NAD+ and sirtuins in aging and disease

doi:10.1016/j.tcb.2014.04.002

Trends in Cell Biology

Volume 24, Issue 8, August 2014, Pages 464-471

https://doi.org/10.1016/j.tcb.2014.04.002 Get rights and content

Highlights

•
NAD⁺ plays a key role in regulating metabolism and circadian rhythm through sirtuins.
•
NAD⁺ becomes limiting during aging, affecting sirtuins’ activities.
•
NAD⁺ decline is likely to be due to a NAD⁺ biosynthesis defect and increased depletion.
•
Supplementing key NAD⁺ intermediates can restore NAD⁺ levels and ameliorate age-associated pathophysiologies.

Nicotinamide adenine dinucleotide (NAD⁺) is a classical coenzyme mediating many redox reactions. NAD⁺ also plays an important role in the regulation of NAD⁺-consuming enzymes, including sirtuins, poly-ADP-ribose polymerases (PARPs), and CD38/157 ectoenzymes. NAD⁺ biosynthesis, particularly mediated by nicotinamide phosphoribosyltransferase (NAMPT), and SIRT1 function together to regulate metabolism and circadian rhythm. NAD⁺ levels decline during the aging process and may be an Achilles’ heel, causing defects in nuclear and mitochondrial functions and resulting in many age-associated pathologies. Restoring NAD⁺ by supplementing NAD⁺ intermediates can dramatically ameliorate these age-associated functional defects, counteracting many diseases of aging, including neurodegenerative diseases. Thus, the combination of sirtuin activation and NAD⁺ intermediate supplementation may be an effective antiaging intervention, providing hope to aging societies worldwide.

Section snippets

NAD⁺ as an essential compound for many enzymatic processes

NAD⁺ was discovered more than a century ago by Sir Arthur Harden, as a low molecular weight substance present in a boiled yeast extract that could stimulate fermentation and alcohol production in vitro [1]. Subsequent studies over the next several decades determined that the structure of NAD⁺ comprised two covalently joined mononucleotides [nicotinamide mononucleotide (NMN) and AMP] and identified the keystone function of NAD⁺ and NADH as enzyme cofactors mediating hydrogen transfer in

NAD⁺ plays a key role in regulating metabolism and circadian rhythm

The canonical role of NAD⁺, mentioned above, is to facilitate hydrogen transfer in key metabolic pathways (Figure 1A). For example, NAD⁺ is converted to NADH in the glyceraldehyde 3-phosphate dehydrogenase step of glycolysis, a pathway in which glucose is converted to pyruvate. Conversion of NAD⁺ to NADH is also important in mitochondrial metabolism. In that compartment, NAD⁺ is converted to NADH in four steps of the mitochondrial tricarboxylic acid (TCA) cycle, in which acetyl-coenzyme A (CoA)

NAD⁺ declines with aging and can be restored by supplementation with NAD⁺ precursors

Several studies have reported that the activity of sirtuins decays with aging 26, 35, 36. The mammalian Sir2 ortholog SIRT1 can be regulated by many mechanisms, including transcriptionally, post-translationally by changes in stability, phosphorylation, and SIRT1-binding proteins, and by changes in NAD⁺ levels [14]. Of these mechanisms regulating SIRT1, a systemic decline in NAD⁺ has emerged as a likely explanation for why aging affects sirtuins. The decline in NAD⁺ was first noticed in

Possible mechanisms for how NAD⁺ levels decline in aging

Why do NAD⁺ levels decline with aging? One possibility is that one or more of the NAD⁺ biosynthetic pathways decline. There is some evidence that levels of NAMPT decline during aging [37], whereas exercise training has the opposite effect, at least in skeletal muscle [42]. Moreover, as discussed above, NAMPT is a major output of the circadian transcription factors BMAL and CLOCK. If the activity of the circadian machinery systemically declined with aging, as appears to be the case in the SCN

Mitochondria as a common target of aging-induced NAD⁺ decline

It is now clear that aging-induced inactivation of SIRT1 has a direct and deleterious effect on mitochondria, as first suggested by the important associations between SIRT1 and PGC-1α [48] and SIRT1 and TFAM [35]. A reduction in SIRT1 activity downregulates mitochondrial biogenesis, oxidative metabolism, and associated antioxidant defense pathways, leading to damage to complex I of the electron transport chain and a decline in mitochondrial function (Figure 4, right). A similar effect could

Prospects for treating neurodegenerative diseases?

Transgenic mice overexpressing SIRT1 throughout the body have been shown to counteract detrimental effects of energy-dense diet and aging and also mimic some physiological phenotypes induced by DR [11]. Furthermore, SIRT1 transgenic mice overexpressing this protein in the brain are protected in mouse models of Alzheimer's disease 53, 54, Parkinson's disease [55], and Huntington's disease 56, 57. In another mouse model, Wallerian degeneration slow (WldS) mice owe their heightened protection

Concluding remarks

Recent studies have indicated that NAD⁺ decline may drive aging through decreased sirtuin activities in the nucleus and mitochondria. NAD⁺ decline might be caused by the defect in NAMPT-mediated NAD⁺ biosynthesis and the PARP-mediated depletion of NAD⁺, both of which appear to occur during the aging process and perhaps in age-associated diseases, including neurodegenerative diseases. Supplementation of key NAD⁺ intermediates, such as NMN and NR, can ameliorate various age-associated

Disclaimer statement

S.I. had a sponsored research agreement with Oriental Yeast Co., Japan and is a cofounder of Metro Midwest Biotech. L.G. consults for GlaxoSmithKline, Chronos, Segterra, and Elysium Health.

Acknowledgments

The authors apologize to those whose work is not cited due to space limitations. They thank members of the Imai laboratory and the Guarente laboratory for critical discussions and suggestions. S.I. is supported by grants from the National Institute on Aging (AG024150, AG037457). L.G. is supported by the Glenn Foundation for Medical Research and grants from the National Institutes of Health.

References (71)

F. Berger
The new life of a centenarian: signalling functions of NAD(P)
Trends Biochem. Sci.
(2004)
P. Chambon
Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme
Biochem. Biophys. Res. Commun.
(1963)
H.A. Krebs et al.
Equilibrium relations between pyridine nucleotides and adenine nucleotides and their roles in the regulation of metabolic processes
Adv. Enzyme Regul.
(1969)
S. Imai
Dissecting systemic control of metabolism and aging in the NAD world: the importance of SIRT1 and NAMPT-mediated NAD biosynthesis
FEBS Lett.
(2011)
R.I. Tennen et al.
Chromatin regulation and genome maintenance by mammalian SIRT6
Trends Biochem. Sci.
(2011)
K.K. Banerjee
dSir2 in the adult fat body, but not in muscles, regulates life span in a diet-dependent manner
Cell Rep.
(2012)
L. Mouchiroud
The NAD⁺/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling
Cell
(2013)
A. Satoh
Sirt1 Extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH
Cell Metab.
(2013)
G. Asher
SIRT1 regulates circadian clock gene expression through PER2 deacetylation
Cell
(2008)
Y. Nakahata
The NAD⁺-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control
Cell
(2008)

H.C. Chang et al.

SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging

Cell

(2013)

S. Imai

“Clocks” in the NAD world: NAD as a metabolic oscillator for the regulation of metabolism and aging

Biochim. Biophys. Acta

(2010)

P. Aksoy

Regulation of intracellular levels of NAD: a novel role for CD38

Biochem. Biophys. Res. Commun.

(2006)

G.S. Young

Decreased cADPR and increased NAD⁺ in the Cd38^−/− mouse

Biochem. Biophys. Res. Commun.

(2006)

H.C. Lee

Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) as messengers for calcium mobilization

J. Biol. Chem.

(2012)

A.P. Gomes

Declining NAD⁺ induces a pseudohypoxic state disrupting nuclear–mitochondrial communication during aging

Cell

(2013)

J. Yoshino

Nicotinamide mononucleotide, a key NAD⁺ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice

Cell Metab.

(2011)

P. Belenky

Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD⁺

Cell

(2007)

P. Bieganowski et al.

Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss–Handler independent route to NAD⁺ in fungi and humans

Cell

(2004)

C. Canto

The NAD⁺ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity

Cell Metab.

(2012)

G. Karamanlidis

Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure

Cell Metab.

(2013)

T. Singh et al.

Inflammatory markers in population studies of aging

Ageing Res. Rev.

(2011)

P. Bai

PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation

Cell Metab.

(2011)

A. Berdichevsky

C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span

Cell

(2006)

G. Donmez

SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10

Cell

(2010)

U. Rass

Defective DNA repair and neurodegenerative disease

Cell

(2007)

B. Gong

Nicotinamide riboside restores cognition through an upregulation of proliferator-activated receptor-gamma coactivator 1alpha regulated beta-secretase 1 degradation and mitochondrial gene expression in Alzheimer's mouse models

Neurobiol. Aging

(2013)

Y. Wang et al.

Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO

Mech. Ageing Dev.

(2006)

M. Gellert

Joining of DNA strands by DNA ligase of E. coli

Cold Spring Harb. Symp. Quant. Biol.

(1968)

A. De Flora

Autocrine and paracrine calcium signaling by the CD38/NAD⁺/cyclic ADP-ribose system

Ann. N. Y. Acad. Sci.

(2004)

S. Imai

Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase

Nature

(2000)

S-J. Lin

Calorie restriction extends yeast life span by lowering the level of NADH

Genes Dev.

(2004)

S. Imai et al.

The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing

Diabetes Obes. Metab.

(2013)

N. Curtin

PARP inhibitors for anticancer therapy

Biochem. Soc. Trans.

(2014)

M.C. Haigis et al.

Mammalian sirtuins: biological insights and disease relevance

Annu. Rev. Pathol.

(2010)

Cited by (953)

In the land of not-unhappiness: On the state-of-the-art of targeting aging and age-related diseases by biomedical research
2024, Mechanisms of Ageing and Development
The concept of the Land of Not-Unhappiness refers to the potential achievement of eliminating the pathologies of the aging process. To inform of how close we are to settling in the land, we summarize and review the achievements of research on anti-aging interventions over the last hundred years with a specific focus on strategies that slow down metabolism, compensate for aging-related losses, and target a broad range of age-related diseases. We critically evaluate the existing interventions labeled as "anti-aging," such as calorie restriction, exercise, stem cell administration, and senolytics, to provide a down-to-earth evaluation of their current applicability in counteracting aging. Throughout the text, we have maintained a light tone to make it accessible to non-experts in biogerontology, and provide a broad overview for those considering conducting studies, research, or seeking to understand the scientific basis of anti-aging medicine.
SIRT1 activation ameliorates rhesus monkey liver fibrosis by inhibiting the TGF-β/smad signaling pathway
2024, Chemico-Biological Interactions
TGF-β/Smad signaling pathway plays an important role in the pathogenesis and progression of liver fibrosis. Silent information regulator 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+) dependent enzyme and responsible for deacetylating the proteins. Increasing numbers of reports have shown that the molecular mechanism of SIRT1 as an effective therapeutic target for liver fibrosis but the transformation is not very clear. In the present study, liver fibrotic tissues were screened by staining with Masson, hematoxylin-eosin staining (H&E) and Immunohistochemistry (IHC) for histopathological observation from the liver biopsy of seventy-seven rhesus monkey, which fixed with 4% paraformaldehyde (PFA) after treatment with high-fat diet (HFD) for two years. And the liver function was further determined by serum biochemical tests. The mRNA levels and protein expression of rat hepatic stellate (HSC-T6) cells were determined after treatment with Resveratrol (RSV) and Nicotinamide (NAM), respectively. The results showed that with the increasing of hepatic fibrosis in rhesus monkeys, the liver function impaired, and the transforming growth factor-β1 (TGF-β1), p-Smad3 (p-Smad3) and alpha-smooth muscle actin (α-SMA) was up-regulated, while SIRT1 and Smad7 were down-regulated. Moreover, when stimulated the HSC-T6 with RSV to activate SIRT1 for 6, 12, and 24 h, the results showed that RSV promoted the expression of smad7, while the expression of TGF-β1, p-Smad3 and α-SMA were inhibited. In contrast, when the cells stimulated with NAM to inhibit SIRT1 for 6, 12, and 24 h, the Smad7 expression was decreased, while TGF-β1, p-Smad3, and α-SMA expressions were increased. These results indicate that SIRT1 acts as an important protective factor for liver fibrosis, which may be attributed to inhibiting the signaling pathway of TGF-β/Smad in hepatic fibrosis of the rhesus monkey.
The therapeutic perspective of NAD<sup>+</sup> precursors in age-related diseases
2024, Biochemical and Biophysical Research Communications
Nicotinamide adenine dinucleotide (NAD⁺) is the fundamental molecule that performs numerous biological reactions and is crucial for maintaining cellular homeostasis. Studies have found that NAD⁺ decreases with age in certain tissues, and age-related NAD⁺ depletion affects physiological functions and contributes to various aging-related diseases. Supplementation of NAD⁺ precursor significantly elevates NAD⁺ levels in murine tissues, effectively mitigates metabolic syndrome, enhances cardiovascular health, protects against neurodegeneration, and boosts muscular strength. Despite the versatile therapeutic functions of NAD⁺ in animal studies, the efficacy of NAD⁺ precursors in clinical studies have been limited compared with that in the pre-clinical study. Clinical studies have demonstrated that NAD⁺ precursor treatment efficiently increases NAD⁺ levels in various tissues, though their clinical proficiency is insufficient to ameliorate the diseases. However, the latest studies regarding NAD⁺ precursors and their metabolism highlight the significant role of gut microbiota. The studies found that orally administered NAD⁺ intermediates interact with the gut microbiome. These findings provide compelling evidence for future trials to further explore the involvement of gut microbiota in NAD⁺ metabolism. Also, the reduced form of NAD⁺ precursor shows their potential to raise NAD⁺, though preclinical studies have yet to discover their efficacy. This review sheds light on NAD⁺ therapeutic efficiency in preclinical and clinical studies and the effect of the gut microbiota on NAD⁺ metabolism.
The enzymes of serine synthesis pathway in cancer metastasis
2024, Biochimica et Biophysica Acta - Molecular Cell Research
Metastasis, the major cause of cancer mortality, requires cancer cells to reprogram their metabolism to adapt to and thrive in different environments, thereby leaving metastatic cells metabolic characteristics different from their parental cells. Mounting research has revealed that the de novo serine synthesis pathway (SSP), a glycolytic branching pathway that consumes glucose carbons for serine makeup and α-ketoglutarate generation and thus supports the proliferation, survival, and motility of cancer cells, is one such reprogrammed metabolic pathway. During different metastatic cascades, the SSP enzyme proteins or their enzymatic activity are both dynamically altered; manipulating their expression or catalytic activity could effectively prevent the progression of cancer metastasis; and the SSP enzymatic proteins could even conduce to metastasis via their nonenzymatic functions. In this article we overview the SSP dynamics during cancer metastasis and put the focuses on the regulatory role of the SSP in metastasis and the underlying mechanisms that mainly involve cellular anabolism/catabolism, redox balance, and epigenetics, aiming to provide a theoretical basis for the development of therapeutic strategies for targeting metastatic lesions.
Mitochondrial targets in hyperammonemia: Addressing urea cycle function to improve drug therapies
2024, Biochemical Pharmacology
The urea cycle (UC) is a critically important metabolic process for the disposal of nitrogen (ammonia) produced by amino acids catabolism. The impairment of this liver-specific pathway induced either by primary genetic defects or by secondary causes, namely those associated with hepatic disease or drug administration, may result in serious clinical consequences. Urea cycle disorders (UCD) and certain organic acidurias are the major groups of inherited rare diseases manifested with hyperammonemia (HA) with UC dysregulation. Importantly, several commonly prescribed drugs, including antiepileptics in monotherapy or polytherapy from carbamazepine to valproic acid or specific antineoplastic agents such as asparaginase or 5-fluorouracil may be associated with HA by mechanisms not fully elucidated. HA, disclosing an imbalance between ammoniagenesis and ammonia disposal via the UC, can evolve to encephalopathy which may lead to significant morbidity and central nervous system damage.
This review will focus on biochemical mechanisms related with HA emphasizing some poorly understood perspectives behind the disruption of the UC and mitochondrial energy metabolism, namely: i) changes in acetyl-CoA or NAD⁺ levels in subcellular compartments; ii) post-translational modifications of key UC-related enzymes, namely acetylation, potentially affecting their catalytic activity; iii) the mitochondrial sirtuins-mediated role in ureagenesis. Moreover, the main UCD associated with HA will be summarized to highlight the relevance of investigating possible genetic mutations to account for unexpected HA during certain pharmacological therapies. The ammonia-induced effects should be avoided or overcome as part of safer therapeutic strategies to protect patients under treatment with drugs that may be potentially associated with HA.
Melatonin ameliorates retinal ganglion cell senescence and apoptosis in a SIRT1-dependent manner in an optic nerve injury model
2024, Biochimica et Biophysica Acta - Molecular Basis of Disease
Melatonin is involved in exerting protective effects in aged-related and neurodegenerative diseases through a silent information regulator type 1 (SIRT1)-dependent pathway. However, little was known about the impact of melatonin on retinal ganglion cell (RGC) senescence and apoptosis following optic nerve crush (ONC). Thus, this study aimed to examine the effects of melatonin on RGC senescence and apoptosis after ONC and investigate the involvement of SIRT1 in this process. To study this, an ONC model was established. EX-527, an inhibitor of SIRT1, was injected intraperitoneally into mice. And melatonin was administrated abdominally into mice after ONC every day. Hematoxylin & eosin staining, retina flat-mounts and optical coherence tomography were used to evaluate the loss of retina cells/neurons. Pattern electroretinogram (p-ERG) was performed to evaluate the function of RGCs. Immunofluorescence and western blot were used to evaluate protein expression. SA-β-gal staining was employed to detect senescent cells. The results demonstrated that melatonin partially rescued the expression of SIRT1 in RGC 3 days after ONC. Additionally, melatonin administration partly rescued the decreased RGC number and ganglion cell complex thickness observed 14 days after ONC. Melatonin also suppressed ONC-induced senescence and apoptosis index. Furthermore, p-ERG showed that melatonin improved the amplitude of P50, N95 and N95/P50 following ONC. Importantly, the protective effects of melatonin were reversed when EX-527 was administered. In summary, this study revealed that melatonin attenuated RGC senescence and apoptosis through a SIRT1-dependent pathway after ONC. These findings provide valuable insights for the treatment of RGC senescence and apoptosis.

View all citing articles on Scopus

View full text

Trends in Cell Biology

ReviewSpecial Focus – MetabolismNAD+ and sirtuins in aging and disease

Highlights

Section snippets

NAD+ as an essential compound for many enzymatic processes

NAD+ plays a key role in regulating metabolism and circadian rhythm

NAD+ declines with aging and can be restored by supplementation with NAD+ precursors

Possible mechanisms for how NAD+ levels decline in aging

Mitochondria as a common target of aging-induced NAD+ decline

Prospects for treating neurodegenerative diseases?

Concluding remarks

Disclaimer statement

Acknowledgments

Trends Biochem. Sci.

Biochem. Biophys. Res. Commun.

Adv. Enzyme Regul.

FEBS Lett.

Trends Biochem. Sci.

Cell Rep.

Cell

Cell Metab.

Cell

Cell

Cell

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Cell

Cell Metab.

Cell

Cell

Cell Metab.

Cell Metab.

Ageing Res. Rev.

Cell Metab.

Cell

Cell

Cell

Neurobiol. Aging

Mech. Ageing Dev.

Joining of DNA strands by DNA ligase of E. coli

Cold Spring Harb. Symp. Quant. Biol.

Autocrine and paracrine calcium signaling by the CD38/NAD+/cyclic ADP-ribose system

Ann. N. Y. Acad. Sci.

Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase

Nature

Calorie restriction extends yeast life span by lowering the level of NADH

Genes Dev.

The importance of NAMPT/NAD/SIRT1 in the systemic regulation of metabolism and ageing

Diabetes Obes. Metab.

PARP inhibitors for anticancer therapy

Biochem. Soc. Trans.

Mammalian sirtuins: biological insights and disease relevance

Annu. Rev. Pathol.

Review
Special Focus – Metabolism
NAD⁺ and sirtuins in aging and disease

NAD⁺ as an essential compound for many enzymatic processes

NAD⁺ plays a key role in regulating metabolism and circadian rhythm

NAD⁺ declines with aging and can be restored by supplementation with NAD⁺ precursors

Possible mechanisms for how NAD⁺ levels decline in aging

Mitochondria as a common target of aging-induced NAD⁺ decline

Autocrine and paracrine calcium signaling by the CD38/NAD⁺/cyclic ADP-ribose system