamide, and nicotinamide riboside)

2.3.3 Dietary Need and Recommended Daily Intake

2.3.4 Factors That Influence Dietary Niacin Requirement

Table 1 Recommended Dietary Allowance (RDA) of Niacin Intake for Humans at

requirement for niacin. Examples in addition to low tryptophan intake are

2.4 Niacin Food Sources

2.5 Risk Factors Predisposing to Niacin Deficiency

Table 2 Preformed Niacin Content in Food

Table 2 Preformed Niacin Content in Food—cont’d

low in bioavailable niacin. Sorghum (millet, jowar) contains suitable amounts

NAMPT1 NRK1 NAPRT1 AFMID

converted to nicotinic acid mononucleotide (NAMN) by the enzyme nic-

3.2 NAD Recycling

3.3 NADPH Synthesis

3.4 NAD and NADP Utilization

reactions require enzymatic cleavage of NAD+ and therefore result in a

3.4.1 Redox Reactions

via the respiratory chain in the mitochondria. In addition, NAD+ reduction

Cholesterol synthesis is a complex biochemical synthesis process that

Fig. 6 Overview of biochemical redox reactions in anabolic processes that utilize

Further important biochemical processes that require NAD+ and

consumption of NADPH and O2 (step 3 in Fig. 6). Cholesterol also is the

3.5 NAD as Substrate

metabolism has resulted in studies testing if increased muscular NAD+ syn-

3.5.1 ADP-Ribosyl Cyclases

3.5.2 Poly(ADP-Ribose) Polymerases (PARPs) or ADP-Ribose

(Johansson, 1999), and eventually of a large protein family of related

Fig. 7 Poly(ADP-ribosyl)ation by PARP1. (A) The chemical structure of a poly(ADP-

It has grown from primarily being regarded as mechanism safeguarding

Table 3 The PARP Enzyme Superfamily

The remaining sirtuins, SIRT4 and SIRT6, preferentially utilize NAD+ to

NAD+ Salvage pathway

Fig. 8 Sirtuin-mediated activities. Sirtuins SIRT1, 2, 3, 5, and 6 utilize NAD+ to remove

moiety, and enzymatically transfers the liberated ADP-ribose moiety to tar-

intake information with the individual facets of the transcription machinery

3.5.4 Indoleamine 2,3-Dioxygenase

Fig. 9 NAD availability regulates ADP-ribosylation and sirtuin-mediated epigenetic

neurotropic support cells, activation of IDO by the proinflammatory factor

3.6 Turnover of PAR and MAR Modifications

The additional moieties of NAD+, the ADP-ribose subunit that was

3.6.2 ADP-Ribosyl Hydrolases (ARH1 and ARH3)

4. NAD: RELEVANCE TO HEALTH AND DISEASE

Furthermore, the shifted ratio also affects enzymatic reactions pertinent to

4.1 NAD Decline During Aging and Age-Related Disorders

a metabolic oscillator that regulates aging and metabolism (Imai, 2009a,

4.2 DNA Damage Accumulation

4.3 Cell Death/Cancer

4.4 Mitochondrial Dysfunction

The reduced availability of NAD+ prevents optimal activity of the mito-

4.4.2 Indirect Connection Between Niacin, NAD, and Mitochondrial