The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immune-driven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescence-related immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging.

Allergy Unit Hospital Regional Universitario de Málaga Instituto de Investigación Biomédica de Málaga ARADyAL Málaga Spain

APC Microbiome Ireland University College Cork Cork Ireland

Christine Kühne Center for Allergy Research and Education Davos Switzerland

Comparative Medicine The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna Medical University Vienna and University Vienna Vienna Austria

Department of Biochemistry and Molecular Biology School of Chemistry Complutense University of Madrid Madrid Spain

Department of Clinical Pharmacy and Pharmacology University Groningen University Medical Center Groningen and QPS NL Groningen The Netherlands

Department of Medicine and Surgery University of Parma Pneumologia Italy

Department of Medicine Section of Pharmacology University of Perugia Perugia Italy

Department of Medicine Surgery and Dentistry Scuola Medica Salernitana University of Salerno Salerno Italy

Department of Medicine University College Cork Cork Ireland

Department of Paediatrics Department of Pulmonology and Phthisiology Comenius University in Bratislava Jessenius Faculty of Medicine in Martin University Teaching Hospital Martin Slovakia

Department of Respiratory Medicine 1st Faculty of Medicine Charles University and Thomayer Hospital Prague Czech Republic

Department of Respiratory Medicine and Allergology Institute for Clinical Science Skane University Hospital Lund Sweden

Department of Respiratory Medicine and Allergology Lung and Allergy research Allergy Asthma and COPD Competence Center Lund University Lund Sweden

Departments of Center of Translational Immunology and Dermatology Allergology University Medical Center Utrecht Utrecht The Netherlands

Division of Pharmacology Utrecht Institute for Pharmaceutical Sciences Faculty of Science Utrecht University Utrecht The Netherlands

Experimental Studies Medicine at National Heart and Lung Institute Imperial College London and Royal Brompton and Harefield Hospital London UK

Institute for Drug Research Pharmacology Unit Faculty of Medicine The Hebrew University of Jerusalem Jerusalem Israel

Institute of Pathophysiology and Allergy Research Center of Pathophysiology Infectiology and Immunology Medical University of Vienna Vienna Austria

Molecular Cell Biology Group National Heart and Lung Institute Imperial College London London UK

School of Microbiology University College Cork Cork Ireland

Swiss Institute of Allergy and Asthma Research University of Zürich Davos Switzerland

Zobrazit více v PubMed

Gorgoulis V, Adams PD, Alimonti A, et al. Cellular senescence: defining a path forward. Cell. 2019;179(4):813‐827. PubMed

Kumar M, Seeger W, Voswinckel R. Senescence‐associated secretory phenotype and its possible role in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2014;51(3):323‐333. PubMed

Wiley CD, Campisi J. The metabolic roots of senescence: mechanisms and opportunities for intervention. Nat Metab. 2021;3(10):1290‐1301. PubMed PMC

Zhu X, Chen Z, Shen W, et al. Inflammation, epigenetics, and metabolism converge to cell senescence and ageing: the regulation and intervention. Signal Transduct Target Ther. 2021;6(1):245. PubMed PMC

Budde J, Skloot G. Aging and susceptibility to pulmonary disease. Compr Physiol. 2022;12(3):3509‐3522. PubMed

Pawelec G, Bronikowski A, Cunnane SC, et al. The conundrum of human immune system “senescence”. Mech Ageing Dev. 2020;192:111357. PubMed PMC

Fulop T, Larbi A, Dupuis G, et al. Immunosenescence and Inflamm‐Aging As two sides of the same coin: friends or foes? Front Immunol. 2017;8:1960. PubMed PMC

Soma T, Nagata M. Immunosenescence, inflammaging, and lung senescence in asthma in the elderly. Biomolecules. 2022;12(10):1456. PubMed PMC

Mogilenko DA, Shchukina I, Artyomov MN. Immune ageing at single‐cell resolution. Nat Rev Immunol. 2022;22(8):484‐498. PubMed PMC

Barnes PJ. Targeting cellular senescence as a new approach to chronic obstructive pulmonary disease therapy. Curr Opin Pharmacol. 2021;56:68‐73. PubMed

Barnes PJ. Oxidative stress in chronic obstructive pulmonary disease. Antioxidants (Basel). 2022;11(5):965. PubMed PMC

Rodriguez‐Coira J, Villasenor A, Izquierdo E, et al. The importance of metabolism for immune homeostasis in allergic diseases. Front Immunol. 2021;12:692004. PubMed PMC

Li D, Shen C, Liu L, et al. PKM2 regulates cigarette smoke‐induced airway inflammation and epithelial‐to‐mesenchymal transition via modulating PINK1/Parkin‐mediated mitophagy. Toxicology. 2022;1:153251. PubMed

Wang M, Deng R. Effects of carbon black nanoparticles and high humidity on the lung metabolome in Balb/c mice with established allergic asthma. Environ Sci Pollut Res Int. 2022;29(43):65100‐65111. PubMed

Blagosklonny MV. The hyperfunction theory of aging: three common misconceptions. Oncoscience. 2021;8:103‐107. PubMed PMC

Xu M, Pirtskhalava T, Farr JN, et al. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24(8):1246‐1256. PubMed PMC

Pezone A, Olivieri F, Napoli MV, Procopio A, Avvedimento EV, Gabrielli A. Inflammation and DNA damage: cause, effect or both. Nat Rev Rheumatol. 2023;19(4):200‐211. PubMed

Nikfarjam S, Singh KK. DNA damage response signaling: a common link between cancer and cardiovascular diseases. Cancer Med. 2022;12(4):4380‐4404. PubMed PMC

Masaldan S, Clatworthy SAS, Gamell C, et al. Iron accumulation in senescent cells is coupled with impaired ferritinophagy and inhibition of ferroptosis. Redox Biol. 2018;14:100‐115. PubMed PMC

Vasileiou PVS, Evangelou K, Vlasis K, et al. Mitochondrial homeostasis and cellular senescence. Cells. 2019;8:7. PubMed PMC

Basisty N, Kale A, Jeon OH, et al. A proteomic atlas of senescence‐associated secretomes for aging biomarker development. PLoS Biol. 2020;18(1):e3000599. PubMed PMC

Parimon T, Hohmann MS, Yao C. Cellular senescence: pathogenic mechanisms in lung fibrosis. Int J Mol Sci. 2021;22(12):6214. PubMed PMC

Barnes PJ, Baker J, Donnelly LE. Cellular senescence as a mechanism and target in chronic lung diseases. Am J Respir Crit Care Med. 2019;200(5):556‐564. PubMed

Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013;38(4):633‐643. PubMed PMC

Brier MR, Blazey T, Raichle ME, et al. Increased white matter glycolysis in humans with cerebral small vessel disease. Nat Aging. 2022;2(11):991‐999. PubMed PMC

Rivera‐Mejias P, Narbona‐Perez AJ, Hasberg L, et al. The mitochondrial protease OMA1 acts as a metabolic safeguard upon nuclear DNA damage. Cell Rep. 2023;42(4):112332. PubMed

Rajabian N, Ikhapoh I, Shahini S, et al. Methionine adenosyltransferase2A inhibition restores metabolism to improve regenerative capacity and strength of aged skeletal muscle. Nat Commun. 2023;14(1):886. PubMed PMC

Loppi SH, Tavera‐Garcia MA, Becktel DA, et al. Increased fatty acid metabolism and decreased glycolysis are hallmarks of metabolic reprogramming within microglia in degenerating white matter during recovery from experimental stroke. J Cereb Blood Flow Metab. 2023;43:1099‐1114. PubMed PMC

Yang Y, Sauve AA. NAD(+) metabolism: bioenergetics, signaling and manipulation for therapy. Biochim Biophys Acta. 2016;1864(12):1787‐1800. PubMed PMC

Braidy N, Berg J, Clement J, et al. Role of nicotinamide adenine dinucleotide and related precursors as therapeutic targets for age‐related degenerative diseases: rationale, biochemistry, pharmacokinetics, and outcomes. Antioxid Redox Signal. 2019;30(2):251‐294. PubMed PMC

Verdin E. NAD(+) in aging, metabolism, and neurodegeneration. Science. 2015;350(6265):1208‐1213. PubMed

Poljsak B, Kovac V, Spalj S, Milisav I. The central role of the NAD+ molecule in the development of Aging and the prevention of chronic age‐related diseases: strategies for NAD+ modulation. Int J Mol Sci. 2023;24(3):2959. PubMed PMC

Shim DW, Cho HJ, Hwang I, et al. Intracellular NAD(+) depletion confers a priming signal for NLRP3 inflammasome activation. Front Immunol. 2021;12:765477. PubMed PMC

Shimada K, Crother TR, Karlin J, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36(3):401‐414. PubMed PMC

Sokolowska M, Chen LY, Liu Y, et al. Prostaglandin E2 inhibits NLRP3 inflammasome activation through EP4 receptor and intracellular cyclic AMP in human macrophages. J Immunol. 2015;194(11):5472‐5487. PubMed PMC

Sharma BR, Karki R, Kanneganti TD. Role of AIM2 inflammasome in inflammatory diseases, cancer and infection. Eur J Immunol. 2019;49(11):1998‐2011. PubMed PMC

Radzikowska U, Eljaszewicz A, Tan G, et al. Rhinovirus‐induced epithelial RIG‐I inflammasome suppresses antiviral immunity and promotes inflammation in asthma and COVID‐19. Nat Commun. 2023;14(1):2329. PubMed PMC

Gluck S, Guey B, Gulen MF, et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol. 2017;19(9):1061‐1070. PubMed PMC

Chien Y, Scuoppo C, Wang X, et al. Control of the senescence‐associated secretory phenotype by NF‐kappaB promotes senescence and enhances chemosensitivity. Genes Dev. 2011;25(20):2125‐2136. PubMed PMC

Grun LK, Maurmann RM, Scholl JN, et al. Obesity drives adipose‐derived stem cells into a senescent and dysfunctional phenotype associated with P38MAPK/NF‐KB axis. Immun Ageing. 2023;20(1):51. PubMed PMC

Zhang J, Zhu J, Zhao B, et al. LTF induces senescence and degeneration in the meniscus via the NF‐kappaB signaling pathway: a study based on integrated bioinformatics analysis and experimental validation. Front Mol Biosci. 2023;10:1134253. PubMed PMC

Schlett JS, Mettang M, Skaf A, et al. NF‐kappaB is a critical mediator of post‐mitotic senescence in oligodendrocytes and subsequent white matter loss. Mol Neurodegener. 2023;18(1):24. PubMed PMC

Li T, Meng Y, Ding P, et al. Pathological implication of CaMKII in NF‐kappaB pathway and SASP during cardiomyocytes senescence. Mech Ageing Dev. 2023;209:111758. PubMed

Xie N, Zhang L, Gao W, et al. NAD(+) metabolism: pathophysiologic mechanisms and therapeutic potential. Signal Transduct Target Ther. 2020;5(1):227. PubMed PMC

Li L, Shi L, Yang S, et al. SIRT7 is a histone desuccinylase that functionally links to chromatin compaction and genome stability. Nat Commun. 2016;7:12235. PubMed PMC

He M, Chiang HH, Luo H, et al. An acetylation switch of the NLRP3 Inflammasome regulates Aging‐associated chronic inflammation and insulin resistance. Cell Metab. 2020;31(3):580‐591.e585. PubMed PMC

Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253‐295. PubMed PMC

Chang HC, Guarente L. SIRT1 and other sirtuins in metabolism. Trends Endocrinol Metab. 2014;25(3):138‐145. PubMed PMC

Jiang W, Wang S, Xiao M, et al. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Mol Cell. 2011;43(1):33‐44. PubMed PMC

Du J, Zhou Y, Su X, et al. Sirt5 is a NAD‐dependent protein lysine demalonylase and desuccinylase. Science. 2011;334(6057):806‐809. PubMed PMC

Wang YP, Zhou LS, Zhao YZ, et al. Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress. EMBO J. 2014;33(12):1304‐1320. PubMed PMC

Zhang XY, Li W, Zhang JR, Li CY, Zhang J, Lv XJ. Roles of sirtuin family members in chronic obstructive pulmonary disease. Respir Res. 2022;23(1):66. PubMed PMC

Wiley CD, Velarde MC, Lecot P, et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab. 2016;23(2):303‐314. PubMed PMC

Sun N, Youle RJ, Finkel T. The mitochondrial basis of aging. Mol Cell. 2016;61(5):654‐666. PubMed PMC

Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal. 2014;20(7):1126‐1167. PubMed PMC

Frein D, Schildknecht S, Bachschmid M, Ullrich V. Redox regulation: a new challenge for pharmacology. Biochem Pharmacol. 2005;70(6):811‐823. PubMed

Brune B, Dehne N, Grossmann N, et al. Redox control of inflammation in macrophages. Antioxid Redox Signal. 2013;19(6):595‐637. PubMed PMC

Frasca D. Senescent B cells in aging and age‐related diseases: their role in the regulation of antibody responses. Exp Gerontol. 2018;107:55‐58. PubMed PMC

Behmoaras J, Gil J. Similarities and interplay between senescent cells and macrophages. J Cell Biol. 2021;220(2):e202010162. PubMed PMC

Yousefzadeh MJ, Flores RR, Zhu Y, et al. An aged immune system drives senescence and ageing of solid organs. Nature. 2021;594(7861):100‐105. PubMed PMC

Schulman IH, Balkan W, Hare JM. Mesenchymal stem cell therapy for Aging frailty. Front Nutr. 2018;5:108. PubMed PMC

Nwabo Kamdje AH, Seke Etet PF, Simo Tagne R, Vecchio L, Lukong KE, Krampera M. Tumor microenvironment uses a reversible reprogramming of mesenchymal stromal cells to mediate pro‐tumorigenic effects. Front Cell Dev Biol. 2020;8:545126. PubMed PMC

Davalli P, Mitic T, Caporali A, Lauriola A, D'Arca D. ROS, cell senescence, and novel molecular mechanisms in Aging and age‐related diseases. Oxid Med Cell Longev. 2016;2016:3565127. PubMed PMC

Kumari R, Jat P. Mechanisms of cellular senescence: cell cycle arrest and senescence associated secretory phenotype. Front Cell Dev Biol. 2021;9:645593. PubMed PMC

Liu Y, Xu R, Gu H, et al. Metabolic reprogramming in macrophage responses. Biomark Res. 2021;9(1):1. PubMed PMC

van Beek AA, van den Bossche J, Mastroberardino PG, de Winther MPJ, Leenen PJM. Metabolic alterations in Aging macrophages: ingredients for Inflammaging? Trends Immunol. 2019;40(2):113‐127. PubMed

Loftus RM, Finlay DK. Immunometabolism: cellular metabolism turns immune regulator. J Biol Chem. 2016;291(1):1‐10. PubMed PMC

van den Bossche J, O'Neill LA, Menon D. Macrophage Immunometabolism: where are we (going)? Trends Immunol. 2017;38(6):395‐406. PubMed

Freemerman AJ, Johnson AR, Sacks GN, et al. Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)‐mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem. 2014;289(11):7884‐7896. PubMed PMC

Tannahill GM, Curtis AM, Adamik J, et al. Succinate is an inflammatory signal that induces IL‐1beta through HIF‐1alpha. Nature. 2013;496(7444):238‐242. PubMed PMC

Covarrubias AJ, Aksoylar HI, Yu J, et al. Akt‐mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. Elife. 2016;5:e11612. PubMed PMC

Tan Z, Xie N, Cui H, et al. Pyruvate dehydrogenase kinase 1 participates in macrophage polarization via regulating glucose metabolism. J Immunol. 2015;194(12):6082‐6089. PubMed PMC

Huang SC, Smith AM, Everts B, et al. Metabolic reprogramming mediated by the mTORC2‐IRF4 signaling Axis is essential for macrophage alternative activation. Immunity. 2016;45(4):817‐830. PubMed PMC

Vats D, Mukundan L, Odegaard JI, et al. Oxidative metabolism and PGC‐1beta attenuate macrophage‐mediated inflammation. Cell Metab. 2006;4(1):13‐24. PubMed PMC

Namgaladze D, Brune B. Macrophage fatty acid oxidation and its roles in macrophage polarization and fatty acid‐induced inflammation. Biochim Biophys Acta. 2016;1861(11):1796‐1807. PubMed

Sokolowska M, Chen LY, Eberlein M, et al. Low molecular weight hyaluronan activates cytosolic phospholipase A2alpha and eicosanoid production in monocytes and macrophages. J Biol Chem. 2014;289(7):4470‐4488. PubMed PMC

Cui J, Shan K, Yang Q, Chen W, Feng N, Chen YQ. Eicosanoid production by macrophages during inflammation depends on the M1/M2 phenotype. Prostaglandins Other Lipid Mediat. 2022;160:106635. PubMed

Martinez FO, Helming L, Milde R, et al. Genetic programs expressed in resting and IL‐4 alternatively activated mouse and human macrophages: similarities and differences. Blood. 2013;121(9):e57‐e69. PubMed

O'Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo‐starvation. Nature. 2013;493(7432):346‐355. PubMed

Minhas PS, Liu L, Moon PK, et al. Macrophage de novo NAD(+) synthesis specifies immune function in aging and inflammation. Nat Immunol. 2019;20(1):50‐63. PubMed PMC

Camell CD, Sander J, Spadaro O, et al. Inflammasome‐driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature. 2017;550(7674):119‐123. PubMed PMC

Stout‐Delgado HW, Cho SJ, Chu SG, et al. Age‐dependent susceptibility to pulmonary fibrosis is associated with NLRP3 Inflammasome activation. Am J Respir Cell Mol Biol. 2016;55(2):252‐263. PubMed PMC

Pence BD, Yarbro JR. Aging impairs mitochondrial respiratory capacity in classical monocytes. Exp Gerontol. 2018;108:112‐117. PubMed

Lumeng CN, Liu J, Geletka L, et al. Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue. J Immunol. 2011;187(12):6208‐6216. PubMed PMC

Bains W. Transglutaminse 2 and EGGL, the protein cross‐link formed by transglutaminse 2, as therapeutic targets for disabilities of old age. Rejuvenation Res. 2013;16(6):495‐517. PubMed PMC

Oh J, Riek AE, Weng S, et al. Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem. 2012;287(15):11629‐11641. PubMed PMC

Yeung F, Hoberg JE, Ramsey CS, et al. Modulation of NF‐kappaB‐dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004;23(12):2369‐2380. PubMed PMC

Jin Y, Takeda Y, Kondo Y, et al. Double deletion of tetraspanins CD9 and CD81 in mice leads to a syndrome resembling accelerated aging. Sci Rep. 2018;8(1):5145. PubMed PMC

Sun S, Xia X, Wang M, Liu B. Investigating physiopathological roles for sirtuins in a mouse model. Methods Mol Biol. 2023;2589:95‐110. PubMed

Liang H, Gao J, Zhang C, et al. Nicotinamide mononucleotide alleviates aluminum induced bone loss by inhibiting the TXNIP‐NLRP3 inflammasome. Toxicol Appl Pharmacol. 2019;362:20‐27. PubMed

Lopez‐Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194‐1217. PubMed PMC

Fan W, Morinaga H, Kim JJ, et al. FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO J. 2010;29(24):4223‐4236. PubMed PMC

Chung S, Ranjan R, Lee YG, et al. Distinct role of FoxO1 in M‐CSF‐ and GM‐CSF‐differentiated macrophages contributes LPS‐mediated IL‐10: implication in hyperglycemia. J Leukoc Biol. 2015;97(2):327‐339. PubMed PMC

Delpoux A, Marcel N, Hess Michelini R, et al. FOXO1 constrains activation and regulates senescence in CD8 T cells. Cell Rep. 2021;34(4):108674. PubMed

Kurupati RK, Haut LH, Schmader KE, Ertl HC. Age‐related changes in B cell metabolism. Aging. 2019;11(13):4367‐4381. PubMed PMC

Budzinska M, Owczarz M, Pawlik‐Pachucka E, Roszkowska‐Gancarz M, Slusarczyk P, Puzianowska‐Kuznicka M. miR‐96, miR‐145 and miR‐9 expression increases, and IGF‐1R and FOXO1 expression decreases in peripheral blood mononuclear cells of aging humans. BMC Geriatr. 2016;16(1):200. PubMed PMC

Frasca D, Diaz A, Romero M, Garcia D, Blomberg BB. B Cell Immunosenescence. Annu Rev Cell Dev Biol. 2020;36:551‐574. PubMed PMC

Stephan RP, Reilly CR, Witte PL. Impaired ability of bone marrow stromal cells to support B‐lymphopoiesis with age. Blood. 1998;91(1):75‐88. PubMed

Nipper AJ, Smithey MJ, Shah RC, Canaday DH, Landay AL. Diminished antibody response to influenza vaccination is characterized by expansion of an age‐associated B‐cell population with low PAX5. Clin Immunol. 2018;193:80‐87. PubMed PMC

Labrie JE 3rd, Sah AP, Allman DM, Cancro MP, Gerstein RM. Bone marrow microenvironmental changes underlie reduced RAG‐mediated recombination and B cell generation in aged mice. J Exp Med. 2004;200(4):411‐423. PubMed PMC

Gibson KL, Wu YC, Barnett Y, et al. B‐cell diversity decreases in old age and is correlated with poor health status. Aging Cell. 2009;8(1):18‐25. PubMed PMC

Martin V, Bryan Wu YC, Kipling D, Dunn‐Walters D. Ageing of the B‐cell repertoire. Philos Trans R Soc Lond B Biol Sci. 2015;370(1676):20140237. PubMed PMC

McKenna RW, Washington LT, Aquino DB, Picker LJ, Kroft SH. Immunophenotypic analysis of hematogones (B‐lymphocyte precursors) in 662 consecutive bone marrow specimens by 4‐color flow cytometry. Blood. 2001;98(8):2498‐2507. PubMed

Alter‐Wolf S, Blomberg BB, Riley RL. Deviation of the B cell pathway in senescent mice is associated with reduced surrogate light chain expression and altered immature B cell generation, phenotype, and light chain expression. J Immunol. 2009;182(1):138‐147. PubMed PMC

Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. Age effects on B cells and humoral immunity in humans. Ageing Res Rev. 2011;10(3):330‐335. PubMed PMC

Li Y, Li Z, Hu F. Double‐negative (DN) B cells: an under‐recognized effector memory B cell subset in autoimmunity. Clin Exp Immunol. 2021;205(2):119‐127. PubMed PMC

Ratliff M, Alter S, Frasca D, Blomberg BB, Riley RL. In senescence, age‐associated B cells secrete TNFalpha and inhibit survival of B‐cell precursors. Aging Cell. 2013;12(2):303‐311. PubMed PMC

Frasca D, Diaz A, Romero M, Landin AM, Blomberg BB. High TNF‐alpha levels in resting B cells negatively correlate with their response. Exp Gerontol. 2014;54:116‐122. PubMed PMC

Rubtsov AV, Rubtsova K, Fischer A, et al. Toll‐like receptor 7 (TLR7)‐driven accumulation of a novel CD11c(+) B‐cell population is important for the development of autoimmunity. Blood. 2011;118(5):1305‐1315. PubMed PMC

Frasca D, McElhaney J. Influence of obesity on pneumococcus infection risk in the elderly. Front Endocrinol (Lausanne). 2019;10:71. PubMed PMC

Russell Knode LM, Naradikian MS, Myles A, et al. Age‐associated B cells express a diverse repertoire of V(H) and Vkappa genes with somatic Hypermutation. J Immunol. 2017;198(5):1921‐1927. PubMed PMC

Rubtsova K, Rubtsov AV, Cancro MP, Marrack P. Age‐associated B cells: a T‐bet‐dependent effector with roles in protective and pathogenic immunity. J Immunol. 2015;195(5):1933‐1937. PubMed PMC

Frasca D, Diaz A, Romero M, Thaller S, Blomberg BB. Metabolic requirements of human pro‐inflammatory B cells in aging and obesity. PloS one. 2019;14(7):e0219545. PubMed PMC

Frasca D, Van der Put E, Riley RL, Blomberg BB. Reduced Ig class switch in aged mice correlates with decreased E47 and activation‐induced cytidine deaminase. J Immunol. 2004;172(4):2155‐2162. PubMed

Rubelt F, Sievert V, Knaust F, et al. Onset of immune senescence defined by unbiased pyrosequencing of human immunoglobulin mRNA repertoires. PloS One. 2012;7(11):e49774. PubMed PMC

Patel CH, Powell JD. Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease. Curr Opin Immunol. 2017;46:82‐88. PubMed PMC

Geltink RIK, Kyle RL, Pearce EL. Unraveling the complex interplay between T cell metabolism and function. Annu Rev Immunol. 2018;36:461‐488. PubMed PMC

Saravia J, Raynor JL, Chapman NM, Lim SA, Chi H. Signaling networks in immunometabolism. Cell Res. 2020;30(4):328‐342. PubMed PMC

Kurniawan H, Kobayashi T, Brenner D. The emerging role of one‐carbon metabolism in T cells. Curr Opin Biotechnol. 2021;68:193‐201. PubMed

Roth‐Walter F, Adcock IM, Benito‐Villalvilla C, et al. Immune modulation via T regulatory cell enhancement: disease‐modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases‐An EAACI position paper of the task force on Immunopharmacology (TIPCO). Allergy. 2021;76(1):90‐113. PubMed

Chen CY, Chen J, He L, Stiles BL. PTEN: tumor suppressor and metabolic regulator. Front Endocrinol (Lausanne). 2018;9:338. PubMed PMC

Huynh A, DuPage M, Priyadharshini B, et al. Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol. 2015;16(2):188‐196. PubMed PMC

Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H. Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol. 2015;16(2):178‐187. PubMed PMC

Sharma MD, Shinde R, McGaha TL, et al. The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment. Sci Adv. 2015;1(10):e1500845. PubMed PMC

Hoxhaj G, Manning BD. The PI3K‐AKT network at the interface of oncogenic signalling and cancer metabolism. Nat Rev Cancer. 2020;20(2):74‐88. PubMed PMC

Gerriets VA, Kishton RJ, Johnson MO, et al. Foxp3 and toll‐like receptor signaling balance T(reg) cell anabolic metabolism for suppression. Nat Immunol. 2016;17(12):1459‐1466. PubMed PMC

Procaccini C, Carbone F, Di Silvestre D, et al. The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity. 2016;44(2):406‐421. PubMed PMC

De Rosa V, Galgani M, Porcellini A, et al. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol. 2015;16(11):1174‐1184. PubMed PMC

Hirahara K, Kokubo K, Aoki A, Kiuchi M, Nakayama T. The role of CD4(+) resident memory T cells in local immunity in the mucosal tissue – protection versus pathology. Front Immunol. 2021;12:616309. PubMed PMC

Bull NC, Kaveh DA, Garcia‐Pelayo MC, Stylianou E, McShane H, Hogarth PJ. Induction and maintenance of a phenotypically heterogeneous lung tissue‐resident CD4(+) T cell population following BCG immunisation. Vaccine. 2018;36(37):5625‐5635. PubMed PMC

Rahimi RA, Nepal K, Cetinbas M, Sadreyev RI, Luster AD. Distinct functions of tissue‐resident and circulating memory Th2 cells in allergic airway disease. J Exp Med. 2020;217(9):e20190865. PubMed PMC

Yeon SM, Halim L, Chandele A, et al. IL‐7 plays a critical role for the homeostasis of allergen‐specific memory CD4 T cells in the lung and airways. Sci Rep. 2017;7(1):11155. PubMed PMC

Pan Y, Kupper TS. Metabolic reprogramming and longevity of tissue‐resident memory T cells. Front Immunol. 2018;9:1347. PubMed PMC

Hotamisligil GS, Bernlohr DA. Metabolic functions of FABPs–mechanisms and therapeutic implications. Nat Rev Endocrinol. 2015;11(10):592‐605. PubMed PMC

Hayne CK, Lafferty MJ, Eglinger BJ, Kane JP, Neher SB. Biochemical analysis of the lipoprotein lipase truncation variant, LPL(S447X), reveals increased lipoprotein uptake. Biochemistry. 2017;56(3):525‐533. PubMed PMC

Goplen NP, Cheon IS, Sun J. Age‐related dynamics of lung‐resident memory CD8(+) T cells in the age of COVID‐19. Front Immunol. 2021;12:636118. PubMed PMC

Huang H, Long L, Zhou P, Chapman NM, Chi H. mTOR signaling at the crossroads of environmental signals and T‐cell fate decisions. Immunol Rev. 2020;295(1):15‐38. PubMed PMC

Lopatin YM, Rosano GM, Fragasso G, et al. Rationale and benefits of trimetazidine by acting on cardiac metabolism in heart failure. Int J Cardiol. 2016;203:909‐915. PubMed

Pan Y, Tian T, Park CO, et al. Survival of tissue‐resident memory T cells requires exogenous lipid uptake and metabolism. Nature. 2017;543(7644):252‐256. PubMed PMC

Vijg J, Suh Y. Functional genomics of ageing. Mech Ageing Dev. 2003;124(1):3‐8. PubMed

Kwon J, Lee B, Chung H. Gerontome: a web‐based database server for aging‐related genes and analysis pipelines. BMC Genomics. 2010;11(Suppl 4):S20. PubMed PMC

Lu RJ, Wang EK, Benayoun BA. Functional genomics of inflamm‐aging and immunosenescence. Brief Funct Genomics. 2021;21(1):43‐55. PubMed PMC

Qi C, Xu CJ, Koppelman GH. The role of epigenetics in the development of childhood asthma. Expert Rev Clin Immunol. 2019;15(12):1287‐1302. PubMed

Reddy PH. Mitochondrial dysfunction and oxidative stress in asthma: implications for mitochondria‐targeted antioxidant therapeutics. Pharmaceuticals (Basel). 2011;4(3):429‐456. PubMed PMC

Wang ZN, Su RN, Yang BY, et al. Potential role of cellular senescence in asthma. Front Cell Dev Biol. 2020;8:59. PubMed PMC

Birch J, Barnes PJ, Passos JF. Mitochondria, telomeres and cell senescence: implications for lung ageing and disease. Pharmacol Ther. 2018;183:34‐49. PubMed

Adcock IM, Mumby S. Glucocorticoids. Handb Exp Pharmacol. 2017;237:171‐196. PubMed

Barnes PJ. Glucocorticosteroids. Handb Exp Pharmacol. 2017;237:93‐115. PubMed

Caramori G, Nucera F, Mumby S, Lo Bello F, Adcock IM. Corticosteroid resistance in asthma: cellular and molecular mechanisms. Mol Aspects Med. 2022;85:100969. PubMed

Stokes CA, Condliffe AM. Phosphoinositide 3‐kinase delta (PI3Kdelta) in respiratory disease. Biochem Soc Trans. 2018;46(2):361‐369. PubMed

To Y , Ito K, Kizawa Y, et al. Targeting phosphoinositide‐3‐kinase‐delta with theophylline reverses corticosteroid insensitivity in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;182(7):897‐904. PubMed PMC

Uddin M, Watz H, Malmgren A, Pedersen F. NETopathic inflammation in chronic obstructive pulmonary disease and severe asthma. Front Immunol. 2019;10:47. PubMed PMC

Yamasaki A, Okazaki R, Harada T. Neutrophils and asthma. Diagnostics (Basel). 2022;12(5):1175. PubMed PMC

Arora S, Dev K, Agarwal B, Das P, Syed MA. Macrophages: their role, activation and polarization in pulmonary diseases. Immunobiology. 2018;223(4–5):383‐396. PubMed PMC

Sokolowska M, Chen LY, Liu Y, et al. Dysregulation of lipidomic profile and antiviral immunity in response to hyaluronan in patients with severe asthma. J Allergy Clin Immunol. 2017;139(4):1379‐1383. PubMed PMC

Schleich F, Graff S, Guissard F, Henket M, Paulus V, Louis R. Asthma in elderly is characterized by increased sputum neutrophils, lower airway caliber variability and air trapping. Respir Res. 2021;22(1):15. PubMed PMC

Aghali A, Khalfaoui L, Lagnado AB, et al. Cellular senescence is increased in airway smooth muscle cells of elderly persons with asthma. Am J Physiol Lung Cell Mol Physiol. 2022;323(5):L558‐L568. PubMed PMC

Reinke SN, Naz S, Chaleckis R, et al. Urinary metabotype of severe asthma evidences decreased carnitine metabolism independent of oral corticosteroid treatment in the U‐BIOPRED study. Eur Respir J. 2021;25(2101733):1733‐2021. PubMed PMC

Esteves P, Blanc L, Celle A, et al. Crucial role of fatty acid oxidation in asthmatic bronchial smooth muscle remodelling. Eur Respir J. 2021;58(5):2004252. PubMed

Sánchez‐Ovando S, Pavlidis S, Kermani NZ, et al. Pathways linked to unresolved inflammation and airway remodelling characterize the transcriptome in two independent severe asthma cohorts. Respirology. 2022;7(10):14302. PubMed PMC

van de Wetering C, Manuel AM, Sharafi M, et al. Glutathione‐S‐transferase P promotes glycolysis in asthma in association with oxidation of pyruvate kinase M2. Redox Biol. 2021;47:102160. PubMed PMC

Delgado‐Dolset MI, Obeso D, Rodriguez‐Coira J, et al. Understanding uncontrolled severe allergic asthma by integration of omic and clinical data. Allergy. 2022;77(6):1772‐1785. PubMed

Ilarregui JM, Bianco GA, Toscano MA, Rabinovich GA. The coming of age of galectins as immunomodulatory agents: impact of these carbohydrate binding proteins in T cell physiology and chronic inflammatory disorders. Ann Rheum Dis. 2005;64(Suppl 4):iv96‐iv103. doi:10.1136/ard.2005.044347 PubMed DOI PMC

Riccio AM, Mauri P, De Ferrari L, et al. Galectin‐3: an early predictive biomarker of modulation of airway remodeling in patients with severe asthma treated with omalizumab for 36 months. Clin Transl Allergy. 2017;7:6. doi:10.1186/s13601-13017-10143-13601 PubMed DOI PMC

Kachroo P, Stewart ID, Kelly RS, et al. Metabolomic profiling reveals extensive adrenal suppression due to inhaled corticosteroid therapy in asthma. Nat Med. 2022;28(4):814‐822. doi:10.1038/s41591-41022-01714-41595 PubMed DOI PMC

Radzikowska U, Rinaldi AO, Celebi Sozener Z, et al. The influence of dietary fatty acids on immune responses. Nutrients. 2019;11(12):2990. PubMed PMC

Cardoso‐Vigueros C, von Blumenthal T, Ruckert B, et al. Leukocyte redistribution as immunological biomarker of corticosteroid resistance in severe asthma. Clin Exp Allergy. 2022;52(10):1183‐1194. PubMed PMC

Ravi A, Goorsenberg AWM, Dijkhuis A, et al. Metabolic differences between bronchial epithelium from healthy individuals and patients with asthma and the effect of bronchial thermoplasty. J Allergy Clin Immunol. 2021;148(5):1236‐1248. doi:10.1016/j.jaci.2020.1212.1653 PubMed DOI

Rodriguez‐Perez N, Schiavi E, Frei R, et al. Altered fatty acid metabolism and reduced stearoyl‐coenzyme a desaturase activity in asthma. Allergy. 2017;72(11):1744‐1752. PubMed

Rago D, Pedersen CT, Huang M, et al. Characteristics and mechanisms of a sphingolipid‐associated childhood asthma Endotype. Am J Respir Crit Care Med. 2021;203(7):853‐863. doi:10.1164/rccm.202008-203206OC PubMed DOI PMC

Jung J, Kim SH, Lee HS, et al. Serum metabolomics reveals pathways and biomarkers associated with asthma pathogenesis. Clin Exp Allergy. 2013;43(4):425‐433. PubMed

Tang X, Rönnberg E, Säfholm J, et al. Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction. Allergy. 2022;4(10):15245. PubMed PMC

Jaiswal AK, Yadav J, Makhija S, et al. Irg1/itaconate metabolic pathway is a crucial determinant of dendritic cells immune‐priming function and contributes to resolute allergen‐induced airway inflammation. Mucosal Immunol. 2022;15(2):301‐313. doi:10.1038/s41385-41021-00462-y PubMed DOI PMC

Runtsch MC, Angiari S, Hooftman A, et al. Itaconate and itaconate derivatives target JAK1 to suppress alternative activation of macrophages. Cell Metab. 2022;34(3):487‐501.e488. doi:10.1016/j.cmet.2022.1002.1002 PubMed DOI

Sokolowska M, Rovati GE, Diamant Z, et al. Current perspective on eicosanoids in asthma and allergic diseases: EAACI task force consensus report, part I. Allergy. 2021;76(1):114‐130. PubMed

Sokolowska M, Rovati GE, Diamant Z, et al. Effects of non‐steroidal anti‐inflammatory drugs and other eicosanoid pathway modifiers on antiviral and allergic responses: EAACI task force on eicosanoids consensus report in times of COVID‐19. Allergy. 2022;77(8):2337‐2354. PubMed PMC

Nucera F, Mumby S, Paudel KR, et al. Role of oxidative stress in the pathogenesis of COPD. Minerva Med. 2022;113(3):370‐404. PubMed

Wu J, Zhao X, Xiao C, et al. The role of lung macrophages in chronic obstructive pulmonary disease. Respir Med. 2022;205:107035. PubMed

Zhang Z, Cheng X, Yue L, et al. Molecular pathogenesis in chronic obstructive pulmonary disease and therapeutic potential by targeting AMP‐activated protein kinase. J Cell Physiol. 2018;233(3):1999‐2006. PubMed

Cheng XY, Li YY, Huang C, Li J, Yao HW. AMP‐activated protein kinase reduces inflammatory responses and cellular senescence in pulmonary emphysema. Oncotarget. 2017;8(14):22513‐22523. PubMed PMC

Baker JR, Donnelly LE. Leukocyte function in COPD: clinical relevance and potential for drug therapy. Int J Chron Obstruct Pulmon Dis. 2021;16:2227‐2242. PubMed PMC

Fujii W, Kapellos TS, Bassler K, et al. Alveolar macrophage transcriptomic profiling in COPD shows major lipid metabolism changes. ERJ Open Res. 2021;7(3):915‐2020. PubMed PMC

Roth‐Walter F. Iron‐deficiency in atopic diseases: innate immune priming by allergens and Siderophores. Front Allergy. 2022;3:859922. PubMed PMC

Baker JM, Hammond M, Dungwa J, et al. Red blood cell‐derived iron alters macrophage function in COPD. Biomedicine. 2021;9(12):1939. PubMed PMC

Ham J, Kim J, Ko YG, Kim HY. The dynamic contribution of neutrophils in the chronic respiratory diseases. Allergy Asthma Immunol Res. 2022;14(4):361‐378. PubMed PMC

Sadiku P, Willson JA, Ryan EM, et al. Neutrophils fuel effective immune responses through gluconeogenesis and glycogenesis. Cell Metab. 2021;33(5):1062‐1064. PubMed PMC

Kuznar‐Kaminska B, Mikula‐Pietrasik J, Witucka A, et al. Serum from patients with chronic obstructive pulmonary disease induces senescence‐related phenotype in bronchial epithelial cells. Sci Rep. 2018;8(1):12940. PubMed PMC

Wiegman CH, Michaeloudes C, Haji G, et al. Oxidative stress‐induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2015;136(3):769‐780. PubMed PMC

Michaeloudes C, Kuo CH, Haji G, et al. Metabolic re‐patterning in COPD airway smooth muscle cells. Eur Respir J. 2017;50(5):1700202. PubMed PMC

Feng Y, Xie M, Liu Q, et al. Changes in targeted metabolomics in lung tissue of chronic obstructive pulmonary disease. J Thorac Dis. 2023;15(5):2544‐2558. PubMed PMC

Li Y, Zhang L, Polverino F, et al. Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD‐derived airway smooth muscle cells. Sci Rep. 2021;11(1):9074. PubMed PMC

Baker JR, Donnelly LE, Barnes PJ. Senotherapy: a new horizon for COPD therapy. Chest. 2020;158(2):562‐570. PubMed

Barnes PJ. Senescence in COPD and its comorbidities. Annu Rev Physiol. 2017;79:517‐539. PubMed

Rao W, Wang S, Duleba M, et al. Regenerative metaplastic clones in COPD lung drive inflammation and fibrosis. Cell. 2020;181(4):848‐864.e818. PubMed PMC

Levine S, Gregory C, Nguyen T, et al. Bioenergetic adaptation of individual human diaphragmatic myofibers to severe COPD. J Appl Physiol (1985). 2002;92(3):1205‐1213. PubMed

Haji G, Wiegman CH, Michaeloudes C, et al. Mitochondrial dysfunction in airways and quadriceps muscle of patients with chronic obstructive pulmonary disease. Respir Res. 2020;21(1):262. PubMed PMC

Balnis J, Drake LA, Vincent CE, et al. SDH subunit C regulates muscle oxygen consumption and fatigability in an animal model of pulmonary emphysema. Am J Respir Cell Mol Biol. 2021;65(3):259‐271. PubMed PMC

Paschalaki K, Rossios C, Pericleous C, et al. Inhaled corticosteroids reduce senescence in endothelial progenitor cells from patients with COPD. Thorax. 2022;77(6):616‐620. PubMed PMC

Muller KC, Welker L, Paasch K, et al. Lung fibroblasts from patients with emphysema show markers of senescence in vitro. Respir Res. 2006;7(1):32. PubMed PMC

Gao W, Yuan C, Zhang J, et al. Klotho expression is reduced in COPD airway epithelial cells: effects on inflammation and oxidant injury. Clin Sci (Lond). 2015;129(12):1011‐1023. PubMed PMC

Pako J, Barta I, Balogh Z, et al. Assessment of the anti‐Aging klotho protein in patients with COPD undergoing pulmonary rehabilitation. COPD. 2017;14(2):176‐180. PubMed

Muller KC, Paasch K, Feindt B, et al. In contrast to lung fibroblasts–no signs of senescence in skin fibroblasts of patients with emphysema. Exp Gerontol. 2008;43(7):623‐628. PubMed

Woldhuis RR, Heijink IH, van den Berge M, et al. COPD‐derived fibroblasts secrete higher levels of senescence‐associated secretory phenotype proteins. Thorax. 2021;76(5):508‐511. PubMed PMC

Woldhuis RR, de Vries M, Timens W, et al. Link between increased cellular senescence and extracellular matrix changes in COPD. Am J Physiol Lung Cell Mol Physiol. 2020;319(1):L48‐L60. PubMed

Schuliga M, Pechkovsky DV, Read J, et al. Mitochondrial dysfunction contributes to the senescent phenotype of IPF lung fibroblasts. J Cell Mol Med. 2018;22(12):5847‐5861. PubMed PMC

Blokland KEC, Nizamoglu M, Habibie H, et al. Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts. Front Pharmacol. 2022;13:989169. PubMed PMC

Hashimoto Y, Sugiura H, Togo S, et al. 27‐hydroxycholesterol accelerates cellular senescence in human lung resident cells. Am J Physiol Lung Cell Mol Physiol. 2016;310(11):L1028‐L1041. PubMed

Wu X, Bos IST, Conlon TM, et al. A transcriptomics‐guided drug target discovery strategy identifies receptor ligands for lung regeneration. Sci Adv. 2022;8(12):eabj9949. PubMed PMC

Adams TS, Schupp JC, Poli S, et al. Single‐cell RNA‐seq reveals ectopic and aberrant lung‐resident cell populations in idiopathic pulmonary fibrosis. Sci Adv. 2020;6(28):eaba1983. PubMed PMC

Nava VE, Khosla R, Shin S, Mordini FE, Bandyopadhyay BC. Enhanced carbonic anhydrase expression with calcification and fibrosis in bronchial cartilage during COPD. Acta Histochem. 2022;124(1):151834. PubMed PMC

Halper‐Stromberg E, Gillenwater L, Cruickshank‐Quinn C, et al. Bronchoalveolar lavage fluid from COPD patients reveals more compounds associated with disease than matched plasma. Metabolites. 2019;9(8):157. PubMed PMC

Mastej E, Gillenwater L, Zhuang Y, Pratte KA, Bowler RP, Kechris K. Identifying protein‐metabolite networks associated with COPD phenotypes. Metabolites. 2020;10(4):124. PubMed PMC

Cruickshank‐Quinn CI, Jacobson S, Hughes G, et al. Metabolomics and transcriptomics pathway approach reveals outcome‐specific perturbations in COPD. Sci Rep. 2018;8(1):17132. PubMed PMC

Madapoosi SS, Cruickshank‐Quinn C, Opron K, et al. Lung microbiota and metabolites collectively associate with clinical outcomes in milder stage chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2022;206(4):427‐439. PubMed PMC

Godbole S, Labaki WW, Pratte KA, et al. A metabolomic severity score for airflow obstruction and emphysema. Metabolites. 2022;12(5):368. PubMed PMC

Hoffman EA, Ahmed FS, Baumhauer H, et al. Variation in the percent of emphysema‐like lung in a healthy, nonsmoking multiethnic sample. The MESA lung study. Ann Am Thorac Soc. 2014;11(6):898‐907. PubMed PMC

Carpenter CM, Zhang W, Gillenwater L, et al. PaIRKAT: a pathway integrated regression‐based kernel association test with applications to metabolomics and COPD phenotypes. PLoS Comput Biol. 2021;17(10):e1008986. PubMed PMC

Park J, Hescott BJ, Slonim DK. Pathway centrality in protein interaction networks identifies putative functional mediating pathways in pulmonary disease. Sci Rep. 2019;9(1):5863. PubMed PMC

Adamko DJ, Nair P, Mayers I, Tsuyuki RT, Regush S, Rowe BH. Metabolomic profiling of asthma and chronic obstructive pulmonary disease: a pilot study differentiating diseases. J Allergy Clin Immunol. 2015;136(3):571‐580.e573. PubMed

Chen Q, Deeb RS, Ma Y, Staudt MR, Crystal RG, Gross SS. Serum metabolite biomarkers discriminate healthy smokers from COPD smokers. PloS One. 2015;10(12):e0143937. PubMed PMC

Gillenwater LA, Pratte KA, Hobbs BD, et al. Plasma metabolomic signatures of chronic obstructive pulmonary disease and the impact of genetic variants on phenotype‐driven modules. Netw Syst Med. 2020;3(1):159‐181. PubMed PMC

Nambiar S, Tan DBA, Clynick B, et al. Untargeted metabolomics of human plasma reveal lipid markers unique to chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Proteomics Clin Appl. 2021;15(2–3):e2000039. PubMed

Zhu T, Li S, Wang J, et al. Induced sputum metabolomic profiles and oxidative stress are associated with chronic obstructive pulmonary disease (COPD) severity: potential use for predictive, preventive, and personalized medicine. EPMA J. 2020;11(4):645‐659. PubMed PMC

Zheng H, Hu Y, Dong L, et al. Predictive diagnosis of chronic obstructive pulmonary disease using serum metabolic biomarkers and least‐squares support vector machine. J Clin Lab Anal. 2021;35(2):e23641. PubMed PMC

Liu D, Meister M, Zhang S, et al. Identification of lipid biomarker from serum in patients with chronic obstructive pulmonary disease. Respir Res. 2020;21(1):242. PubMed PMC

Prokic I, Lahousse L, de Vries M, et al. A cross‐omics integrative study of metabolic signatures of chronic obstructive pulmonary disease. BMC Pulm Med. 2020;20(1):193. PubMed PMC

Viglino D, Martin M, Piche ME, et al. Metabolic profiles among COPD and controls in the CanCOLD population‐based cohort. PloS One. 2020;15(4):e0231072. PubMed PMC

Zhou J, Li Q, Liu C, Pang R, Yin Y. Plasma metabolomics and Lipidomics reveal perturbed metabolites in different disease stages of chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis. 2020;15:553‐565. PubMed PMC

Naz S, Kolmert J, Yang M, et al. Metabolomics analysis identifies sex‐associated metabotypes of oxidative stress and the autotaxin‐lysoPA axis in COPD. Eur Respir J. 2017;49(6):1602322. PubMed PMC

Gillenwater LA, Kechris KJ, Pratte KA, et al. Metabolomic profiling reveals sex specific associations with chronic obstructive pulmonary disease and emphysema. Metabolites. 2021;11(3):161. PubMed PMC

Forde B, Yao L, Shaha R, Murphy S, Lunjani N, O'Mahony L. Immunomodulation by foods and microbes: unravelling the molecular tango. Allergy. 2022;77(12):3513‐3526. PubMed PMC

Ghosh TS, Shanahan F, O'Toole PW. The gut microbiome as a modulator of healthy ageing. Nat Rev Gastroenterol Hepatol. 2022;19(9):565‐584. PubMed PMC

Farr JN, Xu M, Weivoda MM, et al. Targeting cellular senescence prevents age‐related bone loss in mice. Nat Med. 2017;23(9):1072‐1079. PubMed PMC

Assmus B, Urbich C, Aicher A, et al. HMG‐CoA reductase inhibitors reduce senescence and increase proliferation of endothelial progenitor cells via regulation of cell cycle regulatory genes. Circ Res. 2003;92(9):1049‐1055. PubMed

Campbell JP, Turner JE. Debunking the myth of exercise‐induced immune suppression: redefining the impact of exercise on immunological health across the lifespan. Front Immunol. 2018;9:648. PubMed PMC

Ragonnaud E, Biragyn A. Gut microbiota as the key controllers of “healthy” aging of elderly people. Immun Ageing. 2021;18(1):2. PubMed PMC

Brown FF, Bigley AB, Sherry C, et al. Training status and sex influence on senescent T‐lymphocyte redistribution in response to acute maximal exercise. Brain Behav Immun. 2014;39:152‐159. PubMed

Batatinha HAP, Diniz TA, de Souza Teixeira AA, Kruger K, Rosa‐Neto JC. Regulation of autophagy as a therapy for immunosenescence‐driven cancer and neurodegenerative diseases: the role of exercise. J Cell Physiol. 2019;234(9):14883‐14895. PubMed

Simpson RJ. Aging, persistent viral infections, and immunosenescence: can exercise "make space"? Exerc Sport Sci Rev. 2011;39(1):23‐33. PubMed

Domaszewska K, Boraczynski M, Tang YY, et al. Protective effects of exercise become especially important for the Aging immune system in the Covid‐19 era. Aging Dis. 2022;13(1):129‐143. PubMed PMC

Tylutka A, Morawin B, Gramacki A, Zembron‐Lacny A. Lifestyle exercise attenuates immunosenescence; flow cytometry analysis. BMC Geriatr. 2021;21(1):200. PubMed PMC

Simpson RJ, Lowder TW, Spielmann G, Bigley AB, LaVoy EC, Kunz H. Exercise and the aging immune system. Ageing Res Rev. 2012;11(3):404‐420. PubMed

Puri S, Shaheen M, Grover B. Nutrition and cognitive health: a life course approach. Front Public Health. 2023;11:1023907. PubMed PMC

Peroni DG, Hufnagl K, Comberiati P, Roth‐Walter F. Lack of iron, zinc, and vitamins as a contributor to the etiology of atopic diseases. Front Nutr. 2022;9:1032481. PubMed PMC

Venter C, Greenhawt M, Meyer RW, et al. EAACI position paper on diet diversity in pregnancy, infancy and childhood: novel concepts and implications for studies in allergy and asthma. Allergy. 2020;75(3):497‐523. PubMed

Vlieg‐Boerstra B, de Jong N, Meyer R, et al. Nutrient supplementation for prevention of viral respiratory tract infections in healthy subjects: a systematic review and meta‐analysis. Allergy. 2022;77(5):1373‐1388. PubMed

Venter C, Meyer RW, Greenhawt M, et al. Role of dietary fiber in promoting immune health‐An EAACI position paper. Allergy. 2022;77(11):3185‐3198. PubMed

Mello AM, Paroni G, Daragjati J, Pilotto A. Gastrointestinal microbiota and their contribution to healthy Aging. Dig Dis. 2016;34(3):194‐201. PubMed

Maijó M, Clements SJ, Ivory K, Nicoletti C, Carding SR. Nutrition, diet and immunosenescence. Mech Ageing Dev. 2014;136‐137:116‐128. PubMed

Badal VD, Vaccariello ED, Murray ER, et al. The gut microbiome, Aging, and longevity: a systematic review. Nutrients. 2020;12(12):3759. PubMed PMC

Calder PC, Ortega EF, Meydani SN, et al. Nutrition, Immunosenescence, and infectious disease: An overview of the scientific evidence on micronutrients and on modulation of the gut microbiota. Adv Nutrit. 2022;13(5):S1‐S26. PubMed PMC

Carroll JE, Irwin MR, Levine M, et al. Epigenetic Aging and immune senescence in women with insomnia symptoms: findings from the Women's Health Initiative study. Biol Psychiatry. 2017;81(2):136‐144. PubMed PMC

Aiello A, Accardi G, Ali S, et al. Possible association of telomere length with sleep duration. A preliminary pilot study in a Sicilian cohort with centenarians. Transl Med UniSa. 2021;24(1):24‐29. PubMed PMC

Schutte NS, Malouff JM, Keng SL. Meditation and telomere length: a meta‐analysis. Psychol Health. 2020;35(8):901‐915. PubMed

Besedovsky L, Lange T, Born J. Sleep and immune function. Pflugers Arch. 2012;463(1):121‐137. PubMed PMC

Garbarino S, Lanteri P, Sannita WG, Bragazzi NL, Scoditti E. Circadian rhythms, sleep, immunity, and fragility in the elderly: the model of the susceptibility to infections. Front Neurol. 2020;11:558417. PubMed PMC

de Souza Teixeira AA, Lira FS, Rosa‐Neto JC. Aging with rhythmicity. Is it possible? Physical exercise as a pacemaker. Life Sci. 2020;261:118453. PubMed PMC

Losol P, Sokolowska M, Chang YS. Interactions between microbiome and underlying mechanisms in asthma. Respir Med. 2023;208:107118. PubMed

Barcik W, Boutin RCT, Sokolowska M, Finlay BB. The role of lung and gut microbiota in the pathology of asthma. Immunity. 2020;52(2):241‐255. PubMed PMC

Petje LM, Jensen SA, Szikora S, et al. Functional iron‐deficiency in women with allergic rhinitis is associated with symptoms after nasal provocation and lack of iron‐sequestering microbes. Allergy. 2021;76(9):2882‐2886. PubMed PMC

De Luca F, Shoenfeld Y. The microbiome in autoimmune diseases. Clin Exp Immunol. 2019;195(1):74‐85. PubMed PMC

Bosco N, Noti M. The aging gut microbiome and its impact on host immunity. Genes Immun. 2021;22(5–6):289‐303. PubMed PMC

McFarland LV. Epidemiology, risk factors and treatments for antibiotic‐associated diarrhea. Dig Dis. 1998;16(5):292‐307. PubMed

Hou K, Wu ZX, Chen XY, et al. Microbiota in health and diseases. Signal Transduct Target Ther. 2022;7(1):135. PubMed PMC

Crooke SN, Ovsyannikova IG, Poland GA, Kennedy RB. Immunosenescence and human vaccine immune responses. Immun Ageing. 2019;16:25. PubMed PMC

Heintz C, Mair W. You are what you host: microbiome modulation of the aging process. Cell. 2014;156(3):408‐411. PubMed PMC

Aiello A, Farzaneh F, Candore G, et al. Immunosenescence and its hallmarks: how to oppose Aging strategically? A review of potential options for therapeutic intervention. Front Immunol. 2019;10:2247. PubMed PMC

Chotirmall SH, Burke CM. Aging and the microbiome: implications for asthma in the elderly? Expert Rev Respir Med. 2015;9(2):125‐128. PubMed

Bull MJ, Plummer NT. Part 2: treatments for chronic gastrointestinal disease and gut Dysbiosis. Integr Med (Encinitas). 2015;14(1):25‐33. PubMed PMC

Christensen L, Roager HM, Astrup A, Hjorth MF. Microbial enterotypes in personalized nutrition and obesity management. Am J Clin Nutr. 2018;108(4):645‐651. PubMed

Carrasco‐Pozo C, Tan KN, Borges K. Sulforaphane is anticonvulsant and improves mitochondrial function. J Neurochem. 2015;135(5):932‐942. PubMed

Langston‐Cox A, Muccini AM, Marshall SA, et al. Sulforaphane improves syncytiotrophoblast mitochondrial function after in vitro hypoxic and superoxide injury. Placenta. 2020;96:44‐54. PubMed

Sun Z, Niu Z, Wu S, Shan S. Protective mechanism of sulforaphane in Nrf2 and anti‐lung injury in ARDS rabbits. Exp Ther Med. 2018;15(6):4911‐4915. PubMed PMC

Benito‐Villalvilla C, Perez‐Diego M, Angelina A, et al. Allergoid‐mannan conjugates reprogram monocytes into tolerogenic dendritic cells via epigenetic and metabolic rewiring. J Allergy Clin Immunol. 2022;149(1):212‐222.e219. PubMed

Eljaszewicz A, Ruchti F, Radzikowska U, et al. Trained immunity and tolerance in innate lymphoid cells, monocytes, and dendritic cells during allergen‐specific immunotherapy. J Allergy Clin Immunol. 2021;147(5):1865‐1877. PubMed

Netea MG, Dominguez‐Andres J, Barreiro LB, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol. 2020;20(6):375‐388. PubMed PMC

Bergmann K‐C, Raab J, Krause L, et al. Long‐term benefits of targeted micronutrition with the holoBLG lozenge in house dust mite allergic patients. Allergo J Int. 2022;31(6):161‐171.

Ro SH, Fay J, Cyuzuzo CI, et al. SESTRINs: emerging dynamic stress‐sensors in metabolic and environmental health. Front Cell Dev Biol. 2020;8:603421. PubMed PMC

Budanov AV, Lee JH, Karin M. Stressin' Sestrins take an aging fight. EMBO Mol Med. 2010;2(10):388‐400. PubMed PMC

Sun W, Wang Y, Zheng Y, Quan N. The emerging role of Sestrin2 in cell metabolism, and cardiovascular and age‐related diseases. Aging Dis. 2020;11(1):154‐163. PubMed PMC

Segales J, Perdiguero E, Serrano AL, et al. Sestrin prevents atrophy of disused and aging muscles by integrating anabolic and catabolic signals. Nat Commun. 2020;11(1):189. PubMed PMC

Rai N, Venugopalan G, Pradhan R, et al. Exploration of novel anti‐oxidant protein Sestrin in frailty syndrome in elderly. Aging Dis. 2018;9(2):220‐227. PubMed PMC

Ro SH, Nam M, Jang I, et al. Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species. Proc Natl Acad Sci U S A. 2014;111(21):7849‐7854. PubMed PMC

Kim H, An S, Ro SH, et al. Janus‐faced Sestrin2 controls ROS and mTOR signalling through two separate functional domains. Nat Commun. 2015;6:10025. PubMed PMC

Salminen A, Ojala J, Kaarniranta K, Kauppinen A. Mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age‐related diseases. Cell Mol Life Sci. 2012;69(18):2999‐3013. PubMed PMC

Shay JW, Wright WE. Telomeres and telomerase: three decades of progress. Nat Rev Genet. 2019;20(5):299‐309. PubMed

Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 2010;24(22):2463‐2479. PubMed PMC

Chen QM, Bartholomew JC, Campisi J, Acosta M, Reagan JD, Ames BN. Molecular analysis of H2O2‐induced senescent‐like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication. Biochem J. 1998;332(Pt 1):43‐50. PubMed PMC

Hernandez‐Segura A, de Jong TV, Melov S, Guryev V, Campisi J, Demaria M. Unmasking transcriptional heterogeneity in senescent cells. Curr Biol. 2017;27(17):2652‐2660 e2654. PubMed PMC

Chen Z, Trotman LC, Shaffer D, et al. Crucial role of p53‐dependent cellular senescence in suppression of Pten‐deficient tumorigenesis. Nature. 2005;436(7051):725‐730. PubMed PMC

Herranz N, Gallage S, Mellone M, et al. mTOR regulates MAPKAPK2 translation to control the senescence‐associated secretory phenotype. Nat Cell Biol. 2015;17(9):1205‐1217. PubMed PMC

Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence‐associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99‐118. PubMed PMC

Mendelsohn AR, Larrick JW. The NAD+/PARP1/SIRT1 Axis in Aging. Rejuvenation Res. 2017;20(3):244‐247. PubMed

Sabath N, Levy‐Adam F, Younis A, et al. Cellular proteostasis decline in human senescence. Proc Natl Acad Sci U S A. 2020;117(50):31902‐31913. PubMed PMC

Kennedy AL, McBryan T, Enders GH, Johnson FB, Zhang R, Adams PD. Senescent mouse cells fail to overtly regulate the HIRA histone chaperone and do not form robust senescence associated heterochromatin foci. Cell Div. 2010;5:16. PubMed PMC

Lee BY, Han JA, Im JS, et al. Senescence‐associated beta‐galactosidase is lysosomal beta‐galactosidase. Aging Cell. 2006;5(2):187‐195. PubMed

Evangelou K, Gorgoulis VG. Sudan black B, the specific histochemical stain for lipofuscin: a novel method to detect senescent cells. Methods Mol Biol. 2017;1534:111‐119. PubMed

Baker DJ, Childs BG, Durik M, et al. Naturally occurring p16(Ink4a)‐positive cells shorten healthy lifespan. Nature. 2016;530(7589):184‐189. PubMed PMC

Fang L, Zhang M, Li J, Zhou L, Tamm M, Roth M. Airway smooth muscle cell mitochondria damage and Mitophagy in COPD via ERK1/2 MAPK. Int J Mol Sci. 2022;23(22):13987. PubMed PMC

Rovira M, Sereda R, Pladevall‐Morera D, et al. The lysosomal proteome of senescent cells contributes to the senescence secretome. Aging Cell. 2022;21(10):e13707. PubMed PMC

Mizumura K, Cloonan SM, Nakahira K, et al. Mitophagy‐dependent necroptosis contributes to the pathogenesis of COPD. J Clin Invest. 2014;124(9):3987‐4003. PubMed PMC

Tsitoura E, Vasarmidi E, Bibaki E, et al. Accumulation of damaged mitochondria in alveolar macrophages with reduced OXPHOS related gene expression in IPF. Respir Res. 2019;20(1):264. PubMed PMC

Qin L, Fan M, Candas D, et al. CDK1 enhances mitochondrial bioenergetics for radiation‐induced DNA repair. Cell Rep. 2015;13(10):2056‐2063. PubMed PMC

Tilstra JS, Clauson CL, Niedernhofer LJ, Robbins PD. NF‐kappaB in aging and disease. Aging Dis. 2011;2(6):449‐465. PubMed PMC

Hamann L, Ruiz‐Moreno JS, Szwed M, et al. STING SNP R293Q is associated with a decreased risk of Aging‐related diseases. Gerontology. 2019;65(2):145‐154. PubMed

Ising C, Venegas C, Zhang S, et al. NLRP3 inflammasome activation drives tau pathology. Nature. 2019;575(7784):669‐673. PubMed PMC

Mastrocola R, Aragno M, Alloatti G, Collino M, Penna C, Pagliaro P. Metaflammation: tissue‐specific alterations of the NLRP3 inflammasome platform in metabolic syndrome. Curr Med Chem. 2018;25(11):1294‐1310. PubMed

d'Adda di Fagagna F. Living on a break: cellular senescence as a DNA‐damage response. Nat Rev Cancer. 2008;8(7):512‐522. PubMed

Cohen HY, Miller C, Bitterman KJ, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science. 2004;305(5682):390‐392. PubMed

Covarrubias AJ, Kale A, Perrone R, et al. Senescent cells promote tissue NAD(+) decline during ageing via the activation of CD38(+) macrophages. Nat Metab. 2020;2(11):1265‐1283. PubMed PMC

Lu B, Nakamura T, Inouye K, et al. Novel role of PKR in inflammasome activation and HMGB1 release. Nature. 2012;488(7413):670‐674. PubMed PMC

Guo Q, Chen X, Chen J, et al. STING promotes senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the NF‐kappaB signaling pathway. Cell Death Dis. 2021;12(1):13. PubMed PMC

Chini CCS, Peclat TR, Warner GM, et al. CD38 ecto‐enzyme in immune cells is induced during aging and regulates NAD(+) and NMN levels. Nat Metab. 2020;2(11):1284‐1304. PubMed PMC

Kang C, Xu Q, Martin TD, et al. The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4. Science. 2015;349(6255):aaa5612. PubMed PMC

Carroll B, Korolchuk VI. Nutrient sensing, growth and senescence. FEBS J. 2018;285(11):1948‐1958. PubMed PMC

Nsiah‐Sefaa A, McKenzie M. Combined defects in oxidative phosphorylation and fatty acid beta‐oxidation in mitochondrial disease. Biosci Rep. 2016;36(2):e00313. PubMed PMC

Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response‐independent regulator of the senescence‐associated secretory phenotype. EMBO J. 2011;30(8):1536‐1548. PubMed PMC

Estebanez B, de Paz JA, Cuevas MJ, Gonzalez‐Gallego J. Endoplasmic reticulum unfolded protein response, aging and exercise: an update. Front Physiol. 2018;9:1744. PubMed PMC

Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nat Rev Immunol. 2014;14(3):195‐208. PubMed PMC

To M , Takagi D, Akashi K, et al. Sputum plasminogen activator inhibitor‐1 elevation by oxidative stress‐dependent nuclear factor‐kappaB activation in COPD. Chest. 2013;144(2):515‐521. PubMed

Kakkera K, Atchley WT, Kodali M, Bartter T. Ageing and chronic obstructive pulmonary disease: interrelationships. Curr Opin Pulm Med. 2023;29(2):90‐95. PubMed

Zhang Y, Zhang J, Fu Z. Role of autophagy in lung diseases and ageing. Eur Respir Rev. 2022;31(166):220134. PubMed PMC

Kume H, Yamada R, Sato Y, Togawa R. Airway smooth muscle regulated by oxidative stress in COPD. Antioxidants (Basel). 2023;12(1):142. PubMed PMC

Barnes PJ, Baker J, Donnelly LE. Autophagy in asthma and chronic obstructive pulmonary disease. Clin Sci (Lond). 2022;136(10):733‐746. PubMed PMC

Cloonan SM, Kim K, Esteves P, Trian T, Barnes PJ. Mitochondrial dysfunction in lung ageing and disease. Eur Respir Rev. 2020;29(157):200165. PubMed PMC

Barnes PJ. Pulmonary diseases and ageing. Subcell Biochem. 2019;91:45‐74. PubMed

Araya J, Kuwano K. Cellular senescence‐an aging hallmark in chronic obstructive pulmonary disease pathogenesis. Respir Investig. 2022;60(1):33‐44. PubMed

Neri T, Celi A, Tine M, et al. The emerging role of extracellular vesicles detected in different biological fluids in COPD. Int J Mol Sci. 2022;23(9):5136. PubMed PMC

Russell DW, Genschmer KR, Blalock JE. Extracellular vesicles as central mediators of COPD pathophysiology. Annu Rev Physiol. 2022;84:631‐654. PubMed PMC

Cappello F, Caramori G, Campanella C, et al. Convergent sets of data from in vivo and in vitro methods point to an active role of Hsp60 in chronic obstructive pulmonary disease pathogenesis. PloS One. 2011;6(11):e28200. PubMed PMC

Kao CC, Hsu JW, Bandi V, Hanania NA, Kheradmand F, Jahoor F. Glucose and pyruvate metabolism in severe chronic obstructive pulmonary disease. J Appl Physiol (1985). 2012;112(1):42‐47. PubMed PMC

Kutsuzawa T, Shioya S, Kurita D, Haida M. Deoxygenated hemoglobin/myoglobin kinetics of forearm muscles from rest to exercise in patients with chronic obstructive pulmonary disease. Tohoku J Exp Med. 2009;217(1):9‐15. PubMed

Raguso CA, Guinot SL, Janssens JP, Kayser B, Pichard C. Chronic hypoxia: common traits between chronic obstructive pulmonary disease and altitude. Curr Opin Clin Nutr Metab Care. 2004;7(4):411‐417. PubMed

Keir HR, Chalmers JD. Neutrophil extracellular traps in chronic lung disease: implications for pathogenesis and therapy. Eur Respir Rev. 2022;31(163):5136. PubMed PMC

Kim RY, Sunkara KP, Bracke KR, et al. A microRNA‐21‐mediated SATB1/S100A9/NF‐kappaB axis promotes chronic obstructive pulmonary disease pathogenesis. Sci Transl Med. 2021;13(621):eaav7223. PubMed

Bhat TA, Panzica L, Kalathil SG, Thanavala Y. Immune dysfunction in patients with chronic obstructive pulmonary disease. Ann Am Thorac Soc. 2015;12(Suppl 2):S169‐S175. PubMed PMC

Di Stefano A, Dossena F, Gnemmi I, et al. Decreased humoral immune response in the bronchi of rapid decliners with chronic obstructive pulmonary disease. Respir Res. 2022;23(1):200. PubMed PMC

Yu W, Ye T, Ding J, et al. miR‐4456/CCL3/CCR5 pathway in the pathogenesis of tight junction impairment in chronic obstructive pulmonary disease. Front Pharmacol. 2021;12:551839. PubMed PMC

Spagnolo P, Semenzato U. Revealing the pathogenic and ageing‐related mechanisms of the enigmatic idiopathic pulmonary fibrosis (and chronic obstructive pulmonary disease). Curr Opin Pulm Med. 2022;28(4):296‐302. PubMed PMC

Di Stefano A, Ricciardolo FLM, Caramori G, et al. Bronchial inflammation and bacterial load in stable COPD is associated with TLR4 overexpression. Eur Respir J. 2017;49(5):1602006. PubMed

Lo Bello F, Ieni A, Hansbro PM, et al. Role of the mucins in pathogenesis of COPD: implications for therapy. Expert Rev Respir Med. 2020;14(5):465‐483. PubMed

Karim L, Lin CR, Kosmider B, et al. Mitochondrial ribosome dysfunction in human alveolar type II cells in emphysema. Biomedicine. 2022;10(7):1497. PubMed PMC

Goel K, Egersdorf N, Gill A, et al. Characterization of pulmonary vascular remodeling and MicroRNA‐126‐targets in COPD‐pulmonary hypertension. Respir Res. 2022;23(1):349. PubMed PMC

Fang L, Wang X, Zhang M, Khan P, Tamm M, Roth M. MicroRNA‐101‐3p suppresses mTOR and causes mitochondrial fragmentation and cell degeneration in COPD. Can Respir J. 2022;2022:5933324. PubMed PMC

Liu L, Wei Y, Giunta S, He Q, Xia S. Potential role of cellular senescence in pulmonary arterial hypertension. Clin Exp Pharmacol Physiol. 2022;49(10):1042‐1049. PubMed

Poto R, Loffredo S, Palestra F, Marone G, Patella V, Varricchi G. Angiogenesis, lymphangiogenesis, and inflammation in chronic obstructive pulmonary disease (COPD): few certainties and many outstanding questions. Cells. 2022;11(10):1720. PubMed PMC

Barnes PJ. Oxidative stress‐based therapeutics in COPD. Redox Biol. 2020;33:101544. PubMed PMC

Hecker L, Logsdon NJ, Kurundkar D, et al. Reversal of persistent fibrosis in aging by targeting Nox4‐Nrf2 redox imbalance. Sci Transl Med. 2014;6(231):231ra247. PubMed PMC

Hernandez‐Gonzalez F, Faner R, Rojas M, Agustí A, Serrano M, Sellarés J. Cellular senescence in lung fibrosis. Int J Mol Sci. 2021;22(13):7012. PubMed PMC

Chen Y, Evankovich JW, Lear TB, et al. A small molecule NRF2 activator BC‐1901S ameliorates inflammation through DCAF1/NRF2 axis. Redox Biol. 2020;32:101485. PubMed PMC

Mo C, Wang L, Zhang J, et al. The crosstalk between Nrf2 and AMPK signal pathways is important for the anti‐inflammatory effect of berberine in LPS‐stimulated macrophages and endotoxin‐shocked mice. Antioxid Redox Signal. 2014;20(4):574‐588. PubMed PMC

Kohandel Z, Farkhondeh T, Aschner M, Samarghandian S. Nrf2 a molecular therapeutic target for Astaxanthin. Biomed Pharmacother. 2021;137:111374. PubMed

El‐Khouly D, El‐Bakly WM, Awad AS, El‐Mesallamy HO, El‐Demerdash E. Thymoquinone blocks lung injury and fibrosis by attenuating bleomycin‐induced oxidative stress and activation of nuclear factor kappa‐B in rats. Toxicology. 2012;302(2–3):106‐113. PubMed

Kubo H, Asai K, Kojima K, et al. Astaxanthin suppresses cigarette smoke‐induced emphysema through Nrf2 activation in mice. Mar Drugs. 2019;17(12):673. PubMed PMC

El Gazzar M, El Mezayen R, Marecki JC, Nicolls MR, Canastar A, Dreskin SC. Anti‐inflammatory effect of thymoquinone in a mouse model of allergic lung inflammation. Int Immunopharmacol. 2006;6(7):1135‐1142. PubMed

Culpitt SV, Rogers DF, Fenwick PS, et al. Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. Thorax. 2003;58(11):942‐946. PubMed PMC

Birrell MA, McCluskie K, Wong S, Donnelly LE, Barnes PJ, Belvisi MG. Resveratrol, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an NF‐kappaB‐independent mechanism. FASEB J. 2005;19(7):840‐841. PubMed

Yonchuk JG, Foley JP, Bolognese BJ, et al. Characterization of the potent, selective Nrf2 activator, 3‐(Pyridin‐3‐Ylsulfonyl)‐5‐(Trifluoromethyl)‐2H‐Chromen‐2‐one, in cellular and in vivo models of pulmonary oxidative stress. J Pharmacol Exp Ther. 2017;363(1):114‐125. PubMed

Satoh T, Lipton S. Recent advances in understanding NRF2 as a druggable target: development of pro‐electrophilic and non‐covalent NRF2 activators to overcome systemic side effects of electrophilic drugs like dimethyl fumarate. F1000Research. 2017;6:2138. PubMed PMC

Grzegorzewska AP, Seta F, Han R, et al. Dimethyl fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways. Sci Rep. 2017;7(1):41605. PubMed PMC

Hansel TT, Kharitonov SA, Donnelly LE, et al. A selective inhibitor of inducible nitric oxide synthase inhibits exhaled breath nitric oxide in healthy volunteers and asthmatics. FASEB J. 2003;17(10):1298‐1300. PubMed

Yousefzadeh MJ, Zhu Y, McGowan SJ, et al. Fisetin is a senotherapeutic that extends health and lifespan. EBioMedicine. 2018;36:18‐28. PubMed PMC

Zhang L, Tong X, Huang J, et al. Fisetin alleviated Bleomycin‐induced pulmonary fibrosis partly by rescuing alveolar epithelial cells from senescence. Front Pharmacol. 2020;11:55369. PubMed PMC

Omarjee L, Perrot F, Meilhac O, Mahe G, Bousquet G, Janin A. Immunometabolism at the cornerstone of inflammaging, immunosenescence, and autoimmunity in COVID‐19. Aging. 2020;12(24):26263‐26278. PubMed PMC

Mercer PF, Woodcock HV, Eley JD, et al. Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti‐fibrotic agent in IPF. Thorax. 2016;71(8):701‐711. PubMed PMC

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(6):1103‐1112. PubMed PMC

Shen Z, Xuan W, Wang H, et al. miR‐200b regulates cellular senescence and inflammatory responses by targeting ZEB2 in pulmonary emphysema. Art Cells, Nanomed, Biotechnol. 2020;48(1):656‐663. PubMed

Calhoun C, Shivshankar P, Saker M, et al. Senescent cells contribute to the physiological remodeling of aged lungs. J Gerontol A Biol Sci Med Sci. 2016;71(2):153‐160. PubMed PMC

Laberge RM, Sun Y, Orjalo AV, et al. MTOR regulates the pro‐tumorigenic senescence‐associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2015;17(8):1049‐1061. PubMed PMC

Ozsvari B, Nuttall JR, Sotgia F, Lisanti MP. Azithromycin and Roxithromycin define a new family of “senolytic” drugs that target senescent human fibroblasts. Aging. 2018;10(11):3294‐3307. PubMed PMC

Moiseeva O, Deschênes‐Simard X, St‐Germain E, et al. Metformin inhibits the senescence‐associated secretory phenotype by interfering with IKK/NF‐κB activation. Aging Cell. 2013;12(3):489‐498. PubMed

Huang WT, Akhter H, Jiang C, et al. Plasminogen activator inhibitor 1, fibroblast apoptosis resistance, and aging‐related susceptibility to lung fibrosis. Exp Gerontol. 2015;61:62‐75. PubMed PMC

Zhang X, Dong Y, Li WC, Tang BX, Li J, Zang Y. Roxithromycin attenuates bleomycin‐induced pulmonary fibrosis by targeting senescent cells. Acta Pharmacol Sin. 2021;42(12):2058‐2068. PubMed PMC

Disayabutr S, Kim EK, Cha SI, et al. miR‐34 miRNAs regulate cellular senescence in type II alveolar epithelial cells of patients with idiopathic pulmonary fibrosis. PloS One. 2016;11(6):e0158367. PubMed PMC

Zeng Q, Zeng J. Inhibition of miR‐494‐3p alleviates oxidative stress‐induced cell senescence and inflammation in the primary epithelial cells of COPD patients. Int Immunopharmacol. 2021;92:107044. PubMed

Hardeland R. Ageing, Melatonin, and the pro‐ and anti‐inflammatory networks. Int J Mol Sci. 2019;20(5):1223. PubMed PMC

Ahmad T, Sundar IK, Tormos AM, et al. Shelterin telomere protection protein 1 reduction causes telomere attrition and cellular senescence via Sirtuin 1 deacetylase in chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol. 2017;56(1):38‐49. PubMed PMC

Hao J, Ni X, Giunta S, et al. Pyrroloquinoline quinone delays inflammaging induced by TNF‐α through the p16/p21 and Jagged1 signalling pathways. Clin Exp Pharmacol Physiol. 2020;47(1):102‐110. PubMed

Li F, Xu M, Wang M, et al. Roles of mitochondrial ROS and NLRP3 inflammasome in multiple ozone‐induced lung inflammation and emphysema. Respir Res. 2018;19(1):230. PubMed PMC

Schafer MJ, White TA, Iijima K, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017;8:14532. PubMed PMC

Zhu Y, Tchkonia T, Fuhrmann‐Stroissnigg H, et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors. Aging Cell. 2016;15(3):428‐435. PubMed PMC

Lehmann M, Korfei M, Mutze K, et al. Senolytic drugs target alveolar epithelial cell function and attenuate experimental lung fibrosis ex vivo. Eur Respir J. 2017;50(2):1602367. PubMed PMC

Zhu Y, Doornebal EJ, Pirtskhalava T, et al. New agents that target senescent cells: the flavone, fisetin, and the BCL‐X(L) inhibitors, A1331852 and A1155463. Aging. 2017;9(3):955‐963. PubMed PMC

Fuhrmann‐Stroissnigg H, Ling YY, Zhao J, et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun. 2017;8(1):422. PubMed PMC

Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: results from a first‐in‐human, open‐label, pilot study. EBioMedicine. 2019;40:554‐563. PubMed PMC

Yosef R, Pilpel N, Tokarsky‐Amiel R, et al. Directed elimination of senescent cells by inhibition of BCL‐W and BCL‐XL. Nat Commun. 2016;7:11190. PubMed PMC

Walters HE, Cox LS. Generation of a novel model of primary human cell senescence through Tenovin‐6 mediated inhibition of sirtuins. Biogerontology. 2019;20(3):303‐319. PubMed PMC

Baar MP, Brandt RMC, Putavet DA, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to Chemotoxicity and Aging. Cell. 2017;169(1):132‐147.e116. PubMed PMC

Noren Hooten N, Martin‐Montalvo A, Dluzen DF, et al. Metformin‐mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell. 2016;15(3):572‐581. PubMed PMC

Triana‐Martínez F, Picallos‐Rabina P, Da Silva‐Álvarez S, et al. Identification and characterization of cardiac glycosides as senolytic compounds. Nat Commun. 2019;10(1):4731. PubMed PMC

Brown RH, Reynolds C, Brooker A, Talalay P, Fahey JW. Sulforaphane improves the bronchoprotective response in asthmatics through Nrf2‐mediated gene pathways. Respir Res. 2015;16(1):106. PubMed PMC

Duran CG, Burbank AJ, Mills KH, et al. A proof‐of‐concept clinical study examining the NRF2 activator sulforaphane against neutrophilic airway inflammation. Respir Res. 2016;17(1):89. PubMed PMC

Viola A, Munari F, Sanchez‐Rodriguez R, Scolaro T, Castegna A. The metabolic signature of macrophage responses. Front Immunol. 2019;10:1462. PubMed PMC

Mittelbrunn M, Kroemer G. Hallmarks of T cell aging. Nat Immunol. 2021;22(6):687‐698. PubMed

Gerriets VA, Kishton RJ, Nichols AG, et al. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest. 2015;125(1):194‐207. PubMed PMC

Wang H, Franco F, Ho PC. Metabolic regulation of Tregs in cancer: opportunities for immunotherapy. Trends Cancer. 2017;3(8):583‐592. PubMed