The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
Human peripheral late/exhausted memory B cells express a senescent-associated secretory phenotype and preferentially utilize metabolic signaling pathways
Abstract
The percentage of late/exhausted memory (LM) B cells increases with age and we show here that this is associated with a lower influenza vaccine response. To identify novel contributors to the phenotypic and functional changes observed in aged B cells, we sorted the major peripheral B cell subsets [naïve, IgM memory, switched memory (swIg) and late/exhausted memory (LM)] and determined their percentages in the peripheral blood as well as their level of immune activation by measuring basal levels of expression of multiple senescence-associated secretory phenotype (SASP) markers, such as pro-inflammatory cytokines (TNF-α/IL-6/IL-8), inflammatory micro-RNAs (miRs, miR-155/16/93), cell cycle regulators (p16 INK4). We found that only memory B cells express SASP markers, and especially the LM B cell subset, which is also showing spontaneous activation of AMP-activated protein kinase (AMPK), the energy sensing enzyme which is ubiquitously expressed in mammalian cells. LM B cells, but not IgM memory B cells, activate a p38MAPK signaling pathway, downstream of AMPK, leading to the expression of SASP mediators, while class switch recombination is downregulated. These data show that some B cell subsets are more inflammatory than others, that they are pre-activated and that this signaling through metabolic pathways is associated with a senescence phenotype, demonstrating for the first time in human B lymphocytes the link between aging, cellular senescence, SASP and metabolism.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
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?
In the citing paper
“The quality of the humoral immune response declines with age, as aged B cells display a diminished potential to undergo somatic hypermutation154, which could prevent the aged from generating robust neutralizing antibody titers to aid the clearance of natural infection and generate effective immunity against re-infections.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [154]
In the citing paper
“The quality of the humoral immune response declines with age, as aged B cells display a diminished potential to undergo somatic hypermutation154, which could prevent the aged from generating robust neutralizing antibody titers to aid the clearance of natural infection and generate effective immunity against re-infections.”
From SARS-CoV-2, COVID-19 and the aging immune system (2021) · cites this paper as [154]
Citations
Cites
Bradford, M. M. (1976) · Analytical Biochemistry · doi:10.1016/0003-2697(76)90527-3 · Cited by 255,302
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
Inflammatory networks during cellular senescence: causes and consequences.
Freund, A., Orjalo, A. V., Desprez, P.-Y., & Campisi, J. (2010) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2010.03.003 · Cited by 1,354
Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype
Wiley, C. D., Velarde, M. C., Lecot, P., Liu, S., Sarnoski, E. A., Freund, A., Shirakawa, K., Lim, H. W., Davis, S. S., Ramanathan, A., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.11.011 · Cited by 1,275
Systemic inflammation and disease progression in Alzheimer disease
Holmes, C., Cunningham, C., Zotova, E., Woolford, J., Dean, C., Kerr, S., Culliford, D., & Perry, V. H. (2009) · Neurology · doi:10.1212/wnl.0b013e3181b6bb95 · Cited by 1,139
Freund, A., Patil, C. K., & Campisi, J. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.69 · Cited by 1,039
Moir, S. L., Ho, J., Malaspina, A., Wang, W., DiPoto, A. C., O’Shea, M. A., Roby, G. A., Kottilil, S., Arthos, J. A., Proschan, M. A., et al. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20072683 · Cited by 894
Rubtsov, A. V., Rubtsova, K., Fischer, A., Meehan, R. T., Gillis, J. Z., Kappler, J. W., & Marrack, P. (2011) · Blood · doi:10.1182/blood-2011-01-331462 · Cited by 808
A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice
Hao, Y., O'Neill, P., Naradikian, M. S., Scholz, J. L., & Cancro, M. P. (2011) · Blood · doi:10.1182/blood-2011-01-330530 · Cited by 622
Wei, C., Anolik, J. H., Cappione, A., Zheng, B., Pugh-Bernard, A. E., Brooks, J. C., Lee, E.-H., MILNER, E. C. B., & Sanz, I. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.178.10.6624 · Cited by 605
Panda, A., Qian, F., Mohanty, S., van Duin, D., Newman, F. K., Zhang, L., Chen, S., Towle, V., Belshe, R. B., Fikrig, E., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0901022 · Cited by 548
Cancer and ageing: rival demons?
Campisi, J. (2003) · Nature Reviews Cancer · doi:10.1038/nrc1073 · Cited by 512
Mundy, G. R. (2008) · Nutrition Reviews · doi:10.1111/j.1753-4887.2007.tb00353.x · Cited by 485
Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus
Anolik, J. H., Barnard, J., Cappione, A., Pugh-Bernard, A. E., Felgar, R. E., Looney, R. J., & Sanz, I. (2004) · Arthritis & Rheumatism · doi:10.1002/art.20592 · Cited by 454
AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome
Ruderman, N., & Prentki, M. (2004) · Nature Reviews Drug Discovery · doi:10.1038/nrd1344 · Cited by 451
B‐cell diversity decreases in old age and is correlated with poor health status
Gibson, K. L., Wu, Y., Barnett, Y., Duggan, O., Vaughan, R., Kondeatis, E., Nilsson, B., Wikby, A., Kipling, D., & Dunn‐Walters, D. K. (2009) · Aging Cell · doi:10.1111/j.1474-9726.2008.00443.x · Cited by 433
Mundy, G. R. (2007) · Nutrition Reviews · doi:10.1301/nr.2007.dec.s147-s151 · Cited by 409
Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence
Moiseeva, O., Bourdeau, V., Roux, A., Deschênes-Simard, X., & Ferbeyre, G. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01868-08 · Cited by 408
Goronzy, J. J., Fulbright, J. W., Crowson, C. S., Poland, G. A., O'Fallon, W. M., & Weyand, C. M. (2001) · Journal of Virology · doi:10.1128/jvi.75.24.12182-12187.2001 · Cited by 402
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
T cells and aging january 2002 update
Pawelec, G. (2002) · Frontiers in bioscience · doi:10.2741/a831 · Cited by 372
Cellular senescence: putting the paradoxes in perspective
Campisi, J. (2011) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.10.005 · Cited by 368
Frasca, D., Landin, A. M., Lechner, S. C., Ryan, J. G., Schwartz, R., Riley, R. L., & Blomberg, B. B. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.8.5283 · Cited by 333
Self-citationLanna, A., Henson, S. M., Escors, D., & Akbar, A. N. (2014) · Nature Immunology · doi:10.1038/ni.2981 · Cited by 328
Coppé, J.-P., Patil, C. K., Rodier, F., Sun, Y., Muñoz, D. P., Goldstein, J., Nelson, P. S., Desprez, P.-Y., & Campisi, J. (2008) · PLoS Biology · doi:10.1371/journal.pbio.0060301 · Cited by 302
Fecteau, J. F., Côté, G., & Néron, S. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.6.3728 · Cited by 298
Senescence 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
Age effects on B cells and humoral immunity in humans
Frasca, D., Diaz, A., Romero, M., Landin, A. M., & Blomberg, B. B. (2010) · Ageing Research Reviews · doi:10.1016/j.arr.2010.08.004 · Cited by 271
Self-citationColonna-Romano, G., Bulati, M., Aquino, A., Pellicanò, M., Vitello, S., Lio, D., Candore, G., & Caruso, C. (2009) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2009.08.003 · Cited by 270
Ito, T., Suzuki, Y., Mitnaul, L. J., Vines, A., Kida, H., & Kawaoka, Y. (1997) · Virology · doi:10.1006/viro.1996.8323 · Cited by 264
Impact of cellular senescence signature on ageing research
Sikora, E., Arendt, T., Bennett, M., & Narita, M. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2010.10.002 · Cited by 264
Saadoun, D., Terrier, B., Bannock, J. M., Vazquez, T., Massad, C., Kang, I., Joly, F., Rosenzwajg, M., Sène, D., Benech, P. D., et al. (2012) · Arthritis & Rheumatism · doi:10.1002/art.37828 · Cited by 230
Obesity decreases B cell responses in young and elderly individuals
Frasca, D., Ferracci, F., Diaz, A., Romero, M., Lechner, S., & Blomberg, B. B. (2016) · Obesity · doi:10.1002/oby.21383 · Cited by 228
Self-citationOlivieri, F., Lazzarini, R., Recchioni, R., Marcheselli, F., Rippo, M. R., Nuzzo, S., Albertini, M. C., Graciotti, L., Babini, L., Mariotti, S., et al. (2012) · AGE · doi:10.1007/s11357-012-9440-8 · Cited by 206
Sridharan, A., Esposo, M., Kaushal, K., Tay, J., Osann, K., Agrawal, S., Gupta, S., & Agrawal, A. (2011) · AGE · doi:10.1007/s11357-010-9191-3 · Cited by 165
Henson, S. M., Macaulay, R., Riddell, N. E., Nunn, C. J., & Akbar, A. N. (2015) · European Journal of Immunology · doi:10.1002/eji.201445312 · Cited by 146
Intrinsic defects in B cell response to seasonal influenza vaccination in elderly humans
Frasca, D., Diaz, A., Romero, M., Landin, A. M., Phillips, M., Lechner, S. C., Ryan, J. G., & Blomberg, B. B. (2010) · Vaccine · doi:10.1016/j.vaccine.2010.10.023 · Cited by 143
Self-citationAdlowitz, D. G., Barnard, J., Biear, J. N., Cistrone, C., Owen, T., Wang, W., Palanichamy, A., Ezealah, E., Campbell, D., Wei, C., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0128269 · Cited by 137
Cytomegalovirus (CMV) seropositivity decreases B cell responses to the influenza vaccine
Frasca, D., Diaz, A., Romero, M., Landin, A. M., & Blomberg, B. B. (2015) · Vaccine · doi:10.1016/j.vaccine.2015.01.071 · Cited by 116
Self-citationHigh TNF-α levels in resting B cells negatively correlate with their response
Frasca, D., Diaz, A., Romero, M., Landin, A. M., & Blomberg, B. B. (2014) · Experimental Gerontology · doi:10.1016/j.exger.2014.01.004 · Cited by 115
Self-citationCharacterization of naıve, memory and effector CD8+ T cells: effect of age
Gupta, S., Bi, R., Su, K. W., Yel, L., Chiplunkar, S., & Gollapudi, S. V. S. (2004) · Experimental Gerontology · doi:10.1016/j.exger.2003.08.013 · Cited by 107
A Reassessment of IgM Memory Subsets in Humans
Bagnara, D., Squillario, M., Kipling, D., Mora, T., Walczak, A. M., Silva, L. D., Weller, S., Dunn‐Walters, D. K., Weill, J., & Reynaud, C. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500753 · Cited by 106
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
LKB 1 and AMPK : central regulators of lymphocyte metabolism and function
Blagih, J., Krawczyk, C. M., & Jones, R. G. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01157.x · Cited by 91
Association between LTA, TNF and AGER Polymorphisms and Late Diabetic Complications
Lindholm, E., Bakhtadze, E., Cilio, C., Agardh, E., Groop, L., & Agardh, C. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002546 · Cited by 91
Unique biomarkers for B-cell function predict the serum response to pandemic H1N1 influenza vaccine
Frasca, D., Diaz, A., Romero, M., Phillips, M., Mendez, N. V., Landin, A. M., & Blomberg, B. B. (2012) · International Immunology · doi:10.1093/intimm/dxr123 · Cited by 86
Self-citationBuffa, S., Pellicanò, M., Bulati, M., Martorana, A., Goldeck, D., Caruso, C., Pawelec, G., & Colonna‐Romano, G. (2012) · AGE · doi:10.1007/s11357-012-9488-5 · Cited by 83
Frasca, D., Diaz, A., Romero, M., Mendez, N. V., Landin, A. M., Ryan, J., & Blomberg, B. B. (2013) · Vaccine · doi:10.1016/j.vaccine.2013.05.003 · Cited by 79
Self-citationFrasca, D., Diaz, A., Romero, M., Mendez, N. V., Landin, A. M., & Blomberg, B. B. (2013) · Immunity & Ageing · doi:10.1186/1742-4933-10-14 · Cited by 77
Self-citationTumor necrosis factor-a, biologic agents and cardiovascular risk
Sarzi‐Puttini, P., Atzeni, F., Doria, A., Iaccarino, L., & Turiel, M. (2005) · Lupus · doi:10.1191/0961203305lu2220oa · Cited by 69
MicroRNAs miR-155 and miR-16 decrease AID and E47 in B cells from elderly individuals
Frasca, D., Diaz, A., Romero, M., Ferracci, F., & Blomberg, B. B. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1500520 · Cited by 69
Self-citationBoraschi, D., Giudice, G. D., Dutel, C., Ivanoff, B., Rappuoli, R., & Grubeck‐Loebenstein, B. (2010) · Vaccine · doi:10.1016/j.vaccine.2010.03.035 · Cited by 64
Verma, N., Dimitrova, M., Carter, D. M., Crevar, C. J., Ross, T. M., Golding, H., & Khurana, S. (2012) · Journal of Virology · doi:10.1128/jvi.07085-11 · Cited by 60
Cagigi, A., Du, L., Dang, L. V. P., Grützmeier, S., Atlas, A., Chiodi, F., Pan‐Hammarström, Q., & Nilsson, A. (2009) · PLoS ONE · doi:10.1371/journal.pone.0005427 · Cited by 54
Martorana, A., Balistreri, C. R., Bulati, M., Buffa, S., Azzarello, D. M., Camarda, C., Monastero, R., Caruso, C., & Colonna‐Romano, G. (2014) · Immunology Letters · doi:10.1016/j.imlet.2014.06.003 · Cited by 47
Isaacs, J. D. (2009) · Expert Opinion on Biological Therapy · doi:10.1517/14712590903379494 · Cited by 41
Cagigi, A., Rinaldi, S., Martino, A. D., Manno, E. C., Zangari, P., Aquilani, A., Cotugno, N., Nicolosi, L., Villani, A., Bernardi, S., et al. (2013) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2013.10.003 · Cited by 34
Cited by
Sorted by citations
Can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity?
Duggal, N. A., Niemiro, G., Harridge, S. D. R., Simpson, R. J., & Lord, J. M. (2019) · Nature Reviews Immunology · doi:10.1038/s41577-019-0177-9 · Cited by 436
Vaccination in the elderly: The challenge of immune changes with aging
Ciabattini, A., Nardini, C., Santoro, F., Garagnani, P., Franceschi, C., & Medaglini, D. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2018.10.010 · Cited by 411
Aging, obesity, and inflammatory age-related diseases
Frasca, D., Blomberg, B. B., & Paganelli, R. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01745 · Cited by 371
Self-citationSARS-CoV-2, COVID-19 and the aging immune system
Bartleson, J. M., Radenkovic, D., Covarrubias, A. J., Furman, D., Winer, D. A., & Verdin, E. (2021) · Nature Aging · doi:10.1038/s43587-021-00114-7 · Cited by 359
Human CD 8 + EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK
Callender, L. A., Carroll, E. C., Beal, R. W. J., Chambers, E. S., Nourshargh, S., Akbar, A. N., & Henson, S. M. (2017) · Aging Cell · doi:10.1111/acel.12675 · Cited by 278
Metadata
- Authors
- Frasca, D., Diaz, A., Romero, M., & Blomberg, B. B.
- Affiliations
- University of Miami (US)
- Corresponding author
- Frasca, Daniela
- Venue
- Experimental Gerontology
- Publisher
- Elsevier BV
- Published
- 2017-01
- Volume
- 87
- Issue
- Pt A
- Pages
- 113-120
- ISSN
- 0531-5565 (ISSN-L)
- OpenAlex
- W2559849490
- Cited by
- 160
- References
- 57
- Citations by year
- 2026: 10 · 2025: 17 · 2024: 21 · 2023: 14 · 2022: 21 · 2021: 30 · 2020: 15 · 2019: 13 · 2018: 8 · 2017: 10
- FWCI
- 8.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Gerontology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH (R01 AG032576, R21 AI096446, R21 AG042826, R56 AG032576)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- 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
- Keywords
- senescence-associated secretory phenotype, cellular senescence, B cell aging, influenza vaccine response, AMPK, p38 MAPK signaling, metabolic signaling, class switch recombination, p16INK4, inflammatory cytokines, human B lymphocytes
- MeSH terms
- Adult, Aged, Aged, 80 and over, Aging, Cell Line, Female, Hemagglutination Inhibition Tests, Humans, Male, Middle Aged, Biomarkers, B-Lymphocyte Subsets, Cytokines, Cellular Senescence, MAP Kinase Signaling System, MicroRNAs, Metabolic Networks and Pathways, AMP-Activated Protein Kinases
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
