NAD+ metabolism governs the proinflammatory senescence-associated secretome
Open accessAbstract
Cellular senescence is a stable growth arrest that is implicated in tissue ageing and cancer. Senescent cells are characterized by an upregulation of proinflammatory cytokines, which is termed the senescence-associated secretory phenotype (SASP). NAD+ metabolism influences both tissue ageing and cancer. However, the role of NAD+ metabolism in regulating the SASP is poorly understood. Here, we show that nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of the NAD+ salvage pathway, governs the proinflammatory SASP independent of senescence-associated growth arrest. NAMPT expression is regulated by high mobility group A (HMGA) proteins during senescence. The HMGA-NAMPT-NAD+ signalling axis promotes the proinflammatory SASP by enhancing glycolysis and mitochondrial respiration. HMGA proteins and NAMPT promote the proinflammatory SASP through NAD+-mediated suppression of AMPK kinase, which suppresses the p53-mediated inhibition of p38 MAPK to enhance NF-κB activity. We conclude that NAD+ metabolism governs the proinflammatory SASP. Given the tumour-promoting effects of the proinflammatory SASP, our results suggest that anti-ageing dietary NAD+ augmentation should be administered with precision.
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The nutrient sensing pathways mTOR and NAD are involved in SASP regulation.
“In addition, the nutrient sensing pathways, mTOR and NAD, are involved in SASP regulation.56, 57, 58”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [58]
The Results section, “NAD+ metabolism governs the strengths of the proinflammatory SASP” (page unavailable), reports that an increased NAD+/NADH ratio enhances the proinflammatory SASP. The cited paper therefore supports the NAD part of the sentence, but the passages retrieved for mTOR do not establish its role in SASP regulation. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFK866, a specific NAMPT inhibitor, suppresses the proinflammatory SASP and limits pancreatic ductal adenocarcinoma (PDAC) progression.
“the use of FK866, a specific NAMPT inhibitor, suppresses the proinflammatory SASP and limits pancreatic ductal adenocarcinoma (PDAC) progression (Nacarelli et al. 2019).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Nacarelli et al. 2019
The Results sections “NAMPT promotes the proinflammatory SASP” and “NAD+ metabolism promotes cancer progression” identify FK866 as a NAMPT inhibitor and report that it suppresses proinflammatory SASP markers. But the pancreatic mouse-model results do not show that FK866 limits cancer progression; the authors instead say its findings suggest tumor progression associated with overcoming senescence. No page numbers are available in our copy. (LLM, conf=0.89)
Experimental — accuracy not yet measuredIn an oncogenic mouse model, NMN supplementation at 500 mg/kg body weight daily for 13 days significantly increased the pro-inflammatory senescence secretory phenotype and promoted pancreatic ductal adenocarcinoma progression.
“In an oncogenic mouse model, the supplementation with NMN (500 mg/kg body weight daily for 13 days) significantly increased the secretory phenotype associated with pro-inflammatory senescence, promoting pancreatic ductal adenocarcinoma progression.”
From NAD+ Precursors Nicotinamide Mononucleotide (NMN) and Nicotinamide Riboside (NR): Potential Dietary Contribution to Health (2023) · cites this paper as [81]
NAD+/NADH metabolism is a critical regulator of the magnitude of proinflammatory SASP linked to oncogene activation, and this regulation can occur independently of senescence-induced growth arrest.
“NAD+/NADH metabolism was identified as a critical regulator of the magnitude of proinflammatory SASP associated with oncogene activation, and this regulation can be independent of senescence-induced growth arrest239.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [239]
AMPK suppresses p53 mediated inhibition of p38MAPK to enhance NF-κB activity to promote expression of proinflammatory SASP proteins.
“AMPK suppresses p53 mediated inhibition of p38MAPK to enhance NF-κB activity to promote expression of proinflammatory SASP proteins.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Nacarelli et al., 2019
HMGA-NAMPT-NAD+ signaling axis regulates SASP.
“Last year yet another mechanism of SASP regulation demonstrating a novel role of NAD+ metabolism involving HMGA-NAMPT-NAD+ signaling axis in regulating SASP was identified (Nacarelli et al., 2019).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Nacarelli et al., 2019
Inhibition of HMGA1 and NAMPT suppresses OIS initiation showing HMGA-NAMPT-NAD+ signaling promotes proinflammatory SASP through NAD+ mediated suppression of AMPK.
“In accordance with this, inhibition of HMGA1 and NAMPT suppresses OIS initiation showing that HMGA-NAMPT-NAD+ signaling promotes proinflammatory SASP through the NAD+ mediated suppression of AMPK.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Nacarelli et al., 2019
HMGA-NAMPT-NAD+ mediated expression of proinflammatory SASP is independent of CEBPβ activity.
“Thus HMGA-NAMPT-NAD+ mediated expression of proinflammatory SASP is independent of CEBPβ activity.”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Nacarelli et al., 2019
In OIS, HMGA1 upregulates NAMPT through an enhancer element which promotes inflammatory SASP in response to increased NAD+/NADH ratio.
“It was found that in OIS, HMGA1 plays an instrumental role in upregulating NAMPT through an enhancer element which in turn promotes inflammatory SASP in response to an increased NAD+/NADH ratio (Nacarelli et al., 2019).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Nacarelli et al., 2019
High NAD+ levels may promote cancer, at least pancreatic cancer, through changes in senescent cell secretory activity that release pro-inflammatory cytokines.
“high NAD+ levels may lead to cancer promotion (at least in pancreatic cancer) through changes in the secretory activity of senescent cells to release pro-inflammatory cytokines”
From NAD+ in Brain Aging and Neurodegenerative Disorders (2019) · cites this paper as Nacarelli et al., 2019
Treating senescent cells with NMN can heighten the SASP, leading to increased chronic inflammation, and can promote the development of inflammation-driven cancers.
“Treating senescent cells with NMN can heighten the SASP, leading to increased chronic inflammation, and can promote the development of inflammation-driven cancers.”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [131]
Senescent cells upregulate expression of the NAM salvage enzyme NAMPT, and the SASP of senescent cells depends on NAD+ levels.
“senescent cells upregulate the expression of the NAM salvage enzyme NAMPT (BOX 1) and that the SASP of senescent cells depends on NAD+ levels131”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [131]
Cellular senescence is a double-edged sword in cancer.
“These studies also documented that cellular senescence is a cellular state closely associated with various physiological processes and aging-related diseases [4, 5] and is a double-edged sword in cancer [6].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [6]
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“Conversely, increased nicotinamide phosphoribosyltransferase (NAMPT) activity, which salvages NAD+, promotes a “high” proinflammatory SASP in OIS by enhancing glycolysis and mitochondrial respiration (Nacarelli et al. 2019).”
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- Authors
- Nacarelli, T., Lau, L., Fukumoto, T., Zundell, J., Fatkhutdinov, N., Wu, S., Aird, K. M., Iwasaki, O., Kossenkov, A. V., Schultz, D., Noma, K.-I., Baur, J. A., Schug, Z., Tang, H.-Y., Speicher, D. W., David, G., & Zhang, R.
- Affiliations
- The Wistar Institute (US)
- New York University (US)
- University of Pennsylvania (US)
- Corresponding author
- Zhang, Rugang
- ORCID
- Venue
- Nature Cell Biology
- Published
- 2019-02-18
- Volume
- 21
- Issue
- 3
- Pages
- 397-407
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- PMC
- PMC6448588
- OpenAlex
- W2914025980
- Cited by
- 402
- References
- 47
- Citations by year
- 2026: 49 · 2025: 67 · 2024: 70 · 2023: 47 · 2022: 59 · 2021: 47 · 2020: 42 · 2019: 21
- FWCI
- 22.36
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1s10od023586-01, 1s10od023658-01)
- National Institute on Aging (P01AG031862)
- National Cancer Institute (R01CA131582, R01CA160331, R00CA194309, F31CA206387, R21CA155736, R01CA148639, R01CA163377, R50CA221838, R01CA202919, R50CA211199, P50CA228991, T32CA009171, P30CA010815)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK098656)
- Topics
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- NAD+ metabolism, cellular senescence, senescence-associated secretory phenotype, visfatin, NAD+ salvage pathway, HMGA proteins, glycolysis, mitochondrial respiration, AMPK, p53, p38 MAPK, NF-κB, inflammatory cytokines, tissue aging, cancer
- MeSH terms
- Animals, Cell Line, Fibroblasts, Gene Expression Regulation, Humans, NAD, Phenotype, Signal Transduction, Cytokines, Mice, SCID, Mice, Inbred NOD, Cellular Senescence, Mice, Knockout, Inflammation Mediators, p38 Mitogen-Activated Protein Kinases, Nicotinamide Phosphoribosyltransferase
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 ›
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