Manipulation of a Nuclear NAD+ Salvage Pathway Delays Aging without Altering Steady-state NAD+ Levels

Anderson, Rozalyn M.; Bitterman, Kevin J.; Wood, Jason G.; Medvedik, Oliver; Cohen, Haim Y.; Lin, Stephen; Manchester, Jill K.; Gordon, Jeffrey I.; Sinclair, David A.

doi:10.1074/jbc.m111773200

Cited by 275 publications

(252 citation statements)

References 67 publications

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“…NPT1, however, shows a significant (2.24-fold) increase in the old dna2-1 cells, though only a 1.7-fold increase in wild type, which is slightly less than the twofold significance threshold. This is consistent with the proposal that there may be an attempt to increase flux through the NAD ϩ pathway to prolong life span in the old dna2-1 cells (Anderson et al, 2002). For SIR2 itself, we found no significant change (WT yc/oc ϭ 1.37 and dna2-1 yc/oc ϭ 1.67).…”

Section: Expression Trends In Metabolic Genessupporting

confidence: 91%

“…Additional copies of these genes have been shown to increase replicative life span, and they are thought to be important for fueling SIR2-dependent longevity functions, so they might be expected to change in old cells (Lin et al, 2000;Anderson et al, 2002). Unfortunately, PCN1, NMA1, NMA2, and QNS1 were removed from the dataset during the filtering process.…”

Section: Expression Trends In Metabolic Genesmentioning

confidence: 99%

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The Transcriptome of Prematurely Aging Yeast Cells Is Similar to That of Telomerase-deficient Cells

Lesur

Campbell

2004

MBoC

115

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To help define the pathologies associated with yeast cells as they age, we analyzed the transcriptome of young and old cells isolated by elutriation, which allows isolation of biochemical quantities of old cells much further advanced in their life span than old cells prepared by the biotin-streptavidin method. Both 18-generation-old wild-type yeast and 8-generation-old cells from a prematurely aging mutant (dna2-1), with a defect in DNA replication, were evaluated. Genes involved in gluconeogenesis, the glyoxylate cycle, lipid metabolism, and glycogen production are induced in old cells, signifying a shift toward energy storage. We observed a much more extensive generalized stress response known as the environmental stress response (ESR), than observed previously in biotin-streptavidin-isolated cells, perhaps because the elutriated cells were further advanced in their life span. In addition, there was induction of DNA repair genes that fall in the so-called DNA damage "signature" set. In the dna2-1 mutant, energy production genes were also induced. The response in the dna2-1 strain is similar to the telomerase delete response, genes whose expression changes during cellular senescence in telomerase-deficient cells. We propose that these results suggest, albeit indirectly, that old cells are responding to genome instability. INTRODUCTIONMuch aging research is aimed at identifying the processes that lead to the generation of age-related cellular damage and understanding exactly how and where this damage occurs. Recently, there has been renewed focus on model organisms, such as the budding yeast Saccharomyces cerevisiae, for experimental work on aging. Yeast provides a model for contributions to aging made by tissues and organs that consist of constantly proliferating cells, replicative aging. Yeast has many advantages for replicative aging studies, such as its short life span, completely sequenced genome, and well-characterized biology. Individual yeast cells are mortal, and their life span is measured by the number of times they divide, i.e., the number of daughter cells produced by a single mother (Mortimer and Johnston, 1959;Muller et al., 1980). These daughter cells have the potential for a full life span, whereas the mother cell increases in age with each cell division; thus, yeast aging is asymmetric. The probability that an individual yeast cell will produce daughters declines exponentially as a function of its age in cell divisions or generations (Jazwinski et al., 1998). As yeast cells age, their size increases (Mortimer and Johnston, 1959;Nestelbacher, 2000), their cell cycle slows down (Mortimer and Johnston, 1959), their shape is altered (Pichova et al., 1997), their nucleolus tends to be larger and/or more fragmented, and they become sterile (Guarente, 1997). In wild-type cells, extrachromosomal ribosomal DNA circles (ERCs) also accumulate . Cells in the second half of their life span also show a switch to a state inducing increase loss of heterozygosity (LOH) (McMurray and Gottschling, 2003). Although...

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Section: Expression Trends In Metabolic Genessupporting

confidence: 91%

Section: Expression Trends In Metabolic Genesmentioning

confidence: 99%

The Transcriptome of Prematurely Aging Yeast Cells Is Similar to That of Telomerase-deficient Cells

Lesur

Campbell

2004

MBoC

115

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“…1A), which mediates transcriptional silencing at telomeres, silent mating-type loci, and ribosomal DNA repeats (17,19). It has been demonstrated that increased dosage of NPT1, which encodes nicotinic acid phosphoribosyltransferase, enhances Sir2-dependent transcriptional silencing and extends the life span of yeast mother cells (20). Consistent with this finding, deletion of NPT1 causes a loss of Sir2-dependent silencing and abrogates the life span extension by caloric restriction (21,22).…”

mentioning

confidence: 83%

“…Consistent with this finding, deletion of NPT1 causes a loss of Sir2-dependent silencing and abrogates the life span extension by caloric restriction (21,22). Additional copies of other genes, PNC1, NMA1, and NMA2, which encode nicotinamidase and nicotinic acid mononucleotide adenylyltransferase 1 and 2, respectively, also increase telomeric and rDNA silencing (20). Most notably, PNC1 mediates the life span extending effect of caloric restriction, and additional copies of PNC1 increase the replicative life span of yeast mother cells dramatically (23,24).…”

mentioning

confidence: 99%

The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells

Revollo¹,

Grimm²,

Imai

2004

Journal of Biological Chemistry

853

772

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Recent studies have revealed new roles for NAD and its derivatives in transcriptional regulation. The evolutionarily conserved Sir2 protein family requires NAD for its deacetylase activity and regulates a variety of biological processes, such as stress response, differentiation, metabolism, and aging. Despite its absolute requirement for NAD, the regulation of Sir2 function by NAD biosynthesis pathways is poorly understood in mammals. In this study, we determined the kinetics of the NAD biosynthesis mediated by nicotinamide phosphoribosyltransferase (Nampt) and nicotinamide/nicotinic acid mononucleotide adenylyltransferase (Nmnat), and we examined its effects on the transcriptional regulatory function of the mouse Sir2 ortholog, Sir2␣, in mouse fibroblasts. We found that Nampt was the ratelimiting component in this mammalian NAD biosynthesis pathway. Increased dosage of Nampt, but not Nmnat, increased the total cellular NAD level and enhanced the transcriptional regulatory activity of the catalytic domain of Sir2␣ recruited onto a reporter gene in mouse fibroblasts. Gene expression profiling with oligonucleotide microarrays also demonstrated a significant correlation between the expression profiles of Nampt-and Sir2␣-overexpressing cells. These findings suggest that NAD biosynthesis mediated by Nampt regulates the function of Sir2␣ and thereby plays an important role in controlling various biological events in mammals.

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“…Depletion of cellular NAD by poly-(ADP-ribosyl)transferase activation in response to DNA damage results in cell death (6). Increased NAD synthesis has been shown to extend life span in yeast (7) and in Caenorhabditis elegans (8) via activation of an NAD-dependent histone deacetylase, silent information regulator 2 (Sir2) (9). The cellular level of NAD may modulate the sensitivity of cells to apoptotic responses through deacetylation of the p53 tumor suppressor by a human homologue of Sir2 (10).…”

mentioning

confidence: 99%

Molecular Identification of Human Glutamine- and Ammonia-dependent NAD Synthetases

Hara

Yamada

Terashima

et al. 2003

Journal of Biological Chemistry

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NAD synthetase catalyzes the final step in the biosynthesis of NAD. In the present study, we obtained cDNAs for two types of human NAD synthetase (referred as NADsyn1 and NADsyn2). Structural analysis revealed in both NADsyn1 and NADsyn2 a domain required for NAD synthesis from ammonia and in only NADsyn1 an additional carbon-nitrogen hydrolase domain shared with enzymes of the nitrilase family that cleave nitriles as well as amides to produce the corresponding acids and ammonia. Consistent with the domain structures, biochemical assays indicated (i) that both NADsyn1 and NADsyn2 have NAD synthetase activity, (ii) that NADsyn1 uses glutamine as well as ammonia as an amide donor, whereas NADsyn2 catalyzes only ammoniadependent NAD synthesis, and (iii) that mutant NADsyn1 in which Cys-175 corresponding to the catalytic cysteine residue in nitrilases was replaced with Ser does not use glutamine. Kinetic studies suggested that glutamine and ammonia serve as physiological amide donors for NADsyn1 and NADsyn2, respectively. Both synthetases exerted catalytic activity in a multimeric form. In the mouse, NADsyn1 was seen to be abundantly expressed in the small intestine, liver, kidney, and testis but very weakly in the skeletal muscle and heart. In contrast, expression of NADsyn2 was observed in all tissues tested. Therefore, we conclude that humans have two types of NAD synthetase exhibiting different amide donor specificity and tissue distributions. The ammoniadependent synthetase has not been found in eucaryotes until this study. Our results also indicate that the carbon-nitrogen hydrolase domain is the functional domain of NAD synthetase to make use of glutamine as an amide donor in NAD synthesis. Thus, glutamine-dependent NAD synthetase may be classified as a possible glutamine amidase in the nitrilase family. Our molecular identification of NAD synthetases may prove useful to learn more of mechanisms regulating cellular NAD metabolism.The coenzyme NAD has a role in the majority of metabolic redox reactions and represents an essential component of metabolic pathways in all living cells. In a number of signaling pathways, NAD also serves as a precursor of potent calciummobilizing agents such as cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate (1) and serves as a substrate for post-translational modifications of protein, mono-(2-4) and poly(ADP-ribosyl)ations (5). Depletion of cellular NAD by poly-(ADP-ribosyl)transferase activation in response to DNA damage results in cell death (6). Increased NAD synthesis has been shown to extend life span in yeast (7) and in Caenorhabditis elegans (8) via activation of an NAD-dependent histone deacetylase, silent information regulator 2 (Sir2) (9). The cellular level of NAD may modulate the sensitivity of cells to apoptotic responses through deacetylation of the p53 tumor suppressor by a human homologue of Sir2 (10). Recent publications have demonstrated that fluctuation of the NAD level in cells seems to have significant impact on their physiology. Despite the...

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Manipulation of a Nuclear NAD+ Salvage Pathway Delays Aging without Altering Steady-state NAD+ Levels

Cited by 275 publications

References 67 publications

The Transcriptome of Prematurely Aging Yeast Cells Is Similar to That of Telomerase-deficient Cells

The Transcriptome of Prematurely Aging Yeast Cells Is Similar to That of Telomerase-deficient Cells

The NAD Biosynthesis Pathway Mediated by Nicotinamide Phosphoribosyltransferase Regulates Sir2 Activity in Mammalian Cells

Molecular Identification of Human Glutamine- and Ammonia-dependent NAD Synthetases

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