Advertisement

GeroScience

pp 1–19 | Cite as

Inflammaging phenotype in rhesus macaques is associated with a decline in epithelial barrier-protective functions and increased pro-inflammatory function in CD161-expressing cells

  • Edith M. Walker
  • Nadia Slisarenko
  • Giovanni L. Gerrets
  • Patricia J. Kissinger
  • Elizabeth S. Didier
  • Marcelo J. Kuroda
  • Ronald S. Veazey
  • S. Michal Jazwinski
  • Namita RoutEmail author
Original Article

Abstract

The development of chronic inflammation, called inflammaging, contributes to the pathogenesis of age-related diseases. Although it is known that both B and T lymphocyte compartments of the adaptive immune system deteriorate with advancing age, the impact of aging on immune functions of Th17-type CD161-expressing innate immune cells and their role in inflammaging remain incompletely understood. Here, utilizing the nonhuman primate model of rhesus macaques, we report that a dysregulated Th17-type effector function of CD161+ immune cells is associated with leaky gut and inflammatory phenotype of aging. Higher plasma levels of inflammatory cytokines IL-6, TNF-α, IL-1β, GM-CSF, IL-12, and Eotaxin correlated with elevated markers of gut permeability including LPS-binding protein (LBP), intestinal fatty acid binding protein (I-FABP), and sCD14 in aging macaques. Further, older macaques displayed significantly lower frequencies of circulating Th17-type immune cells comprised of CD161+ T cell subsets, NK cells, and innate lymphoid cells. Corresponding with the increased markers of gut permeability, production of the type-17 cytokines IL-17 and IL-22 was impaired in CD161+ T cell subsets and NK cells, along with a skewing towards IFN-γ cytokine production. These findings suggest that reduced frequencies of CD161+ immune cells along with a specific loss in Th17-type effector functions contribute to impaired gut barrier integrity and systemic inflammation in aging macaques. Modulating type-17 immune cell functions via cytokine therapy or dietary interventions towards reducing chronic inflammation in inflammaging individuals may have the potential to prevent or delay age-related chronic diseases and improve immune responses in the elderly population.

Keywords

Inflammaging Leaky gut CD161+ cells I-FABP LBP sCD14 

Notes

Acknowledgments

The authors acknowledge Mary Barnes and Melissa Pattison of the Pathogen Detection and Quantification Core of Tulane National Primate Research Center (TNPRC) for assistance with the multiplex cytokine detection assays and use of the Bioplex-200 instrumentation, and the clinical veterinary staff in the Division of Veterinary Medicine at TNPRC for coordinating the blood collections. Technical assistance of the flow cytometry core facility staff at the TNPRC is greatly appreciated.

Author contributions

Namita Rout was responsible for the study design, data analysis and interpretation and wrote the manuscript. Edith Walker coordinated the overall work including sample collection procedures and conducting the flow cytometry data analysis and in vitro functional assays and helped with manuscript preparation. Nadia Slisarenko and Giovanni Gerrets helped with sample collection and processing and data analysis. Elizabeth S. Didier and Marcelo J. Kuroda provided samples and contributed to the study design. Patricia Kissinger performed the statistical data analyses. Ronald S. Veazey and S. Michal Jazwinski helped with overall data interpretation. All authors read and approved the final manuscript. All authors helped edit and reviewed the final manuscript.

Funding information

This study was supported by the National Institute of General Medical Sciences grant P20 GM103629, as well as the National Institutes of Health (NIH) base grant for TNPRC OD011104-54. The support of NIH grants U42 OD010568 and U42 OD024282 for the macaque breeding colony at TNPRC and additional support from the NIH grants AI097059, AG052349, HL139278 funded studies is acknowledged.

Compliance with ethical standards

Ethics statement

This study was performed using samples collected from nonhuman primates. All procedures were approved by the TNPRC Institutional Animal Care and Use Committee, Animal Welfare Assurance A-4499-01, and were performed in accordance with the Guide for the Care and Use of Laboratory Animals, National Research Council, 2011. The TNPRC maintains an AAALAC-I accredited animal care and use program.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11357_2019_99_Fig10_ESM.png (136 kb)
ESM 1

Circulating levels of γ-chain cytokines and growth factors in healthy young, aging and old group of macaques. Data were obtained using Luminex multiplex cytokine assays for cytokines, chemokines and growth factors. (a) The common cytokine receptor gamma-chain family (γ-chain) cytokines including IL-2, IL-7, and IL-15 levels shown in plasma from rhesus macaques stratified into 3 age-groups comprising young adults 5–10 years (blue bars; n = 18), aging adults 15–20 years (green bars; n = 15), and old adults ≥20 years old (red bars; n = 11). (b) Results are shown for means (+ S.E.M.) of growth factors including the neurotrophic factors platelet-derived growth factor BB (PDGF-BB), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF); as well as for the angiogenic growth factors fibroblast growth factor (FGF-2), and vascular endothelial growth factors (VEGF-A & VEGF-D). No significant differences were found between the three age groups as determined by Mann-Whitney test. (PNG 136 kb)

11357_2019_99_MOESM1_ESM.tiff (1.1 mb)
High resolution image (TIFF 1086 kb)
11357_2019_99_Fig11_ESM.png (94 kb)
ESM 2

Effect of age on frequencies of circulating T cells, NK cells and innate lymphoid cells. Frequencies are shown for (a) adaptive immune cell subsets including total CD3+ T and the CD4+ and CD8+ T cell subsets, and (b) innate cells including CD3-CD8α + NK cells and lineage-negative CD127+ ILCs in PBMCs from 12 young macaques (black bars) and 8 aging/old macaques >15 years old (gray bars). Comparisons were measured by Mann-Whitney test. (c) Spearman rank correlations were measured from results comparing age and frequencies of total CD3+ T, NK and ILCs were examined in the two groups of macaques using Spearman rank correlations. P < 0.05 was considered statistically significant. (PNG 93 kb)

11357_2019_99_MOESM2_ESM.tiff (471 kb)
High resolution image (TIFF 471 kb)
11357_2019_99_Fig9_ESM.png (250 kb)
ESM 3

Intracellular cytokine production by T cell and NK cells in young and aging/older macaques (>15 years old). Results demonstrate the production of IFN-γ, IL-17, and IL-22 by CD4+ and CD8+ T cells, and NK cells from PBMC after 16 h stimulation with PMA/Ionomycin. Data obtained from PBMC of 12 young macaques (black bars) and 8 aging macaques (gray bars) and results were presented as means (+ S.E.M.) after subtraction of background levels from unstimulated cells incubated with medium alone. Significant differences between each group were determined by Mann-Whitney test. P < 0.05 was considered statistically significant. (PNG 249 kb)

11357_2019_99_MOESM3_ESM.tiff (354 kb)
High resolution image (TIFF 353 kb)

References

  1. Aldemir H et al (2005) Cutting edge: lectin-like transcript 1 is a ligand for the CD161 receptor. J Immunol 175:7791–7795.  https://doi.org/10.4049/jimmunol.175.12.7791 CrossRefPubMedGoogle Scholar
  2. Asquith M, Haberthur K, Brown M, Engelmann F, Murphy A, Al-Mahdi Z, Messaoudi I (2012) Age-dependent changes in innate immune phenotype and function in rhesus macaques (Macaca mulatta). Pathobiol Aging Age Relat Dis 2:2.  https://doi.org/10.3402/pba.v2i0.18052 CrossRefGoogle Scholar
  3. Bettcher BM, Neuhaus J, Wynn MJ, Elahi FM, Casaletto KB, Saloner R, Fitch R, Karydas A, Kramer JH (2019) Increases in a pro-inflammatory chemokine, MCP-1, are related to decreases in memory over time. Front Aging Neurosci 11:25.  https://doi.org/10.3389/fnagi.2019.00025 CrossRefPubMedPubMedCentralGoogle Scholar
  4. Billerbeck E et al (2010) Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties. Proc Natl Acad Sci U S A 107:3006–3011.  https://doi.org/10.1073/pnas.0914839107 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Bruunsgaard H, Andersen-Ranberg K, Hjelmborg J, Pedersen BK, Jeune B (2003) Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am J Med 115:278–283.  https://doi.org/10.1016/s0002-9343(03)00329-2 CrossRefPubMedGoogle Scholar
  6. Calder PC et al (2017) Health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition. Ageing Res Rev 40:95–119.  https://doi.org/10.1016/j.arr.2017.09.001 CrossRefPubMedGoogle Scholar
  7. Cannistra SA, Rambaldi A, Spriggs DR, Herrmann F, Kufe D, Griffin JD (1987) Human granulocyte-macrophage colony-stimulating factor induces expression of the tumor necrosis factor gene by the U937 cell line and by normal human monocytes. J Clin Invest 79:1720–1728.  https://doi.org/10.1172/JCI113012 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Cesari M, Penninx BWJH, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, Tracy RP, Rubin SM, Harris TB, Pahor M (2003) Inflammatory markers and cardiovascular disease (The Health, Aging and Body Composition [Health ABC] Study). Am J Cardiol 92:522–528CrossRefGoogle Scholar
  9. Chantry D, Turner M, Brennan F, Kingsbury A, Feldmann M (1990) Granulocyte-macrophage colony stimulating factor induces both HLA-DR expression and cytokine production by human monocytes. Cytokine 2:60–67CrossRefGoogle Scholar
  10. Ciabattini A, Nardini C, Santoro F, Garagnani P, Franceschi C, Medaglini D (2018) Vaccination in the elderly: the challenge of immune changes with aging. Semin Immunol 40:83–94.  https://doi.org/10.1016/j.smim.2018.10.010 CrossRefPubMedGoogle Scholar
  11. Clark RI et al (2015) Distinct shifts in microbiota composition during drosophila aging impair intestinal function and drive mortality. Cell Rep 12:1656–1667.  https://doi.org/10.1016/j.celrep.2015.08.004 CrossRefPubMedPubMedCentralGoogle Scholar
  12. De Martinis M, Franceschi C, Monti D, Ginaldi L (2005) Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 579:2035–2039.  https://doi.org/10.1016/j.febslet.2005.02.055 CrossRefPubMedGoogle Scholar
  13. Didier ES, Sugimoto C, Bowers LC, Khan IA, Kuroda MJ (2012) Immune correlates of aging in outdoor-housed captive rhesus macaques (Macaca mulatta). Immun Ageing 9:25.  https://doi.org/10.1186/1742-4933-9-25 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Didier ES, MacLean AG, Mohan M, Didier PJ, Lackner AA, Kuroda MJ (2016) Contributions of Nonhuman Primates to Research on Aging. Vet Pathol 53:277–290.  https://doi.org/10.1177/0300985815622974 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Fergusson JR, Fleming VM, Klenerman P (2011) CD161-expressing human T cells. Front Immunol 2:36.  https://doi.org/10.3389/fimmu.2011.00036 CrossRefPubMedPubMedCentralGoogle Scholar
  16. Fergusson JR et al (2014) CD161 defines a transcriptional and functional phenotype across distinct human T cell lineages. Cell Rep 9:1075–1088.  https://doi.org/10.1016/j.celrep.2014.09.045 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Fergusson JR et al (2016) CD161(int)CD8+ T cells: a novel population of highly functional, memory CD8+ T cells enriched within the gut. Mucosal Immunol 9:401–413.  https://doi.org/10.1038/mi.2015.69 CrossRefPubMedGoogle Scholar
  18. Forsey RJ, Thompson JM, Ernerudh J, Hurst TL, Strindhall J, Johansson B, Nilsson BO, Wikby A (2003) Plasma cytokine profiles in elderly humans. Mech Ageing Dev 124:487–493CrossRefGoogle Scholar
  19. Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254.  https://doi.org/10.1111/j.1749-6632.2000.tb06651.x CrossRefPubMedGoogle Scholar
  20. Fulop T, Larbi A, Dupuis G, le Page A, Frost EH, Cohen AA, Witkowski JM, Franceschi C (2017) Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? Front Immunol 8:1960.  https://doi.org/10.3389/fimmu.2017.01960 CrossRefPubMedGoogle Scholar
  21. Ghosh S et al (2015) Elevated muscle TLR4 expression and metabolic endotoxemia in human aging. J Gerontol A Biol Sci Med Sci 70:232–246.  https://doi.org/10.1093/gerona/glu067 CrossRefPubMedGoogle Scholar
  22. Giorda R, Rudert WA, Vavassori C, Chambers WH, Hiserodt JC, Trucco M (1990) NKR-P1, a signal transduction molecule on natural killer cells. Science 249:1298–1300CrossRefGoogle Scholar
  23. Hamilton JA, Anderson GP (2004) Mini ReviewGM-CSF Biology. GM-CSF Biology Growth Factors 22:225–231.  https://doi.org/10.1080/08977190412331279881 CrossRefPubMedGoogle Scholar
  24. Hearps AC et al (2012) Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 11:867–875.  https://doi.org/10.1111/j.1474-9726.2012.00851.x CrossRefPubMedGoogle Scholar
  25. Heidenreich S, Gong JH, Schmidt A, Nain M, Gemsa D (1989) Macrophage activation by granulocyte/macrophage colony-stimulating factor. Priming for enhanced release of tumor necrosis factor-alpha and prostaglandin E2. J Immunol 143:1198–1205PubMedGoogle Scholar
  26. Il'yasova D, Colbert LH, Harris TB, Newman AB, Bauer DC, Satterfield S, Kritchevsky SB (2005) Circulating levels of inflammatory markers and cancer risk in the health aging and body composition cohort. Cancer Epidemiol Biomarkers Prev 14:2413–2418.  https://doi.org/10.1158/1055-9965.EPI-05-0316 CrossRefPubMedGoogle Scholar
  27. Justice JN et al (2017) Relationships of depressive behavior and sertraline treatment with walking speed and activity in older female nonhuman primates. Geroscience 39:585–600.  https://doi.org/10.1007/s11357-017-9999-1 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Kurioka A, Klenerman P, Willberg CB (2018) Innate-like CD8+ T-cells and NK cells: converging functions and phenotypes. Immunology.  https://doi.org/10.1111/imm.12925 CrossRefGoogle Scholar
  29. Lane MA (2000) Nonhuman primate models in biogerontology. Exp Gerontol 35:533–541CrossRefGoogle Scholar
  30. Lanier LL, Chang C, Phillips JH (1994) Human NKR-P1A. A disulfide-linked homodimer of the C-type lectin superfamily expressed by a subset of NK and T lymphocytes. J Immunol 153:2417–2428PubMedGoogle Scholar
  31. Lee OJ et al (2014) Circulating mucosal-associated invariant T cell levels and their cytokine levels in healthy adults. Exp Gerontol 49:47–54.  https://doi.org/10.1016/j.exger.2013.11.003 CrossRefPubMedGoogle Scholar
  32. Lee JS et al (2015) Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity 43:727–738.  https://doi.org/10.1016/j.immuni.2015.09.003 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Lee WJ, Liao YC, Wang YF, Lin IF, Wang SJ, Fuh JL (2018) Plasma MCP-1 and cognitive decline in patients with Alzheimer’s disease and mild cognitive impairment: a two-year follow-up study. Sci Rep 8:1280.  https://doi.org/10.1038/s41598-018-19807-y CrossRefPubMedPubMedCentralGoogle Scholar
  34. Liu J et al (2019) Among older adults, age-related changes in the stool microbiome differ by HIV-1 serostatus. EBioMedicine 40:583–594.  https://doi.org/10.1016/j.ebiom.2019.01.033 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Lo BC et al (2019) IL-22 preserves gut epithelial integrity and promotes disease remission during chronic Salmonella infection. J Immunol 202:956–965.  https://doi.org/10.4049/jimmunol.1801308 CrossRefPubMedGoogle Scholar
  36. Maggi L et al (2010) CD161 is a marker of all human IL-17-producing T-cell subsets and is induced by RORC. Eur J Immunol 40:2174–2181.  https://doi.org/10.1002/eji.200940257 CrossRefPubMedGoogle Scholar
  37. Mansfield AS, Nevala WK, Dronca RS, Leontovich AA, Shuster L, Markovic SN (2012) Normal ageing is associated with an increase in Th2 cells, MCP-1 (CCL1) and RANTES (CCL5), with differences in sCD40L and PDGF-AA between sexes. Clin Exp Immunol 170:186–193.  https://doi.org/10.1111/j.1365-2249.2012.04644.x CrossRefPubMedPubMedCentralGoogle Scholar
  38. Mattison JA et al (2012) Impact of caloric restriction on health and survival in rhesus monkeys from the NIA study. Nature 489:318–321.  https://doi.org/10.1038/nature11432 CrossRefPubMedGoogle Scholar
  39. Maxwell JR et al (2015) Differential roles for Interleukin-23 and Interleukin-17 in intestinal immunoregulation. Immunity 43:739–750.  https://doi.org/10.1016/j.immuni.2015.08.019 CrossRefPubMedGoogle Scholar
  40. McNerlan SE, Rea IM, Alexander HD (2002) A whole blood method for measurement of intracellular TNF-alpha, IFN-gamma and IL-2 expression in stimulated CD3+ lymphocytes: differences between young and elderly subjects. Exp Gerontol 37:227–234CrossRefGoogle Scholar
  41. Miko A et al (2018) Gender difference in the effects of interleukin-6 on grip strength—a systematic review and meta-analysis. BMC Geriatr 18:107.  https://doi.org/10.1186/s12877-018-0798-z CrossRefPubMedPubMedCentralGoogle Scholar
  42. Mitchell EL, Davis AT, Brass K, Dendinger M, Barner R, Gharaibeh R, Fodor AA, Kavanagh K (2017) Reduced intestinal motility, mucosal barrier function, and inflammation in aged monkeys. J Nutr Health Aging 21:354–361.  https://doi.org/10.1007/s12603-016-0725-y CrossRefPubMedPubMedCentralGoogle Scholar
  43. Mucida D, Salek-Ardakani S (2009) Regulation of TH17 cells in the mucosal surfaces. J Allergy Clin Immunol 123:997–1003.  https://doi.org/10.1016/j.jaci.2009.03.016 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Novak J, Dobrovolny J, Novakova L, Kozak T (2014) The decrease in number and change in phenotype of mucosal-associated invariant T cells in the elderly and differences in men and women of reproductive age. Scand J Immunol 80:271–275.  https://doi.org/10.1111/sji.12193 CrossRefPubMedGoogle Scholar
  45. O'Keeffe J, Doherty DG, Kenna T, Sheahan K, O'Donoghue DP, Hyland JM, O’Farrelly C (2004) Diverse populations of T cells with NK cell receptors accumulate in the human intestine in health and in colorectal cancer. Eur J Immunol 34:2110–2119.  https://doi.org/10.1002/eji.200424958 CrossRefPubMedGoogle Scholar
  46. Ouyang W, Kolls JK, Zheng Y (2008) The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity 28:454–467.  https://doi.org/10.1016/j.immuni.2008.03.004 CrossRefPubMedPubMedCentralGoogle Scholar
  47. Penninx BW et al (2004) Inflammatory markers and incident mobility limitation in the elderly. J Am Geriatr Soc 52:1105–1113.  https://doi.org/10.1111/j.1532-5415.2004.52308.x CrossRefPubMedGoogle Scholar
  48. Pitcher CJ et al (2002) Development and homeostasis of T cell memory in rhesus macaque. J Immunol 168:29–43.  https://doi.org/10.4049/jimmunol.168.1.29 CrossRefPubMedGoogle Scholar
  49. Povoleri GAM et al (2018) Human retinoic acid-regulated CD161(+) regulatory T cells support wound repair in intestinal mucosa. Nat Immunol 19:1403–1414.  https://doi.org/10.1038/s41590-018-0230-z CrossRefPubMedPubMedCentralGoogle Scholar
  50. Reiner AP et al (2013) Soluble CD14: genomewide association analysis and relationship to cardiovascular risk and mortality in older adults. Arterioscler Thromb Vasc Biol 33:158–164.  https://doi.org/10.1161/ATVBAHA.112.300421 CrossRefPubMedGoogle Scholar
  51. Rendon JL, Li X, Akhtar S, Choudhry MA (2013) Interleukin-22 modulates gut epithelial and immune barrier functions following acute alcohol exposure and burn injury. Shock 39:11–18.  https://doi.org/10.1097/SHK.0b013e3182749f96 CrossRefPubMedPubMedCentralGoogle Scholar
  52. Rera M, Clark RI, Walker DW (2012) Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proc Natl Acad Sci U S A 109:21528–21533.  https://doi.org/10.1073/pnas.1215849110 CrossRefPubMedPubMedCentralGoogle Scholar
  53. Robinson AA, Abraham CR, Rosene DL (2018) Candidate molecular pathways of white matter vulnerability in the brain of normal aging rhesus monkeys. Geroscience 40:31–47.  https://doi.org/10.1007/s11357-018-0006-2 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Roth GS, Mattison JA, Ottinger MA, Chachich ME, Lane MA, Ingram DK (2004) Aging in rhesus monkeys: relevance to human health interventions. Science 305:1423–1426.  https://doi.org/10.1126/science.1102541 CrossRefPubMedGoogle Scholar
  55. Rout N (2016) Enhanced Th1/Th17 functions of CD161+ CD8+ T cells in mucosal tissues of rhesus macaques. PLoS one 11:e0157407.  https://doi.org/10.1371/journal.pone.0157407 CrossRefPubMedPubMedCentralGoogle Scholar
  56. Rout N, Greene J, Yue S, O'Connor D, Johnson RP, Else JG, Exley MA, Kaur A (2012) Loss of effector and anti-inflammatory natural killer T lymphocyte function in pathogenic simian immunodeficiency virus infection. PLoS Pathog 8:e1002928.  https://doi.org/10.1371/journal.ppat.1002928 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Salvioli S, Capri M, Valensin S, Tieri P, Monti D, Ottaviani E, Franceschi C (2006) Inflamm-aging, cytokines and aging: state of the art, new hypotheses on the role of mitochondria and new perspectives from systems biology. Curr Pharm Des 12:3161–3171CrossRefGoogle Scholar
  58. Schaap LA et al (2009) Higher inflammatory marker levels in older persons: associations with 5-year change in muscle mass and muscle strength. J Gerontol A biol Sci Med Sci 64:1183–1189.  https://doi.org/10.1093/gerona/glp097 CrossRefPubMedGoogle Scholar
  59. Shobin E et al (2017) Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey. Geroscience 39:199–220.  https://doi.org/10.1007/s11357-017-9965-y CrossRefPubMedPubMedCentralGoogle Scholar
  60. Simanek AM, Dowd JB, Pawelec G, Melzer D, Dutta A, Aiello AE (2011) Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. PLoS one 6:e16103.  https://doi.org/10.1371/journal.pone.0016103 CrossRefPubMedPubMedCentralGoogle Scholar
  61. Steele AK et al (2014) Contribution of intestinal barrier damage, microbial translocation and HIV-1 infection status to an inflammaging signature. PLoS one 9:e97171.  https://doi.org/10.1371/journal.pone.0097171 CrossRefPubMedPubMedCentralGoogle Scholar
  62. Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, Blumberg RS, Xavier RJ, Mizoguchi A (2008) IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest 118:534–544.  https://doi.org/10.1172/JCI33194 CrossRefPubMedPubMedCentralGoogle Scholar
  63. Thevaranjan N et al (2017) Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21:455-466 e454.  https://doi.org/10.1016/j.chom.2017.03.002 CrossRefGoogle Scholar
  64. Tran L, Greenwood-Van Meerveld B (2013) Age-associated remodeling of the intestinal epithelial barrier. J Gerontol A Biol Sci Med Sci 68:1045–1056.  https://doi.org/10.1093/gerona/glt106 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Trollor JN et al (2012) The association between systemic inflammation and cognitive performance in the elderly: the Sydney memory and ageing study. Age (Dordr) 34:1295–1308.  https://doi.org/10.1007/s11357-011-9301-x CrossRefGoogle Scholar
  66. van der Geest KSM, Kroesen BJ, Horst G, Abdulahad WH, Brouwer E, Boots AMH (2018) Impact of aging on the frequency, phenotype, and function of CD161-expressing T cells. Front Immunol 9:752.  https://doi.org/10.3389/fimmu.2018.00752 CrossRefPubMedPubMedCentralGoogle Scholar
  67. Walker LJ, Tharmalingam H, Klenerman P (2014) The rise and fall of MAIT cells with age. Scand J Immunol 80:462–463.  https://doi.org/10.1111/sji.12237 CrossRefPubMedPubMedCentralGoogle Scholar
  68. Wei J, Xu H, Davies JL, Hemmings GP (1992) Increase of plasma IL-6 concentration with age in healthy subjects. Life Sci 51:1953–1956.  https://doi.org/10.1016/0024-3205(92)90112-3 CrossRefPubMedGoogle Scholar
  69. Wilson QN, Wells M, Davis AT, Sherrill C, Tsilimigras MCB, Jones RB, Fodor AA, Kavanagh K (2018) Greater microbial translocation and vulnerability to metabolic disease in healthy aged female monkeys. Sci Rep 8:11373.  https://doi.org/10.1038/s41598-018-29473-9 CrossRefPubMedPubMedCentralGoogle Scholar
  70. Yaffe K, Lindquist K, Penninx BW, Simonsick EM, Pahor M, Kritchevsky S, Launer L, Kuller L, Rubin S, Harris T (2003) Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology 61:76–80CrossRefGoogle Scholar
  71. Yasui T et al (2007) Changes in serum cytokine concentrations during the menopausal transition. Maturitas 56:396–403.  https://doi.org/10.1016/j.maturitas.2006.11.002 CrossRefPubMedGoogle Scholar
  72. Yousefzadeh MJ et al (2018) Circulating levels of monocyte chemoattractant protein-1 as a potential measure of biological age in mice and frailty in humans. Aging Cell 17.  https://doi.org/10.1111/acel.12706 CrossRefGoogle Scholar

Copyright information

© American Aging Association 2019

Authors and Affiliations

  1. 1.Division of MicrobiologyTulane National Primate Research CenterCovingtonUSA
  2. 2.School of Public Health & Tropical MedicineTulane UniversityNew OrleansUSA
  3. 3.Center for Comparative Medicine and California National Primate Research CenterUniversity of California DavisDavisUSA
  4. 4.Division of Comparative PathologyTulane National Primate Research CenterCovingtonUSA
  5. 5.Tulane Center for AgingTulane UniversityNew OrleansUSA

Personalised recommendations