Immunosenescence in aging: between immune cells depletion and cytokines up-regulation

Maria Teresa Ventura, Marco Casciaro, Sebastiano Gangemi, Rosalba Buquicchio, Maria Teresa Ventura, Marco Casciaro, Sebastiano Gangemi, Rosalba Buquicchio

Abstract

Background: The immunosenescence is a relatively recent chapter, correlated with the linear extension of the average life began in the nineteenth century and still in progress. The most important feature of immunosenescence is the accumulation in the "immunological space" of memory and effector cells as a result of the stimulation caused by repeated clinical and subclinical infections and by continuous exposure to antigens (inhalant allergens, food, etc.). This state of chronic inflammation that characterizes senescence has a significant impact on survival and fragility. In fact, the condition of frail elderly occurs less frequently in situations characterized by poor contact with viral infections and parasitic diseases. Furthermore the immunosenescence is characterized by a particular "remodelling" of the immune system, induced by oxidative stress. Apoptosis plays a central role in old age, a period in which the ability of apoptosis can change. The remodelling of apoptosis, together with the Inflammaging and the up-regulation of the immune response with the consequent secretion of pro-inflammatory lymphokines represents the major determinant of the rate of aging and longevity, as well as of the most common diseases related with age and with tumors. Other changes occur in the innate immunity, the first line of defence providing rapid, but unspecific and incomplete protection, consisting mostly of monocytes, natural killer cells and dendritic cells, acting up to the establishment of a adaptive immune response, which is slower, but highly specific, which cellular substrate consists of T and B lymphocytes. The markers of "Inflammaging" in adaptive immunity in centenarians are characterized by a decrease in T cells "naive." The reduction of CD8 virgins may be related to the risk of morbidity and death, as well as the combination of the increase of CD8+ cells and reduction of CD4+ T cells and the reduction of CD19+ B cells. The immune function of the elderly is weakened to due to the exhaustion of T cell-virgin (CD95-), which are replaced with the clonal expansion of CD28-T cells.

Conclusions: The increase of pro-inflammatory cytokines is associated with dementia, Parkinson's disease, atherosclerosis, diabetes type 2, sarcopenia and a high risk of morbidity and mortality. A correct modulation of immune responses and apoptotic phenomena can be useful to reduce age-related degenerative diseases, as well as inflammatory and neoplastic diseases.

References

    1. Manton KG, Vaupel JW. Survival after the age of 80 in the United States, Sweden, France, England, and Japan. N Engl J Med. 1995;333:1232–1235. doi: 10.1056/NEJM199511023331824.
    1. Christensen K, Doblhammer G, Rau R, Vaupel JW. Ageing populations: the challenges ahead. Lancet. 2009;374:1196–1208. doi: 10.1016/S0140-6736(09)61460-4.
    1. Kirkwood TB. Understanding the odd science of aging. Cell. 2005;120:437–447. doi: 10.1016/j.cell.2005.01.027.
    1. Troen BR. The biology of aging. Mt Sinai J Med. 2003;70:3–22.
    1. Jeune B, Brønnum-Hansen H. Trends in health expectancy at age 65 for various health indicators, 1987–2005, Denmark. Eur J Ageing. 2008;5:279. doi: 10.1007/s10433-008-0100-x.
    1. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev. 2007;128:92–105. doi: 10.1016/j.mad.2006.11.016.
    1. Cevenini E, Monti D, Franceschi C. Inflamm-ageing. Curr Opin Clin Nutr Metab Care. 2013;16:14–20. doi: 10.1097/MCO.0b013e32835ada13.
    1. Minciullo PL, Catalano A, Mandraffino G, Casciaro M, Crucitti A, Maltese G, Morabito N, Lasco A, Gangemi S, Basile G. Inflammaging and anti-inflammaging: the role of cytokines in extreme longevity. Arch Immunol Ther Exp. 2016;64:111–126. doi: 10.1007/s00005-015-0377-3.
    1. Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med. 2000;51:245–270. doi: 10.1146/annurev.med.51.1.245.
    1. Gangemi S, Basile G, Monti D, Merendino RA, Di Pasquale G, Bisignano U, Nicita-Mauro V, Franceschi C. Age-related modifications in circulating IL-15 levels in humans. Mediat Inflamm. 2005;2005:245–247. doi: 10.1155/MI.2005.245.
    1. Gangemi S, Parisi P, Ricciardi L, Saitta S, Minciullo PL, Cristani MT, Nicita-Mauro V, Saija A, Basile G. Is interleukin-22 a possible indicator of chronic heart failure’s progression? Arch Gerontol Geriatr. 2010;50:311–314. doi: 10.1016/j.archger.2009.05.003.
    1. Basile G, Paffumi I, D’Angelo AG, Figliomeni P, Cucinotta MD, Pace E, Ferraro M, Saitta S, Lasco A, Gangemi S. Healthy centenarians show high levels of circulating interleukin-22 (IL-22) Arch Gerontol Geriatr. 2012;54:459–461. doi: 10.1016/j.archger.2011.05.004.
    1. Monti D, Ostan R, Borelli V, Castellani G, Franceschi C. Inflammaging and human longevity in the omics era. Mech Ageing Dev. 2017;165(Part B):129–138. doi: 10.1016/j.mad.2016.12.008.
    1. Di Bona D, Vasto S, Capurso C, Christiansen L, Deiana L, Franceschi C, Hurme M, Mocchegiani E, Rea M, Lio D, Candore G, Caruso C. Effect of interleukin-6 polymorphisms on human longevity: a systematic review and meta-analysis. Ageing Res Rev. 2009;8:36–42. doi: 10.1016/j.arr.2008.09.001.
    1. Pel-Littel RE, Schuurmans MJ, Emmelot-Vonk MH, Verhaar HJ. Frailty: defining and measuring of a concept. J Nutr Health Aging. 2009;13:390–394. doi: 10.1007/s12603-009-0051-8.
    1. Evans WJ, Paolisso G, Abbatecola AM, Corsonello A, Bustacchini S, Strollo F, Lattanzio F. Frailty and muscle metabolism dysregulation in the elderly. Biogerontology. 2010;11:527–536. doi: 10.1007/s10522-010-9297-0.
    1. Liochev SI. Reactive oxygen species and the free radical theory of aging. Free Radic Biol Med. 2013;60:1–4. doi: 10.1016/j.freeradbiomed.2013.02.011.
    1. Ginaldi L, De Martinis M, Monti D, Franceschi C. The immune system in the elderly: activation-induced and damage-induced apoptosis. Immunol Res. 2004;30:81–94. doi: 10.1385/IR:30:1:081.
    1. De Martinis M, Franceschi C, Monti D, Ginaldi L. Apoptosis remodeling in immunosenescence: implications for strategies to delay ageing. Curr Med Chem. 2007;14:1389–1397. doi: 10.2174/092986707780831122.
    1. Minciullo PL, Inferrera A, Navarra M, Calapai G, Magno C, Gangemi S. Oxidative stress in benign prostatic hyperplasia: a systematic review. Urol Int. 2015;94:249–254. doi: 10.1159/000366210.
    1. Jackson JG, Pant V, Li Q, Chang LL, Quintas-Cardama A, Garza D, Tavana O, Yang P, Manshouri T, Li Y, El-Naggar AK, Lozano G. p53-mediated senescence impairs the apoptotic response to chemotherapy and clinical outcome in breast cancer. Cancer Cell. 2012;21:793–806. doi: 10.1016/j.ccr.2012.04.027.
    1. Cristani M, Speciale A, Saija A, Gangemi S, Minciullo PL, Cimino F. Circulating advanced oxidation protein products as oxidative stress biomarkers and progression mediators in pathological conditions related to inflammation and immune dysregulation. Curr Med Chem. 2016;23:3862–3882. doi: 10.2174/0929867323666160902154748.
    1. Dorn GW., 2nd Molecular mechanisms that differentiate apoptosis from programmed necrosis. Toxicol Pathol. 2013;41:227–234. doi: 10.1177/0192623312466961.
    1. Ostan R, Bucci L, Capri M, Salvioli S, Scurti M, Pini E, Monti D, Franceschi C. Immunosenescence and immunogenetics of human longevity. Neuroimmunomodulation. 2008;15:224–240. doi: 10.1159/000156466.
    1. Ford DW, Jensen GL, Hartman TJ, Wray L, Smiciklas-Wright H. Association between dietary quality and mortality in older adults: a review of the epidemiological evidence. J Nutr Gerontol Geriatr. 2013;32:85–105. doi: 10.1080/21551197.2013.779622.
    1. Buchner N, Ale-Agha N, Jakob S, Sydlik U, Kunze K, Unfried K, Altschmied J, Haendeler J. Unhealthy diet and ultrafine carbon black particles induce senescence and disease associated phenotypic changes. Exp Gerontol. 2013;48:8–16. doi: 10.1016/j.exger.2012.03.017.
    1. Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908:244–254. doi: 10.1111/j.1749-6632.2000.tb06651.x.
    1. Maicher A, Kastner L, Dees M, Luke B. Deregulated telomere transcription causes replication-dependent telomere shortening and promotes cellular senescence. Nucleic Acids Res. 2012;40:6649–6659. doi: 10.1093/nar/gks358.
    1. George AJ, Ritter MA. Thymic involution with ageing: obsolescence or good housekeeping? Immunol Today. 1996;17:267–272. doi: 10.1016/0167-5699(96)80543-3.
    1. Cossarizza A, Ortolani C, Paganelli R, Barbieri D, Monti D, Sansoni P, Fagiolo U, Castellani G, Bersani F, Londei M, Franceschi C. CD45 isoforms expression on CD4+ and CD8+ T cells throughout life, from newborns to centenarians: implications for T cell memory. Mech Ageing Dev. 1996;86:173–195. doi: 10.1016/0047-6374(95)01691-0.
    1. Haynes L, Eaton SM, Burns EM, Randall TD, Swain SL. CD4 T cell memory derived from young naive cells functions well into old age, but memory generated from aged naive cells functions poorly. Proc Natl Acad Sci USA. 2003;100:15053–15058. doi: 10.1073/pnas.2433717100.
    1. Vallejo AN. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol Rev. 2005;205:158–169. doi: 10.1111/j.0105-2896.2005.00256.x.
    1. Schwaiger S, Wolf AM, Robatscher P, Jenewein B, Grubeck-Loebenstein B. IL-4-producing CD8+ T cells with a CD62L ++(bright) phenotype accumulate in a subgroup of older adults and are associated with the maintenance of intact humoral immunity in old age. J Immunol. 2003;170:613–619. doi: 10.4049/jimmunol.170.1.613.
    1. Sansoni P, Vescovini R, Fagnoni F, Biasini C, Zanni F, Zanlari L, Telera A, Lucchini G, Passeri G, Monti D, Franceschi C, Passeri M. The immune system in extreme longevity. Exp Gerontol. 2008;43:61–65. doi: 10.1016/j.exger.2007.06.008.
    1. Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Lofgren S, Nilsson BO, Ernerudh J, Pawelec G, Johansson B. An immune risk phenotype, cognitive impairment, and survival in very late life: impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci. 2005;60:556–565. doi: 10.1093/gerona/60.5.556.
    1. Sikora E. Activation-induced and damage-induced cell death in aging human T cells. Mech Ageing Dev. 2015;151:85–92. doi: 10.1016/j.mad.2015.03.011.
    1. Kollar S, Berta L, Vasarhelyi ZE, Balog A, Vasarhelyi B, Rigo J, Jr, Toldi G. Impact of aging on calcium influx and potassium channel characteristics of T lymphocytes. Oncotarget. 2015;6:13750–13756. doi: 10.18632/oncotarget.3808.
    1. Li G, Yu M, Lee W-W, Tsang M, Krishnan E, Weyand CM, Goronzy JJ. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat Med. 2012;18:1518–1524. doi: 10.1038/nm.2963.
    1. Lages CS, Suffia I, Velilla PA, Huang B, Warshaw G, Hildeman DA, Belkaid Y, Chougnet C. Functional regulatory T cells accumulate in aged hosts and promote chronic infectious disease reactivation. J Immunol. 2008;181:1835–1848. doi: 10.4049/jimmunol.181.3.1835.
    1. Colonna-Romano G, Bulati M, Aquino A, Vitello S, Lio D, Candore G, Caruso C. B cell immunosenescence in the elderly and in centenarians. Rejuvenation Res. 2008;11:433–439. doi: 10.1089/rej.2008.0664.
    1. Antonaci S, Jirillo E, Ventura MT, Garofalo AR, Bonomo L. Lipoprotein-induced inhibition of plaque-forming cell generation and natural killer cell frequency in aged donors. Ann Immunol. 1984;135:241–249.
    1. Weksler ME, Szabo P. The effect of age on the B-cell repertoire. J Clin Immunol. 2000;20:240–249. doi: 10.1023/A:1006659401385.
    1. Paganelli R, Quinti I, Fagiolo U, Cossarizza A, Ortolani C, Guerra E, Sansoni P, Pucillo LP, Scala E, Cozzi E, et al. Changes in circulating B cells and immunoglobulin classes and subclasses in a healthy aged population. Clin Exp Immunol. 1992;90:351–354. doi: 10.1111/j.1365-2249.1992.tb07954.x.
    1. Ventura M. Determination of total IgA, IgA1 and IgA2 in the serum and saliva of an aged population. Recenti Prog Med. 1985;76:576–577.
    1. Ventura MT. Evaluation of IgA1-IgA2 levels in serum and saliva of young and elderly people. Allergol Immunopathol. 1991;19:183–185.
    1. Pritz T, Lair J, Ban M, Keller M, Weinberger B, Krismer M, Grubeck-Loebenstein B. Plasma cell numbers decrease in bone marrow of old patients. Eur J Immunol. 2015;45:738–746. doi: 10.1002/eji.201444878.
    1. Buffa S, Pellicano M, Bulati M, Martorana A, Goldeck D, Caruso C, Pawelec G, Colonna-Romano G. A novel B cell population revealed by a CD38/CD24 gating strategy: CD38(−) CD24 (−) B cells in centenarian offspring and elderly people. Age. 2013;35:2009–2024. doi: 10.1007/s11357-012-9488-5.
    1. Rosenberg C, Bovin NV, Bram LV, Flyvbjerg E, Erlandsen M, Vorup-Jensen T, Petersen E. Age is an important determinant in humoral and T cell responses to immunization with hepatitis B surface antigen. Hum Vaccin Immunother. 2013;9:1466–1476. doi: 10.4161/hv.24480.
    1. Nomellini V, Gomez CR, Kovacs EJ. Aging and impairment of innate immunity. Contrib Microbiol. 2008;15:188–205. doi: 10.1159/000136358.
    1. Antonaci S, Jirillo E, Ventura MT, Garofalo AR, Bonomo L. Non-specific immunity in aging: deficiency of monocyte and polymorphonuclear cell-mediated functions. Mech Ageing Dev. 1984;24:367–375. doi: 10.1016/0047-6374(84)90121-0.
    1. De Martinis M, Sirufo MM, Ginaldi L. Allergy and Aging: an old/new emerging health issue. Aging Dis. 2017;8:162–175. doi: 10.14336/AD.2016.0831.
    1. Simon AK, Hollander GA, McMichael A. Evolution of the immune system in humans from infancy to old age. Proc R Soc B Biol Sci. 2015;282:20143085. doi: 10.1098/rspb.2014.3085.
    1. Gupta S. Role of dendritic cells in innate and adaptive immune response in human aging. Exp Gerontol. 2014;54:47–52. doi: 10.1016/j.exger.2013.12.009.
    1. Prakash S, Agrawal S, Cao JN, Gupta S, Agrawal A. Impaired secretion of interferons by dendritic cells from aged subjects to influenza: role of histone modifications. Age. 2013;35:1785–1797. doi: 10.1007/s11357-012-9477-8.
    1. Della Bella S, Bierti L, Presicce P, Arienti R, Valenti M, Saresella M, Vergani C, Villa ML. Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin Immunol. 2007;122:220–228. doi: 10.1016/j.clim.2006.09.012.
    1. Davalos AR, Coppe JP, Campisi J, Desprez PY. Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev. 2010;29:273–283. doi: 10.1007/s10555-010-9220-9.
    1. Sebastian C, Herrero C, Serra M, Lloberas J, Blasco MA, Celada A. Telomere shortening and oxidative stress in aged macrophages results in impaired STAT5a phosphorylation. J Immunol. 2009;183:2356–2364. doi: 10.4049/jimmunol.0901131.
    1. Ventura MT, Serlenga E, Tortorella C, Antonaci S. In vitro vitamin E and selenium supplementation improves neutrophil-mediated functions and monocyte chemoattractant protein-1 production in the elderly. Cytobios. 1994;77:225–232.
    1. Butcher SK, Chahal H, Nayak L, Sinclair A, Henriquez NV, Sapey E, O’Mahony D, Lord JM. Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans. J Leukoc Biol. 2001;70:881–886.
    1. Chen MM, Palmer JL, Plackett TP, Deburghgraeve CR, Kovacs EJ. Age-related differences in the neutrophil response to pulmonary pseudomonas infection. Exp Gerontol. 2014;54:42–46. doi: 10.1016/j.exger.2013.12.010.
    1. Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol. 2007;5:577–582. doi: 10.1038/nrmicro1710.
    1. Ventura MT, Crollo R, Lasaracina E. In vitro zinc correction of natural killer (NK) activity in the elderly. Clin Exp Immunol. 1986;64:223–224.
    1. Borrego F, Alonso MC, Galiani MD, Carracedo J, Ramirez R, Ostos B, Pena J, Solana R. NK phenotypic markers and IL2 response in NK cells from elderly people. Exp Gerontol. 1999;34:253–265. doi: 10.1016/S0531-5565(98)00076-X.
    1. Solana R, Campos C, Pera A, Tarazona R. Shaping of NK cell subsets by aging. Curr Opin Immunol. 2014;29:56–61. doi: 10.1016/j.coi.2014.04.002.
    1. Krishnaraj R. Senescence and cytokines modulate the NK cell expression. Mech Ageing Dev. 1997;96:89–101. doi: 10.1016/S0047-6374(97)00045-6.
    1. Almeida-Oliveira A, Smith-Carvalho M, Porto LC, Cardoso-Oliveira J, Ribeiro Ados S, Falcao RR, Abdelhay E, Bouzas LF, Thuler LC, Ornellas MH, Diamond HR. Age-related changes in natural killer cell receptors from childhood through old age. Hum Immunol. 2011;72:319–329. doi: 10.1016/j.humimm.2011.01.009.
    1. Camous X, Pera A, Solana R, Larbi A. NK cells in healthy aging and age-associated diseases. J Biomed Biotechnol. 2012;2012:195956. doi: 10.1155/2012/195956.
    1. Wikby A, Nilsson BO, Forsey R, Thompson J, Strindhall J, Lofgren S, Ernerudh J, Pawelec G, Ferguson F, Johansson B. The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning. Mech Ageing Dev. 2006;127:695–704. doi: 10.1016/j.mad.2006.04.003.
    1. Vasto S, Colonna-Romano G, Larbi A, Wikby A, Caruso C, Pawelec G. Role of persistent CMV infection in configuring T cell immunity in the elderly. Immun Ageing. 2007;4:2. doi: 10.1186/1742-4933-4-2.
    1. Weiskopf D, Weinberger B, Grubeck-Loebenstein B. The aging of the immune system. Transpl Int. 2009;22:1041–1050. doi: 10.1111/j.1432-2277.2009.00927.x.

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever