The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
A sestrin-dependent Erk–Jnk–p38 MAPK activation complex inhibits immunity during aging
Open accessAbstract
Mitogen-activated protein kinases (MAPKs) including Erk, Jnk and p38 regulate diverse cellular functions and are thought to be controlled by independent upstream activation cascades. Here we show that the sestrins bind to and coordinate simultaneous Erk, Jnk and p38 MAPK activation in T lymphocytes within a new immune-inhibitory complex (sestrin-MAPK activation complex (sMAC)). Whereas sestrin ablation resulted in broad reconstitution of immune function in stressed T cells, inhibition of individual MAPKs allowed only partial functional recovery. T cells from old humans (>65 years old) or mice (16-20 months old) were more likely to form the sMAC, and disruption of this complex restored antigen-specific functional responses in these cells. Correspondingly, sestrin deficiency or simultaneous inhibition of all three MAPKs enhanced vaccine responsiveness in old mice. Thus, disruption of sMAC provides a foundation for rejuvenating immunity during aging.
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
“Senescent T cells in mice and humans both exhibit an increase in phosphorylated γH2Ax subunits in the cytosol as an indicator of increased ATM kinase activity, increased DNA damage, and a DNA-damage senescence phenotype [353, 354].”
From Guidelines for the use of flow cytometry and cell sorting in immunological studies (third edition) (2021) · cites this paper as [353]
Experimental — accuracy not yet measuredIn the citing paper
“P38 inhibits cell cycle progression by activating P53, P21, and P16 [64].”
From Immunosenescence: a key player in cancer development (2020) · cites this paper as [64]
In the citing paper
“For example, previous studies performed on classical CD4 T cell subsets described reduced proliferation, lower secretion of interleukin-2 (IL-2) cytokine (7, 8), and accumulation of metabolic defects (9), along with higher production of pro-inflammatory mediators (10).”
From Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes (2019) · cites this paper as [9]
In the citing paper
“The knockout of sMAC restored T cell activity (antigen-specific proliferation and cytokine production) from older humans, and enhanced responsiveness to influenza vaccination in the aged mice (196).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [196]
In the citing paper
“Sestrins, the mammalian products of the Sesn1, Sesn2, and Sesn3 genes, are a family of stress sensing proteins (196).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [196]
In the citing paper
“The authors identified a complex named sestrin-dependent MAPK activation complex (sMAC) that simultaneously coordinates the activation of each MAPK that controls a functional response.”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [196]
In the citing paper
“For example, a block at the level of p38-MAPK by sestrins causes age-related signaling defects in effector and memory CD45RA+/CCR7− T cells (195, 196).”
From Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention (2019) · cites this paper as [196]
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
Mammalian MAP kinase signalling cascades
Chang, L., & Karin, M. (2001) · Nature · doi:10.1038/35065000 · Cited by 5,118
Self-citationAMPK: a nutrient and energy sensor that maintains energy homeostasis
Hardie, D. G., Ross, F. A., & Hawley, S. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3311 · Cited by 4,602
Mitogen-Activated Protein Kinase Pathways Mediated by ERK, JNK, and p38 Protein Kinases
Johnson, G. L., & Lapadat, R. (2002) · Science · doi:10.1126/science.1072682 · Cited by 4,295
A Vaccine to Prevent Herpes Zoster and Postherpetic Neuralgia in Older Adults
Oxman, M. N., Levin, M. J., Johnson, G. R., Schmader, K. E., Straus, S. E., Gelb, L. D., Arbeit, R. D., Simberkoff, M. S., Gershon, A. A., Davis, L. E., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa051016 · Cited by 2,412
mTOR is a key modulator of ageing and age-related disease
Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013) · Nature · doi:10.1038/nature11861 · Cited by 1,676
The coming acceleration of global population ageing
Lutz, W., Sanderson, W. C., & Scherbov, S. (2008) · Nature · doi:10.1038/nature06516 · Cited by 1,489
p53 Target Genes Sestrin1 and Sestrin2 Connect Genotoxic Stress and mTOR Signaling
Budanov, A. V., & Karin, M. (2008) · Cell · doi:10.1016/j.cell.2008.06.028 · Cited by 1,326
Self-citationCauses, consequences, and reversal of immune system aging
Montecino-Rodriguez, E., Berent-Maoz, B., & Dorshkind, K. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64096 · Cited by 793
MAPK phosphatases — regulating the immune response
Liu, Y., Shepherd, E. G., & Nelin, L. D. (2007) · Nature reviews. Immunology · doi:10.1038/nri2035 · Cited by 679
CD28− T cells: their role in the age-associated decline of immune function
Weng, N., Akbar, A. N., & Goronzy, J. J. (2009) · Trends in Immunology · doi:10.1016/j.it.2009.03.013 · Cited by 630
Self-citationChen, R. E., & Thorner, J. W. (2007) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2007.05.003 · Cited by 618
Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies
Lee, J. H., Budanov, A. V., Park, E. J., Birse, R., Kim, T. E., Perkins, G. A., Ocorr, K., Ellisman, M. H., Bodmer, R., Bier, E., et al. (2010) · Science · doi:10.1126/science.1182228 · Cited by 570
Self-citationOh, J. Z., Ravindran, R., Chassaing, B., Carvalho, F. A., Maddur, M. S., Bower, M., Hakimpour, P., Gill, K. P., Nakaya, H. I., Yarovinsky, F., et al. (2014) · Immunity · doi:10.1016/j.immuni.2014.08.009 · Cited by 541
Are senescence and exhaustion intertwined or unrelated processes that compromise immunity?
Akbar, A. N., & Henson, S. M. (2011) · Nature Reviews Immunology · doi:10.1038/nri2959 · Cited by 474
Self-citationChantranupong, L., Wolfson, R. L., Orozco, J. M., Saxton, R. A., Scaria, S. M., Bar-Peled, L., Spooner, E., Isasa, M., Gygi, S. P., & Sabatini, D. M. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.09.014 · Cited by 466
Mechanism of Action of A-769662, a Valuable Tool for Activation of AMP-activated Protein Kinase
Göransson, O., McBride, A., Hawley, S. A., Ross, F. A., Shpiro, N., Foretz, M., Viollet, B., Hardie, D. G., & Sakamoto, K. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m706536200 · Cited by 452
The ageing immune system: is it ever too old to become young again?
Dorshkind, K. A., Montecino‐Rodriguez, E., & Signer, R. A. J. (2008) · Nature reviews. Immunology · doi:10.1038/nri2471 · Cited by 424
p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells
Henson, S. M., Lanna, A., Riddell, N. E., Franzese, O., Macaulay, R., Griffiths, S. J., Puleston, D. J., Watson, A. S., Simon, A. K., Tooze, S. A., et al. (2014) · Journal of Clinical Investigation · doi:10.1172/jci75051 · Cited by 389
Self-citationFoxOs Inhibit mTORC1 and Activate Akt by Inducing the Expression of Sestrin3 and Rictor
Chen, C.-C., Jeon, S., Bhaskar, P. T., Nogueira, V., Sundararajan, D., Tonic, I., Park, Y., & Hay, N. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.03.008 · Cited by 374
The many paths to p38 mitogen-activated protein kinase activation in the immune system
Ashwell, J. D. (2006) · Nature reviews. Immunology · doi:10.1038/nri1865 · Cited by 370
Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viability
Budanov, A. V., Shoshani, T., Faerman, A., Zelin, E., Kamer, I., Kalinski, H., Gorodin, S., Fishman, A., Chajut, A., Einat, P., et al. (2002) · Oncogene · doi:10.1038/sj.onc.1205877 · Cited by 364
Li, G., Yu, M., Lee, W.-W., Tsang, M., Krishnan, E., Weyand, C. M., & Goronzy, J. J. (2012) · Nature Medicine · doi:10.1038/nm.2963 · Cited by 349
Sestrins Orchestrate Cellular Metabolism to Attenuate Aging
Lee, J. H., Budanov, A. V., & Karin, M. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.08.018 · Cited by 344
Self-citationSestrins inhibit mTORC1 kinase activation through the GATOR complex
Parmigiani, A., Nourbakhsh, A., Ding, B., Wang, W., Kim, Y. C., Akopiants, K., Guan, K.-L., Karin, M., & Budanov, A. V. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.10.019 · Cited by 336
Self-citationLanna, A., Henson, S. M., Escors, D., & Akbar, A. N. (2014) · Nature Immunology · doi:10.1038/ni.2981 · Cited by 328
Self-citationMaintenance of metabolic homeostasis by Sestrin2 and Sestrin3
Lee, J. H., Budanov, A. V., Talukdar, S., Park, E. J., Park, H. L., Park, H.-W., Bandyopadhyay, G., Li, N., Aghajan, M., Jang, I., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.08.004 · Cited by 295
Self-citationSenescence of T Lymphocytes: Implications for Enhancing Human Immunity
Akbar, A. N., Henson, S. M., & Lanna, A. (2016) · Trends in Immunology · doi:10.1016/j.it.2016.09.002 · Cited by 285
Self-citationVelasco-Miguel, S., Buckbinder, L., Jean, P., Gelbert, L., Talbott, R. L., Laidlaw, J. L., Seizinger, B. R., & Kley, N. (1999) · Oncogene · doi:10.1038/sj.onc.1202274 · Cited by 252
Reversible Senescence in Human CD4+CD45RA+CD27− Memory T Cells
Di Mitri, D., Azevedo, R. I., Henson, S. M., Libri, V., Riddell, N. E., Macaulay, R., Kipling, D., Soares, M. V. D., Battistini, L., & Akbar, A. N. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100978 · Cited by 231
Self-citationPlunkett, F. J., Franzese, O., Finney, H. M., Fletcher, J. M., Belaramani, L. L., Salmon, M., Dokal, I., Webster, D., Lawson, A. D. G., & Akbar, A. N. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.12.7710 · Cited by 222
Self-citationPeng, M., Yin, N., & Li, M. O. (2014) · Cell · doi:10.1016/j.cell.2014.08.038 · Cited by 220
Peeters, H., Debeer, P., Bairoch, A., Wilquet, V., Huysmans, C., Parthoens, E., Fryns, J. P., Gewillig, M. H. M. L., Nakamura, Y., Niikawa, N., et al. (2003) · Human Genetics · doi:10.1007/s00439-003-0917-5 · Cited by 117
Round, J. L., Humphries, L. A., Tomassian, T., Mittelstadt, P. R., Zhang, M., & Miceli, M. C. (2006) · Nature Immunology · doi:10.1038/ni1422 · Cited by 117
Targeting dendritic cell signaling to regulate the response to immunization
Escors, D., Lopes, L., Lin, R., Hiscott, J., Akira, S., Davis, R. J., & Collins, M. K. (2008) · Blood · doi:10.1182/blood-2007-11-122408 · Cited by 116
Self-citationImmune senescence and vaccines to prevent herpes zoster in older persons
Levin, M. J. (2012) · Current Opinion in Immunology · doi:10.1016/j.coi.2012.06.002 · Cited by 114
Müller-Durovic, B., Lanna, A., Covre, L. P., Mills, R. S., Henson, S. M., & Akbar, A. N. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600590 · Cited by 104
Self-citationSESN-1 is a positive regulator of lifespan in Caenorhabditis elegans
Yang, Y.-L., Loh, K.-S., Liou, B.-Y., Chu, I., Kuo, C., Chen, H., & Chen, C. (2013) · Experimental Gerontology · doi:10.1016/j.exger.2012.12.011 · Cited by 75
Lanna, A., Coutavas, E., Levati, L., Seidel, J., Rustin, M. H. A., Henson, S. M., Akbar, A. N., & Franzese, O. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301409 · Cited by 62
Self-citationp53 Strikes mTORC1 by Employing Sestrins
Hay, N. (2008) · Cell Metabolism · doi:10.1016/j.cmet.2008.08.010 · Cited by 52
Flagged first, then by citations
Cited by
Sorted by citations
The twilight of immunity: emerging concepts in aging of the immune system
Nikolich-Žugich, J. (2018) · Nature Immunology · doi:10.1038/s41590-017-0006-x · Cited by 1,240
Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)
Cossarizza, A., Chang, H., Radbruch, A., Acs, A., Adam, D., Adam‐Klages, S., Agace, W. W., Aghaeepour, N., Akdiş, M., Allez, M., et al. (2019) · European Journal of Immunology · doi:10.1002/eji.201970107 · Cited by 1,007
Immunosenescence: molecular mechanisms and diseases
Liu, Z., Liang, Q., Ren, Y., Guo, C., Ge, X., Wang, L., Cheng, Q., Luo, P., Zhang, Y., & Han, X. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01451-2 · Cited by 1,082
Mittelbrunn, M., & Kroemer, G. (2021) · Nature Immunology · doi:10.1038/s41590-021-00927-z · Cited by 702
Aiello, A., Farzaneh, F., Candore, G., Caruso, C., Davinelli, S., Gambino, C. M., Ligotti, M. E., Zareian, N., & Accardi, G. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.02247 · Cited by 693
Metadata
- Authors
- Lanna, A., Gomes, D. C. O., Muller-Durovic, B., McDonnell, T., Escors, D., Gilroy, D. W., Lee, J. H., Karin, M., & Akbar, A. N.
- Affiliations
- University of Oxford (GB)
- University College London (GB)
- Complejo Hospitalario de Navarra (ES)
- University of Michigan (US)
- University of California San Diego (US)
- Corresponding author
- Lanna, Alessio
- Akbar, Arne N
- ORCID
- Venue
- Nature Immunology
- Published
- 2017-01-23
- Volume
- 18
- Issue
- 3
- Pages
- 354-363
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC5321575
- OpenAlex
- W2581238721
- Cited by
- 284
- References
- 39
- Citations by year
- 2026: 16 · 2025: 34 · 2024: 38 · 2023: 23 · 2022: 36 · 2021: 42 · 2020: 48 · 2019: 24 · 2018: 14 · 2017: 9
- FWCI
- 11.64
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Wellcome Trust (AZR00630, 110229/Z/15/Z)
- Medical Research Council (MR/M003833/1, MR/N017749/1, MR/P00184X/1)
- Biotechnology and Biological Sciences Research Council (BB/L005336/1, BB/E019188/1, BB/J006750/1, BB/L005328/1)
- National Institute on Aging (R21AG045432)
- National Cancer Institute (P01CA128814)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- sestrins, ERK MAPK, JNK MAPK, p38 MAPK, T cells, immunosenescence, MAPK signaling, vaccine response, immune rejuvenation, aged mice
- MeSH terms
- Immunosenescence, Sestrins, Adult, Aged, Aged, 80 and over, Aging, Animals, Cells, Cultured, Female, Heat-Shock Proteins, Humans, Immunity, Male, Middle Aged, Signal Transduction, CD4-Positive T-Lymphocytes, RNA, Small Interfering, Extracellular Signal-Regulated MAP Kinases, MAP Kinase Kinase 4, Mice, Young Adult
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
