Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway
Abstract
Aging represents a state of paradox where chronic inflammation is associated with declining immune responses. Dendritic cells (DCs) are the major APCs responsible for initiating an immune response. However, DC functions in aging have not been studied in detail. In this study, we have compared the innate immune functions of monocyte-derived myeloid DCs from elderly subjects with DCs from young individuals. We show that although phenotypically comparable, DCs from the aging are functionally different from DCs from the young. In contrast to DCs from the young, DCs from elderly individuals display 1) significantly reduced capacity to phagocytose Ags via macropinocytosis and endocytosis as determined by flow cytometry; 2) impaired capacity to migrate in vitro in response to the chemokines MIP-3β and stromal cell-derived factor-1; and 3) significantly increased LPS and ssRNA-induced secretion of TNF-α and IL-6, as determined by ELISA. Investigations of intracellular signaling revealed reduced phosphorylation of AKT in DCs from the aging, indirectly suggesting decreased activation of the PI3K pathway. Because the PI3K-signaling pathway plays a positive regulatory role in phagocytosis and migration, and also functions as a negative regulator of TLR signaling by inducing activation of p38 MAPK, this may explain the aberrant innate immune functioning of DCs from elderly subjects. Results from real-time PCR and protein expression by flow cytometry demonstrated an increased expression of phosphatase and tensin homolog, a negative regulator of the PI3K-signaling pathway, in DCs from the aging. Increased phosphatase and tensin homolog may thus be responsible for the defect in AKT phosphorylation and, therefore, the altered innate immune response of DCs from elderly humans.
Integrity signals
Registry
Cites
Statistics
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?
Circulating numbers, phenotypes, and costimulatory molecule expression of myeloid and plasmacytoid DCs appear intact in older individuals.
“Circulating numbers of myeloid and plasmacytoid DCs, their phenotypes, and their ability to express costimulatory molecules appear to be intact in older individuals”
From Successful and Maladaptive T Cell Aging (2017) · cites this paper as Agrawal et al., 2007
In humans, aged subjects show reduced mobilization of Langerhans cells from skin to lymphoid organs upon TNF-alpha stimulation, and an age-associated increase in TLR4- and TLR8-dependent cytokine production in MDDCs.
“In humans, a reduced mobilization of LCs from the skin to lymphoid organs upon TNF-alpha stimulation have been shown in aged subjects [56], while an age-associated increase in TLR4- and TLR8-dependent cytokine production has been observed in human MDDCs [59].”
From Aging of the immune system: Focus on inflammation and vaccination (2016) · cites this paper as [59]
Aged DCs maintain the ability to upregulate chemokines and chemokine receptors but exhibit decreased migratory capacity in response to stimuli.
“In addition, aged DCs maintain the ability to upregulate chemokines and chemokine receptors but exhibit decreased migratory capacity in response to stimuli (114).”
From Aging and Lung Disease (2020) · cites this paper as [114]
Altered PRR expression and/or changes in downstream signaling cascades may underlie dysregulated DC responses in older persons.
“Altered PRR expression and/or changes in downstream signaling cascades may underlie dysregulated DC responses in older persons (114, 116).”
From Aging and Lung Disease (2020) · cites this paper as [114]
Despite comparable cell numbers, differentiation, and morphology in the young and aged, DCs from older persons exhibit impaired phagocytosis of antigen.
“Despite comparable cell numbers, differentiation, and morphology in the young and aged, DCs from older persons exhibit impaired phagocytosis of antigen (113, 114).”
From Aging and Lung Disease (2020) · cites this paper as [114]
Cites
Dendritic cells and the control of immunity
Banchereau, J., & Steinman, R. M. (1998) · Nature · doi:10.1038/32588 · Cited by 14,244 · see citing works
Immunobiology of Dendritic Cells
Banchereau, J., Brière, F., Caux, C., Davoust, J. M., Lebecque, S., Liu, Y., Pulendran, B., & Palucka, K. (2000) · Annual Review of Immunology · doi:10.1146/annurev.immunol.18.1.767 · Cited by 6,612 · see citing works
The Dendritic Cell System and its Role in Immunogenicity
Steinman, R. M. (1991) · Annual Review of Immunology · doi:10.1146/annurev.iy.09.040191.001415 · Cited by 4,659 · see citing works
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism
Engelman, J. A., Luo, J., & Cantley, L. C. (2006) · Nature Reviews Genetics · doi:10.1038/nrg1879 · Cited by 3,330 · see citing works
Fadok, V. A., Bratton, D. L., Konowal, A., Freed, P. W., Westcott, J. Y., & Henson, P. M. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1112 · Cited by 3,166 · see citing works
Maehama, T., & Dixon, J. E. (1998) · Journal of Biological Chemistry · doi:10.1074/jbc.273.22.13375 · Cited by 3,104 · see citing works
Sallusto, F., Cella, M., Danieli, C., & Lanzavecchia, A. (1995) · The Journal of Experimental Medicine · doi:10.1084/jem.182.2.389 · Cited by 2,501 · see citing works
Cantley, L. C., & Neel, B. G. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.8.4240 · Cited by 2,007 · see citing works
Toll-like receptors control activation of adaptive immune responses
Schnare, M., Barton, G. M., Czopik, A. K., Takeda, K., Akira, S., & Medzhitov, R. M. (2001) · Nature Immunology · doi:10.1038/ni712 · Cited by 1,364 · see citing works
Sauter, B., Albert, M. L., Francisco, L. M., Larsson, M., Somersan, S., & Bhardwaj, N. (2000) · The Journal of Experimental Medicine · doi:10.1084/jem.191.3.423 · Cited by 1,357 · see citing works
The Multiple Roles of PTEN in Tumor Suppression
Di Cristofano, A., & Pandolfi, P. P. (2000) · Cell · doi:10.1016/s0092-8674(00)80674-1 · Cited by 1,182 · see citing works
Age-related changes in lymphocyte development and function
Linton, P. J., & Dorshkind, K. A. (2004) · Nature Immunology · doi:10.1038/ni1033 · Cited by 1,180 · see citing works
Jonuleit, H., Kühn, U., Müller, G., Steinbrink, K., Paragnik, L., Schmitt, E., Knop, J. X. F. R., & Enk, A. (1997) · European Journal of Immunology · doi:10.1002/eji.1830271209 · Cited by 1,163 · see citing works
Dendritic-cell trafficking to lymph nodes through lymphatic vessels
Randolph, G. J., Angeli, V., & Swartz, M. A. (2005) · Nature Reviews Immunology · doi:10.1038/nri1670 · Cited by 1,111 · see citing works
Araki, N., Johnson, M. T., & Swanson, J. A. (1996) · The Journal of cell biology · doi:10.1083/jcb.135.5.1249 · Cited by 949 · see citing works
Guha, M., & Mackman, N. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203298200 · Cited by 799 · see citing works
Sun, H., Lesche, R., Li, D., Liliental, J., Zhang, H., Gao, J., Gavrilova, N. J., Mueller, B., Liu, X., & Wu, H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.11.6199 · Cited by 796 · see citing works
Agrawal, S., Agrawal, A., Doughty, B. L., Gerwitz, A., Blenis, J., Dyke, T. E. V., & Pulendran, B. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.10.4984 · Cited by 726 · see citing works
Self-citationAging and proinflammatory cytokines
Bruunsgaard, H., Pedersen, M., & Pedersen, B. K. (2001) · Current Opinion in Hematology · doi:10.1097/00062752-200105000-00001 · Cited by 690 · see citing works
PTEN: Life as a Tumor Suppressor
Simpson, L., & Parsons, R. E. (2001) · Experimental Cell Research · doi:10.1006/excr.2000.5130 · Cited by 679 · see citing works
Increased cytokine production in mononuclear cells of healthy elderly people
Fagiolo, U., Cossarizza, A., Scala, E., Fanales‐Belasio, E., Ortolani, C., Cozzi, E., Monti, D., Franceschi, C., & Paganelli, R. (1993) · European Journal of Immunology · doi:10.1002/eji.1830230950 · Cited by 665 · see citing works
Cutting edge: impaired toll-like receptor expression and function in aging
Renshaw, M., Rockwell, J., Engleman, C., Gewirtz, A., Katz, J., & Sambhara, S. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.9.4697 · Cited by 626 · see citing works
PI3K and negative regulation of TLR signaling
Fukao, T., & Koyasu, S. (2003) · Trends in Immunology · doi:10.1016/s1471-4906(03)00139-x · Cited by 612 · see citing works
PTEN: a tumour suppressor that functions as a phospholipid phosphatase
Maehama, T. (1999) · Trends in Cell Biology · doi:10.1016/s0962-8924(99)01519-6 · Cited by 591 · see citing works
PI3K-mediated negative feedback regulation of IL-12 production in DCs
Fukao, T., Tanabe, M., Terauchi, Y., Ota, T., Matsuda, S., Asano, T., Kadowaki, T., Takeuchi, T., & Koyasu, S. (2002) · Nature Immunology · doi:10.1038/ni825 · Cited by 529 · see citing works
Inflammation and the Degenerative Diseases of Aging
McGeer, P. L., & McGeer, E. G. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1332.007 · Cited by 519 · see citing works
Sensing Pathogens and Tuning Immune Responses
Pulendran, B., Palucka, K., & Banchereau, J. (2001) · Science · doi:10.1126/science.1062060 · Cited by 463 · see citing works
p150Ship, a signal transduction molecule with inositol polyphosphate-5-phosphatase activity.
Lioubin, M. N., Algate, P. A., Tsai, S., Carlberg, K., Aebersold, A., & Rohrschneider, L. R. (1996) · Genes & Development · doi:10.1101/gad.10.9.1084 · Cited by 418 · see citing works
Increase of plasma IL-6 concentration with age in healthy subjects
Wei, J., Xu, H., Davies, J. L., & Hemmings, G. P. (1992) · Life Sciences · doi:10.1016/0024-3205(92)90112-3 · Cited by 402 · see citing works
Pawelec, G. (1998) · Frontiers in bioscience · doi:10.2741/a266 · Cited by 357 · see citing works
PTEN: from pathology to biology
Sulis, M. L. (2003) · Trends in Cell Biology · doi:10.1016/s0962-8924(03)00175-2 · Cited by 342 · see citing works
Association of circulating TNF-α and IL-6 with ageing and parkinsonism
Dobbs, R. J., Charlett, A., Purkiss, A. G., Dobbs, S. M., Weller, C., & Peterson, D. W. (1999) · Acta Neurologica Scandinavica · doi:10.1111/j.1600-0404.1999.tb00721.x · Cited by 324 · see citing works
Haynes, L., Eaton, S. M., Burns, E. M., Randall, T. D., & Swain, S. L. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2433717100 · Cited by 270 · see citing works
Martin, M., Schifferle, R. E., Cuesta, N., Vogel, S. N., Katz, J., & Michalek, S. M. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.171.2.717 · Cited by 259 · see citing works
Antigen-independent changes in naive CD4 T cells with aging.
Linton, P. J., Haynes, L., Klinman, N. R., & Swain, S. L. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.184.5.1891 · Cited by 248 · see citing works
Kellermann, S., Hudak, S. A., Oldham, E. R., Liu, Y.-J., & McEvoy, L. M. (1999) · PubMed · Cited by 244 · see citing works
Utsuyama, M., Hirokawa, K., Kurashima, C., Fukayama, M., Inamatsu, T., Suzuki, K., Hashimoto, W., & Sato, K. (1992) · Mechanisms of Ageing and Development · doi:10.1016/0047-6374(92)90016-7 · Cited by 239 · see citing works
Deng, Y., Jing, Y., Campbell, A. E., & Gravenstein, S. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.6.3437 · Cited by 230 · see citing works
Kellermann, S., Hudak, S. A., Oldham, E. R., Liu, Y.-J., & McEvoy, L. M. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.7.3859 · Cited by 205 · see citing works
Circulating, Interferon‐Producing Plasmacytoid Dendritic Cells Decline During Human Ageing
Shodell, M., & Siegal, F. P. (2002) · Scandinavian Journal of Immunology · doi:10.1046/j.1365-3083.2002.01148.x · Cited by 189 · see citing works
Lung, T. L., Saurwein-Teissl, M., Parson, W., Schönitzer, D., & Grubeck-Loebenstein, B. (2000) · Vaccine · doi:10.1016/s0264-410x(99)00494-6 · Cited by 161 · see citing works
Defective dendritic cell migration and activation of adaptive immunity in PI3Kγ‐deficient mice
Prete, A. D., Vermi, W., Dander, E., Otero, K., Barberis, L., Luini, W., Bernasconi, S., Sironi, M., Santoro, A., Garlanda, C., et al. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600361 · Cited by 155 · see citing works
Chemokine signalling: pivoting around multiple phosphoinositide 3‐kinases
Curnock, A. P., Logan, M. K., & Ward, S. G. (2002) · Immunology · doi:10.1046/j.1365-2567.2002.01345.x · Cited by 151 · see citing works
Phosphoinositide 3‐kinase: a key biochemical signal for cell migration in response to chemokines
Sotsios, Y., & Ward, S. G. (2000) · Immunological Reviews · doi:10.1034/j.1600-065x.2000.17712.x · Cited by 147 · see citing works
Early activation defects in T lymphocytes from aged mice
Miller, R. A., Gorcia, G., Kirk, C. J., & Witkowski, J. M. (1997) · Immunological Reviews · doi:10.1111/j.1600-065x.1997.tb01029.x · Cited by 146 · see citing works
The aging immune system: Primary and secondary alterations of immune reactivity in the elderly
Wick, G., & Grubeck‐Loebenstein, B. (1997) · Experimental Gerontology · doi:10.1016/s0531-5565(96)00152-0 · Cited by 142 · see citing works
Steger, M. M., Maczek, C., & Grubeck-Loebenstein, B. (1996) · Clinical & Experimental Immunology · doi:10.1046/j.1365-2249.1996.d01-790.x · Cited by 138 · see citing works
Intrinsic versus environmental influences on T‐cell responses in aging
Linton, P., Li, S. P., Zhang, Y., Bautista, B., Huynh, Q. L., & Trinh, T. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00266.x · Cited by 115 · see citing works
Characterization 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 · see citing works
Self-citationNew Players in TLR-Mediated Innate Immunity: PI3K and Small Rho GTPases
Ruse, M., & Knaus, U. G. (2006) · Immunologic Research · doi:10.1385/ir:34:1:33 · Cited by 104 · see citing works
Dong, R., Cwynarski, K., Entwistle, A., Marelli‐Berg, F. M., Dazzi, F., Simpson, E., Goldman, J. M., Melo, J. V., Lechler, R. I., Bellantuono, I., et al. (2003) · Blood · doi:10.1182/blood-2002-06-1841 · Cited by 101 · see citing works
Effect of Aging on Epidermal Dendritic Cell Populations in C57BL/6J Mice
Sprecher, E., Becker, Y., Kraal, G., Hall, E. J., Harrison, D. G., & Shultz, L. D. (1990) · Journal of Investigative Dermatology · doi:10.1111/1523-1747.ep12874586 · Cited by 91 · see citing works
Chemokine mediated control of dendritic cell migration and function
Gunn, M. D. (2003) · Seminars in Immunology · doi:10.1016/j.smim.2003.08.004 · Cited by 82 · see citing works
Cumberbatch, M., Dearman, R. J., & Kimber, I. (2002) · Immunology · doi:10.1046/j.1365-2567.2002.01381.x · Cited by 78 · see citing works
Phosphatidylinositol 3‐kinase regulation of fluid phase endocytosis
Clague, M. J., Thorpe, C., & Jones, A. T. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)00576-u · Cited by 76 · see citing works
Effect of Aging on Bone Marrow-Derived Murine CD11c+CD4-CD8 - Dendritic Cell Function
Grolleau‐Julius, A., Garg, M. R., Mo, R., Stoolman, L. L., & Yung, R. L. (2006) · The Journals of Gerontology Series A · doi:10.1093/gerona/61.10.1039 · Cited by 69 · see citing works
Surface markers and transendothelial migration of dendritic cells from elderly subjects
Pietschmann, P., Hahn, P., Kudlacek, S., Thomas, R., & Peterlik, M. (2000) · Experimental Gerontology · doi:10.1016/s0531-5565(99)00089-3 · Cited by 68 · see citing works
Effects of age on antibody affinity maturation
Dunn‐Walters, D. K., Banerjee, M., & Mehr, R. (2003) · Biochemical Society Transactions · doi:10.1042/bst0310447 · Cited by 60 · see citing works
Epidermal langerhans cell density and contact sensitivity in young and aged BALB/c mice
Choi, K. L., & Sauder, D. N. (1987) · Mechanisms of Ageing and Development · doi:10.1016/0047-6374(87)90087-x · Cited by 51 · see citing works
Abnormalities of B cells and dendritic cells in SAMP1 mice
Haruna, H., Inaba, M., Inaba, K., Taketani, S., Sugiura, K., Fukuba, Y., Doi, H., Toki, J., Tokunaga, R., & Ikehara, S. (1995) · European Journal of Immunology · doi:10.1002/eji.1830250528 · Cited by 51 · see citing works
Age-related changes of signal transduction in T cells
Hirokawa, K. (1999) · Experimental Gerontology · doi:10.1016/s0531-5565(98)00067-9 · Cited by 49 · see citing works
Molecular interactions of FDCs with B cells in aging
Szakal, A. K. (2002) · Seminars in Immunology · doi:10.1016/s1044-5323(02)00059-3 · Cited by 48 · see citing works
Ineffective humoral immunity in the elderly
McGlauchlen, K., & Vogel, L. A. (2003) · Microbes and Infection · doi:10.1016/j.micinf.2003.09.001 · Cited by 46 · see citing works
Efficacy of anti-influenza peptide vaccine in aged mice
Ben-Yedidia, T., Abel, L., Arnon, R., & Globerson, A. (1998) · Mechanisms of Ageing and Development · doi:10.1016/s0047-6374(98)00045-1 · Cited by 41 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Macrophage death and defective inflammation resolution in atherosclerosis
Tabas, I. (2010) · Nature Reviews Immunology · doi:10.1038/nri2675 · Cited by 1,120 · see citing works
Age-dependent dysregulation of innate immunity
Shaw, A. C., Goldstein, D. R., & Montgomery, R. R. (2013) · Nature Reviews Immunology · doi:10.1038/nri3547 · Cited by 1,061 · see citing works
Aging of the innate immune system
Shaw, A. C., Joshi, S., Greenwood, H., Panda, A., & Lord, J. M. (2010) · Current Opinion in Immunology · doi:10.1016/j.coi.2010.05.003 · Cited by 647 · see citing works
Natural and Sun-Induced Aging of Human Skin
Rittie, L., & Fisher, G. J. (2015) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a015370 · Cited by 600 · see citing works
Solana, R., Tarazona, R., Gayoso, I., Lesur, O., Dupuis, G., & Fulop, T. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.04.008 · Cited by 567 · see citing works
Innate Immune Function by Toll-like Receptors: Distinct Responses in Newborns and the Elderly
Kollmann, T. R., Levy, O., Montgomery, R. R., & Goriely, S. (2012) · Immunity · doi:10.1016/j.immuni.2012.10.014 · Cited by 572 · see citing works
Immunosenescence and human vaccine immune responses
Crooke, S. N., Ovsyannikova, I. G., Poland, G. A., & Kennedy, R. B. (2019) · Immunity & Ageing · doi:10.1186/s12979-019-0164-9 · Cited by 530 · see citing works
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 · see citing works
“In contrast, other recent studies have demonstrated increased production of TNF-a, IL-6, and IFN-a from monocyte-derived DCs from older compared with young participants in response to TLR ligands (38, 39).”
ResultThe aging lung: Physiology, disease, and immunity
Schneider, J. L., Rowe, J. H., Garcia-de-Alba, C., Kim, C. F., Sharpe, A. H., & Haigis, M. C. (2021) · Cell · doi:10.1016/j.cell.2021.03.005 · Cited by 500 · see citing works
Human innate immunosenescence: causes and consequences for immunity in old age
Panda, A., Arjona, A., Sapey, E., Bai, F., Fikrig, E., Montgomery, R. R., Lord, J. M., & Shaw, A. C. (2009) · Trends in Immunology · doi:10.1016/j.it.2009.05.004 · Cited by 502 · see citing works
Cho, S. J., & Stout-Delgado, H. W. (2020) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034610 · Cited by 458 · see citing works
Aging of the immune system: Focus on inflammation and vaccination
Pinti, M., Appay, V., Campisi, J., Frasca, D., Fülöp, T., Sauce, D., Larbi, A., Weinberger, B., & Cossarizza, A. (2016) · European Journal of Immunology · doi:10.1002/eji.201546178 · Cited by 439 · see citing works
The immune system and aging: A review
Castelo-Branco, C., & Soveral, I. (2014) · Gynecological Endocrinology · doi:10.3109/09513590.2013.852531 · Cited by 449 · see citing works
Successful and Maladaptive T Cell Aging
Goronzy, J. J., & Weyand, C. M. (2017) · Immunity · doi:10.1016/j.immuni.2017.03.010 · Cited by 362 · see citing works
Aging and Immune Function: Molecular Mechanisms to Interventions
Ponnappan, S., & Ponnappan, U. (2011) · Antioxidants & Redox Signaling · doi:10.1089/ars.2010.3228 · Cited by 339 · see citing works
Sex, the aging immune system, and chronic disease
Bupp, M. G. (2015) · Cellular Immunology · doi:10.1016/j.cellimm.2015.02.002 · Cited by 333 · see citing works
Aging of the Immune System as a Prognostic Factor for Human Longevity
Larbi, A., Franceschi, C., Mazzatti, D. J., Solana, R., Wikby, A., & Pawelec, G. (2008) · Physiology · doi:10.1152/physiol.00040.2007 · Cited by 316 · see citing works
Interconnections between Inflammageing and Immunosenescence during Ageing
Teissier, T., Boulanger, É., & Cox, L. S. (2022) · Cells · doi:10.3390/cells11030359 · Cited by 310 · see citing works
The role of efferocytosis in atherosclerosis
Kojima, Y., Weissman, I. L., & Leeper, N. J. (2017) · Circulation · doi:10.1161/circulationaha.116.025684 · Cited by 289 · see citing works
Jing, Y., Shaheen, E., Drake, R. R., Chen, N., Gravenstein, S., & Deng, Y. (2009) · Human Immunology · doi:10.1016/j.humimm.2009.07.005 · Cited by 284 · see citing works
The Confluence of Sex Hormones and Aging on Immunity
Gubbels Bupp, M. R., Potluri, T., Fink, A. L., & Klein, S. L. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01269 · Cited by 277 · see citing works
Aging, inflammation, immunity and periodontal disease
Ebersole, J. L., Graves, C. L., González, O. A., Dawson, D. R., Morford, L. A., Emecen‐Huja, P., Hartsfield, J. K., Huja, S. S., Pandruvada, S. N. M., & Wallet, S. M. (2016) · Periodontology 2000 · doi:10.1111/prd.12135 · Cited by 308 · see citing works
Quinn, K. M., Fox, A., Harland, K. L., Russ, B. E., Li, J., Nguyen, T. H. O., Loh, L., Olshanksy, M., Naeem, H., Tsyganov, K., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.05.057 · Cited by 262 · see citing works
Wang, L., Chen, Y., Sternberg, P., & Cai, J. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-1099 · Cited by 267 · see citing works
Macrophages in age-related chronic inflammatory diseases
Oishi, Y., & Manabe, I. (2016) · npj Aging and Mechanisms of Disease · doi:10.1038/npjamd.2016.18 · Cited by 262 · see citing works
Oh, S. J., Lee, J. K., & Shin, O. S. (2019) · Immune Network · doi:10.4110/in.2019.19.e37 · Cited by 261 · see citing works
Impaired functions of peripheral blood monocyte subpopulations in aged humans
Nyugen, J., Agrawal, S., Gollapudi, S., & Gupta, S. (2010) · Journal of Clinical Immunology · doi:10.1007/s10875-010-9448-8 · Cited by 249 · see citing works
Self-citationImpact of aging on dendritic cell functions in humans
Agrawal, A., & Gupta, S. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2010.06.004 · Cited by 246 · see citing works
Self-citationIBD across the age spectrum—is it the same disease?
Ruel, J., Ruane, D., Mehandru, S., Gower‐Rousseau, C., & Colombel, J. (2013) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2013.240 · Cited by 237 · see citing works
Sovran, B., Hugenholtz, F., Elderman, M. E., van Beek, A. A., Graversen, K., Huijskes, M., Boekschoten, M. V., Savelkoul, H. F. J., de Vos, P., Dekker, J. P., et al. (2019) · Scientific Reports · doi:10.1038/s41598-018-35228-3 · Cited by 237 · see citing works
Immune System Dysfunction in the Elderly
Eduardo Fuentes, Q., FUENTES, M., Alarcón, M. A., & Palomo, I. F. (2017) · Anais da Academia Brasileira de Ciências · doi:10.1590/0001-3765201720160487 · Cited by 234 · see citing works
Dysregulation of human Toll-like receptor function in aging
Shaw, A. C., Panda, A., Joshi, S. R., Qian, F., Allore, H. G., & Montgomery, R. R. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2010.10.007 · Cited by 215 · see citing works
Age-related changes in immune function: Effect on airway inflammation
Busse, P. J., & Mathur, S. K. (2010) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2010.08.011 · Cited by 209 · see citing works
Iske, J., Seyda, M., Heinbokel, T., Maenosono, R., Minami, K., Nian, Y., Quante, M., Falk, C. S., Azuma, H., Martin, F., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18039-x · Cited by 211 · see citing works
On phagocytes and macular degeneration
Guillonneau, X., Eandi, C. M., Paques, M., Sahel, J.-A., Sapieha, P., & Sennlaub, F. (2017) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2017.06.002 · Cited by 185 · see citing works
Chougnet, C. A., Thacker, R. I., Shehata, H. M., Hennies, C. M., Lehn, M. A., Lages, C. S., & Janssen, E. M. (2015) · The Journal of Immunology · doi:10.4049/jimmunol.1501006 · Cited by 187 · see citing works
Hallmarks of aging and immunosenescence: Connecting the dots
Rodrigues, L. P., Teixeira, V. R., Alencar‐Silva, T., Simonassi-Paiva, B., Pereira, R. W., Pogue, R. E., & Carvalho, J. L. (2021) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2021.01.006 · Cited by 187 · see citing works
Targeting Inflammation and Immunosenescence to Improve Vaccine Responses in the Elderly
Pereira, B. I., Xu, X., & Akbar, A. N. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.583019 · Cited by 182 · see citing works
Psarras, A., Alase, A. A., Antanaviciute, A., Carr, I., Yusof, M. Y. M., Wittmann, M., Emery, P., Tsokos, G. C., & Vital, E. M. J. (2020) · Nature Communications · doi:10.1038/s41467-020-19918-z · Cited by 177 · see citing works
Age-related immune alterations and cerebrovascular inflammation
Finger, C. E., Moreno‐González, I., Gutiérrez, A., Moruno-Manchon, J. F., & McCullough, L. D. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01361-1 · Cited by 177 · see citing works
Derhovanessian, E., Solana, R., Larbi, A., & Pawelec, G. (2008) · Immunity & Ageing · doi:10.1186/1742-4933-5-11 · Cited by 169 · see citing works
Parallels in Immunometabolic Adipose Tissue Dysfunction with Ageing and Obesity
Trim, W. V., Turner, J. E., & Thompson, D. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00169 · Cited by 167 · see citing works
Aging, inflammation and cancer
Bottazzi, B., Ríboli, E., & Mantovani, A. (2018) · Seminars in Immunology · doi:10.1016/j.smim.2018.10.011 · Cited by 167 · see citing works
Renert-Yuval, Y., Del Duca, E., Pavel, A. B., Fang, M., Lefferdink, R., Wu, J., Diaz, A., Estrada, Y. D., Canter, T., Zhang, N., et al. (2021) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2021.01.001 · Cited by 168 · see citing works
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 · see citing works
Self-citationIncreased Reactivity of Dendritic Cells from Aged Subjects to Self-Antigen, the Human DNA
Agrawal, A., Tay, J., Ton, S., Agrawal, S., & Gupta, S. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.182.2.1138 · Cited by 165 · see citing works
Self-citationThe Role of Stress Factors during Aging of the Immune System
Bauer, M. E., Jeckel, C. M. M., & Luz, C. (2009) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2008.03966.x · Cited by 167 · see citing works
Understanding immunosenescence and its impact on vaccination of older adults
Allen, J. C., Toapanta, F. R., Chen, W. H., & Tennant, S. M. (2020) · Vaccine · doi:10.1016/j.vaccine.2020.11.002 · Cited by 157 · see citing works
Innate immune responses in the ageing lung.
Boe, D. M., Boule, L. A., & Kovacs, E. J. (2016) · Clinical and Experimental Immunology · doi:10.1111/cei.12881 · Cited by 156 · see citing works
Skeletal muscle regeneration and impact of aging and nutrition
Domingues-Faria, C., Vasson, M.-P., Goncalves-Mendes, N., Boirie, Y., & Walrand, S. (2016) · Ageing Research Reviews · doi:10.1016/j.arr.2015.12.004 · Cited by 157 · see citing works
Role of Dendritic Cells in Inflammation and Loss of Tolerance in the Elderly
Agrawal, A., Agrawal, S., & Gupta, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00896 · Cited by 154 · see citing works
Self-citationThe Dynamics of B Cell Aging in Health and Disease
de Mol, J., Kuiper, J., Tsiantoulas, D., & Foks, A. C. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.733566 · Cited by 155 · see citing works
Qian, F., Wang, X., Zhang, L., Lin, A., Zhao, H., Fikrig, E., & Montgomery, R. R. (2011) · The Journal of Infectious Diseases · doi:10.1093/infdis/jir048 · Cited by 151 · see citing works
Impaired Dendritic Cell Function in Aging Leads to Defective Antitumor Immunity
Grolleau‐Julius, A., Harning, E. K., Close, L. A., & Yung, R. L. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5769 · Cited by 151 · see citing works
Stout-Delgado, H. W., Yang, X. T., Walker, W. E., Tesar, B. M., & Goldstein, D. R. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.10.6747 · Cited by 148 · see citing works
Paradoxical changes in innate immunity in aging: recent progress and new directions
Montgomery, R. R., & Shaw, A. C. (2015) · Journal of Leukocyte Biology · doi:10.1189/jlb.5mr0315-104r · Cited by 147 · see citing works
Immunosenescence: signaling pathways, diseases and therapeutic targets
Fu, Y., Wang, B., Alu, A., Hong, W., Hong, L., He, X., Shi, H., Cheng, P., & Yang, X. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02371-z · Cited by 157 · see citing works
Zhou, L., Leonard, A., Pavel, A. B., Malik, K., Raja, A., Glickman, J., Estrada, Y. D., Peng, X., del Duca, E., Sanz-Cabanillas, J., et al. (2019) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2019.01.015 · Cited by 146 · see citing works
Aging and its impact on innate immunity and inflammation: Implications for periodontitis
Hajishengallis, G. (2013) · Journal of Oral Biosciences · doi:10.1016/j.job.2013.09.001 · Cited by 147 · see citing works
Leukocyte function in the aging immune system
Desai, A., Grolleau‐Julius, A., & Yung, R. L. (2010) · Journal of Leukocyte Biology · doi:10.1189/jlb.0809542 · Cited by 141 · see citing works
Crooke, S. N., Ovsyannikova, I. G., Poland, G. A., & Kennedy, R. B. (2019) · Experimental Gerontology · doi:10.1016/j.exger.2019.110632 · Cited by 143 · see citing works
Dysbiosis, malnutrition and enhanced gut-lung axis contribute to age-related respiratory diseases
Saint‐Criq, V., Lugo‐Villarino, G., & Thomas, M. (2020) · Ageing Research Reviews · doi:10.1016/j.arr.2020.101235 · Cited by 143 · see citing works
The Role of Immunosenescence in Neurodegenerative Diseases
Costantini, E., D’Angelo, C., & Reale, M. (2018) · Mediators of Inflammation · doi:10.1155/2018/6039171 · Cited by 133 · see citing works
A Role for Immature Myeloid Cells in Immune Senescence
Enioutina, E. Y., Bareyan, D., & Daynes, R. A. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1002987 · Cited by 130 · see citing works
Impact of aging on antigen presentation cell function of dendritic cells
Wong, C. K., & Goldstein, D. R. (2013) · Current Opinion in Immunology · doi:10.1016/j.coi.2013.05.016 · Cited by 129 · see citing works
Immunosenescence and Challenges of Vaccination against Influenza in the Aging Population.
Reber, A. J., Chirkova, T., Kim, J. H., Cao, W., Biber, R., Shay, D. K., & Sambhara, S. R. (2012) · Europe PMC (PubMed Central) · Cited by 128 · see citing works
Behzad, H., Huckriede, A. L. W., Haynes, L., Gentleman, B., Coyle, K. M., Wilschut, J., Kollmann, T. R., Reed, S. G., & McElhaney, J. E. (2011) · The Journal of Infectious Diseases · doi:10.1093/infdis/jir769 · Cited by 128 · see citing works
The Immune Landscape of Visceral Adipose Tissue During Obesity and Aging
Khan, S. M., Chan, Y. T., Revelo, X. S., & Winer, D. A. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00267 · Cited by 126 · see citing works
Hallmarks and detection techniques of cellular senescence and cellular ageing in immune cells
Zhou, D., Borsa, M., & Simon, A. K. (2021) · Aging Cell · doi:10.1111/acel.13316 · Cited by 129 · see citing works
Aging of the Innate Immune System: An Update
Mahbub, S., Brubaker, A. L., & Kovacs, E. J. (2011) · Current Immunology Reviews · doi:10.2174/157339511794474181 · Cited by 125 · see citing works
Wang, Q., & Zennadi, R. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124259 · Cited by 124 · see citing works
Immunosenescence in vertebrates and invertebrates
Müller, L., Fülöp, T., & Pawelec, G. (2013) · Immunity & Ageing · doi:10.1186/1742-4933-10-12 · Cited by 117 · see citing works
Rheumatoid Arthritis: A Role for Immunosenescence?
Lindström, T. M., & Robinson, W. H. (2010) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2010.02965.x · Cited by 122 · see citing works
Messaoudi, I., Totonchy, J. E., Totonchy, T., Kreklywich, C. N., Haberthur, K., Springgay, L., Brien, J. D., Diamond, M., DeFilippis, V. R., & Streblow, D. N. (2013) · PLoS neglected tropical diseases · doi:10.1371/journal.pntd.0002343 · Cited by 118 · see citing works
Phagocyte dysfunction, tissue aging and degeneration
Li, W. (2013) · Ageing Research Reviews · doi:10.1016/j.arr.2013.05.006 · Cited by 114 · see citing works
A Rationale for Age-Adapted Immunosuppression in Organ Transplantation
Krenzien, F., Elkhal, A., Quante, M., Biefer, H. R. C., Hirofumi, U., Gabardi, S., & Tullius, S. G. (2015) · Transplantation · doi:10.1097/tp.0000000000000842 · Cited by 116 · see citing works
Hou, Y., Chen, M., Bian, Y., Hu, Y., Chuan, J., Zhong, L., Zhu, Y., & Tong, R. (2024) · npj Vaccines · doi:10.1038/s41541-024-00874-4 · Cited by 116 · see citing works
Zhu, W., Germain, C., Liu, Z., Sebastian, Y., Devi-Marulkar, P., Knockaert, S., Brohawn, P. Z., Lehmann, K. P., Damotte, D., Validire, P., et al. (2015) · OncoImmunology · doi:10.1080/2162402x.2015.1051922 · Cited by 113 · see citing works
Biology of Dendritic Cells in Aging
Agrawal, A., Agrawal, S., Tay, J., & Gupta, S. (2007) · Journal of Clinical Immunology · doi:10.1007/s10875-007-9127-6 · Cited by 112 · see citing works
Self-citationImpact of age on T cell signaling: A general defect or specific alterations?
Larbi, A., Pawelec, G., Wong, S. C., Goldeck, D., Tai, J. J.-Y., & Fulop, T. (2011) · Ageing Research Reviews · doi:10.1016/j.arr.2010.09.008 · Cited by 108 · see citing works
Innate immunesenescence: underlying mechanisms and clinical relevance
Hazeldine, J., & Lord, J. M. (2015) · Biogerontology · doi:10.1007/s10522-014-9514-3 · Cited by 104 · see citing works
Ocular Surface Disease and Dacryoadenitis in Aging C57BL/6 Mice
McClellan, A. J., Volpe, E. A., Zhang, X., Darlington, G., Li, D., Pflugfelder, S. C., & de Paiva, C. S. (2014) · American Journal Of Pathology · doi:10.1016/j.ajpath.2013.11.019 · Cited by 104 · see citing works
Pérez, K., Ciotlos, S., McGirr, J., Limbad, C., Doi, R., Nederveen, J. P., Nilsson, M. I., Winer, D. A., Evans, W. J., Tarnopolsky, M. A., et al. (2022) · Aging · doi:10.18632/aging.204435 · Cited by 105 · see citing works
The inflammatory status of the elderly: The intestinal contribution
Schiffrin, E. J., Morley, J. E., Donnet‐Hughes, A., & Guigoz, Y. (2009) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2009.07.011 · Cited by 103 · see citing works
Moretto, M. M., Lawlor, E. M., & Khan, I. A. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.181.11.7977 · Cited by 102 · see citing works
Overcoming immune dysfunction in the elderly: trained immunity as a novel approach
Bulut, O., Kilic, G., Domínguez-Andrés, J., & Netea, M. G. (2020) · International Immunology · doi:10.1093/intimm/dxaa052 · Cited by 99 · see citing works
Lu, Y., Tan, C. T. Y., Nyunt, M. S. Z., Mok, E. W. H., Camous, X., Kared, H., Fülöp, T., Feng, L., Ng, T. P., & Larbi, A. (2016) · Oncotarget · doi:10.18632/oncotarget.8939 · Cited by 98 · see citing works
Correction of age-associated defects in dendritic cells enables CD4+ T cells to eradicate tumors
Zhivaki, D., Kennedy, S. N., Park, J., Borriello, F., Devant, P., Cao, A., Bahleda, K. M., Murphy, S. M., Aubin, C., Evavold, C. L., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.026 · Cited by 101 · see citing works
Channappanavar, R., & Perlman, S. M. (2020) · Journal of Clinical Investigation · doi:10.1172/jci144115 · Cited by 92 · see citing works
Thomas, A. L., Lehn, M. A., Janssen, E. M., Hildeman, D. A., & Chougnet, C. A. (2022) · Scientific Reports · doi:10.1038/s41598-022-21920-y · Cited by 94 · see citing works
Aging and Neutrophils: There Is Still Much To Do
Fortin, C. F., McDonald, P. P., Lesur, O., & Fülöp, T. (2008) · Rejuvenation Research · doi:10.1089/rej.2008.0750 · Cited by 94 · see citing works
Immunity and ageing in man: Annual review 2006/2007
Pawelec, G., & Larbi, A. (2007) · Experimental Gerontology · doi:10.1016/j.exger.2007.09.009 · Cited by 94 · see citing works
Autophagy and Immune Senescence
Zhang, H., Puleston, D. J., & Simon, A. K. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.06.001 · Cited by 93 · see citing works
Alcohol, aging, and innate immunity
Boulé, L. A., & Kovacs, E. J. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.4ru1016-450r · Cited by 92 · see citing works
Sex Differences in Genetic Associations With Longevity
Zeng, Y., Nie, C., Min, J., Chen, H., Liu, X., Ye, R., Chen, Z., Bai, C., Xie, E., Yin, Z., et al. (2018) · JAMA Network Open · doi:10.1001/jamanetworkopen.2018.1670 · Cited by 90 · see citing works
Enumeration of human peripheral blood dendritic cells throughout the life
Orsini, G., Legitimo, A., Failli, A., Massei, F., Biver, P., & Consolini, R. (2012) · International Immunology · doi:10.1093/intimm/dxs006 · Cited by 91 · see citing works
Immunosenescence of Polymorphonuclear Neutrophils
Weßels, I., Jansen, J., Rink, L., & Uciechowski, P. (2010) · The Scientific World JOURNAL · doi:10.1100/tsw.2010.14 · Cited by 89 · see citing works
Agrawal, S., Gupta, S., & Agrawal, A. (2010) · PLoS ONE · doi:10.1371/journal.pone.0013418 · Cited by 90 · see citing works
Self-citationDendritic cells and aging: consequences for autoimmunity
Agrawal, A., Sridharan, A., Prakash, S., & Agrawal, H. (2011) · Expert Review of Clinical Immunology · doi:10.1586/eci.11.77 · Cited by 89 · see citing works
Self-citationThe NLRP3 Inflammasome as a Critical Actor in the Inflammaging Process
Sebastian-Valverde, M., & Pasinetti, G. M. (2020) · Cells · doi:10.3390/cells9061552 · Cited by 89 · see citing works
- Authors
- Agrawal, A., Agrawal, S., Cao, J.-N., Su, H., Osann, K., & Gupta, S.
- Affiliations
- University of California, Irvine (US)
- Division of Basic and Clinical Immunology, University of California , Irvine, CA 92697
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-06-01
- Volume
- 178
- Issue
- 11
- Pages
- 6912-6922
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1508177354
- Cited by
- 435
- References
- 64
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 20 · 2023: 18 · 2022: 20 · 2021: 20 · 2020: 33 · 2019: 28 · 2018: 29 · 2017: 26 · 2016: 22 · 2015: 22 · 2014: 28 · 2013: 34 · 2012: 21
- FWCI
- 8.05
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of California, Irvine
- National Institute on Aging (AG-027512, R21AG027512)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Keywords
- dendritic cells, aging, innate immunity, phosphoinositide 3-kinase signaling, Akt phosphorylation, phagocytosis, dendritic cell migration, chemokines, CCL19, CXCL12, TNF-α, interleukin-6, lipopolysaccharide, phosphatase and tensin homolog, chronic inflammation, p38 MAPK, Toll-like receptor signaling
- MeSH terms
- Phosphoinositide-3 Kinase Inhibitors, Adult, Aged, Aged, 80 and over, Aging, Cell Count, Cell Differentiation, Cells, Cultured, Dendritic Cells, Humans, Immunity, Innate, Monocytes, Signal Transduction, Up-Regulation, Cytokines, Inflammation Mediators, Jurkat Cells, Phosphatidylinositol 3-Kinases, PTEN Phosphohydrolase
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
