The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Nicotinamide and PNC1 govern lifespan extension by calorie restriction in Saccharomyces cerevisiae
Open accessAbstract
Calorie restriction extends lifespan in a broad range of organisms, from yeasts to mammals. Numerous hypotheses have been proposed to explain this phenomenon, including decreased oxidative damage and altered energy metabolism. In Saccharomyces cerevisiae, lifespan extension by calorie restriction requires the NAD+-dependent histone deacetylase, Sir2 (ref. 1). We have recently shown that Sir2 and its closest human homologue SIRT1, a p53 deacetylase, are strongly inhibited by the vitamin B3 precursor nicotinamide. Here we show that increased expression of PNC1 (pyrazinamidase/nicotinamidase 1), which encodes an enzyme that deaminates nicotinamide, is both necessary and sufficient for lifespan extension by calorie restriction and low-intensity stress. We also identify PNC1 as a longevity gene that is responsive to all stimuli that extend lifespan. We provide evidence that nicotinamide depletion is sufficient to activate Sir2 and that this is the mechanism by which PNC1 regulates longevity. We conclude that yeast lifespan extension by calorie restriction is the consequence of an active cellular response to a low-intensity stress and speculate that nicotinamide might regulate critical cellular processes in higher organisms.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Several studies highlight how the external environment and the genetic background of an organism have pivotal roles in the aging process by affecting events that maintain epigenetic information 2,3 .”
From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [3]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“NAM, in contrast, is a well reported and widely used sirtuin inhibitor31 and has been recently shown to inhibit NAD+-consuming activities in vivo24.”
From NRK1 controls nicotinamide mononucleotide and nicotinamide riboside metabolism in mammalian cells (2016) · cites this paper as [31]
In the citing paper
“In response to calorie restriction, the yeast NAD biosynthetic gene that catalyses the first and rate-limiting step in NAD+ biosynthesis, PNC1, is induced46.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [46]
In the citing paper
“The resulting availability of NAD+ increases SIR2 activity, which boosts mitochondrial respiration and suppresses recombinant DNA recombination11,46, a known cause of ageing in yeast47.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [46]
In the citing paper
“The upregulation of the NAD salvage pathway, which recycles NAD+ from nicotinamide, was first shown to extend lifespan and mimic caloric restriction in yeast cells46.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [46]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Genomic Expression Programs in the Response of Yeast Cells to Environmental Changes
Gasch, A. P., Spellman, P. T., Kao, C. M., Carmel-Harel, O., Eisen, M. B., Storz, G., Botstein, D., & Brown, P. O. (2000) · Molecular Biology of the Cell · doi:10.1091/mbc.11.12.4241 · Cited by 4,815
Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase
Imai, S.-I., Armstrong, C. M., Kaeberlein, M., & Guarente, L. (2000) · Nature · doi:10.1038/35001622 · Cited by 3,510
hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase
Vaziri, H., Dessain, S. K., Eaton, E. N., Imai, S., Frye, R. A., Pandita, T. K., Guarente, L., & Weinberg, R. A. (2001) · Cell · doi:10.1016/s0092-8674(01)00527-x · Cited by 2,690
Kaeberlein, M., McVey, M., & Guarente, L. (1999) · Genes & Development · doi:10.1101/gad.13.19.2570 · Cited by 2,253 · cited 1×
“Cells with an additional copy of SIR2 live 30% longer than the wild type, whereas sir2Δ strains age prematurel”
BackgroundNegative Control of p53 by Sir2α Promotes Cell Survival under Stress
Luo, J., Nikolaev, A. Y., Imai, S.-I., Chen, D., Su, F., Shiloh, A., Guarente, L., & Gu, W. (2001) · Cell · doi:10.1016/s0092-8674(01)00524-4 · Cited by 2,081
Lin, S.-J., Defossez, P.-A., & Guarente, L. (2000) · Science · doi:10.1126/science.289.5487.2126 · Cited by 1,775
Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans
Tissenbaum, H. A., & Guarente, L. (2001) · Nature · doi:10.1038/35065638 · Cited by 1,603
Extrachromosomal rDNA circles—a cause of aging in yeast
Sinclair, D. A., & Guarente, L. (1997) · Cell · doi:10.1016/s0092-8674(00)80493-6 · Cited by 1,500
Self-citationThe Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors
Virág, L., & Szabó, C. (2002) · Pharmacological Reviews · doi:10.1124/pr.54.3.375 · Cited by 1,373
Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respiration
Lin, S.-J., Kaeberlein, M., Andalis, A. A., Sturtz, L. A., Defossez, P.-A., Culotta, V. C., Fink, G. R., & Guarente, L. (2002) · Nature · doi:10.1038/nature00829 · Cited by 1,057
Bitterman, K. J., Anderson, R. M., Cohen, H. Y., Latorre-Esteves, M., & Sinclair, D. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m205670200 · Cited by 1,002
Self-citationThe silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases
Landry, J., Sutton, A., Tafrov, S. T., Heller, R. C., Stebbins, J., Pillus, L., & Sternglanz, R. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.110148297 · Cited by 970
Smith, J. S., Brachmann, C. B., Celic, I., Kenna, M. A., Muhammad, S., Starai, V. J., Avalos, J. L., Escalante-Semerena, J. C., Grubmeyer, C., Wolberger, C., et al. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.12.6658 · Cited by 718
A public database for gene expression in human cancers.
Lal, A., Lash, A., Altschul, S. F., Velculescu, V. E., Zhang, L., McLendon, R. E., Marra, M. A., Prange, C. K., Morin, P. J., Polyák, K., et al. (1999) · PubMed · Cited by 414
An intervention resembling caloric restriction prolongs life span and retards aging in yeast
Jiang, J. C., Jaruga, E., Repnevskaya, M. V., & Jazwinski, S. M. (2000) · The FASEB Journal · doi:10.1096/fj.00-0242fje · Cited by 383
Aksoy, S., Szumlanski, C. L., & Weinshilboum, R. M. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36700-5 · Cited by 295
Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O., Cohen, H. Y., Lin, S., Manchester, J. K., Gordon, J. I., & Sinclair, D. A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m111773200 · Cited by 295
Self-citationLongevity Regulation by Drosophila Rpd3 Deacetylase and Caloric Restriction
Rogina, B., Helfand, S. L., & Frankel, S. A. (2002) · Science · doi:10.1126/science.1078986 · Cited by 276
Role of NAD+ in the Deacetylase Activity of the SIR2-like Proteins
Landry, J. W., Slama, J. T., & Sternglanz, R. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.3854 · Cited by 254
Tanny, J. C., & Moazed, D. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.2.415 · Cited by 253
S-Adenosylmethionine-dependent Methylation inSaccharomyces cerevisiae
Niewmierzycka, A., & Clarke, S. G. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.2.814 · Cited by 226
Lin, S., Manchester, J. K., & Gordon, J. I. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m103509200 · Cited by 188
Kaeberlein, M. R., Andalis, A. A., Fink, G. R., & Guarente, L. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.22.8056-8066.2002 · Cited by 143
Identification and functional analysis of the Saccharomyces cerevisiae nicotinamidase gene, PNC1
Ghislain, M., Talla, E., & François, J. M. (2002) · Yeast · doi:10.1002/yea.810 · Cited by 130
Sandmeier, J. J., Celic, I., Boeke, J. D., & Smith, J. S. (2002) · Genetics · doi:10.1093/genetics/160.3.877 · Cited by 120
Grant, R., & Kapoor, V. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.70041759.x · Cited by 91
Kassem, H. S., Sangar, V., Cowan, R. A., Clarke, N. W., & Margison, G. P. (2002) · International Journal of Cancer · doi:10.1002/ijc.10631 · Cited by 88
The role of peroxisomes in aging
P�richon, R., Bourre, J. M., Kelly, J. F., & Roth, G. S. (1998) · Cellular and Molecular Life Sciences · doi:10.1007/s000180050192 · Cited by 67
Effect of stress on the life span of the yeast Saccharomyces cerevisiae.
Święciło, A., Krawiec, Z., Wawryn, J., Bartosz, G., & Biliński, T. (2000) · Acta Biochimica Polonica · doi:10.18388/abp.2000_4015 · Cited by 33
Ünkefer, C. J., & London, R. E. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)43354-0 · Cited by 27
Cited by
Sorted by citations
Therapeutic potential of resveratrol: the in vivo evidence
Baur, J. A., & Sinclair, D. A. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2060 · Cited by 3,958
Self-citationSmall molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan
Howitz, K. T., Bitterman, K. J., Cohen, H. Y., Lamming, D. W., Lavu, S., Wood, J. G., Zipkin, R. E., Chung, P., Kisielewski, A., Zhang, L.-L., et al. (2003) · Nature · doi:10.1038/nature01960 · Cited by 3,796
Self-citationStress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
Brunet, A., Sweeney, L. B., Sturgill, J. F., Chua, K. F., Greer, P. L., Lin, Y., Tran, H., Ross, S. E., Mostoslavsky, R., Cohen, H. Y., et al. (2004) · Science · doi:10.1126/science.1094637 · Cited by 3,239
Self-citationBroken Limits to Life Expectancy
Oeppen, J., & Vaupel, J. W. (2002) · Science · doi:10.1126/science.1069675 · Cited by 2,819
Mammalian Sirtuins: Biological Insights and Disease Relevance
Haigis, M. C., & Sinclair, D. A. (2010) · Annual Review of Pathology: Mechanisms of Disease · doi:10.1146/annurev.pathol.4.110807.092250 · Cited by 2,085
Self-citation
Metadata
- Authors
- Anderson, R. M., Bitterman, K. J., Wood, J. G., Medvedik, O., & Sinclair, D. A.
- Affiliations
- Harvard University (US)
- Corresponding author
- Sinclair, David A.
- Venue
- Nature
- Published
- 2003-05
- Volume
- 423
- Issue
- 6936
- Pages
- 181-185
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4802858
- OpenAlex
- W2006806054
- Cited by
- 736
- References
- 30
- Citations by year
- 2026: 18 · 2025: 17 · 2024: 11 · 2023: 10 · 2022: 26 · 2021: 18 · 2020: 24 · 2019: 23 · 2018: 30 · 2017: 26 · 2016: 29 · 2015: 35 · 2014: 30 · 2013: 24 · 2012: 39
- FWCI
- 13.20
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R37AG028730, P01AG027916, R01AG028730, R01AG019719, R01AG019972)
- National Institute of General Medical Sciences (R01GM068072)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fungal and yeast genetics research
- Keywords
- caloric restriction, lifespan extension, nicotinamide, Sir2, SIRT1, NAD+-dependent histone deacetylase, longevity genes, Saccharomyces cerevisiae, aging
- MeSH terms
- Cell Nucleus, Cytoplasm, Energy Metabolism, Histone Deacetylases, Longevity, NAD, Niacin, Nicotinamidase, Niacinamide, Saccharomyces cerevisiae, Gene Expression Regulation, Fungal, Heat-Shock Response, Gene Silencing, Saccharomyces cerevisiae Proteins, Caloric Restriction, Sirtuins, Silent Information Regulator Proteins, Saccharomyces cerevisiae, Sirtuin 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
