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Aging is a major risk factor for many types of cancer, and the molecular mechanisms implicated in aging, progeria syndromes, and cancer pathogenesis display considerable similarities. Maintaining redox homeostasis, efficient signal transduction, and mitochondrial metabolism are essential for genome integrity and preventing progression to cellular senescence or tumorigenesis. NAD+ is a central signaling molecule involved in these and other cellular processes implicated in age-related diseases and cancer. Growing evidence implicates NAD+ decline as a major feature of accelerated aging progeria syndromes and normal aging. Administration of NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) offer promising therapeutic strategies to improve health, progeria comorbidities, and cancer therapies. This review summarizes insights from the study of aging and progeria syndromes and discusses the implications and therapeutic potential of the underlying molecular mechanisms involved in aging and how they may contribute to tumorigenesis. Expected final online publication date for the Annual Review of Cancer Biology Volume 3 is March 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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CA03CH06_Bohr ARI 12 January 2019 11:26
Annual Review of Cancer Biology
NAD+Metabolism in Aging
and Cancer
Tyler G. Demarest,1,2 Mansi Babbar,1
Mustafa N. Okur,1Xiuli Dan,1Deborah L. Croteau,1
Nima B. Fakouri,1Mark P. Mattson,2
and Vilhelm A. Bohr1
1Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of
Health, Baltimore, Maryland 21224, USA; email: vbohr@nih.gov
2Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health,
Baltimore, Maryland 21224, USA
Annu. Rev. Cancer Biol. 2019. 3:105–30
First published as a Review in Advance on
November 9, 2018
The Annual Review of Cancer Biology is online at
cancerbio.annualreviews.org
https://doi.org/10.1146/annurev-cancerbio-
030518-055905
This is a work of the US Government and is not
subject to copyright protection in the United
States
Keywords
aging, cancer, NAD+, progeria, metabolism, mitochondria
Abstract
Aging is a major risk factor for many types of cancer, and the molecular
mechanisms implicated in aging, progeria syndromes, and cancer pathogene-
sis display considerable similarities. Maintaining redox homeostasis, efficient
signal transduction, and mitochondrial metabolism is essential for genome
integrity and for preventing progression to cellular senescence or tumori-
genesis. NAD+is a central signaling molecule involved in these and other
cellular processes implicated in age-related diseases and cancer. Growing
evidence implicates NAD+decline as a major feature of accelerated aging
progeria syndromes and normal aging. Administration of NAD+precur-
sors such as nicotinamide riboside (NR) and nicotinamide mononucleotide
(NMN) offer promising therapeutic strategies to improve health, progeria
comorbidities, and cancer therapies. This review summarizes insights from
the study of aging and progeria syndromes and discusses the implications
and therapeutic potential of the underlying molecular mechanisms involved
in aging and how they may contribute to tumorigenesis.
105
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INTRODUCTION
Aging is the leading risk factor for many diseases including cancer. Hallmarks of aging (Lopez-Otin
et al. 2013) and cancer have recently been proposed (Hanahan & Weinberg 2011). The identifi-
cation of hallmarks of aging and associated disease states is a key first step toward understanding
complex disease processes. Metabolic decline, one hallmark of aging, can lead to obesity, insulin
resistance, oxidative stress, DNA damage, and tumorigenesis (Caliskan et al. 2018, Giovannucci
et al. 2010, Ligibel 2012, Nawab et al. 2017, Renehan et al. 2008). The underlying molecu-
lar mechanisms of this physiological decline are not well understood. The central metabolite,
nicotinamide adenine dinucleotide (NAD+), is emerging as an important aging metabolite that
may be a common link between age-related genome instability, metabolic decline, and associated
comorbidities such as diabetes, neurodegeneration, and cancer.
Aging and cancer share many common underlying features. For example, genome instabil-
ity, characterized by an accumulation of oxidative DNA damage combined with a decrease in
DNA repair capacity, can lead to the accumulation of mutations that initiate tumorigenesis (Bohr
et al. 1998). Recruitment of DNA repair proteins is crucial to repair DNA damage. Following
DNA single-strand breaks (SSBs), double-strand breaks (DSBs), and other type of DNA damage,
poly(ADP-ribose) polymerases (PARPs) catalyze the poly(ADP-ribosylation) of damaged DNA
and proteins as an initial recruitment signal via the consumption of NAD+. For this reason, PARP1
is often considered a guardian of genome integrity. However, if DNA damage is not repaired, and
PARP activation is persistent, declining cellular NAD+can impair sirtuin (SIRT) activities, thus
altering epigenetic chromatin structure (Fritze et al. 1997) and gene transcription involved in
mitochondrial metabolism (reviewed in Fang et al. 2016b). These pathways can lead to mitochon-
drial dysfunction characterized by increased oxidative stress and decreased energy production in
the form of ATP. This can promote inflammation and initiate a feedforward cycle of oxidative
stress that exacerbates cellular injury (Bryan et al. 2013). Many hallmarks are shared by physio-
logical aging and cancer pathogenesis (Figure 1). We propose that the cellular response to these
metabolic perturbations likely dictates whether cells follow the aging pathway toward senescence
and apoptosis or initiate uncontrolled proliferation and tumorigenesis. With NAD+as the central
metabolite connecting these cellular processes, we focus on the roles of the bioenergetics and
redox regulation of different NAD+species.
NAD+BIOSYNTHESIS
NAD+metabolism is a dynamic redox cycle that functions to shuttle electrons throughout cells
to maintain redox homeostasis and bioenergetics. NAD+is synthesized through several pathways
discussed in detail in recent reviews (Fang et al. 2017, Yoshino et al. 2017) and summarized in
Figure 2. De novo synthesis of NAD+accounts for a minority of the total NAD+pool, while the
majority of NAD+comes from recycling the NAD+breakdown product nicotinamide (NAM)
by the salvage pathway enzyme NAM phosphoribosyltransferase (NAMPT) to nicotinamide
mononucleotide (NMN) and back to NAD+via NMN adenyltransferases 1–3 (NMNATs)
(Chiarugi et al. 2012, Nikiforov et al. 2015).
NAD+/NADH ALTERATIONS IN AGING
Contrary to the notion of a continual decline with age, physiological aging is accompanied by
a biphasic shift in basal metabolic rate, which increases from adolescence to adulthood and only
begins to decline by around the middle of the second decade of life in humans (Baker & Peleg 2017).
106 Demarest et al.
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Epigenetic alterations
Redox imbalance
Genome instability
PARP activation
Metabolic dysfunction
Altered sirtuin activity
Altered cellular
communication
Inammation
Apoptosis
Cell senescence
Telomere attrition Impaired autophagy
NAD+ decline
Cell proliferation
NAD+ alterations
(NAMPT
overexpression)
Increased autophagy Telomere lengthening
(telomerase overexpression)
Angiogenesis
AGING CANCER
Figure 1
Interactions between hallmarks of aging and cancer. Common underlying cellular processes involved in
aging and cancer (middle), including alterations in redox state, can initiate oxidative stress leading to genome
stability, metabolic dysfunction, and poly(ADP-ribose) polymerase (PARP) activation, which can repair
endogenous DNA damage or initiate persistent cellular dysfunction. Chronic PARP activation can deplete
cellular nicotinamide adenine dinucleotide (NAD+) and thus impair sirtuin activity and autophagy, which
can lead to further metabolic decline and cell death or senescence, leading to age-related cellular dysfunction
(teal). On the other hand, following persistent PARP activation, cellular maladaptation can upregulate
nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting NAD+salvage pathway enzyme, and
enhance autophagy and cellular metabolism to promote uncontrolled cellular proliferation and
tumorigenesis (purple).
While it is still unknown at what age cellular NAD+decreases, it has been reported to decline with
age in many tissues including liver, skin, muscle, pancreas, and adipose tissue (Fang et al. 2017).
Importantly, in the human brain, there is a significant decline in the NAD+/NADH redox state
with age because of the gradual decline in NAD+, coupled with the gradual increase in NADH (Zhu
et al. 2015a). The small decline in NAD+with age observed via magnetic resonance spectroscopy,
coupled with the increase in NADH (Zhu et al. 2015a), highlights the importance of measuring
multiple NAD+metabolites to gain insight into age- and disease-associated alterations in redox
homeostasis. Moreover, the decline in NAD+concomitant with the accumulation of NADH
indicates a dysfunction in NAD+regeneration, anaerobic glycolysis, or oxidative phosphorylation,
which would also result in a reduced capacity to generate ATP. The following sections highlight the
interactions between NAD+metabolism in the context of aging, progerias, and their involvement
in various cancers.
NAD+IN PREMATURE AGING DISORDERS AND CANCER
Premature aging syndromes, or progerias, are usually caused by mutations in DNA repair proteins
that lead to profound genome instability and the accumulation of mutations. Intriguingly, despite
the accumulation of DNA mutations, only some progeria syndromes have a high incidence of
cancer (Vermeij et al. 2016). The major progerias include xeroderma pigmentosum (XP), Werner
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Trp
IDO
QA
NAMN
QPRT
NRK1/2
NAR
NAPRT
NA NMNAT1–3
NAAD
NADS NAD+
NMN
NADH
SIRTs/PARPs
NMNAT1–3 NAMPT
(poly)ADPr
NRK1/2
NR
TCA NADP(H)
PPP
NADPH
Genome integrity maintenance
NAM
Redox
homeostasis
Mitochondrial
metabolism
Nucleic acid
synthesis
Figure 2
Convergence of nicotinamide adenine dinucleotide (NAD+) metabolites for genome maintenance. The de
novo synthesis of NAD+begins from the conversion of dietary precursor tryptophan (Trp) to quinolinic
acid (QA) by indoleamine 2,3-dioxygenase (IDO). QA is converted to nicotinamide adenine mononucleotide
(NAMN) by quinolinate phosphoribosyl transferase (QPRT). NAMN is also synthesized via nicotinic acid
riboside (NAR) by nicotinamide riboside kinases 1 and 2 (NRK1/2) or indirectly via nicotinic acid (NA) by
nicotinate phosphoribosyltransferase (NAPRT). NAMN is adenylated to nicotinic acid adenine dinucleotide
(NAAD) via nicotinamide mononucleotide adenyltransferases 1–3 (NMNATs) before NAD+synthesis via
NAD synthetase (NADS). NAD+is reduced by tricarboxylic acid (TCA) cycle enzymes to NADH, which
acts as the principle electron donor to complex I of the mitochondrial electron transport chain to support
mitochondrial metabolism. The corresponding phosphorylated redox pair NADP/NADPH are crucial TCA
cycle intermediates that provide reducing equivalents for endogenous antioxidant defense systems to
maintain redox homeostasis, while NADPH production via the pentose phosphate pathway (PPP) is critical
for nucleotide synthesis. Sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs) consume NAD+to
produce ADP ribose (ADPr) and nicotinamide (NAM), which is recycled to nicotinamide mononucleotide
(NMN) by the salvage pathway enzyme nicotinamide phosphoribosyltransferase (NAMPT) and adenylated
to NAD+by NMNATs. Nicotinamide riboside (NR) is an NAD+precursor that can bypass the NAMPT
salvage pathway via conversion to NMN by NRK1/2. These factors converge to prevent DNA damage,
facilitate repair of the nuclear genome, and prevent genome instability.
(WRN), Bloom (BLM), Cockayne (CS), and Hutchinson-Gilford (HG) syndromes. Of these,
XP, WRN, and BLM have a high incidence of cancer, while no elevated incidence of cancer has
been reported in CS and HG patients. CS and XP type A cells have decreased NAD+levels,
in part due to the persistent activation of PARP1 (Fang et al. 2014, Scheibye-Knudsen et al.
2014). So why does WRN have a high incidence of osteosarcoma, while CS patients do not get
cancer? This may be due to the different age of onset of these disorders. WRN and BLM are
segmental progerias, with the onset of advanced aging symptoms presenting in the second decade
of life, while CS and HG patients exhibit a failure-to-thrive phenotype from birth. CSB can
promote cell proliferation via the degradation of p53, and knockdown of CSB sensitizes cancer
cells to chemotherapeutic-induced apoptosis (Proietti-De-Santis et al. 2018). Additionally, CS
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cells are resistant to UV-induced mutagenesis, which may explain the lack of cancer in CS (Reid-
Bayliss et al. 2016). In XP, the accumulation of mutations with UV exposure to sunlight probably
contributes to their susceptibility to skin cancer (Bradford et al. 2011). The compounding effect
of advanced age in WRN and BLM is likely to be part of the reason an increased incidence of
cancer is observed, but this requires further research (Lebel & Monnat 2018).
NAD+metabolism has emerged as a potential target for cancer treatments. In cancer, NAD+
and the major NAD+metabolites [e.g., NAD(P)H] participate in multiple physiological processes
that can modulate cancer cell metabolism, survival, progression, and invasion. Some of the many
enzymes utilizing NAD+metabolites as substrates that are involved in various mechanisms of
carcinogenesis are reviewed in Table 1, and major NAD+-synthesizing and -consuming enzymes
including NAMPT, NMNATs, SIRTs, PARPs, and cluster of differentiation 38 (CD38) are
discussed below.
NAMPT IN CANCER
Maintenance of cellular and tissue NAD+in healthy cells occurs predominantly via the salvage
pathway (Chiarugi et al. 2012). NAMPT is the rate-limiting enzyme of this pathway and is up-
regulated in multiple cancer cell lines (Bajrami et al. 2012, Cagnetta et al. 2015, Cea et al. 2012,
Hasmann & Schemainda 2003). NAMPT exists in both intracellular (iNAMPT) and extracel-
lular (eNAMPT) forms. Multiple human malignancies exhibit increased NAMPT (extracellular
and intracellular) expression, which increases cellular NAD+and can enhance many hallmarks of
cancer, including proliferation, invasion, angiogenesis, metabolic dysfunction, inflammation, and
resistance to apoptosis.
eNAMPT is also known as pre-B cell colony-enhancing factor or visfatin. It is secreted by
adipocytes; by immune cells, including lipopolysaccharide-activated monocytes, leucocytes, lym-
phocytes, pre-B cells, and tumor cells (Grolla et al. 2016); and by cancer cells under nutrient
deprivation due to limited blood supply (Zhao et al. 2014), inflammatory response, and cellular
stress. Studies report that eNAMPT may act as a growth factor or cytokine; however, the under-
lying mechanisms and importance of extracellular NAM and NMN synthesis by eNAMPT are
not completely understood.
eNAMPT and iNAMPT expressions are increased in numerous malignancies (Table 1). High
NAMPT (intracellular and extracellular) levels are linked with higher tumor grade, metastasis, and
poor survival (Long et al. 2012, Neubauer et al. 2015, Santidrian et al. 2014). These data indicate
that higher cellular NAD+levels may represent a hallmark for some cancers that promote cancer
initiation or progression. This is contrary to aged cells and tissues, which generally display a
decline in NAD+. Due to its many roles in cell health and metabolism, NAMPT has received
considerable attention as a potential therapeutic target for cancer treatment.
ANTICANCER EFFECT OF NAMPT INHIBITORS
In the past two decades, inhibition of the salvage NAD+biosynthesis pathway has emerged as a po-
tential anticancer strategy. Increased NAMPT expression in some tumors is a biomarker and a ther-
apeutic target for anticancer therapies. GMX1777/CHS828 and APO866/FK866 are well-studied
and specific NAMPT inhibitors (NAMPTi) with affinities in the nanomolar range. NAMPT inhi-
bition regulates the expression of multiple genes important for predicting recurrence-free survival
and may serve as a prognostic marker in breast and colorectal cancers (Zhou et al. 2014).
To achieve the full potential of NAMPTi, there is a need to identify biomarkers for patients who
may respond positively to NAMPTi treatment. As outlined in Figure 2, multiple routes of NAD+
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Table 1 Role of NAD(P)(H) metabolism in cancer
Metabolite Enzymes Alterations Cancer types Physiological effects References
NAD+NAMPT Overexpression iNAMPT: Pancreatic ductal
adenocarcinoma, oral squamous cell
carcinoma, breast cancer, colorectal
carcinoma, gastric cancer,
endometrial adenocarcinoma, ovarian
serous adenocarcinoma, melanoma,
myeloma, astrocytoma, thyroid
carcinoma, malignant lymphomas,
prostate cancer
eNAMPT: breast cancer, bladder
cancer, colorectal cancer, endometrial
cancer, gastric cancer, glioblastoma,
non-small-cell lung cancer,
esophageal cancer, oral squamous cell
carcinoma, pancreatic cancer
Increases NAD+
NAMPT inhibition suppresses Erk activity and
causes G2/M cell cycle arrest in glioblastoma
multiforme.
NAMPT inhibitor–mediated glycolysis suppression
is followed by reduced carbon flux through the
TCA (tricarboxylic acid) cycle, leading to inhibition
of aspartate/alanine and purine/pyrimidine
metabolism, which eventually causes cell death.
Melanoma cells release NAMPT. This eNAMPT
acts as a cytokine, activating MAPK, PI3K/AKT,
ERK1/2, STAT3, and NF-κB to support tumor
progression and invasion.
eNAMPT supports angiogenesis via increased
synthesis and secretion of FGF-2 and CCL2 in
human mammary epithelial cells and VEGF in
human umbilical vein endothelial cells.
Bi et al. 2011; Lu
et al. 2014;
Nergiz Avcio˘
glu
et al. 2015;
Shackelford
et al. 2013a,b;
B. Wang et al.
2011; G. Wang
et al. 2016; X.Y.
Wang et al.
2017; Yang
et al. 2016
SIRT1
SIRT5
SIRT6
Overexpression Colorectal cancer, thyroid cancer,
hepatocellular carcinoma, leukemia,
lung cancer, osteosarcoma
SIRT1 attenuates p53, PTEN, and E2F1 to avoid
stress-mediated apoptosis; stabilizes oncogenes
FOXO1 and PGC1αto boost mitochondrial
biogenesis; and increases N-Myc to enhance
epithelial-to-mesenchymal transition and cancer
cell metastasis.
SIRT5 enhances amino acid metabolism and
supports cancer cell proliferation.
SIRT6 enhances inflammation, angiogenesis, and
metastasis in pancreatic cancer.
SIRT6 endorses osteosarcoma cell migration and
invasion via the ERK1/2–MMP9 pathway.
Chalkiadaki &
Guarente 2015,
Wang et al.
2018
SIRT1
SIRT2
SIRT3
SIRT4
SIRT6
Downregulation Bladder cancer, breast cancer,
colorectal cancer, glioblastoma
multiforme, liver cancer, lung cancer,
prostate cancer, ovarian cancer
SIRT1 inhibits cancer cell proliferation via
suppressing β-catenin and survivin signaling.
SIRT2 inhibits APC/C (anaphase-promoting
complex/cyclosome).
SIRT3 downregulation activates HIF1αand induces
glycolysis and angiogenesis pathways.
SIRT4 and SIRT6 represses glutaminolysis and
tumor growth.
Chalkiadaki &
Guarente 2015,
Lin et al. 2017
(Continued )
110 Demarest et al.
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Table 1 (Continued )
Metabolite Enzymes Alterations Cancer types Physiological effects References
NAD+PARPs Overexpression Breast cancer, gastric cancer,
melanoma, small-cell lung cancer
PARPs confer protection against anticancer
genotoxic drugs.
PARP1 boosts cancer cell proliferation by inhibiting
the Sp1 signaling pathway.
PARP5a enhances telomere elongation.
Green et al. 2015,
Y. Liu et al.
2016, Rodriguez
et al. 2013,
Yang et al. 2013
NADK Gain-of-
function
mutant
NADK-I90F
Pancreatic ductal adenocarcinoma Increases transformation of normal pancreatic ductal
cells
NADK 10F mutation imparts increased activity to
NADK, thereby elevating NADPH levels.
Tedeschi et al.
2016
IDH3αOverexpression Breast cancer, lung cancer Enhances metabolic reprogramming and
angiogenesis via HIF1αactivation
Zeng et al. 2015
ALDH1 Overexpression Cancer stem cells of lung
adenocarcinoma, breast cancer,
esophageal cancer, melanoma, and
colorectal cancer
Enhances malignant transformation and metastasis
and promotes resistance to anticancer
chemo(radio)therapy
Clark & Palle
2016
BRCA1 Downregulation
(mutation or
promoter
methylation)
Breast cancer, ovarian cancer Suppression modulates cell cycle checkpoint and
DNA repair, contributing to genomic instability.
Wang 2012
MDH2 Overexpression Prostate cancer, uterine cancer Confers prostate cancer and uterine cancer cell
resistance to docetaxel and doxorubicin, respectively
MDH2 inhibition suppresses tumor growth via
inhibition of HIF1α, VEGF, and GLUT1 in
colorectal cancer cells.
Ban et al. 2016
NMNAT2 Overexpression Colorectal cancer Unknown: increased NAD+?Cui et al. 2016
CD38 Overexpression Chronic lymphocytic leukemia,
prostate cancer
Promotes cancer cell proliferation and migration via
activation of ZAP70 and ERK1/2 pathways
Japp et al. 2015,
Malavasi et al.
2011
NADH LDHA Overexpression,
downregula-
tion
Breast cancer, renal cell carcinoma,
esophageal squamous cell carcinoma
LDHA promotes the Warburg effect, tumorigenesis,
cell growth, cell migration, and lactic acid
generation, which aids in cancer cell invasion and
metastasis.
LDHA downregulation in hepatocellular carcinoma
boosts EO9-induced DNA damage apoptosis.
Furuta et al.
2010, Miao
et al. 2013
(Continued )
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Table 1 (Continued )
Metabolite Enzymes Alterations Cancer types Physiological effects References
NADP+IDH1
IDH2
Mutations (IDH1
Arg132, IDH2
Arg140 and
Arg172)
Gliomas, biliary cancer, leukemia,
prostate cancer, colorectal cancer
Produces oncometabolite D-2 hydroxyglutarate;
increases nutrient consumption, which supports
cancer cell proliferation; stabilizes HIF1αto
promote angiogenesis; and suppresses
differentiation via the inhibition of HNF4α
Madala et al.
2018, Reitman
& Yan 2010,
Saha et al. 2014
NADPH NQO1 Downregulation:
loss-of-function
polymorphisms
(R139W, P187S,
and C609T)
Colorectal cancer, digestive tract
cancer, esophageal squamous cell
carcinoma
Wild-type NQO1 activates AMPK-mediated
suppression of the cancer cell–proliferation
mTOR/S6K/4E-BP1 pathway.
Lafuente et al.
2000, Lee et al.
2015, Yang et al.
2012, Zhang
et al. 2003
Overexpression Breast cancer, pancreatic cancer,
colorectal cancer,
cholangiocarcinoma, uterine cervical
cancer, melanoma, lung cancer,
adrenal cancer, bladder cancer, liver
cancer, ovary cancer, thyroid cancer
Stabilizes HIF1α, promotes redox homeostasis,
and is selectively utilized to develop bioreductive
anticancer drugs
Oh & Park 2015,
Oh et al. 2016
NOX1 Overexpression Colorectal cancer Increases cell proliferation and migration via
activation of EGFR/PI3K/AKT and
Wnt/β-catenin pathways and suppresses p53
activity via SIRT1 activation
Skonieczna et al.
2017
NOX2 Overexpression Gastric cancer Increases ROS production, contributing to DNA
damage and genomic instability
P. Wang et al.
2015
NOX4 Overexpression Lung cancer, liver cancer, melanoma,
gastric cancer, pancreatic cancer,
renal cell carcinoma
Enhances metastasis via TGFβand
JAK2/STAT3 signaling
Upregulates AKT, NF-κB, and VEGF in
pancreatic cancer to promote cancer survival
and angiogenesis
Promotes tumor development in chronic myeloid
leukemia by activating the PI3K/AKT pathway
and inhibiting PP1 phosphatase
Regulates HIF2αexpression in renal cell
carcinoma
Targeted using Fulvene-5 in mouse endothelial
tumors
Bonner &
Arbiser 2012,
Gao et al. 2017,
Skonieczna
et al. 2017
(Continued )
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Table 1 (Continued )
Metabolite Enzymes Alterations Cancer types Physiological effects References
NADPH NOX5 Overexpression Barrett’s esophagus–associated
adenocarcinoma, malignant
melanoma, prostate cancer, breast
cancer, brain cancer, colorectal
cancer, lung cancer, ovarian cancer
Activates COX2 and NF-κB signaling in Barrett’s
esophagus–associated adenocarcinoma
Roy et al. 2015,
Si et al. 2007
ME2 Overexpression Melanoma, glioblastoma multiforme Promotes cancer cell proliferation, migration, and
invasion by modulating cellular ATP levels,
activating AMPK and PI3K/AKT, and inhibiting
acetyl-CoA carboxylase and PTEN activity
Decrease in ME2 expression has been linked to
induction of senescence.
Chang et al.
2015, C.P.
Cheng et al.
2016
G6PDH Overexpression Cervical cancer, melanoma, breast
cancer, colorectal cancer, endometrial
cancer, cervical cancer, prostate
cancer, lung cancer
Accelerates the pentose phosphate pathway (PPP),
and therefore nucleotide precursor and NADPH
synthesis, thereby facilitating DNA
replication/repair and redox homeostasis
Aids tumorigenesis and angiogenesis in NIH3T3
Furuta et al. 2010
Abbreviations: ALDH, aldehyde dehydrogenase; BRCA, breast cancer; CD38, cluster of differentiation 38; CYP, cytochrome P450 reductase; eNAMPT, extracellular NAMPT; G6PDH,
glucose-6-phosphate dehydrogenase; HIF1α, hypoxia-inducible factor 1 alpha; IDH, isocitrate dehydrogenase; iNAMPT, intracellular NAMPT; LDH, lactate dehydrogenase; MDH, malate
dehydrogenase; ME, malic enzyme; NAD+, nicotinamide adenine dinucleotide; NADK, NAD+kinase; NAMPT: nicotinamide phosphoribosyltransferase; NMNAT, nicotinamide
mononucleotide adenylyltransferase; NOX, NADPH oxidase; NQO1, NAD(P)H quinone oxidoreductase; PARP, poly(ADP-ribose) polymerase; ROS, reactive oxygen species; SIRT, sirtuin.
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biosynthesis may make NAMPTi particularly useful in certain cancer types that primarily rely on
the salvage pathway. Accordingly, studies have reported that patients with increased NAMPT
expression are more sensitive to NAMPTi. For example, isocitrate dehydrogenase 1 (IDH1)-mutant
cancers also show increased sensitivity to NAD+depletion (Tateishi et al. 2015). Mutant IDH1
downregulates the Preiss-Handler pathway’s enzyme nicotinate phosphoribosyltransferase, re-
sulting in reduced NAD+levels and increased sensitivity to NAMPTi. Various oncogenic signals
are also associated with increased NAMPT or NAD+levels. For instance, activation of the onco-
gene c-Myc increases NAMPT messenger RNA (mRNA) transcription, which may facilitate tumor
progression in cancers (Menssen et al. 2012).
Various clinical trials have been conducted to exploit the antitumor potential of NAMPT in-
hibition; however, this approach has thus far shown low efficacy and high toxicities. Oral and
intravenous administration of NAMPTi are associated with various toxicities, including throm-
bocytopenia, skin rash, lymphopenia, and gastrointestinal effects such as esophagitis, diarrhea, and
vomiting. Reduced efficacy of NAMPTi may be attributed to increased NAD+biosynthesis via
the de novo or Preiss-Handler pathways. Therefore, targeting the NMNATs as the final step in
NAD+synthesis may represent a more effective and targeted approach for NAD+depletion in
tumor cells.
NMNATs
Mammalian cells have three isoforms of NMNATs (NMNAT1–3), which are localized to the
nucleus (NMNAT1), the cytoplasmic membrane of the Golgi apparatus (NMNAT2), and the
mitochondria (NMNAT3) (Lau et al. 2010). While NAMPT has been considered the rate-limiting
step of the NAD+salvage pathway, it is important to note that NAD+production from any of the
biosynthetic pathways requires NMNATs as the terminal step for NAD+synthesis (Buonvicino
et al. 2018). NMNATs have been predominantly studied for their neuroprotective role in axonal
degeneration in the central nervous system (CNS) (Ali et al. 2013). Interestingly, NMNAT2,
which is cytoplasmic and highly expressed in the CNS, was recently demonstrated to contribute
to both the cytoplasmic and mitochondrial NAD+pools (Cambronne et al. 2016). This means
that mitochondrial NAD+is critically important to maintain cell health in the CNS. Moreover,
NMNAT2 mRNA levels have been reported to decline in models of Alzheimer’s disease and
precede neurodegeneration (Ljungberg et al. 2012), while a single-nucleotide polymorphism in
NMNAT3 has been identified in a Dutch cohort of familial Alzheimer’s disease (Liu et al. 2007).
In contrast to the decline in NMNAT expression implicated in age-related neurodegenera-
tive diseases, NMNAT2 overexpression has been reported in colorectal cancer (Cui et al. 2016),
melanoma, and neuroblastoma (Buonvicino et al. 2018). Therefore, targeting NMNATs could be
more efficacious than targeting upstream NAMPT. Indeed, recent reports indicate that an NAD+
analog called Vacor inhibits NAD+synthesis and potentiates cytotoxicity by targeting NAMPT
and NMNAT2/3 in melanoma and neuroblastoma cell lines (Buonvicino et al. 2018). These results
support the development of specific NMNAT inhibitors as a potentially useful clinical treatment
option for cancers overexpressing multiple pathways of the NAD+synthesis machinery.
PARPs
PARP1–3 are major NAD+consumers, with PARP1 being the best understood. PARPs are in-
volved in DNA damage repair, chromatin modification, transcription regulation, inflammation,
cell death, and energy metabolism (reviewed in Dulaney et al. 2017). PARPs require NAD+as
a substrate to generate poly(ADP-ribose) (PAR) polymers and NAM at sites of DNA damage.
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PARPs are initiating components of the cellular stress response that are activated immediately
following DNA damage to recruit components of the DNA repair machinery. PARP1 is involved
in SSB and DSB repair by promoting the homologous recombination (HR) pathway over the
error-prone nonhomologous end joining (NHEJ) pathway. For example, PARP1 activity is re-
quired for the recruitment of BRCA1 to repair DSBs via HR (Li & Yu 2013). However, in the
absence of BRCA1, such as in many breast cancers, the inability to repair DNA via HR activates
alternative NHEJ, which promotes the accumulation of mutations and eventual tumorigenesis.
Increases in PARP activity have been linked to both the suppression and the progression of
tumorigenesis. This discrepancy may be due to PARPs’ role in DNA repair, which may prevent
mutation accumulation and cancer formation, but may also aid in cancer cell survival following
tumor initiation. For example, high-PARP expression in patients with breast cancer (Green et al.
2015), gastric cancer (Y. Liu et al. 2016), melanoma (Rodriguez et al. 2013), and small-cell lung
cancer (Kim et al. 2014) is linked with poor prognosis, whereas pancreatic cancer patients with
high PARP expression exhibit improved survival (Klauschen et al. 2012). Thus, the activation of
PARPs may be beneficial in pancreatic cancer, whereas inhibition of PARPs would be beneficial
in other cancers.
PARP inhibitors (PARPi) represent a suitable strategy in cancer therapy when tumors are
defective in HR DNA repair (i.e., loss of BRCA1 and BRCA2). Accordingly, several PARPi have
reached late-stage clinical trials, and olaparib is currently approved by the US Food and Drug
Administration (FDA) for the treatment of BRCA-deficient cancers (Dulaney et al. 2017). Tumor
cells that lack BRCA1 are extremely dependent on repair via Polθand alternative NHEJ for their
survival (Ceccaldi et al. 2015). PARPi kill tumor cells in several different ways: (a) PARPi can cause
synthetic lethality due to increased SSB formation during DNA replication, which can proceed
to DSBs that cannot be repaired (Bryant et al. 2005); (b) PARP may be “trapped” on the DNA
to physically impede the DNA repair machinery; and (c) PARPi can facilitate death by mutation
accumulation due to the reliance on error-prone NHEJ. Thus, PARP1 inhibition limits the ability
of tumor cells to repair DNA and proliferate when they bear mutations rendering them defective
in HR (Dulaney et al. 2017). The future development of combination therapies with PARPi and
other strategies to impair PARP activity with less toxicity will hopefully improve the efficacy and
tolerability of PARPi treatment in cancer patients.
SIRTUINS
SIRTs were first identified as major determinants of lifespan (Tissenbaum & Guarente 2001)
that are required for the robust life extension afforded by calorie restriction in multiple species
[reviewed by Guarente (2005), Lin & Guarente (2003), Minor et al. (2010), and Sinclair (2005)].
There are currently seven SIRT isoforms (SIRT1–7), identified with different subcellular local-
izations (e.g., SIRT3–5 are mitochondrial) and functions [reviewed by Houtkooper et al. (2012)
and Imai & Guarente (2014)]. SIRTs require NAD+as a cosubstrate to posttranslationally modify
target proteins, producing ADP-ribose and NAM. Evidence demonstrates that SIRTs have dual
roles in cancer and may function as tumor suppressors or initiate tumorigenesis (Song & Surh
2012). Mechanistically, most SIRT isoforms deacetylate proteins including histones and modu-
late the transcription of key genes, including the master regulator of mitochondrial biogenesis,
PGC1α. SIRT1 also directs cell cycle progression by modulating p53 activity via deacetylation.
Since SIRT activity is known to decline with age, likely as a result of declining NAD+, the loss
of SIRT-mediated tumor suppressor function may be a critical step leading to tumorigenesis. On
the other hand, SIRT1 is overexpressed in multiple malignancies (Table 1). Activated SIRT1
diminishes tumor suppressors such as p53, PTEN, and retinoblastoma protein and stabilizes
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oncogenes such as MYCN to enhance epithelial-to-mesenchymal transition and cancer cell metas-
tasis (Shackelford et al. 2013b). SIRT2 is overexpressed in numerous cancers including prostate,
colorectal, and hepatocellular carcinoma (Cheng et al. 2018, Yang et al. 2017). Mechanistically,
SIRT2 has been demonstrated to deacetylate and activate glucose-6-phosphate dehydrogenase,
thereby enhancing NADPH production and promoting cancer cell proliferation (Xu et al. 2016).
SIRT3–5 are located in mitochondria, where they play numerous roles in mitochondrial
metabolic regulation. For example, SIRT3 has been identified as an essential mediator of some
of the beneficial effects of caloric restriction (Qiu et al. 2010) and adaptive responses to energetic
challenges in the brain (A. Cheng et al. 2016). Mechanistically, SIRT3 deacetylates IDH2 (Yu
et al. 2012) and superoxide disumutase 2 (Liu et al. 2017), resulting in the increased production
of NADPH for reactive oxygen species (ROS) detoxification. Accordingly, SIRT3 modulation has
been implicated as an oncogene and tumor suppressor in cancer (reviewed in Torrens-Mas et al.
2017). Similarly, SIRT4 has also been identified as a deacetylase that acts as a tumor suppressor
in numerous malignancies (Zhu et al. 2014).
SIRT5 is unique among sirtuins in that it is a very weak deacetylase, but it acts predominantly as a
lysine desuccinylase, demalonylase, and deglutyrase for the modulation of numerous mitochondrial
metabolic enzymes (Zhang et al. 2017). The diverse roles for SIRT5 in metabolic reprogramming
in cancer have been recently reviewed (Bringman-Rodenbarger et al. 2018). In brief, SIRT5 is
generally overexpressed in tumor tissues relative to native normal tissues, and it demalonylates
GAPDH and other glycolytic enzymes, resulting in elevated energy production via glycolysis
(Nishida et al. 2015). SIRT5 also interacts with and regulates numerous TCA (tricarboxylic acid)
cycle enzymes via desuccinylation including mitochondrial complex I (NADH dehydrogenase)
(Marcon et al. 2015), complex II (succinate dehydrogenase) (Park et al. 2013), and IDH2 (Zhou
et al. 2016).
SIRT6 deacetylase activity modulates DNA repair in telomeres and participates in nuclear DSB
repair by recruiting PARP1 to DNA breaks (McCord et al. 2009, Michishita et al. 2008, Van Meter
et al. 2016). SIRT6 also participates in base excision repair to remove oxidatively damaged DNA
(Mostoslavsky et al. 2006). Accordingly, transgenic SIRT6-overexpressing mice display several
health benefits including increased lifespan, improved glucose tolerance, and reduced adipose
inflammation (Roichman et al. 2017). This suggests that SIRT6 has important roles in genome
integrity maintenance and metabolic programming. The role of SIRT6 in cancer has recently
been reviewed (Dong et al. 2016). Intriguingly, conflicting results have shown that SIRT6 is
overexpressed or downregulated depending on cancer type (Table 1), and this therefore requires
further investigation.
SIRT7 has been implicated in aging and cancer physiology but is relatively poorly characterized.
This may be due to the relatively low enzyme activity of SIRT7. Despite the limitations in our
current understanding of SIRT7, it is thought to play a role in RNA metabolism by regulating
RNA polymerase expression and is localized to the nucleoli, where ribosomal RNA is transcribed
(Ford et al. 2006). Like other SIRTs, SIRT7 plays a key role in metabolic regulation. For example,
SIRT7-knockout mice develop fatty liver disease, and overexpression of SIRT7 can reverse these
effects (Yoshizawa et al. 2014). Increasing our understanding of SIRT7 regulatory mechanisms
may provide insight into mechanisms of metabolic dysregulation in age-related disorders and
comorbidities like cancer.
Overall, the involvement of many SIRT isoforms highlights the complex relationships be-
tween the epigenetic modulation of cellular transcription, cell cycle progression, and metabolic
regulation. Importantly, these processes are nearly all influenced by NAD+bioavailability and
posttranslational modifications of key metabolic enzymes. Since SIRTs play numerous crucial
roles in the aging process, future research should focus on understanding the SIRT-mediated
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regulation of metabolic pathways in relation to age-related diseases and the proclivity for cancer
development and progression.
CD38 IN AGING AND CANCER
CD38 is an NAD+-consuming ectoenzyme originally discovered for its extracellular role in innate
immune activation. Emerging evidence demonstrates that CD38 is the major enzyme responsible
for NAD+decline in physiological aging (Camacho-Pereira et al. 2016). CD38-knockout mice
have elevated NAD+levels in multiple tissues (Camacho-Pereira et al. 2016, Sahar et al. 2011,
Young et al. 2006). Contrary to the idea that elevated NAD+may facilitate cancer formation, CD38
knockout impedes tumorigenesis and halts the progression of lung cancer in murine models (Bu
et al. 2018). This implicates a tumorigenic role for CD38 in inflammatory immune system activa-
tion. Indeed, low-CD38 expression has been associated with proinflammatory prostate cancer cells
(X. Liu et al. 2016). Moreover, recent research also proposes that CD38 is a diagnostic marker for
aggressive prostate cancer (Sahoo et al. 2018) and is involved in the pathophysiology of other can-
cers such as multiple myelomas (Chini et al. 2018). Accordingly, the FDA has approved the mon-
oclonal antibody targeted to CD38, daratumumab, for the treatment of patients with relapsed or
refractory multiple myeloma (Raedler 2016). These data suggest a role for CD38 modulation of the
immune response in cancer development/progression, a possibility that requires further research.
METABOLIC AND MITOCHONDRIAL (DYS)FUNCTION
IN AGING AND CANCER
Mitochondrial metabolism declines with age, and cells may adapt by utilizing alternative biofuels
depending on local bioavailability within the given cellular and tissue environment. Cell fate
is largely determined by mitochondria, which dictate whether cells survive or die by necrotic
or apoptotic cell death pathways. Mitochondria can initiate cell death through the release of
apoptosis-inducing factor (AIF) or cytochrome c, which initiates the formation of the apoptosome
and caspase activation. Intriguingly, AIF release is downstream of persistent PARP activation,
in which PAR polymer accumulation can permeabilize the outer mitochondrial membrane that
results in cell death known as parthanatos (Andrabi et al. 2008).
If cells enduring age-related metabolic decline do not die, they could persist in a metaboli-
cally dysfunctional state or they may exit the cell cycle and enter senescence (discussed in detail
below). If cells persist in a dysfunctional state, they could initiate a maladaptive metabolic switch
toward the utilization of glucose and upregulate NAD+synthesis pathways, which initiates a series
of incompletely understood events that may initiate tumorigenesis. Since there are a myriad of
metabolic signaling pathways modulated by NAD+metabolites, we focus on the roles of other
NAD+metabolites as putative determinants of aging and cancer.
NADH
NAD+is reduced to NADH by pyruvate dehydrogenase and the TCA cycle enzymes malate
dehydrogenase and α-ketoglutarate dehydrogenase (αKGDH). NADH acts as the principle elec-
tron donor to complex I (NADH dehydrogenase) of the mitochondrial electron transport chain
to support mitochondrial oxidative phosphorylation to generate ATP. Mitochondrial function,
including complex I function, declines with age (Stefanatos & Sanz 2011). The resulting decline
in NAD+/NADH redox state has been reported to initiate a pseudohypoxic state that upregu-
lates many oncogenic signaling pathways such as the canonical hypoxia-inducible factor 1 alpha
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(HIF1α) pathway (Gomes et al. 2013). HIF1αcan upregulate the expression of many stress re-
sponse genes such as vascular endothelial growth factor, which promotes angiogenesis and can
provide nutrients to malignant cells and encourage metastasis. Moreover, the production of more
NADH may force cells to rely on glycolysis via NADH utilizing the enzyme lactate dehydrogenase
to produce lactate and also regenerate NAD+. This characteristic Warburg shift in metabolism
promotes tumorigenesis (Warburg 1956).
Lactate dehydrogenase (LDH) is encoded by two genes, LDHA and LDHB. The gene products
of LDHA and LDHB combine to form five isozymes of tetrameric LDH. Tetrameric structures
containing a majority of LDHA proteins primarily drive the forward reaction, reducing pyruvate
to lactate by consuming NADH to regenerate NAD+. Isozymes containing the majority of LDHB
proteins catalyze the reverse reaction (Ross et al. 2010). Elevated lactate is observed with aging
and has been proposed to be a hallmark of the aging process (Houtkooper et al. 2011, Ross et al.
2010). Since LDH is a critical component of anaerobic glycolysis and the Warburg shift is a
key observation in cancer cells, it is not surprising that LDH is also overexpressed in several
forms of cancer (Furuta et al. 2010). Elevated LDH has also been associated with poor prognosis
for cancer patients (Thonsri et al. 2017). Increased NADH production implies a mitochondrial
deficit; however, many TCA cycle enzymes also act as NAD(P)H redox cycling enzymes and are
implicated in aging and cancer development.
NADPH
NADPH is an essential TCA cycle intermediate for endogenous antioxidant defense systems (e.g.,
glutathione and thioredoxin peroxidase systems) to maintain redox homeostasis. As a substrate for
many important enzymes, NADPH is involved in the regulation of cell growth, differentiation,
antioxidant systems, immune cell activation, and nucleic acid synthesis. NADPH production via
the pentose phosphate pathway is critical for nucleotide synthesis support of DNA replication
and repair. Given that NADPH plays numerous crucial roles in maintaining metabolic homeo-
stasis, perturbations in NADPH redox state and mutations in NADP(H)-dependent enzymes are
associated with age-related pathologies and cancer.
Isocitrate Dehydrogenases
IDH1 and IDH2 reduce NADP+to NADPH to catalyze the decarboxylation of isocitrate to α-
ketoglutarate (αKG) in the TCA cycle. IDH1 and IDH2 are commonly mutated in gliomas at sites
Arg132 and Arg140/172, respectively. Mutations at the arginine residue alters substrate (isocitrate)
binding to the enzyme’s active site, which results in a decline in αKG. Intriguingly, mutant IDH
isoforms produce oncometabolite D-2 hydroxyglutarate (2-HG) using NADPH as a substrate,
resulting in reduced αKG levels and an altered NADP/NADPH redox ratio. Corresponding
increases in 2-HG inhibit αKG-dependent dioxygenases, including prolyl hydroxylase (PHD),
which promotes the stabilization of HIF1α. The phenomenon where alterations in redox state or
TCA cycle activity occurs has been described as pseudohypoxia (Gomes et al. 2013, MacKenzie
et al. 2007). Interestingly, the addition of a cell-permeable derivative of αKG can reverse the
pseudohypoxic state by reactivating the degradation of HIF1αby PHD (MacKenzie et al. 2007).
The consumption of NADPH by IDH may also compromise endogenous antioxidant de-
fense systems, resulting in more oxidatively damaged proteins, lipids, and DNA (Madala et al.
2018). Therefore, elevated oncometabolite 2-HG levels may serve as a diagnostic and prognos-
tic marker, specifically in gliomas. Enasidenib, an IDH2-R140Q and IDH2-R172H inhibitor, is
currently used as a treatment for acute myeloid leukemia, and glioma-specific vaccines targeting
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IDH1-R132H are also in clinical trials (Madala et al. 2018). Since IDH mutations result in dimin-
ished NADPH for antioxidant defense enzymes and αKG levels, downstream αKGDH function
may also be compromised; the resulting redox imbalance and HIF1αstabilization can facilitate
tumorigenesis and could serve as a promising therapeutic target.
α-Ketoglutarate Dehydrogenase
αKGDH reduces NAD+to NADH for the decarboxylation of α-ketoglutarate to succinyl-
coenzyme A, the precursor to succinate, which is the principle substrate for cellular energy gener-
ation at mitochondrial complex II (succinate dehydrogenase). Intriguingly, supplementation with
αKG has been demonstrated to extend lifespan in Caenorhabditis elegans by as much as 50% (Chin
et al. 2014). Lifespan extension by αKG was mediated by a reduction in cell metabolic rate via
the inhibition of ATP synthase and the activation of autophagy (Chin et al. 2014). Moreover,
αKGDH dysfunction is implicated in age-related pathology such as neurodegenerative disorders
(Gibson et al. 2005). This may be because αKGDH has been identified as a major source of ROS
generation (Starkov et al. 2004) and plays an important role in regulating cancer cell metabolic
plasticity (Vatrinet et al. 2017).
αKGDH has been reported to possess ADP-ribosyltransferase activity (Pankotai et al. 2009)
and therefore may act within the mitochondria to regulate metabolic activities through post-
translational modifications. Despite the observation of polyADP-ribosylation in mitochondrial
extracts (Lai et al. 2008, Masmoudi & Mandel 1987) and PARP localization to the mitochon-
dria (Rossi et al. 2009, Du et al. 2003), the presence of a mitochondrial PARP isoform remains
controversial. Given the role of αKGDH in generating substrates necessary for mitochondrial
energy metabolism, the production of ROS, and the potential ADP-ribosyltransferase activity
of αKGDH, more attention is warranted to the role and putative therapeutic value of targeting
αKGDH and αKG in the regulation of age-related pathologies and cancer.
AUTOPHAGY, MITOPHAGY, AND NAD+
Autophagy is activated in response to nutrient deprivation, via inhibition of the mTOR pathway,
to recycle damaged cellular components to amino acid building blocks, while mitophagy may be
triggered in nutrient-rich conditions to remove damaged mitochondria that adversely affect cell
health (Youle & Narendra 2011). Accumulating evidence advocates that rates of autophagy and
mitophagy decline with age (Fang et al. 2017, Moreira et al. 2017, Shi et al. 2017). NAD+precursor
treatment may improve age-related pathology by restoring autophagy/mitophagy (Fang et al. 2014,
2016a; Kerr et al. 2017; Lin & Qin 2013; Scheibye-Knudsen et al. 2014). Intriguingly, an excellent
review detailing the role of autophagy in cancer reports that the initiation of cancer occurs under
conditions where autophagy is also compromised (Santana-Codina et al. 2017). This indicates
that the decline in autophagy observed during aging may be a key factor that predisposes aged
individuals to cancer. Following cancer cell initiation, autophagy is vastly upregulated to provide
the amount of amino acids and nutrients required to support uncontrolled cellular proliferation
(Kimmelman & White 2017, Santana-Codina et al. 2017). Interestingly, malignant cells not only
upregulate autophagy to meet these bioenergetic needs but also have been reported to sequester
extracellular metabolites through a process known as macropinocytosis. Collectively, these data
imply that the metabolic adaption in response to the aging process may dictate cell fate and
represent a therapeutic opportunity to treat age-related diseases and cancer.
Mitochondrial quality control, the balance between mitochondrial biogenesis and mitophagy,
is critical to maintain cellular energy and redox homeostasis. The turnover of damaged
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mitochondria helps prevent excessive generation of ROS, which protects the nuclear and mi-
tochondrial genome from DNA damage, thus preventing DNA mutations and promoting cell
survival under energetic stress (Chourasia et al. 2015). Research from the Finkel group demon-
strated that mitophagy drastically declines in the hippocampus with age (Sun et al. 2015). Since
neuronal activity is bioenergetically demanding, the age-dependent decline in mitophagy may
contribute to metabolic decline and neurodegeneration. Contrarily, diminished mitochondrial
function combined with an increase in oxidative damage may promote a metabolic shift toward
glycolysis, which could predispose aged tissues toward tumorigenesis. Importantly, mitophagy
has been shown to promote mitochondrial health in age-related disorders (Ryu et al. 2016). In-
terestingly, two main regulatory proteins of mitophagy, parkin and NIX/BNIP3L, are frequently
deleted or silenced in a variety of human cancers (Springer & Macleod 2016), implying that the in-
duction of mitophagy may represent a therapeutic strategy to help restore a healthy mitochondrial
pool and improve metabolic dysfunction in aging and cancer.
SENESCENCE AND NAD+
As we age, senescent cells accumulate and wreak havoc in our body. Senescent cells are metaboli-
cally active but irreversibly cell cycle–arrested cells that degrade organ function, promote inflam-
mation, and have both pro- and anticancer properties. Senescent cells are also a hallmark of aging
(Lopez-Otin et al. 2013). They secrete proinflammatory markers, extracellular matrix proteases,
and chemokines to surrounding cells, and collectively this phenotype is called secretory-associated
senescence phenotype (SASP) (Coppe et al. 2010). SASP promotes cancer and aging. There are
many stimuli that encourage the development of senescent cells, including oncogene expression,
DNA damage exposure, replication stress, telomere erosion, and mitochondrial dysfunction (van
Deursen 2014, Wiley et al. 2016). Senescent cells also display a protective role because cells can
enter a senescent state after DNA damage, and this represents a major tumor-suppressor mech-
anism (Rodier et al. 2007, Campisi & d’Adda di Fagagna 2007). Consequently, senescent cells
possess both pro- and anticancer properties depending on the biological context.
A recent study established a causal role for senescent cells in age-related physical deterioration
and decreased lifespan in mice (Xu et al. 2018). Since the health and lifespan of mice have been
shown to be improved by the removal of senescent cells (Baker et al. 2011, Xu et al. 2018), inves-
tigators have sought out drugs that could preferentially kill senescent cells. These drugs are called
senolytics. Two of the first compounds identified were dasatinib and quercetin; each individually
killed senescent cells, but with different efficiencies depending on cell type. Consequently, senes-
cent cell killing was more effective if the two drugs were combined (Zhu et al. 2015b). Dasatinib is
a tyrosine kinase inhibitor and known to induce apoptosis (Montero et al. 2011, Xue et al. 2012).
Quercetin was also described as a kinase inhibitor (Bruning 2013) but is also a CD38 inhibitor
(Escande et al. 2013). This raises the question of whether modulation of NAD+contributes to the
senolytic activity of this drug and, further, if other NAD+modulators may attenuate senescence.
Interestingly, in cells with mitochondrial dysfunction–associated senescence, a modified SASP
program was executed (Wiley et al. 2016). These cells were characterized as having lower
NAD+/NADH ratios and lacking the IL-1 (interleukin 1)-associated inflammation due to 5
AMP-activated protein kinase (AMPK)-mediated p53 activation. Consequently, high NAD+may
be negatively associated with the development of senescent cell phenotypes. In support of this
concept, a recent paper demonstrated that AMPK activation could lead to increased NAD+
and prevent oxidative stress–induced senescence (Han et al. 2016). Further, they showed that
NAMPT was significantly decreased in H2O2-induced senescent cells and that AMPK activation
reversed this. Additionally, there are other lines of evidence that indicate that low NAD+may be a
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common feature found in senescent cells (Ziegler et al. 2015), and thus NAD+is a druggable
target. Since senescence and mitochondrial dysfunction are both intimately associated with can-
cer and aging, additional research is needed to more thoroughly investigate their relationship to
NAD+biosynthesis and decomposition.
NAD+AS A THERAPEUTIC TARGET IN CANCER
AND AGING DISORDERS
Although emerging data support the beneficial and protective role of NAD+supplementation in
age-related neurodegenerative and premature aging diseases (Fang et al. 2016a, Hou et al. 2018,
Scheibye-Knudsen et al. 2014), its role in preventing or treating cancer remains controversial.
There are conflicting studies on the effect of NAD+on cancer cell proliferation and death. For
example, a high dose (1000 mg/kg) of NAM can inhibit breast tumor growth in mice, whereas in
pancreatic islet cells, 350 mg/kg of NAM increased the incidence of streptozotocin-induced cancer
(Surjana et al. 2010). Further studies are needed to eliminate unwanted effects of NAD+admin-
istration in cancerous cells or the toxicity from NAMPT inhibition to neighboring healthy cells.
Subsequent studies have revealed that NAMPT inhibition results in the attenuation of glycol-
ysis and the activation of autophagy, indicating that NAD+-depleted cancer cells experience an
energy crisis, which may ultimately result in cell death (Cea et al. 2012, Sharif et al. 2016, Tan
et al. 2015). The multifaceted roles of NAD+on energy production, DNA repair, antioxidant
defenses, and many other signal transduction pathways make this metabolite a gem-like substance
for cell survival and homeostasis. However, processes like DNA repair and energy metabolism
are also hijacked by cancer cells to enhance their survival and proliferation capacity without ac-
tivating cell death pathways, making NAD+a potential contributing factor for tumorigenesis as
well. Thus, maintaining NAD+at optimum levels throughout the lifespan might be essential to
prevent metabolic maladaptation, age-related neurodegeneration, and cancer formation. In sce-
narios which are at low risk for cancer development, such as in CS patients, the benefits of NAD+
precursor treatment would be predicted to largely outweigh the risks. Therefore, interventions
modulating NAD+levels should be considered with caution, as they may either promote or sup-
press cancer formation and progression, depending on the timing of treatment and biological
context.
COMMENTARY
NAD+metabolism serves as a central signaling hub that links numerous bioenergetic, redox,
transcription, and DNA repair processes. The reviewed evidence suggests that the metabolic
adaptation to cellular stressors encountered during the aging process may alter redox homeostasis
to facilitate the progression of cellular senescence or neoplastic transformation (Figure 3). The
recognition and increasing study of the diverse roles of NAD+metabolites may uncover novel
therapeutic targets for age-related pathologies and cancer. Moreover, while NAD+precursor
treatment is emerging as an efficacious intervention for the prevention of numerous age-related
pathologies, the therapeutic potential for NAD+precursors in cancer is not well understood. It
is possible in some instances that boosting NAD+metabolism could fuel cell proliferation and
exacerbate cancer progression and metastasis. On the other hand, supplementation with NAD+
precursors could also prevent or shift cancer cell metabolism in a favorable manner and decrease
uncontrolled proliferation. Therefore, the most optimal anticancer clinical strategy will likely
involve individual patient profiling to identify treatments with maximal efficacy for the particular
metabolic and genetic profile of the patient’s cancer.
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Metabolic stress
NADH
ATP
PAR
TCA
αKG
NADP+
NAD+
NAD+
NAD+
SASP immune regulation
NAM
eNAMPT
NMN
NAM
NADPH
Oxidative
phosphorylation
2-HG
HIF1α
Glycolysis
PA
NAD
+
DNA damage
Aging
SIRTs
Healthy aging
DNA repair
Redox
homeostasis
Tumorigenesis Senescence
ROS
LDHA NAD+/NADH
NADPH/NADP+
PAR Ps
CD38
NAD+
p21p53
Figure 3
Metabolic adaptation to cellular stress associated with aging dictates cell fate. ROS cause DNA damage, and
metabolic stress initiates alterations in metabolism and cell signaling pathways toward repair and the
restoration of redox homeostasis (teal). Failure to restore homeostasis can lead to a decline in metabolism
associated with cellular senescence (blue) or can upregulate tumorigenic metabolic pathways (purple), such as
glycolysis. Senescent cells also release inflammatory cytokines, which may also lead to tumor formation.
Abbreviations: 2-HG, D-2 hydroxyglutarate; αKG, α-ketoglutarate; eNAMPT, extracellular NAMPT;
HIF1α, hypoxia-inducible factor 1 alpha; IDH2, isocitrate dehydrogenase 2; LDHA, lactate dehydrogenase
A; NAD+, nicotinamide adenine dinucleotide; NAM, nicotinamide; NAMPT, nicotinamide
phosphoribosyltransferase; NMN, nicotinamide mononucleotide; PAR, poly(ADP-ribose); PARPs,
poly(ADP-ribose) polymerases; ROS, reactive oxygen species; SASP, secretory-associated senescence
phenotype; SIRTs, sirtuins; TCA, tricarboxylic acid cycle.
DISCLOSURE STATEMENT
The Bohr Laboratory has cooperative research and development agreements with ChromaDex to
study the effects of nicotinamide riboside (NR) supplementation on neurodegeneration.
ACKNOWLEDGMENTS
This research was supported by the Intramural Research Program of the NIH, National Institute
on Aging. We would like to thank Marc Raley for his assistance designing figures, and Kyle Hoban
and Jong-Hyuk Lee for their critical reading of the manuscript.
122 Demarest et al.
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Annual Review of
Cancer Biology
Volume 3, 2019
Contents
A Joint Odyssey into Cancer Genetics
Suzanne Cory and Jerry M. Adams ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp1
Targeting Therapies for the p53 Protein in Cancer Treatments
Arnold J. Levine ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp21
The Hallmarks of Ferroptosis
Scott J. Dixon and Brent R. Stockwell ppppppppppppppppppppppppppppppppppppppppppppppppppppppp35
Cancer Immunotherapy: Beyond Checkpoint Blockade
Michael Dougan, Glenn Dranoff, and Stephanie K. Dougan ppppppppppppppppppppppppppppppp55
Natural Killer Cells in Cancer Immunotherapy
Jeffrey S. Miller and Lewis L. Lanier pppppppppppppppppppppppppppppppppppppppppppppppppppppppp77
NAD+Metabolism in Aging and Cancer
Tyler G. Demarest, Mansi Babbar, Mustafa N. Okur, Xiuli Dan,
Deborah L. Croteau, Nima B. Fakouri, Mark P. Mattson, and Vilhelm A. Bohr ppp105
PARP Trapping Beyond Homologous Recombination and Platinum
Sensitivity in Cancers
Junko Murai and Yves Pommier ppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp131
Deciphering Human Tumor Biology by Single-Cell
Expression Profiling
Itay Tirosh and Mario L. Suv`appppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp151
Aberrant RNA Splicing in Cancer
Luisa Escobar-Hoyos, Katherine Knorr, and Omar Abdel-Wahab ppppppppppppppppppppppp167
Circulating Tumor DNA: Clinical Monitoring and Early Detection
Ryan B. Corcoran pppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppppp187
MiT/TFE Family of Transcription Factors, Lysosomes, and Cancer
Rushika M. Perera, Chiara Di Malta, and Andrea Ballabio ppppppppppppppppppppppppppppp203
Organoid Models for Cancer Research
Hans Clevers and David A. Tuveson ppppppppppppppppppppppppppppppppppppppppppppppppppppppp223
Resistance to PARP Inhibitors: Lessons from Preclinical Models of
BRCA-Associated Cancer
Ewa Gogola, Sven Rottenberg, and Jos Jonkers pppppppppppppppppppppppppppppppppppppppppppp235
Annu. Rev. Cancer Biol. 2019.3:105-130. Downloaded from www.annualreviews.org
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CA03-TOC ARI 15 January 2019 14:14
Dietary Fat and Sugar in Promoting Cancer Development
and Progression
Marcus D. Goncalves, Benjamin D. Hopkins, and Lewis C. Cantley pppppppppppppppppppp255
HSP90: Enabler of Cancer Adaptation
Alex M. Jaeger and Luke Whitesell pppppppppppppppppppppppppppppppppppppppppppppppppppppppp275
Biology and Therapy of Dominant Fusion Oncoproteins Involving
Transcription Factor and Chromatin Regulators in Sarcomas
Jennifer A. Perry, Bo Kyung Alex Seong, and Kimberly Stegmaier pppppppppppppppppppppp299
Roles of the cGAS-STING Pathway in Cancer Immunosurveillance
and Immunotherapy
Seoyun Yum, Minghao Li, Arthur E. Frankel, and Zhijian J. Chen pppppppppppppppppppp323
Functional Genomics for Cancer Research: Applications In Vivo
and In Vitro
Thomas A. O’Loughlin and Luke A. Gilbert pppppppppppppppppppppppppppppppppppppppppppppp345
Targeting Cancer at the Intersection of Signaling and Epigenetics
Stephanie Guerra and Karen Cichowski ppppppppppppppppppppppppppppppppppppppppppppppppppp365
Academic Discovery of Anticancer Drugs: Historic
and Future Perspectives
Alessandro Carugo and Giulio F. Draetta ppppppppppppppppppppppppppppppppppppppppppppppppp385
Aiding and Abetting: How the Tumor Microenvironment Protects
Cancer from Chemotherapy
Eleanor C. Fiedler and Michael T. Hemann pppppppppppppppppppppppppppppppppppppppppppppp409
Taming the Heterogeneity of Aggressive Lymphomas
for Precision Therapy
Ryan M. Young, James D. Phelan, Arthur L. Shaffer III,
George W. Wright, Da Wei Huang, Roland Schmitz, Calvin Johnson,
Thomas Oellerich, Wyndham Wilson, and Louis M. Staudt pppppppppppppppppppppppppp429
The Fanconi Anemia Pathway in Cancer
Joshi Niraj, Anniina F¨arkkil¨a, and Alan D. D’Andrea pppppppppppppppppppppppppppppppppp457
Errata
An online log of corrections to Annual Review of Cancer Biology articles may be found at
http://www.annualreviews.org/errata/cancerbio
Annu. Rev. Cancer Biol. 2019.3:105-130. Downloaded from www.annualreviews.org
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... Nicotinamide adenine dinucleotide (NAD + ) is an essential cofactor in cellular metabolic processes (Demarest et al., 2019). NAD + levels demonstrate age-related decline which is in turn linked to decline of mitochondrial and stem cell function (Zhang et al., 2016). ...
... In mitochondria, NADH (NAD + bound by hydrogen) generated in TCA cycle from NAD + is necessary for oxidative phosphorylation to produce ATP (Martínez-Reyes and Chandel, 2020). NAD + is also a substrate for NAD + -dependent enzymes that can be grouped in three main categories: poly (ADP-ribose) polymerases (PARPs), CD38, and sirtuins (Demarest et al., 2019). These NAD + -dependent enzymes results in breakdown of NAD + to cyclic ADP-ribose (ADPR) and nicotinamide (NAM, aka vitamin B3), and NAM is recycled into NAD + by the salvage NAD + synthesis pathway (Chiarugi et al., 2012). ...
Article
Full-text available
Nicotinamide adenine dinucleotide (NAD ⁺ ) is an essential molecule for living organisms. CD38 is a key NAD ⁺ -dependent enzyme which breaks down NAD ⁺ to cyclic ADP-ribose (ADPR) and nicotinamide (NAM, vitamin B3), and NAM can be recycled to synthesize NAD ⁺ . CD38 expression is consistently silenced by methylation in prostate cancer and progressively downregulated in advanced castration-resistant prostate cancer, suggesting a connection between NAD ⁺ and prostate carcinogenesis as well as prostate cancer progression. However, the functional interplay between NAD ⁺ , CD38, and NAM remains largely uncharacterized in prostate cancer cells. In this study, we generated stable LNCaP95 cell clones expressing varying levels of CD38 upon induction by doxycycline. We demonstrate that CD38 overexpression resulted in growth suppression and apoptosis accompanied by cleavage of poly (ADP-ribose) polymerase 1 (PARP1). CD38 overexpression also dramatically reduced intracellular NAD ⁺ levels and decreased mitochondrial respiration as measured by oxygen consumption rate. We further show that some but not all of these CD38-induced phenotypes could be rescued by exogenous NAM. Treatment of cells with NAM rescued CD38-induced apoptosis and mitochondrial stress but did not restore intracellular NAD ⁺ levels. We also found that NAM demonstrated biphasic effect on mitochondria function, a finding that can be explained by the dual role of NAM as both a precursor of NAD ⁺ and also as a suppressor of a number of NAD ⁺ -dependent enzymes. Collectively, these findings provide additional insight supporting the functional relevance of CD38 loss in prostate cancer by linking cell-autonomous regulation of mitochondrial function and prostate cancer.
... This is because cancer metabolism-related agents can potentially enhance the therapeutic effect when combined with conventional chemotherapies [6,7]. Recently, the biochemical pathway of nicotinamide adenine dinucleotide (NAD) has received much attention among these cancer metabolism researches [8][9][10][11][12][13][14]. The NAD is a major co-enzyme of glyceraldehyde-3-phosphate dehydrogenase (G3PDH) in glycolysis, a major glucose metabolic pathway in cancer cells, and is also involved in tricarboxylic acid (TCA) cycle and oxidative phosphorylation in cancer cells [15,16]. ...
... There are three types of biochemical pathways in NAD such as de novo, preiss-handler, and salvage pathways. Among them, the salvage pathway consists of two-step pathway in which NAD is first synthesized from nicotinamide (NAM) to nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyltransferase (NAMPT) enzyme followed by NMN to NAD by nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme [8][9][10][11]. In this two-step pathway, the reaction of NAMPT is mainly the rate-limiting step, and the high levels of NAD are observed in many chemotherapy-resistant cancer cells due to over-expression of the corresponding enzyme [8,10,18,19]. ...
Article
Daporinad (FK866) is one of the highly specific inhibitors of nicotinamide phosphoribosyl transferase (NAMPT) and known to have its unique mechanism of action that induces the tumor cell apoptosis. In this study, a simple and sensitive liquid chromatography-quadrupole-time-of-flight-mass spectrometric (LC-qTOF-MS) assay has been developed for the evaluation of drug metabolism and pharmacokinetics (DMPK) properties of Daporinad in mice. A simple protein precipitation method using acetonitrile (ACN) was used for the sample preparation and the pre-treated samples were separated by a C18 column. The calibration curve was evaluated in the range of 1.02~2220 ng/mL and the quadratic regression (weighted 1/concentration2) was used for the best fit of the curve with a correlation coefficient ≥ 0.99. The qualification run met the acceptance criteria of ±25% accuracy and precision values for QC samples. The dilution integrity was verified for 5, 10 and 30-fold dilution and the accuracy and precision of the dilution QC samples were also satisfactory within ±25% of the nominal values. The stability results indicated that Daporinad was stable for the following conditions: short-term (4 h), long-term (2 weeks), freeze/thaw (three cycles). This qualified method was successfully applied to intravenous (IV) pharmacokinetic (PK) studies of Daporinad in mice at doses of 5, 10 and 30 mg/kg. As a result, it showed a linear PK tendency in the dose range from 5 to 10 mg/kg, but a non-linear PK tendency in the dose of 30 mg/kg. In addition, in vitro and in vivo metabolite identification (Met ID) studies were conducted to understand the PK properties of Daporinad and the results showed that a total of 25 metabolites were identified as ten different types of metabolism in our experimental conditions. In conclusion, the LC-qTOF-MS assay was successfully developed for the quantification of Daporinad in mouse plasma as well as for its in vitro and in vivo metabolite identification.
... Just like Sir2 in RLS, phosphoenolpyruvate carboxykinase (Pck1), increases CLS and enhances gluconeogenesis (Orlandi et al. 2017). Addition of NAD precursors in yeast CLS is envisioned to involve mechanisms that would unravel metabolic pathways affecting CLS and secondly, identifying biochemical strategies governing the decline of NAD levels in aged cells Demarest et al. 2019). ...
Article
Full-text available
Molecular causes of aging and longevity interventions have witnessed an upsurge in the last decade. The resurgent interests in the application of small molecules as potential geroprotectors and/or pharmacogenomics point to nicotinamide adenine dinucleotide (NAD) and its precursors, nicotinamide riboside, nicotinamide mononucleotide, nicotinamide, and nicotinic acid as potentially intriguing molecules. Upon supplementation, these compounds have shown to ameliorate aging related conditions and possibly prevent death in model organisms. Besides being a molecule essential in all living cells, our understanding of the mechanism of NAD metabolism and its regulation remain incomplete owing to its omnipresent nature. Here we discuss recent advances and techniques in the study of chronological lifespan (CLS) and replicative lifespan (RLS) in the model unicellular organism Saccharomyces cerevisiae. We then follow with the mechanism and biology of NAD precursors and their roles in aging and longevity. Finally, we review potential biotechnological applications through engineering of microbial lifespan, and laid perspective on the promising candidature of alternative redox compounds for extending lifespan.
... Drugs combating NAD + depletion NAD + has been shown to play a unique role in aging through DNA repair and epigenetics [72]. The flavonoids luteolinidin and luteolin are able to inhibit the enzyme CD38 which is responsible for the age-related depletion of NAD + in cells [73]. ...
Article
Geroprotectors slow down aging and promote healthy longevity in model animals. Although hundreds of compounds have been shown to extend the life of laboratory model organisms, clinical studies on potential geroprotectors are exceedingly rare, especially in healthy elders. This review aims to classify potential geroprotectors based on the mechanisms by which they influence aging. These pharmacological interventions can be classified into the following groups: those that prevent oxidation; proteostasis regulators; suppressors of genomic instability; epigenetic drugs; those that preserve mitochondrial function; inhibitors of aging-associated signaling pathways; hormetins; senolytics/senostatics; anti-inflammatory drugs; antifibrotic agents; neurotrophic factors; factors preventing the impairment of barrier function; immunomodulators; and prebiotics, metabiotics, and enterosorbents.
... Numerous pre-clinical studies have shown the CRM-like properties of these precursors upon supplementation, which can prolong life-and healthspan, promote mitochondrial function, induce autophagy and act cardioprotective and neuroprotective, among others (77,(153)(154)(155)(156)(157). NAD + concentrations decline with age (156,158) and replenishing these levels harbors therapeutic potential in humans (157,(159)(160)(161)(162)(163)(164). ...
Article
Full-text available
The human diet and dietary patterns are closely linked to the health status. High-calorie Western-style diets have increasingly come under scrutiny as their caloric load and composition contribute to the development of non-communicable diseases, such as diabetes, cancer, obesity, and cardiovascular disorders. On the other hand, calorie-reduced and health-promoting diets have shown promising results in maintaining health and reducing disease burden throughout aging. More recently, pharmacological Caloric Restriction Mimetics (CRMs) have gained interest of the public and scientific community as promising candidates that mimic some of the myriad of effects induced by caloric restriction. Importantly, many of the CRM candidates activate autophagy, prolong life- and healthspan in model organisms and ameliorate diverse disease symptoms without the need to cut calories. Among others, glycolytic inhibitors (e.g., D-allulose, D-glucosamine), hydroxycitric acid, NAD+ precursors, polyamines (e.g., spermidine), polyphenols (e.g., resveratrol, dimethoxychalcones, curcumin, EGCG, quercetin) and salicylic acid qualify as CRM candidates, which are naturally available via foods and beverages. However, it is yet unclear how these bioactive substances contribute to the benefits of healthy diets. In this review, we thus discuss dietary sources, availability and intake levels of dietary CRMs. Finally, since translational research on CRMs has entered the clinical stage, we provide a summary of their effects in clinical trials.
Article
Adult neurogenesis, the process by which neurons are generated in certain areas of the adult brain, declines in an age-dependent manner and is one potential target for extending cognitive healthspan. Aging is a major risk factor for neurodegenerative diseases and, as lifespans are increasing, these health challenges are becoming more prevalent. An age-associated loss in neural stem cell number and/or activity could cause this decline in brain function, so interventions that reverse aging in stem cells might increase the human cognitive healthspan. In this review, we describe the involvement of adult neurogenesis in neurodegenerative diseases and address the molecular mechanistic aspects of neurogenesis that involve some of the key aggregation-prone proteins in the brain (i.e., tau, Aβ, α-synuclein, …). We summarize the research pertaining to interventions that increase neurogenesis and regulate known targets in aging research, such as mTOR and sirtuins. Lastly, we share our outlook on restoring the levels of neurogenesis to physiological levels in elderly individuals and those with neurodegeneration. We suggest that modulating neurogenesis represents a potential target for interventions that could help in the fight against neurodegeneration and cognitive decline.
Chapter
In most solid tumors, malignant cells coexist with non-cancerous host tissue comprised of a variety of extracellular matrix components and cell types, notably fibroblasts, immune cells, and endothelial cells. It is becoming increasingly evident that the non-cancerous host tissue, often referred to as the tumor stroma or the tumor microenvironment, wields tremendous influence in the proliferation, survival, and metastatic ability of cancer cells. The tumor stroma has an active biological role in the transmission of signals, such as growth factors and chemokines that activate oncogenic signaling pathways by autocrine and paracrine mechanisms. Moreover, the constituents of the stroma define the mechanical properties and the physical features of solid tumors, which influence cancer progression and response to therapy. Inspired by the emerging importance of tumor-stroma crosstalk and oncogenic physical forces, numerous biosensors, or advanced imaging and analysis techniques have been developed and applied to investigate complex and challenging questions in cancer research. These techniques facilitate measurements and biological readouts at scales ranging from subcellular to tissue-level with unprecedented level of spatial and temporal precision. Here we examine the application of biosensor technology for studying the complex and dynamic multiscale interactions of the tumor-host system.
Article
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Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on the safety of an extension of use of the novel food (NF) nicotinamide riboside chloride (NRC) pursuant to Regulation (EU) 2015/2283. The assessment addresses the use of NRC in 'meal replacement products' and 'nutritional drink mixes' at levels up to 300 mg/day for the general population, and in food for special medical purposes (FSMP) and total diet replacement for weight control (TDRWC) (as per Regulation (EU) No 609/2013) at levels up to 500 mg/day in adults. Benchmark dose modelling was carried out on data from the 90-day oral toxicity studies in rats relevant to the safety assessment. Considering the lack of tolerable upper intake level (UL) for nicotinamide in infants and the narrow margin of exposure between the estimated intake in infants and the lower confidence bound of the benchmark doses (BMDL 05) estimated by the models, the Panel concludes that the safety of the NF has not been established for use in 'meal replacement products' and 'nutritional drink mixes' under the proposed conditions of use. For FSMP and TDRWC, the proposed maximum use level corresponds to an intake of 210 mg nicotinamide per day, which is below the current UL for nicotinamide of 900 mg/day for adults. The Panel considers that the NF is as safe as pure nicotinamide for use in FSMP and TDRWC. The Panel, however, notes experimental data which indicate several pathways by which intakes of nicotinamide (or its precursors), at levels that are substantially higher than the physiological requirement, might cause adverse effects. The Panel considers that further investigations are required and that a re-evaluation of the UL for nicotinamide may be warranted.
Article
NAD⁺ is a fundamental molecule in human life and health as it participates in energy metabolism, cell signalling, mitochondrial homeostasis, and in dictating cell survival or death. Emerging evidence from preclinical and human studies indicates an age-dependent reduction of cellular NAD⁺, possibly due to reduced synthesis and increased consumption. In preclinical models, NAD⁺ repletion extends healthspan and / or lifespan and mitigates several conditions, such as premature ageing diseases and neurodegenerative diseases. These findings suggest that NAD⁺ replenishment through NAD⁺ precursors has great potential as a therapeutic target for ageing and age-predisposed diseases, such as Alzheimer’s disease. Here, we provide an updated review on the biological activity, safety, and possible side effects of NAD⁺ precursors in preclinical and clinical studies. Major NAD⁺ precursors focused on by this review are nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and the new discovered dihydronicotinamide riboside (NRH). In summary, NAD⁺ precursors have an exciting therapeutic potential for ageing, metabolic and neurodegenerative diseases.
Article
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Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.
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