Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and disease
Introduction
A change in metabolism has been implicated in the mechanisms of several age-associated diseases such as diabetes, cancers and neurodegenerative diseases (e.g. Parkinson’s disease) 1., 2.•, 3.. Calorie restriction (CR) has been shown to decrease the incidence or delay the onset of some of these diseases 4., 5.. It is currently unclear how CR ameliorates these diseases. CR extends the life span of a spectrum of organisms and so far it is the only regimen known to extend the life span of mammals 4., 5.. Recent studies show that the benefit of CR requires nicotinamide adenine dinucleotide (NAD) and Sir2p [6•], a key regulator of life span in both yeast and animals 7., 8.. Sir2p exhibits an NAD-dependent histone deacetylase activity that is conserved among Sir2p-family members and is required for chromatin silencing and life-span extension 9., 10., 11.. The requirement of NAD for Sir2p activity suggests that Sir2p is likely to be regulated by the metabolic state of cells. It is therefore likely that CR delays and/or prevents age-associated diseases by regulating NAD metabolism or Sir2p activity, or both.
In this review, we discuss the emerging roles of NAD as a signalling factor in transcriptional regulation, ageing and human diseases. We also discuss the roles the Sir2p family, one molecular target of NAD-mediated metabolic regulation, in age-associated diseases.
Section snippets
NAD metabolism and biological functions
NAD is synthesised via two major pathways in both prokaryotic and eukaryotic systems (Figure 1) 12., 13., 14., 15.•, 16.. In one pathway, NAD is synthesised from tryptophan (the de novo pathway). In the other pathway, NAD is generated by recycling degraded NAD products such as nicotinamide (the salvage pathway). In yeast, the de novo pathway consists of six enzymatic steps (catalysed by the BNA genes) and one non-enzymatic reaction. The last enzymatic reaction is catalysed by a quinolinate
The NAD : NADH ratio
The NAD : NADH ratio plays an important role in regulating the intracellular redox state and is often considered as a read out of the metabolic state. Many metabolic enzymes are regulated by the NAD : NADH ratio, such as the glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase and the pyruvate dehydrogenase complex, which converts pyruvate to acetyl-CoA, a substrate for the TCA cycle [17]. It has been well documented that the NAD : NADH ratio fluctuates in response to a change in
A role for NAD in transcriptional regulation
Recent studies show that the NAD salvage pathway plays an important role in transcriptional silencing at the telomere and rDNA loci 13., 14., 15.•. The nucleolar silencing regulator Sir2p is required for silencing at these loci 13., 14., 15.•. The silencing status of these loci is thus considered as a read out of the Sir2p activity. Similar to Sir2p, components of the salvage pathway affect silencing in a dose-dependent manner 14., 15.•. Therefore, the salvage pathway is thought to increase
Yeast
Recent studies in yeast have provided insight into the molecular mechanisms underlying CR-mediated life-span extension 6.•, 37.•. Both Sir2p and NAD are essential for CR-mediated life-span extension: the benefit of CR is abolished by deleting either SIR2 or NPT1 [6•]. The requirement of NAD for Sir2p activity suggests CR may work by increasing the available NAD pool for Sir2p activity. Interestingly, overexpression of Npt1p, which is assumed to increase the flux through the salvage pathway,
A role for NAD in human disease
Several age-related diseases have been directly or indirectly associated with a change in NAD level or NAD/NADH redox state. As discussed above, the NAD/NADH redox state regulates the co-repressor CtBP activity and therefore plays a role in carcinogenesis [2•]. In addition, NAD/NADH may also regulate the tumour suppressor p53 via Sir2p 21., 22.. PARP1 overactivation has been implicated in the mechanisms underlying type 1 diabetes. PARP1 utilises NAD as a substrate and participates in DNA-base
Conclusions
NAD has emerged as a putative metabolic regulator of transcription, longevity and several age-associated diseases, including diabetes, cancer and neurodegenerative diseases. CR has been shown to decrease the incidence or delay the onset of some of these diseases. Studies in yeast suggest that CR might function by increasing the NAD level and/or the NAD : NADH ratio. It is thus possible that CR ameliorates these human diseases by a similar mechanism (Figure 3). Further studies are required to
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
We thank Dean P Jones at Emory University for suggestions; and M Haigis, F Picard and M Viswanathan for critical reading of the manuscript. Our laboratory is supported by grants from the National Institute of Health, The Ellison Medical Foundation, The Seaver Institute, and the Howard and Linda Stern Fund.
References (46)
- et al.
Telomeric and rDNA silencing in Saccharomyces cerevisiae are dependent on a nuclear NAD(+) salvage pathway
Genetics
(2002) - Matthew CK, Van Holde KE, Ahern KG: Biochemistry, edn 3. Boston: Addison-Wesley;...
Physiology and pathophysiology of poly(ADP-ribosyl)ation
Bioessays.
(2001)- et al.
Is ischemia involved in the pathogenesis of murine cerebral malaria?
Am. J. Pathol.
(2001) - et al.
In vivo role of NAD(P)H : quinone oxidoreductase 1 (NQO1) in the regulation of intracellular redox state and accumulation of abdominal adipose tissue
J. Biol. Chem.
(2001) - et al.
Metabolic effects of aldose reductase inhibition during low-flow ischemia and reperfusion
Am. J. Physiol.
(1998) - et al.
Mouse lacking NAD+-linked glycerol phosphate dehydrogenase has normal pancreatic beta cell function but abnormal metabolite pattern in skeletal muscle
Arch. Biochem. Biophys.
(2000) - Sies H: Metabolic Compartmentation. London: Academic Press;...
- et al.
Increase in NAD but not ATP and GTP concentrations in rat liver by dehydroepiandrosterone feeding
Pol. J. Pharmacol.
(2001) - et al.
p53 mutant mice that display early ageing-associated phenotypes
Nature
(2002)