Metabolic reprogramming in inflammaging and aging in T cells

Abstract

Aging represents an emerging challenge for public health due to the declined immune responses against pathogens, weakened vaccination efficacy, and disturbed tissue homeostasis. Metabolic alterations in cellular and systemic levels are also known to be cardinal features of aging. Moreover, cellular metabolism has emerged to provide regulations to guide immune cell behavior via modulations on signaling cascades and epigenetic landscape, and the aberrant aging process in immune cells can lead to inflammaging, a chronic and low-grade inflammation that facilitates aging by perturbing homeostasis in tissues and organs. Here, we review how the metabolic program in T cells is influenced by the aging process and how aged T cells modulate inflammaging. In addition, we discuss the potential approaches to reverse or ameliorate aging by rewiring the metabolic programming of immune cells.

Key words： immunometabolism; inflammaging; T cells

References

1 Yerinde C, Siegmund B, Glauben R et al. Metabolic control of epigenetics and its role in CD8⁺ T cell differentiation and function. Front Immunol 2019;10:2718.

2 Bevilacqua A, Li Z, Ho PC. Metabolic dynamics instruct CD8⁺ T-cell differentiation and functions. Eur J Immunol 2022;52:541–9.

3 van der Windt GJ, Pearce EL. Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev 2012;249:27–42.

4 Geltink RIK, Kyle RL, Pearce EL. Unraveling the complex interplay between T cell metabolism and function. Annu Rev Immunol 2018;36:461–88.

5 Pearce EL, Walsh Matthew C, Cejas PJ et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009;460:103–7.

6 Araki K, Turner AP, Shaffer VO et al. mTOR regulates memory CD8 T-cell differentiation. Nature 2009;460:108–12.

7 van der Windt GJ, Everts B, Chang CH et al. Mitochondrial respiratory capacity is a critical regulator of CD8⁺ T cell memory development. Immunity 2012;36:68–78.

8 Cogliati S, Frezza C, Soriano ME et al. Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 2013;155:160–71.

9 van der Windt GJ, O’Sullivan D, Everts B et al. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. Proc Natl Acad Sci U S A 2013;110:14336–41.

10 Geiger H, de Haan G, Florian MC. The ageing haematopoietic stem cell compartment. Nat Rev Immunol 2013;13:376–89.

11 Beerman I, Bhattacharya D, Zandi S et al. Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion. Proc Natl Acad Sci U S A 2010;107:5465–70.

12 Rossi DJ, Bryder D, Zahn JM et al. Cell intrinsic alterations underlie hematopoietic stem cell aging. Proc Natl Acad Sci U S A 2005;102:9194–9.

13 Juliusson G, Antunovic P, Derolf A et al. Age and acute myeloid leukemia: real world data on decision to treat and outcomes from the Swedish Acute Leukemia Registry. Blood 2009;113:4179–87.

14 Guidi N, Sacma M, Ständker L et al. Osteopontin attenuates aging-associated phenotypes of hematopoietic stem cells. EMBO J 2017;36:1463.

15 Ergen AV, Boles NC, Goodell MA. Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing. Blood 2012;119:2500–9.

16 Kuribayashi W, Oshima M, Itokaza N et al. Limited rejuvenation of aged hematopoietic stem cells in young bone marrow niche. J Exp Med 2021;218:e20192283.

17 Shaw AC, Joshi S, Greenwood H et al. Aging of the innate immune system. Curr Opin Immunol 2010;22:507–13.

18 Butcher S, Chahel H, Lord JM. Review article: ageing and the neutrophil: no appetite for killing? Immunology 2000;100:411–6.

19 Barkaway A, Rolas L, Joulia R et al. Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage. Immunity 2021;54:1494–510.e7.

20 Sapey E, Greenwood H, Walton G et al. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood 2014;123:239–48.

21 Renshaw M, Rockwell J, Engleman C et al. Cutting edge: impaired Toll-like receptor expression and function in aging. J Immunol 2002;169:4697–701.

22 Boehmer ED, Goral J, Faunce DE et al. Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression. J Leukoc Biol 2004;75:342–9.

23 van Duin D, Mohanty S, Thomas V et al. Age-associated defect in human TLR-1/2 function. J Immunol 2007;178:970–5.

24 Gruver AL, Hudson LL, Sempowski GD. Immunosenescence of ageing. J Pathol 2007;211:144–56.

25 den Braber I, Mugwagwa T, Vrisekoop N et al. Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans. Immunity 2012;36:288–97.

26 Hale JS, Boursalian TE, Turk GL et al. Thymic output in aged mice. Proc Natl Acad Sci U S A 2006;103:8447–52.

27 Ahmed M, Lanzer KG, Yager EJ et al. Clonal expansions and loss of receptor diversity in the naive CD8 T cell repertoire of aged mice. J Immunol 2009;182:784–92.

28 Decman V, Laidlaw BJ, Doering TA et al. Defective CD8 T cell responses in aged mice are due to quantitative and qualitative changes in virus-specific precursors. J Immunol 2012;188:1933–41.

29 Britanova OV, Putintseva Ekaterina V, Shugay M et al. Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J Immunol 2014;192:2689–98.

30 Schober K, Voit F, Grassmann S et al. Reverse TCR repertoire evolution toward dominant low-affinity clones during chronic CMV infection. Nat Immunol 2020;21:434–41.

31 Yager EJ, Ahmed M, Lanzer K et al. Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med 2008;205:711–23.

32 Mittelbrunn M, Kroemer G. Hallmarks of T cell aging. Nat Immunol 2021;22:687–98.

33 Sportes C, Hakim FT, Memon SA et al. Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naive T cell subsets. J Exp Med 2008;205:1701–14.

34 Cho BK, Rao VP, Ge Q et al. Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med 2000;192:549–56.

35 Haluszczak C, Akue AD, Hamilton SE et al. The antigen-specific CD8+ T cell repertoire in unimmunized mice includes memory phenotype cells bearing markers of homeostatic expansion. J Exp Med 2009;206:435–48.

36 White JT, Cross EW, Burchill MA et al. Virtual memory T cells develop and mediate bystander protective immunity in an IL-15-dependent manner. Nat Commun 2016;7:11291.

37 Linton PJ, Haynes L, Klinman NR et al. Antigen-independent changes in naive CD4 T cells with aging. J Exp Med 1996;184:1891–900.

38 Decman V, Laidlaw BJ, Dimenna LJ et al. Cell-intrinsic defects in the proliferative response of antiviral memory CD8 T cells in aged mice upon secondary infection. J Immunol 2010;184:5151–9.

39 Kapasi ZF, Murali-Krishna K, McRae ML et al. Defective generation but normal maintenance of memory T cells in old mice. Eur J Immunol 2002;32:1567–73.

40 Franco F, Jaccard A, Romero P et al. Metabolic and epigenetic regulation of T-cell exhaustion. Nat Metab 2020;2:1001–12.

41 Mogilenko DA, Shpynov O, Andhey PS et al. Comprehensive profiling of an aging immune system reveals clonal GZMK⁺ CD8⁺ T cells as conserved hallmark of inflammaging. Immunity 2021;54:99–115.e12.

42 Akbar AN, Henson SM, Lanna A. Senescence of T lymphocytes: implications for enhancing human immunity. Trends Immunol 2016;37:866–76.

43 Fali T, Papagno L, Bayard C et al. New insights into lymphocyte differentiation and aging from telomere length and telomerase activity measurements. J Immunol 2019;202:1962–9.

44 Terao C, Suzuki A, Momozawa Y et al. Chromosomal alterations among age-related haematopoietic clones in Japan. Nature 2020;584:130–5.

45 Nijnik A, Woodbine L, Marchetti C et al. DNA repair is limiting for haematopoietic stem cells during ageing. Nature 2007;447:686–90.

46 Li Y, Shen Y, Hohensinner P et al. Deficient activity of the nuclease MRE11A induces T cell aging and promotes arthritogenic effector functions in patients with rheumatoid arthritis. Immunity 2016;45:903–16.

47 Derhovanessian E, Larbi A, Pawelec G. Biomarkers of human immunosenescence: impact of Cytomegalovirus infection. Curr Opin Immunol 2009;21:440–5.

48 Nishioka T, Shimizu J, Iida R et al. CD4⁺CD25⁺Foxp3⁺ T cells and CD4⁺CD25^-Foxp3⁺ T cells in aged mice. J Immunol 2006;176:6586–93.

49 Sharma S, Dominguez AL, Lustgarten J. High accumulation of T regulatory cells prevents the activation of immune responses in aged animals. J Immunol 2006;177:8348–55.

50 Guo Z, Wang G, Wu B et al. DCAF1 regulates Treg senescence via the ROS axis during immunological aging. J Clin Invest 2020;130:5893–908.

51 Elyahu Y, Hekselman I, Eizenberg-Magar I et al. Aging promotes reorganization of the CD4 T cell landscape toward extreme regulatory and effector phenotypes. Sci Adv 2019;5:eaaw8330.

52 Eaton SM, Burns EM, Kusser K et al. Age-related defects in CD4 T cell cognate helper function lead to reductions in humoral responses. J Exp Med 2004;200:1613–22.

53 Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 2014;69:S4–9.

54 Ferrucci L, Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol 2018;15:505–22.

55 Baruch K, Deczkowska A, David E et al. Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science 2014;346:89–93.

56 Desdin-Mico G, Soto-Heredero G, Aranda JF et al. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 2020;368:1371–6.

57 Kale A, Sharma A, Stolzing A et al. Role of immune cells in the removal of deleterious senescent cells. Immun Ageing 2020;17.

58 Quinn KM, Hussain T, Kraus F et al. Metabolic characteristics of CD8⁺ T cell subsets in young and aged individuals are not predictive of functionality. Nat Commun 2020;11:2857.

59 Nicoli F, Cabral-Piccin MP, Papagno L et al. Altered basal lipid metabolism underlies the functional impairment of naive CD8⁺ T cells in elderly humans. J Immunol 2022;208:562–70.

60 Davenport B, Eberlein J, van der Heide V et al. Aging of antiviral CD8⁺ memory T cells fosters increased survival, metabolic adaptations, and lymphoid tissue homing. J Immunol 2019;202:460–75.

61 Kaech SM, Cui W. Transcriptional control of effector and memory CD8⁺ T cell differentiation. Nat Rev Immunol 2012;12:749–61.

62 Vellai T, Takacs-Vellai K, Zhang Y et al. Genetics: influence of TOR kinase on lifespan in C. elegans. Nature 2003;426:620.

63 Harrison DE, Strong R, Sharp ZD et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460:392–5.

64 Childs BG, Durik M, Baker DJ et al. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med 2015;21:1424–35.

65 Kim E. Mechanisms of amino acid sensing in mTOR signaling pathway. Nutr Res Pract 2009;3:64–71.

66 Sancak Y, Peterson TR, Shaul YD et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008;320:1496–501.

67 Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003;115:577–90.

68 Gwinn DM, Shackelford DB, Egan DF et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214–26.

69 Tavernarakis N. Ageing and the regulation of protein synthesis: a balancing act? Trends Cell Biol 2008;18:228–35.

70 Steffen KK, Dillin A. A ribosomal perspective on proteostasis and aging. Cell Metab 2016;23:1004–12.

71 Leidal AM, Levine B, Debnath J. Autophagy and the cell biology of age-related disease. Nat Cell Biol 2018;20:1338–48.

72 Romero Y, Bueno M, Ramirez R et al. mTORC1 activation decreases autophagy in aging and idiopathic pulmonary fibrosis and contributes to apoptosis resistance in IPF fibroblasts. Aging Cell 2016;15:1103–12.

73 Pyo JO, Yoo SM, Ahn HH et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat Commun 2013;4:2300.

74 Lanna A, Gomes Daniel CO, Muller-Durovic B et al. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat Immunol 2017;18:354–63.

75 Ron-Harel N, Notarangelo G, Ghergurovich JM et al. Defective respiration and one-carbon metabolism contribute to impaired naive T cell activation in aged mice. Proc Natl Acad Sci U S A 2018;115:13347–52.

76 Moskowitz DM, Zhang DW, Hu B et al. Epigenomics of human CD8 T cell differentiation and aging. Sci Immunol 2017;2:eaag0192.

77 Vaena S, Chakraborty P, Lee HG et al. Aging-dependent mitochondrial dysfunction mediated by ceramide signaling inhibits antitumor T cell response. Cell Rep 2021;35:109076.

78 Phadwal K, Alegre-Abarrategui J, Watson AS et al. A novel method for autophagy detection in primary cells: impaired levels of macroautophagy in immunosenescent T cells. Autophagy 2012;8:677–89.

79 Xu X, Araki K, Li S et al. Autophagy is essential for effector CD8⁺ T cell survival and memory formation. Nat Immunol 2014;15:1152–61.

80 Puleston DJ, Zhang H, Powell TJ et al. Autophagy is a critical regulator of memory CD8⁺ T cell formation. Elife 2014;3:e03706.

81 Bharath LP, Agrawal M, McCambridge G et al. Metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation. Cell Metab 2020;32:44–55.e6.

82 Kujoth GC, Hiona A, Pugh TD et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 2005;309:481–4.

83 Trifunovic A, Wredenberg A, Falkenberg M et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 2004;429:417–23.

84 Poewe W, Seppi K, Tanner C et al. Parkinson disease. Nat Rev Dis Primers 2017;3:17013.

85 Lucking CB, Dürr A, Bonifati V et al. Association between early-onset Parkinson’s disease and mutations in the parkin gene. N Engl J Med 2000;342:1560–7.

86 Valente EM, Abou-Sleiman PM, Caputo V et al. Hereditary early-onset Parkinson’s disease caused by mutations in PINK1. Science 2004;304:1158–60.

87 Hsieh CH, Shaltouki A, Gonzalez AE et al. Functional impairment in Miro degradation and mitophagy is a shared feature in familial and sporadic Parkinson’s disease. Cell Stem Cell 2016;19:709–24.

88 Wang W, Zhao F, Ma X et al. Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances. Mol Neurodegener 2020;15:30.

89 Liguori I, Russo G, Curcio F et al. Oxidative stress, aging, and diseases. Clin Interv Aging 2018;13:757–72.

90 Chandel NS. Mitochondria as signaling organelles. BMC Biol 2014;12:34.

91 Sena LA, Li S, Jairaman A et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 2013;38:225–36.

92 Yu YR, Imrichova H, Wang H et al. Disturbed mitochondrial dynamics in CD8⁺ TILs reinforce T cell exhaustion. Nat Immunol 2020;21:1540–51.

93 Becklund BR, Purton JF, Ramsey C et al. The aged lymphoid tissue environment fails to support naive T cell homeostasis. Sci Rep 2016;6:30842.

94 Rathmell JC, Farkash EA, Gao W et al. IL-7 enhances the survival and maintains the size of naive T cells. J Immunol 2001;167:6869–76.

95 Wofford JA, Wieman HL, Jacobs SR et al. IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood 2008;111:2101–11.

96 Surh CD, Sprent J. Homeostasis of naive and memory T cells. Immunity 2008;29:848–62.

97 Cui G, Staron MM, Gray SM et al. IL-7-induced glycerol transport and TAG synthesis promotes memory CD8⁺ T cell longevity. Cell 2015;161:750–61.

98 Utsuyama M, Wakikawa A, Tamura T et al. Impairment of signal transduction in T cells from old mice. Mech Ageing Dev 1997;93:131–44.

99 Angenendt A, Steiner R, Knörck A et al. Orai, STIM, and PMCA contribute to reduced calcium signal generation in CD8⁺ T cells of elderly mice. Aging (Albany NY) 2020;12:3266–86.

100 Miller RA, Jacobson B, Weil G et al. Diminished calcium influx in lectin-stimulated T cells from old mice. J Cell Physiol 1987;132:337–42.

101 Zophel D, Hof C, Lis A. Altered Ca²⁺ homeostasis in immune cells during aging: role of ion channels. Int J Mol Sci 2020;22:110.

102 Sukumar M, Liu J, Ji Y et al. Inhibiting glycolytic metabolism enhances CD8⁺ T cell memory and antitumor function. J Clin Invest 2013;123:4479–88.

103 Chen C, Liu Y, Liu Y et al. mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells. Sci Signal 2009;2:ra75.

104 Mannick JB, Del Giudice G, Lattanzi M et al. mTOR inhibition improves immune function in the elderly. Sci Transl Med 2014;6:268ra179.

105 Mannick JB, Morris M, Hockey HP et al. TORC1 inhibition enhances immune function and reduces infections in the elderly. Sci Transl Med 2018;10:eaaq1564.

106 Barzilai N, Crandall JP, Kritchevsky SB et al. Espeland, metformin as a tool to target aging. Cell Metab 2016;23:1060–5.

107 Eikawa S, Nishida M, Mizukami S et al. Immune-mediated anti-tumor effect by type 2 diabetes drug, metformin. Proc Natl Acad Sci U S A 2015;112:1809–14.

108 Zhang H, Ryu D, Wu Y et al. NAD⁺ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 2016;352:1436–43.

109 Signorile A, Sgaramella G, Bellomo F et al. Prohibitins: a critical role in mitochondrial functions and implication in diseases. Cells 2019;8:71.

110 Vannini N, Campos V, Girotra M et al. The NAD-booster nicotinamide riboside potently stimulates hematopoiesis through increased mitochondrial clearance. Cell Stem Cell 2019;24:405–18.e7.

111 Sun X, Cao B, Naval-Sanchez M et al. Nicotinamide riboside attenuates age-associated metabolic and functional changes in hematopoietic stem cells. Nat Commun 2021;12:2665.

112 Madeo F, Eisenberg T, Pietrocola F et al. Spermidine in health and disease. Science 2018;359:eaan2788.

113 Eisenberg T, Abdellatif M, Schroeder S et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat Med 2016;22:1428–38.

114 Denk D, Petrocelli V, Conche C et al. Expansion of T memory stem cells with superior anti-tumor immunity by Urolithin A-induced mitophagy. Immunity 2022;55:2059–73.e8.

115 Meydani SN, Barklund MP, Liu S et al. Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am J Clin Nutr 1990;52:557–63.

116 Sakai S, Moriguchi S. Long-term feeding of high vitamin E diet improves the decreased mitogen response of rat splenic lymphocytes with aging. J Nutr Sci Vitaminol (Tokyo) 1997;43:113–22.

117 Zhang H, Davies KJA, Forman HJ. Oxidative stress response and Nrf2 signaling in aging. Free Radic Biol Med 2015;88:314–36.

118 Meryk A, Grasse M, Balasco L et al. Antioxidants N-acetylcysteine and vitamin C improve T cell commitment to memory and long-term maintenance of immunological memory in old mice. Antioxidants (Basel) 2020;9:1152.

119 Anderson RM, Shanmuganayagam D, Weindruch R. Caloric restriction and aging: studies in mice and monkeys. Toxicol Pathol 2009;37:47–51.

120 Heilbronn LK, Ravussin E. Calorie restriction and aging: review of the literature and implications for studies in humans. Am J Clin Nutr 2003;78:361–9.

121 Bruss MD, Khambatta CF, Ruby MA et al. Calorie restriction increases fatty acid synthesis and whole body fat oxidation rates. Am J Physiol Endocrinol Metab 2010;298:E108–16.

122 Messaoudi I, Warner J, Fischer M et al. Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proc Natl Acad Sci U S A 2006;103:19448–53.

123 Yan X, Imano N, Tamaki K et al. The effect of caloric restriction on the increase in senescence-associated T cells and metabolic disorders in aged mice. PLoS One 2021;16:e0252547.