Immunometabolic responses according to physical fitness status and lifelong exercise during aging: New roads for exercise immunology

Ageing Research Reviews - Tập 68 - Trang 101341 - 2021
Camila S. Padilha1, Caique Figueiredo1, Luciele Guerra Minuzzi1, Patricia Chimin2, Rafael Deminice2, Karsten Krüger3, José Cesar Rosa-Neto4, Fabio Santos Lira1
1Exercise and Immunometabolism Research Group, Postgraduation Program in Movement Sciences, Department of Physical Education, Universidade Estadual Paulista (UNESP), Presidente Prudente, São Paulo, Brazil
2Laboratory of Biochemistry Exercise, Department of Physical Education, Faculty of Physical Education and Sport, State University of Londrina, Londrina, Brazil
3Institute of Sports Science, Department of Exercise Physiology and Sports Therapy, University of Giessen, Giessen, Germany
4Immunometabolism Research Group, Department of Cell Biology and Development, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil

Tài liệu tham khảo

Aguiar, 2019, Influence of body fat on oxidative stress and telomere length of master athletes, J. Strength Cond. Res., 10.1519/JSC.0000000000002932 Almeida, 2016, Metabolic pathways in T cell activation and lineage differentiation, Semin. Immunol., 28, 514, 10.1016/j.smim.2016.10.009 Antunes, 2019, Anti-inflammatory response to acute exercise is related with intensity and physical fitness, J. Cell. Biochem., 120, 5333, 10.1002/jcb.27810 Astrand, 1973, Reduction in maximal oxygen uptake with age, J. Appl. Physiol., 35, 649, 10.1152/jappl.1973.35.5.649 Auffray, 2007, Monitoring of blood vessels and tissues by a population of monocytes with patrolling behavior, Science, 317, 666, 10.1126/science.1142883 Aw, 2018, Monocyte subsets in atherosclerosis and modification with exercise in humans, Antioxidants, 7, 196, 10.3390/antiox7120196 Azizbeigi, 2015, Effect of moderate and high resistance training intensity on indices of inflammatory and oxidative stress, Res. Sports Med., 23, 73, 10.1080/15438627.2014.975807 Bauer, 2018, Remembering pathogen dose: long-term adaptation in innate immunity, Trends Immunol., 39, 438, 10.1016/j.it.2018.04.001 Bishop, 2014, Effect of acute and regular exercise on growth hormone secretagogue receptor-1a expression in human lymphocytes, T cell subpopulation and monocytes, Brain Behav. Immun., 39, 172, 10.1016/j.bbi.2013.09.017 Biswas, 2012, Orchestration of metabolism by macrophages, Cell Metab., 15, 432, 10.1016/j.cmet.2011.11.013 Booth, 2017, Role of inactivity in chronic diseases: evolutionary insight and pathophysiological mechanisms, Physiol. Rev., 97, 1351, 10.1152/physrev.00019.2016 Bratic, 2013, The role of mitochondria in aging, J. Clin. Invest., 123, 951, 10.1172/JCI64125 Butcher, 2001, Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans, J. Leukoc. Biol., 70, 881, 10.1189/jlb.70.6.881 Cabral-Santos, 2015, Similar anti-inflammatory acute responses from moderate-intensity continuous and high-intensity intermittent exercise, J. Sports Sci. Med., 14, 849 Cabral-Santos, 2019, Interleukin-10 responses from acute exercise in healthy subjects: a systematic review, J. Cell. Physiol., 234, 9956, 10.1002/jcp.27920 Calçada, 2014, The role of low-grade inflammation and metabolic flexibility in aging and nutritional modulation thereof: a systems biology approach, Mech. Ageing Dev., 136-137, 138, 10.1016/j.mad.2014.01.004 Chang, 2016, Emerging concepts of T cell metabolism as a target of immunotherapy, Nat. Immunol., 17, 364, 10.1038/ni.3415 Chapman, 2014, mTOR links environmental signals to t cell fate decisions, Front. Immunol., 5, 686 Chen, 2013, Molecular mechanisms of T cell co-stimulation and co-inhibition, Nat. Rev. Immunol., 13, 227, 10.1038/nri3405 Chen, 2019, Meta-inflammaging at the crossroad of geroscience, Aging Med. (Milton), 2, 157, 10.1002/agm2.12078 Conte, 2020, Mitochondria, immunosenescence and inflammaging: a role for mitokines?, Semin. Immunopathol., 10.1007/s00281-020-00813-0 Curi, 2017, A past and present overview of macrophage metabolism and functional outcomes, Clin. Sci., 131, 1329, 10.1042/CS20170220 de Araújo, 2015, Elderly men with moderate and intense training lifestyle present sustained higher antibody responses to influenza vaccine, Age Dordr., 37, 105, 10.1007/s11357-015-9843-4 De Rosa, 2015, Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants, Nat. Immunol., 16, 1174, 10.1038/ni.3269 de Souza Teixeira, 2020, Aging with rhythmicity. Is it possible? Physical exercise as a pacemaker, Life Sci., 261, 10.1016/j.lfs.2020.118453 Delgoffe, 2009, mTOR: taking cues from the immune microenvironment, Immunology, 127, 459, 10.1111/j.1365-2567.2009.03125.x Delgoffe, 2011, The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2, Nat. Immunol., 12, 295, 10.1038/ni.2005 Deretic, 2013, Autophagy in infection, inflammation and immunity, Nat. Rev. Immunol., 13, 722, 10.1038/nri3532 Desch, 2014, Dendritic cell subsets require cis-activation for cytotoxic CD8 T-cell induction, Nat. Commun., 5, 4674, 10.1038/ncomms5674 Diaz, 2016, Patterns of sedentary behavior in US middle-age and older adults: the REGARDS study, Med. Sci. Sports Exerc., 48, 430, 10.1249/MSS.0000000000000792 Dietz, 2015, Management of obesity: improvement of health-care training and systems for prevention and care, Lancet, 385, 2521, 10.1016/S0140-6736(14)61748-7 Ding, 2016, The economic burden of physical inactivity: a global analysis of major non-communicable diseases, Lancet, 388, 1311, 10.1016/S0140-6736(16)30383-X Dobbs, 2014 Dorneles, 2019, Cardiorespiratory fitness modulates the proportions of monocytes and T helper subsets in lean and obese men, Scand. J. Med. Sci. Sports, 29, 1755, 10.1111/sms.13506 Dorneles, 2019, Physical fitness modulates the expression of CD39 and CD73 on CD4(+) CD25(-) and CD4(+) CD25(+) T cells following high intensity interval exercise, J. Cell. Biochem., 120, 10726, 10.1002/jcb.28364 Dorneles, 2021, Levels of cardiorespiratory fitness in men exerts strong impact on lymphocyte function after mitogen stimulation, J. Appl. Physiol. (1985), 10.1152/japplphysiol.01051.2020 Ekelund, 2016, Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women, Lancet, 388, 1302, 10.1016/S0140-6736(16)30370-1 Elsner, 2019, Exercise-induced BDNF production by mononuclear cells of sedentary and physically active obese men, J. Sports Med. Phys. Fitness Ezema, 2014, Effect of aerobic exercise training on cardiovascular parameters and CD4 cell count of people living with human immunodeficiency virus/acquired immune deficiency syndrome: a randomized controlled trial, Niger. J. Clin. Pract., 17, 543, 10.4103/1119-3077.141414 Febbraio, 2005, Contraction-induced myokine production and release: is skeletal muscle an endocrine organ?, Exerc. Sport Sci. Rev., 33, 114, 10.1097/00003677-200507000-00003 Fragala, 2011, Leukocyte beta2-adrenergic receptor expression in response to resistance exercise, Med. Sci. Sports Exerc., 43, 1422, 10.1249/MSS.0b013e31820b88bc Freedland, 2004, Examining the relationship between obesity and prostate cancer, Rev. Urol., 6, 73 Friedman, 2016, The long road to leptin, J. Clin. Invest., 126, 4727, 10.1172/JCI91578 Frontera, 1991, A cross-sectional study of muscle strength and mass in 45- to 78-yr-old men and women, J. Appl. Physiol. (1985), 71, 644, 10.1152/jappl.1991.71.2.644 Frontera, 2000, Aging of skeletal muscle: a 12-yr longitudinal study, J. Appl. Physiol. (1985), 88, 1321, 10.1152/jappl.2000.88.4.1321 Fukuzumi, 1996, Endotoxin-induced enhancement of glucose influx into murine peritoneal macrophages via GLUT1, Infect. Immun., 64, 108, 10.1128/iai.64.1.108-112.1996 Fulop, 2016, From inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation, Biogerontology, 17, 147, 10.1007/s10522-015-9615-7 Gatza, 2011, Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease, Sci. Transl. Med., 3, 10.1126/scitranslmed.3001975 Gerosa-Neto, 2020, High- and moderate-intensity training modify LPS-induced ex-vivo interleukin-10 production in obese men in response to an acute exercise bout, Cytokine, 136, 10.1016/j.cyto.2020.155249 Gerriets, 2015, Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation, J. Clin. Invest., 125, 194, 10.1172/JCI76012 Gleeson, 2007, Immune function in sport and exercise, J. Appl. Physiol. (1985), 103, 693, 10.1152/japplphysiol.00008.2007 Glick, 2010, Autophagy: cellular and molecular mechanisms, J. Pathol., 221, 3, 10.1002/path.2697 Guarami, 2003, Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2, Mol Cell., 11, 1457, 10.1016/S1097-2765(03)00220-X Gwinn, 2008, AMPK phosphorylation of raptor mediates a metabolic checkpoint, Mol. Cell, 30, 214, 10.1016/j.molcel.2008.03.003 Hall, 2016, TOR and paradigm change: cell growth is controlled, Mol. Biol. Cell, 27, 2804, 10.1091/mbc.e15-05-0311 Hallal, 2012, Global physical activity levels: surveillance progress, pitfalls, and prospects, Lancet, 380, 247, 10.1016/S0140-6736(12)60646-1 Hamers, 2019, Human monocyte heterogeneity as revealed by high-dimensional mass cytometry, Arterioscler. Thromb. Vasc. Biol., 39, 25, 10.1161/ATVBAHA.118.311022 Handzlik, 2013, The influence of exercise training status on antigen-stimulated IL-10 production in whole blood culture and numbers of circulating regulatory T cells, Eur. J. Appl. Physiol., 113, 1839, 10.1007/s00421-013-2614-y Hara, 2015, ATP regulation in bioproduction, Microb. Cell Fact., 14, 198, 10.1186/s12934-015-0390-6 Hara, 2002, Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action, Cell, 110, 177, 10.1016/S0092-8674(02)00833-4 Harris, 1953, Chemotaxis of monocytes, Br. J. Exp. Pathol., 34, 276 Haschemi, 2012, The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism, Cell Metab., 15, 813, 10.1016/j.cmet.2012.04.023 Hearps, 2012, Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function, Aging Cell, 11, 867, 10.1111/j.1474-9726.2012.00851.x Herzig, 2018, AMPK: guardian of metabolism and mitochondrial homeostasis, Nat. Rev. Mol. Cell Biol., 19, 121, 10.1038/nrm.2017.95 Hsieh, 2020, M2b macrophage subset decrement as an indicator of cognitive function in Alzheimer’s disease, Psychiatry Clin. Neurosci., 74, 383, 10.1111/pcn.13000 Infantino, 2011, The mitochondrial citrate carrier: a new player in inflammation, Biochem. J., 438, 433, 10.1042/BJ20111275 Inoue, 2020, Acute increases in brain-derived neurotrophic factor following high or moderate-intensity exercise is accompanied with better cognition performance in obese adults, Sci. Rep., 10, 10.1038/s41598-020-70326-1 Intlekofer, 2005, Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin, Nat. Immunol., 6, 1236, 10.1038/ni1268 Jacinto, 2004, Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive, Nat. Cell Biol., 6, 1122, 10.1038/ncb1183 Jakubzick, 2013, Minimal differentiation of classical monocytes as they survey steady-state tissues and transport antigen to lymph nodes, Immunity, 39, 599, 10.1016/j.immuni.2013.08.007 Jenny, 2012, Inflammation in aging: cause, effect, or both?, Discov. Med., 13, 451 Jung, 2019, Metabolism as a guiding force for immunity, Nat. Cell Biol., 21, 85, 10.1038/s41556-018-0217-x Kang, 2008, De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR, J. Leukoc. Biol., 83, 1230, 10.1189/jlb.1207851 Kapellos, 2019, Human monocyte subsets and phenotypes in major chronic inflammatory diseases, Front. Immunol., 10, 2035, 10.3389/fimmu.2019.02035 Kim, 2002, mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery, Cell, 110, 163, 10.1016/S0092-8674(02)00808-5 Kim, 2003, GbetaL, a positive regulator of the rapamycin-sensitive pathway required for the nutrient-sensitive interaction between raptor and mTOR, Molecular Cell, 11, 895, 10.1016/S1097-2765(03)00114-X Klysz, 2015, Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation, Vol. 8, ra97 Koch, 2011, Mechanisms of T cell development and transformation, Annu. Rev. Cell Dev. Biol., 27, 539, 10.1146/annurev-cellbio-092910-154008 Krüger, 2007, T cell homing and exercise, Exerc. Immunol. Rev., 13, 37 Krüger, 2008, Exercise-induced redistribution of T lymphocytes is regulated by adrenergic mechanisms, Brain Behav. Immun., 22, 324, 10.1016/j.bbi.2007.08.008 Krüger, 2009, Exercise affects tissue lymphocyte apoptosis via redox-sensitive and Fas-dependent signaling pathways, Am. J. Physiol. Regul. Integr. Comp. Physiol., 296, R1518, 10.1152/ajpregu.90994.2008 Krüger, 2016, The immunomodulatory effects of physical activity, Curr. Pharm. Des., 22, 3730, 10.2174/1381612822666160322145107 Kusy, 2015, Sprinters versus long-distance runners: how to grow old healthy, Exerc. Sport Sci. Rev., 43, 57, 10.1249/JES.0000000000000033 Landmann, 1992, Beta-adrenergic receptors in human leukocyte subpopulations, Eur. J. Clin. Invest., 22, 30 Lanna, 2014, The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells, Nat. Immunol., 15, 965, 10.1038/ni.2981 Larson, 2016, Ly6C(+) monocyte efferocytosis and cross-presentation of cell-associated antigens, Cell Death Differ., 23, 997, 10.1038/cdd.2016.24 Lavin, 2020, Effects of aging and lifelong aerobic exercise on basal and exercise-induced inflammation, J. Appl. Physiol. (1985), 128, 87, 10.1152/japplphysiol.00495.2019 Lee, 2012, Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy, Lancet, 380, 219, 10.1016/S0140-6736(12)61031-9 León, 2007, Monocyte-derived dendritic cells formed at the infection site control the induction of protective T helper 1 responses against Leishmania, Immunity, 26, 519, 10.1016/j.immuni.2007.01.017 Lewis, 2009, Mortality, health outcomes, and body mass index in the overweight range: a science advisory from the American Heart Association, Circulation, 119, 3263, 10.1161/CIRCULATIONAHA.109.192574 Li, 2018, Macrophage polarization and meta-inflammation, Transl. Res., 191, 29, 10.1016/j.trsl.2017.10.004 Linehan, 2014, Aging impairs peritoneal but not bone marrow-derived macrophage phagocytosis, Aging Cell, 13, 699, 10.1111/acel.12223 Linke, 2017, mTORC1 and mTORC2 as regulators of cell metabolism in immunity, FEBS Lett., 591, 3089, 10.1002/1873-3468.12711 Liu, 2017, α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming, Nat. Immunol., 18, 985, 10.1038/ni.3796 Longo, 2019, Adipose tissue dysfunction as determinant of obesity-associated metabolic complications, Int. J. Mol. Sci., 20, 10.3390/ijms20092358 Lumeng, 2007, Increased inflammatory properties of adipose tissue macrophages recruited during diet-induced obesity, Diabetes, 56, 16, 10.2337/db06-1076 Luo, 2011, Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1, Cell, 145, 732, 10.1016/j.cell.2011.03.054 Lurier, 2017, Transcriptome analysis of IL-10-stimulated (M2c) macrophages by next-generation sequencing, Immunobiology, 222, 847, 10.1016/j.imbio.2017.02.006 Macdougall, 2018, Visceral adipose tissue immune homeostasis is regulated by the crosstalk between adipocytes and dendritic cell subsets, Cell Metab., 27, 588, 10.1016/j.cmet.2018.02.007 Mah, 2017, Glycolytic requirement for NK cell cytotoxicity and cytomegalovirus control, JCI Insight, 2, 10.1172/jci.insight.95128 Makowski, 2020, Immunometabolism: from basic mechanisms to translation, Immunol. Rev., 295, 5, 10.1111/imr.12858 Mills, 1999, Nonselective beta blockade attenuates the recruitment of CD62L(-)T lymphocytes following exercise, Eur. J. Appl. Physiol. Occup. Physiol., 79, 531, 10.1007/s004210050548 Minuzzi, 2017, Lifelong training improves anti-inflammatory environment and maintains the number of regulatory T cells in masters athletes, Eur. J. Appl. Physiol., 117, 1131, 10.1007/s00421-017-3600-6 Minuzzi, 2018, Effects of lifelong training on senescence and mobilization of T lymphocytes in response to acute exercise, Exerc. Immunol. Rev., 24, 72 Minuzzi, 2019, Lifelong exercise practice and immunosenescence: master athletes cytokine response to acute exercise, Cytokine, 115, 1, 10.1016/j.cyto.2018.12.006 Minuzzi, 2021, Immunometabolism and covid-19: could lifelong exercise training have a protective effect?, Immunometabolism, 3, 10.20900/immunometab20210001 Moon, 2015, mTORC1-induced HK1-Dependent glycolysis regulates NLRP3 inflammasome activation, Cell Rep., 12, 102, 10.1016/j.celrep.2015.05.046 Müller-Durovic, 2016, Killer cell lectin-like receptor G1 inhibits NK cell function through activation of adenosine 5’-monophosphate-activated protein kinase, J. Immunol., 197, 2891, 10.4049/jimmunol.1600590 Murray, 1992, Sympathetic and immune interactions during dynamic exercise. Mediation via a beta 2-adrenergic-dependent mechanism, Circulation, 86, 203, 10.1161/01.CIR.86.1.203 NCD-RisC, 2017, Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children, adolescents, and adults, Lancet, 390, 2627, 10.1016/S0140-6736(17)32129-3 Newsholme, 1985, The role of high rates of glycolysis and glutamine utilization in rapidly dividing cells, Biosci. Rep., 5, 393, 10.1007/BF01116556 Newsholme, 1986, Metabolism of glucose, glutamine, long-chain fatty acids and ketone bodies by murine macrophages, Biochem. J., 239, 121, 10.1042/bj2390121 Newsholme, 1987, Rates of utilization and fates of glucose, glutamine, pyruvate, fatty acids and ketone bodies by mouse macrophages, Biochem. J., 242, 631, 10.1042/bj2420631 Nicholson, 2016, The immune system, Essays Biochem., 60, 275, 10.1042/EBC20160017 O’Neill, 2013, Metabolism of inflammation limited by AMPK and pseudo-starvation, Nature, 493, 346, 10.1038/nature11862 O’Neill, 2016, A guide to immunometabolism for immunologists, Nat. Rev. Immunol., 16, 553, 10.1038/nri.2016.70 O’Sullivan, 2015, Targeting T cell metabolism for therapy, Trends Immunol., 36, 71, 10.1016/j.it.2014.12.004 Nojima, 2003, The mammalian target of rapamycin (mTOR) partner, raptor, binds the mTOR substrates p70 S6 kinase and 4E-BP1 through their TOR signaling (TOS) motif, Journal of Biology Chemistry, 278, 15461, 10.1074/jbc.C200665200 Oestreich, 2012, Master regulators or lineage-specifying? Changing views on CD4+ T cell transcription factors, Nat. Rev. Immunol., 12, 799, 10.1038/nri3321 Oishi, 2016, Integrated regulation of the cellular metabolism and function of immune cells in adipose tissue, Clin. Exp. Pharmacol. Physiol., 43, 294, 10.1111/1440-1681.12539 Ortega, 2016, The “bioregulatory effect of exercise” on the innate/inflammatory responses, J. Physiol. Biochem., 72, 361, 10.1007/s13105-016-0478-4 Pascual, 2005, A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma, Nature, 437, 759, 10.1038/nature03988 Pawelec, 2017, Does the human immune system ever really become "senescent"?, F1000Res, 4, 1323, 10.12688/f1000research.11297.1 Pawelec, 2018, Age and immunity: what is “immunosenescence”?, Exp. Gerontol., 105, 4, 10.1016/j.exger.2017.10.024 Pawelec, 2001, Altered T cell signalling in ageing, Mech. Ageing Dev., 122, 1613, 10.1016/S0047-6374(01)00290-1 Pearce, 2010, Metabolism in T cell activation and differentiation, Curr. Opin. Immunol., 22, 314, 10.1016/j.coi.2010.01.018 Pearce, 2013, Metabolic pathways in immune cell activation and quiescence, Immunity, 38, 633, 10.1016/j.immuni.2013.04.005 Pearce, 2003, Control of effector CD8+ T cell function by the transcription factor Eomesodermin, Science, 302, 1041, 10.1126/science.1090148 Pedersen, 2009, The diseasome of physical inactivity--and the role of myokines in muscle--fat cross talk, J. Physiol., 587, 5559, 10.1113/jphysiol.2009.179515 Pedersen, 2017, Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease, Eur. J. Clin. Invest., 47, 600, 10.1111/eci.12781 Pedersen, 2016, Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution, Cell Metab., 23, 554, 10.1016/j.cmet.2016.01.011 Perkins, 2020, Effects of aging and lifelong aerobic exercise on expression of innate immune components in human skeletal muscle, J. Appl. Physiol. (1985), 10.1152/japplphysiol.00615.2020 Petersen, 2005, The anti-inflammatory effect of exercise, J. Appl. Physiol. (1985), 98, 1154, 10.1152/japplphysiol.00164.2004 Powell, 2012, Regulation of immune responses by mTOR, Annu. Rev. Immunol., 30, 39, 10.1146/annurev-immunol-020711-075024 Powers, 2010, Reactive oxygen species are signalling molecules for skeletal muscle adaptation, Exp. Physiol., 95, 1, 10.1113/expphysiol.2009.050526 Poznanski, 2018, Immunometabolism of T cells and NK cells: metabolic control of effector and regulatory function, Inflamm. Res., 67, 813, 10.1007/s00011-018-1174-3 Radak, 2019, Exercise effects on physiological function during aging, Free Radic. Biol. Med., 132, 33, 10.1016/j.freeradbiomed.2018.10.444 Rigsby, 1992, Effects of exercise training on men seropositive for the human immunodeficiency virus-1, Med. Sci. Sports Exerc., 24, 6, 10.1249/00005768-199201000-00003 Robinson, 2015, Short-term high-intensity interval and moderate-intensity continuous training reduce leukocyte TLR4 in inactive adults at elevated risk of type 2 diabetes, J. Appl. Physiol. (1985), 119, 508, 10.1152/japplphysiol.00334.2015 Rodriguez, 2021, Immunosenescence study of t cells: a systematic review, Front. Immunol., 15, 604591, 10.3389/fimmu.2020.604591 Ross, 2018, Lower resting and exercise-induced circulating angiogenic progenitors and angiogenic T cells in older men, Am. J. Physiol. Heart Circ. Physiol., 314, H392, 10.1152/ajpheart.00592.2017 Ruffino, 2016, Moderate-intensity exercise alters markers of alternative activation in circulating monocytes in females: a putative role for PPARgamma, Eur. J. Appl. Physiol., 116, 1671, 10.1007/s00421-016-3414-y Saare, 2020, Monocytes present age-related changes in phospholipid concentration and decreased energy metabolism, Aging Cell, 19, 10.1111/acel.13127 Santoro, 2020, Inflammaging, hormesis and the rationale for anti-aging strategies, Ageing Res. Rev., 10.1016/j.arr.2020.101142 Santos, 2020, Dynamics of anthropometric indices in a large paired cohort with 10 years of follow-up: paving the way to sarcopenic obesity, Front. Endocrinol. (Lausanne), 11, 209, 10.3389/fendo.2020.00209 Saunders, 2001, Rapamycin in transplantation: a review of the evidence, Kidney Int ., 59, 3, 10.1046/j.1523-1755.2001.00460.x Schmelzle, 2000, TOR, a central controller of cell growth, Cell, 103, 253, 10.1016/S0092-8674(00)00117-3 Selak, 2005, Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase, Cancer Cell, 7, 77, 10.1016/j.ccr.2004.11.022 Serbina, 2003, TNF/iNOS-producing dendritic cells mediate innate immune defense against bacterial infection, Immunity, 19, 59, 10.1016/S1074-7613(03)00171-7 Shao, 2019, Alpha7 nicotinic acetylcholine receptor alleviates inflammatory bowel disease through induction of AMPK-mTOR-p70S6K-Mediated autophagy, Inflammation, 42, 1666, 10.1007/s10753-019-01027-9 Shaw, 2010, Aging of the innate immune system, Curr. Opin. Immunol., 22, 507, 10.1016/j.coi.2010.05.003 Shi, 2011, Monocyte recruitment during infection and inflammation, Nat. Rev. Immunol., 11, 762, 10.1038/nri3070 Silveira, 2016, Macrophage polarization: implications on metabolic diseases and the role of exercise, Crit. Rev. Eukaryot. Gene Expr., 26, 115, 10.1615/CritRevEukaryotGeneExpr.2016015920 Simoes, 2017, Longer telomere length in elite master sprinters: relationship to performance and body composition, Int. J. Sports Med., 38, 1111, 10.1055/s-0043-120345 Simpson, 2011, Aging, persistent viral infections, and immunosenescence: can exercise “make space”?, Exerc. Sport Sci. Rev., 39, 23, 10.1097/JES.0b013e318201f39d Simpson, 2014, Special issue on exercise immunology: current perspectives on aging, health and extreme performance, Brain Behav. Immun., 39, 1, 10.1016/j.bbi.2014.03.006 Simpson, 2015, Exercise and the regulation of immune functions, Prog. Mol. Biol. Transl. Sci., 135, 355, 10.1016/bs.pmbts.2015.08.001 Simpson, 2016, Human cytomegalovirus infection and the immune response to exercise, Exerc Immunol Ver, 22, 8 Simpson, 2020, Can exercise affect immune function to increase susceptibility to infection?, Exerc. Immunol. Rev., 26, 8 Solana, 2012, Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans, Semin. Immunol., 24, 331, 10.1016/j.smim.2012.04.008 Sotak, 2020, Adipocytokines and thyreopathies, Vnitr. Lek., 66, 47, 10.36290/vnl.2020.035 Spielmann, 2011, Aerobic fitness is associated with lower proportions of senescent blood T-cells in man, Brain Behav. Immun., 25, 1521, 10.1016/j.bbi.2011.07.226 Suzuki, 2019, Chronic inflammation as an immunological abnormality and effectiveness of exercise, Biomolecules, 9, 223, 10.3390/biom9060223 Szabo, 2000, A novel transcription factor, T-bet, directs Th1 lineage commitment, Cell, 100, 655, 10.1016/S0092-8674(00)80702-3 Tanaka, 2008, Endurance exercise performance in masters athletes: age-associated changes and underlying physiological mechanisms, J. Physiol., 586, 55, 10.1113/jphysiol.2007.141879 Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature, 496, 238, 10.1038/nature11986 Tarique, 2015, Phenotypic, functional, and plasticity features of classical and alternatively activated human macrophages, Am. J. Respir. Cell Mol. Biol., 53, 676, 10.1165/rcmb.2015-0012OC Teixeira, 2021, Lifelong exercise improvement in effector-1 memory CD4+ response and anti-inflammatory profile are related to clock gene expression in master athletes, Exerc. Immunol. Rev. Thompson, 2011, Rethinking the regulation of cellular metabolism, Cold Spring Harb. Symp. Quant. Biol., 76, 23, 10.1101/sqb.2012.76.010496 Tsai, 2016, Exercise training alleviates hypoxia-induced mitochondrial dysfunction in the lymphocytes of sedentary males, Sci. Rep., 6, 10.1038/srep35170 Turner, 2016, Is immunosenescence influenced by our lifetime "dose" of exercise?, Biogerontology, 17, 581, 10.1007/s10522-016-9642-z Vander Haar, 2007, Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40, Nat. Cell Biol., 9, 316, 10.1038/ncb1547 Varela, 2018, Mapping the historical development of physical activity and health research: a structured literature review and citation network analysis, Prev. Med., 111, 466, 10.1016/j.ypmed.2017.10.020 Vats, 2006, Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation, Cell Metab., 4, 13, 10.1016/j.cmet.2006.05.011 Voehringer, 2002, Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1), Blood, 100, 3698, 10.1182/blood-2002-02-0657 Von Ah Morano, 2020, The role of glucose homeostasis on immune function in response to exercise: the impact of low or higher energetic conditions, J. Cell. Physiol., 235, 3169, 10.1002/jcp.29228 Waickman, 2012, mTOR, metabolism, and the regulation of T-cell differentiation and function, Immunol. Rev., 249, 43, 10.1111/j.1600-065X.2012.01152.x Walsh, 2018, Recommendations to maintain immune health in athletes, Eur. J. Sport Sci., 18, 820, 10.1080/17461391.2018.1449895 Wang, 2018, Glycolytic stimulation is not a requirement for M2 macrophage differentiation, Cell Metab., 28, 463, 10.1016/j.cmet.2018.08.012 Warburg, 1956, On the origin of cancer cells, Science, 123, 309, 10.1126/science.123.3191.309 Warren, 2012, Leptin and cognition, Dement. Geriatr. Cogn. Disord., 33, 410, 10.1159/000339956 WHO, 2010 WHO, 2018 Wolf, 2014, Interleukin-6 and its receptors: a highly regulated and dynamic system, Cytokine, 70, 11, 10.1016/j.cyto.2014.05.024 Wolf, 2019, The ontogeny of monocyte subsets, Front. Immunol., 10, 1642, 10.3389/fimmu.2019.01642 Wu, 2001, Sex differences of body fat distribution and cardiovascular dysmetabolic factors in old age, Age Ageing, 30, 331, 10.1093/ageing/30.4.331 Yang, 2012, mTOR and metabolic pathways in T cell quiescence and functional activation, Semin Immunol., 24, 421, 10.1016/j.smim.2012.12.004 Yarbro, 2020, Macrophage immunometabolism and inflammaging: roles of mitochondrial dysfunction, cellular senescence, CD38, and NAD, Immunometabolism, 2, 10.20900/immunometab20200026 Yeung, 2004, Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase, EMBO J., 23, 2369, 10.1038/sj.emboj.7600244 Zeng, 2013, mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function, Nature, 499, 485, 10.1038/nature12297 Zhang, 2015, Pharmacological activation of PPAR gamma ameliorates vascular endothelial insulin resistance via a non-canonical PPAR gamma-dependent nuclear factor-kappa B trans-repression pathway, Eur. J. Pharmacol., 754, 41, 10.1016/j.ejphar.2015.02.004 Zhang, 2016, Mammalian target of rapamycin complex 2 controls CD8 t cell memory differentiation in a Foxo1-dependent manner, Cell Rep., 14, 1206, 10.1016/j.celrep.2015.12.095 Zhang, 2017, Astrocytic process plasticity and IKKbeta/NF-kappaB in central control of blood glucose, blood pressure, and body weight, Cell Metab., 25, 1091, 10.1016/j.cmet.2017.04.002 Zhang, 2020, Injection suppresses production of Interleukin-6 by activating autophagy through the AMPK-mTOR pathway in lipopolysaccharide-stimulated macrophages, Oxid. Med. Cell. Longev., 2020 Zheng, 2007, A role for mammalian target of rapamycin in regulating T cell activation versus anergy, J. Immunol., 178, 2163, 10.4049/jimmunol.178.4.2163 Ziegler-Heitbrock, 2010, Nomenclature of monocytes and dendritic cells in blood, Blood, 116, e74, 10.1182/blood-2010-02-258558