Trends in Cell Biology
ReviewSpecial Focus – MetabolismNAD+ and sirtuins in aging and disease
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)
The new life of a centenarian: signalling functions of NAD(P)
Trends Biochem. Sci.
(2004)Nicotinamide mononucleotide activation of new DNA-dependent polyadenylic acid synthesizing nuclear enzyme
Biochem. Biophys. Res. Commun.
(1963)- et al.
Equilibrium relations between pyridine nucleotides and adenine nucleotides and their roles in the regulation of metabolic processes
Adv. Enzyme Regul.
(1969) Dissecting systemic control of metabolism and aging in the NAD world: the importance of SIRT1 and NAMPT-mediated NAD biosynthesis
FEBS Lett.
(2011)- et al.
Chromatin regulation and genome maintenance by mammalian SIRT6
Trends Biochem. Sci.
(2011) dSir2 in the adult fat body, but not in muscles, regulates life span in a diet-dependent manner
Cell Rep.
(2012)The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling
Cell
(2013)Sirt1 Extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH
Cell Metab.
(2013)SIRT1 regulates circadian clock gene expression through PER2 deacetylation
Cell
(2008)The NAD+-dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control
Cell
(2008)
SIRT1 mediates central circadian control in the SCN by a mechanism that decays with aging
Cell
“Clocks” in the NAD world: NAD as a metabolic oscillator for the regulation of metabolism and aging
Biochim. Biophys. Acta
Regulation of intracellular levels of NAD: a novel role for CD38
Biochem. Biophys. Res. Commun.
Decreased cADPR and increased NAD+ in the Cd38−/− mouse
Biochem. Biophys. Res. Commun.
Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (NAADP) as messengers for calcium mobilization
J. Biol. Chem.
Declining NAD+ induces a pseudohypoxic state disrupting nuclear–mitochondrial communication during aging
Cell
Nicotinamide mononucleotide, a key NAD+ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice
Cell Metab.
Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+
Cell
Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss–Handler independent route to NAD+ in fungi and humans
Cell
The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity
Cell Metab.
Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure
Cell Metab.
Inflammatory markers in population studies of aging
Ageing Res. Rev.
PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation
Cell Metab.
C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life span
Cell
SIRT1 suppresses beta-amyloid production by activating the alpha-secretase gene ADAM10
Cell
Defective DNA repair and neurodegenerative disease
Cell
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
Overlapping and distinct functions for a Caenorhabditis elegans SIR2 and DAF-16/FOXO
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.
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