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NAD + Metabolism in Aging and Cancer

March 2019
Annual Review of Cancer Biology 3(1)

DOI:10.1146/annurev-cancerbio-030518-055905

Authors:

Tyler G Demarest

Spark Therapeutics, Inc.

Mansi Babbar

National Institutes of Health

Nazir Oku.

Xiuli Dan

National Institutes of Health

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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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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).

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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

NAMN

QPRT

NRK1/2

NAR

NAPRT

NA NMNAT1–3

NAAD

NADS NAD+

NMN

NADH

SIRTs/PARPs

NMNAT1–3 NAMPT

(poly)ADPr

NRK1/2

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 )

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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+

SASP immune regulation

NAM

eNAMPT

NMN

NAM

NADPH

Oxidative

phosphorylation

2-HG

HIF1α

Glycolysis

NAD

NAM

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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CA03CH06_Bohr ARI 12 January 2019 11:26

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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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CD38-Induced Apoptosis and Mitochondrial Damage is Restored by Nicotinamide in Prostate Cancer

Article

Full-text available

May 2022

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.

Quantitative Analysis of Daporinad (FK866) and Its In Vitro and In Vivo Metabolite Identification Using Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometry

Article

Mar 2022
MOLECULES

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.

The role of NAD and NAD precursors on longevity and lifespan modulation in the budding yeast, Saccharomyces cerevisiae

Article

Full-text available

Apr 2022
BIOGERONTOLOGY

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.

Targeting aging mechanisms: pharmacological perspectives

Article

Feb 2022
TRENDS ENDOCRIN MET

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.

Caloric Restriction Mimetics in Nutrition and Clinical Trials

Article

Full-text available

Sep 2021

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.

Two Photon Fluorescence Lifetime Imaging of Reduced Nicotinamide Adenine Dinucleotide in Brain Research

Chapter

Jan 2022

Neurogenesis in Aging and Age-related Neurodegenerative Diseases

Article

Apr 2022

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.

Molecular sensors for detection of tumor-stroma crosstalk

Chapter

Feb 2022
ADV CANCER RES

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.

Extension of use of nicotinamide riboside chloride as a novel food pursuant to Regulation (EU) 2015/2283

Article

Full-text available

Nov 2021

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.

Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing

Article

Sep 2021
MECH AGEING DEV

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.

Senolytics improve physical function and increase lifespan in old age

Article

Full-text available

Aug 2018
NAT MED

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.

NAD + supplementation normalizes key Alzheimer’s features and DNA damage responses in a new AD mouse model with introduced DNA repair deficiency

Article

Full-text available

Feb 2018

Emerging findings suggest that compromised cellular bioenergetics and DNA repair contribute to the pathogenesis of Alzheimer’s disease (AD), but their role in disease-defining pathology is unclear. We developed a DNA repair-deficient 3xTgAD/Polβ+/− mouse that exacerbates major features of human AD including phosphorylated Tau (pTau) pathologies, synaptic dysfunction, neuronal death, and cognitive impairment. Here we report that 3xTgAD/Polβ+/− mice have a reduced cerebral NAD⁺/NADH ratio indicating impaired cerebral energy metabolism, which is normalized by nicotinamide riboside (NR) treatment. NR lessened pTau pathology in both 3xTgAD and 3xTgAD/Polβ+/− mice but had no impact on amyloid β peptide (Aβ) accumulation. NR-treated 3xTgAD/Polβ+/− mice exhibited reduced DNA damage, neuroinflammation, and apoptosis of hippocampal neurons and increased activity of SIRT3 in the brain. NR improved cognitive function in multiple behavioral tests and restored hippocampal synaptic plasticity in 3xTgAD mice and 3xTgAD/Polβ+/− mice. In general, the deficits between genotypes and the benefits of NR were greater in 3xTgAD/Polβ+/− mice than in 3xTgAD mice. Our findings suggest a pivotal role for cellular NAD⁺ depletion upstream of neuroinflammation, pTau, DNA damage, synaptic dysfunction, and neuronal degeneration in AD. Interventions that bolster neuronal NAD⁺ levels therefore have therapeutic potential for AD.

Beyond Brooding on Oncometabolic Havoc in IDH-Mutant Gliomas and AML: Current and Future Therapeutic Strategies

Article

Full-text available

Feb 2018

Isocitrate dehydrogenases 1 and 2 (IDH1,2), the key Krebs cycle enzymes that generate NADPH reducing equivalents, undergo heterozygous mutations in >70% of low- to mid-grade gliomas and ~20% of acute myeloid leukemias (AMLs) and gain an unusual new activity of reducing the α-ketoglutarate (α-KG) to D-2 hydroxyglutarate (D-2HG) in a NADPH-consuming reaction. The oncometabolite D-2HG, which accumulates >35 mM, is widely accepted to drive a progressive oncogenesis besides exacerbating the already increased oxidative stress in these cancers. More importantly, D-2HG competes with α-KG and inhibits a large number of α-KG-dependent dioxygenases such as TET (Ten-eleven translocation), JmjC domain-containing KDMs (histone lysine demethylases), and the ALKBH DNA repair proteins that ultimately lead to hypermethylation of the CpG islands in the genome. The resulting CpG Island Methylator Phenotype (CIMP) accounts for major gene expression changes including the silencing of the MGMT (O6-methylguanine DNA methyltransferase) repair protein in gliomas. Glioma patients with IDH1 mutations also show better therapeutic responses and longer survival, the reasons for which are yet unclear. There has been a great surge in drug discovery for curtailing the mutant IDH activities, and arresting tumor proliferation; however, given the unique and chronic metabolic effects of D-2HG, the promise of these compounds for glioma treatment is uncertain. This comprehensive review discusses the biology, current drug design and opportunities for improved therapies through exploitable synthetic lethality pathways, and an intriguing oncometabolite-inspired strategy for primary glioblastoma.

Sirtuin5 contributes to colorectal carcinogenesis by enhancing glutaminolysis in a deglutarylation-dependent manner

Article

Full-text available

Feb 2018

Reversible post-translational modifications represent a mechanism to control tumor metabolism. Here we show that mitochondrial Sirtuin5 (SIRT5), which mediates lysine desuccinylation, deglutarylation, and demalonylation, plays a role in colorectal cancer (CRC) glutamine metabolic rewiring. Metabolic profiling identifies that deletion of SIRT5 causes a marked decrease in 13C-glutamine incorporation into tricarboxylic-acid (TCA) cycle intermediates and glutamine-derived non-essential amino acids. This reduces the building blocks required for rapid growth. Mechanistically, the direct interaction between SIRT5 and glutamate dehydrogenase 1 (GLUD1) causes deglutarylation and functional activation of GLUD1, a critical regulator of cellular glutaminolysis. Consistently, GLUD1 knockdown diminishes SIRT5-induced proliferation, both in vivo and in vitro. Clinically, overexpression of SIRT5 is significantly correlated with poor prognosis in CRC. Thus, SIRT5 supports the anaplerotic entry of glutamine into the TCA cycle in malignant phenotypes of CRC via activating GLUD1.

Boolean analysis identifies CD38 as a biomarker of aggressive localized prostate cancer

Article

Full-text available

Jan 2018

The introduction of serum Prostate Specific Antigen (PSA) testing nearly 30 years ago has been associated with a significant shift towards localized disease and decreased deaths due to prostate cancer. Recognition that PSA testing has caused over diagnosis and over treatment of prostate cancer has generated considerable controversy over its value, and has spurred efforts to identify prognostic biomarkers to distinguish patients who need treatment from those that can be observed. Recent studies show that cancer is heterogeneous and forms a hierarchy of tumor cell populations. We developed a method of identifying prostate cancer differentiation states related to androgen signaling using Boolean logic. Using gene expression data, we identified two markers, CD38 and ARG2, that group prostate cancer into three differentiation states. Cancers with CD38-, ARG2- expression patterns, corresponding to an undifferentiated state, had significantly lower 10-year recurrence-free survival compared to the most differentiated group (CD38+ARG2+). We carried out immunohistochemical (IHC) staining for these two markers in a single institution (Stanford; n = 234) and multi-institution (Canary; n = 1326) cohorts. IHC staining for CD38 and ARG2 in the Stanford cohort demonstrated that combined expression of CD38 and ARG2 was prognostic. In the Canary cohort, low CD38 protein expression by IHC was significantly associated with recurrence-free survival (RFS), seminal vesicle invasion (SVI), extra-capsular extension (ECE) in univariable analysis. In multivariable analysis, ARG2 and CD38 IHC staining results were not independently associated with RFS, overall survival, or disease-specific survival after adjusting for other factors including SVI, ECE, Gleason score, pre-operative PSA, and surgical margins.

CSB: An Emerging Actionable Target for Cancer Therapy

Article

Feb 2018

The DNA repair protein Cockayne syndrome group B (CSB) is frequently found overexpressed in cancer cells. High CSB levels favor tumor cell proliferation whilst inhibiting apoptosis. Conversely, the suppression of CSB has significant anticancer effects. In this manuscript we describe CSB downregulation as a potential new therapeutic approach in cancer.

Identification of the Nicotinamide Salvage Pathway as a New Toxification Route for Antimetabolites

Article

Feb 2018
CHEM BIOL

Interest in the modulation of nicotinamide adenine dinucleotide (NAD) metabolome is gaining great momentum because of its therapeutic potential in different human disorders. Suppression of nicotinamide salvage by nicotinamide phosphoribosyl transferase (NAMPT) inhibitors, however, gave inconclusive results in neoplastic patients because several metabolic routes circumvent the enzymatic block converging directly on nicotinamide mononucleotide adenylyl transferases (NMNATs) for NAD synthesis. Unfortunately, NMNAT inhibitors have not been identified. Here, we report the identification of Vacor as a substrate metabolized by the consecutive action of NAMPT and NMNAT2 into the NAD analog Vacor adenine dinucleotide (VAD). This leads to inhibition of both enzymes, as well as NAD-dependent dehydrogenases, thereby causing unprecedented rapid NAD depletion, glycolytic block, energy failure, and necrotic death of NMNAT2-proficient cancer cells. Conversely, lack of NMNAT2 expression confers complete resistance to Vacor. Remarkably, Vacor prompts VAD formation and growth suppression in NMNAT2-positive neuroblastoma and melanoma xenografts. Our data show the first evidence of harnessing the entire nicotinamide salvage pathway for antimetabolic strategies.

The Pharmacology of CD38/NADase: An Emerging Target in Cancer and Diseases of Aging

Article

Feb 2018
TRENDS PHARMACOL SCI

Recent reports indicate that intracellular NAD levels decline in tissues during chronological aging, and that therapies aimed at increasing cellular NAD levels could have beneficial effects in many age-related diseases. The protein CD38 (cluster of differentiation 38) is a multifunctional enzyme that degrades NAD and modulates cellular NAD homeostasis. At the physiological level, CD38 has been implicated in the regulation of metabolism and in the pathogenesis of multiple conditions including aging, obesity, diabetes, heart disease, asthma, and inflammation. Interestingly, many of these functions are mediated by CD38 enzymatic activity. In addition, CD38 has also been identified as a cell-surface marker in hematologic cancers such as multiple myeloma, and a cytotoxic anti-CD38 antibody has been approved by the FDA for use in this disease. Although this is a remarkable development, killing CD38-positive tumor cells with cytotoxic anti-CD38 antibodies is only one of the potential pharmacological uses of targeting CD38. The present review discusses the biology of the CD38 enzyme and the current state of development of pharmacological tools aimed at CD38, and explores how these agents may represent a novel approach for treating human conditions including cancer, metabolic disease, and diseases of aging.

HBx-elevated SIRT2 promotes HBV replication and hepatocarcinogenesis

Article

Jan 2018
BIOCHEM BIOPH RES CO

Sirtuin 2 (SIRT2) is a class III histone deacetylase that has been implicated to promote HCC development. However, the functional role of SIRT2 in HBV is still unclear. In this study, we found that HBV could upregulate SIRT2 expression. Additionally, HBx could activate SIRT2 promoter to upregulate the mRNA and protein level of SIRT2. Furthermore, we found that SIRT2 could facilitate HBV transcription and replication. Finally, we demonstrated that upregulation of SIRT2 by HBx promoted hepatocarcinogenesis. In summary, our findings revealed a novel function of SIRT2 in HBV and HBV-mediated HCC. First, SIRT2 could promote HBV replication. And then HBx-elevated SIRT2 could enhance the transformation of HBV-mediated HCC. Those findings highlight the potential role of SIRT2 in HBV and HBV-mediated HCC by interaction with HBx.

SIRT6 expression and oxidative DNA damage in individuals with prediabetes and type 2 diabetes mellitus

Article

Feb 2018
GENE

Sirtuins (SIRTs) is a family of NAD⁺ dependent histone deacetylases. SIRT6 takes play in glucose homeostasis, genomic stability and DNA repair. Although increased oxidative DNA damage and decreased DNA repair activity were determined in diabetes mellitus, the possible relation between level of oxidative DNA damage and SIRT6 expression has not been investigated so far. We determined SIRT6 expression and urinary 8-hydroxy deoxyguanosine (8-OHdG) levels, marker of oxidative DNA damage, in cases with prediabetes (PreDM) and type 2 diabetes mellitus (T2DM). SIRT6 gene expression was determined in peripheral blood leukocytes of 70 patients with type 2 diabetes, 50 cases in prediabetic stage and 40 healthy subjects. SIRT6 mRNA levels were determined by quantitive real time- polymerase chain reaction. SIRT6 protein was detected by immunocytochemical staining. Urinary 8-hydroxy deoxyguanosine (8-OHdG) levels were measured by ELISA. There was no significant difference between groups for SIRT6 mRNA level. SIRT6 immunopositivity in T2DM group was lower when compared to those in preDM group (P < 0.05). SIRT6 positive cell number in T2DM and preDM groups were lower in comparison to control group (P < 0.01 for both), however, when study groups were subdivided into two groups according to their age, the difference between preDM and control groups disappeared in both mid-aged and old-aged groups. The urinary 8-OHdG level was found to be higher in the T2DM group in comparison to preDM group (P < 0.05). When age is taken into consideration, urinary 8-OHdG level in the T2DM group was found to be higher than those in both preDM and control groups in the old-aged cases but no significant difference was determined between groups in the mid-aged cases. There was no relation between SIRT6 expression and urinary 8-OHDG excretion. It was concluded that SIRT6 may take play in development of T2DM but this effect seems to be independent from repair of oxidative DNA damage.

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