Research Progress on Inflammaging in Aplastic Anemia

doi:10.3870/j.issn.1672-0741.25.08.032

Abstract

Abstract: As the global population ages at an accelerating pace,the burden of age-related hematological diseases is increasing.Inflammaging,a chronic,systemic,low-grade inflammatory state associated with aging,has been linked to various age-related diseases,including cardiovascular,cerebrovascular,and neurodegenerative disorders.However,its specific mechanistic role in aplastic anemia(AA)—a bone marrow failure—remains systematically unelucidated.This review comprehensively summarizes inflammaging and its underlying mechanisms,with a particular focus on its role in AA.We aim to elucidate how AA contributes to inflammaging in patients through a bone marrow microenvironment-hematopoietic stem cells-immune system triad network,thereby providing a rationale for future AA prevention and treatment.

Key words: inflammaging, aplastic anemia, bone marrow failure

CLC Number:

R556.5

Chen Ke, Yang Xiangdong , Yang Qianqian et al. Research Progress on Inflammaging in Aplastic Anemia[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(2): 302-307.

References

[1] 中华医学会血液学分会红细胞疾病(贫血)学组.再生障碍性贫血诊断与治疗中国指南(2022年版)[J].中华血液学杂志,2022,43(11):881-888.
Red Blood Cell Disease(Anemia)Study Group,Chinese Society of Hematology,Chinese Medical Association.Chinese guideline for the diagnosis and treatment of aplastic anemia(2022)[J].Chinese Journal of Hematology,2022,43(11):881-888.
[2] 何琪杨,刘光慧,保志军,等.中国衰老与抗衰老专家共识(2019年)[J].老年医学与保健,2019,25(5):551-553.
He Q Y,Liu G H,Bao Z J,et al.Expert consensuses of China for aging and antiaging(2019 edition)[J].Geriatrics and Health Care,2019,25(5):551-553.
[3] Franceschi C,Bonafè M,Valensin S,et al.Inflamm-aging.An evolutionary perspective on immunosenescence[J].Ann N Y Acad Sci,2000,908:244-254.
[4] Coperchini F,Greco A,Teliti M,et al.Inflamm-ageing:How cytokines and nutrition shape the trajectory of ageing[J].Cytokine Growth Factor Rev,2025,82:31-42.
[5] St Sauver J,Rocca W,LeBrasseur N,et al.Inflammatory biomarkers,multi-morbidity,and biologic aging[J].J Int Med Res,2022,50(7):03000605221109393.
[6] Puzianowska-Kuź nicka M,Owczarz M,Wieczorowska-Tobis K,et al.Interleukin-6 and C-reactive protein,successful aging,and mortality:The PolSenior study[J].Immun Ageing,2016,13:21.
[7] Povar-Echeverría M,Auquilla-Clavijo P E,Andrès E,et al.Interleukin-6 could be a potential prognostic factor in ambulatory elderly patients with stable heart failure:Results from a pilot study[J].J Clin Med,2021,10(3):504.
[8] Rink L,Cakman I,Kirchner H.Altered cytokine production in the elderly[J].Mech Ageing Dev,1998,102(2/3):199-209.
[9] Michaud M,Balardy L,Moulis G,et al.Proinflammatory cytokines,aging,and age-related diseases[J].J Am Med Dir Assoc,2013,14(12):877-882.
[10] Rea I M,Gibson D S,McGilligan V,et al.Age and age-related diseases:Role of inflammation triggers and cytokines[J].Front Immunol,2018,9:586.
[11] Kaushik S,Tasset I,Arias E,et al.Autophagy and the hallmarks of aging[J].Ageing Res Rev,2021,72:101468.
[12] Aman Y,Schmauck-Medina T,Hansen M,et al.Autophagy in healthy aging and disease[J].Nat Aging,2021,1(8):634-650.
[13] Ge Y,Zhou M,Chen C,et al.Role of AMPK mediated pathways in autophagy and aging[J].Biochimie,2022,195:100-113.
[14] Ramos E L P,de Sousa Neto I V,Pinto A P,et al.Mechanisms underlying the interplay between autophagy and the inflammasome in age-related diseases:Implications for exercise immunology[J].Ageing Res Rev,2025,110:102821.
[15] Deretic V,Levine B.Autophagy balances inflammation in innate immunity[J].Autophagy,2018,14(2):243-251.
[16] Luo J,Mills K,le Cessie S,et al.Ageing,age-related diseases and oxidative stress:What to do next[J].Ageing Res Rev,2020,57:100982.
[17] Wei Y,Jia S,Ding Y,et al.Balanced basal-levels of ROS(redox-biology),and very-low-levels of pro-inflammatory cytokines(cold-inflammaging),as signaling molecules can prevent or slow-down overt-inflammaging,and the aging-associated decline of adaptive-homeostasis[J].Exp Gerontol,2023,172:112067.
[18] Abdallah R,Badran S,Badran A,et al.Ziziphus nummularia extract attenuates inflammatory markers in RAW 264.7 macrophages[J].Sci Rep,2025,15:26362.
[19] Cuadrado A,Manda G,Hassan A,et al.Transcription factor NRF2 as a therapeutic target for chronic diseases:A systems medicine approach[J].Pharmacol Rev,2018,70(2):348-383.
[20] Abais J M,Xia M,Zhang Y,et al.Redox regulation of NLRP3 inflammasomes:ROS as trigger or effector[J].Antioxid Redox Signal,2015,22(13):1111-1129.
[21] Dominguez L J,Veronese N,Barbagallo M.Magnesium and the hallmarks of aging[J].Nutrients,2024,16(4):496.
[22] Li Z,Li S,Chen W,et al.Mitochondrial dysfunction:Related diseases,influencing factors,and detection[J].Interdiscip Med,2025,3(5):e20250005.
[23] De Gaetano A,Solodka K,Zanini G,et al.Molecular mechanisms of mtDNA-mediated inflammation[J].Cells,2021,10(11):2898.
[24] Huang H,Li G,He Y,et al.Cellular succinate metabolism and signaling in inflammation:Implications for therapeutic intervention[J].Front Immunol,2024,15:1404441.
[25] Singh A,Schurman S H,Bektas A,et al.Aging and inflammation[J].Cold Spring Harb Perspect Med,2024,14(6):a041197.
[26] Khaledi M,Poureslamfar B,Alsaab H O,et al.The role of gut microbiota in human metabolism and inflammatory diseases:A focus on elderly individuals[J].Ann Microbiol,2024,74(1):1.
[27] Ticinesi A,Nouvenne A,Cerundolo N,et al.Gut microbiota,muscle mass and function in aging:A focus on physical frailty and sarcopenia[J].Nutrients,2019,11(7):1633.
[28] Caldarelli M,Rio P,Marrone A,et al.Inflammaging:The next challenge-exploring the role of gut microbiota,environmental factors,and sex differences[J].Biomedicines,2024,12(8):1716.
[29] Pan I,Issac P K,Rahman M M,et al.Gut-brain axis a key player to control gut dysbiosis in neurological diseases[J].Mol Neurobiol,2024,61(12):9873-9891.
[30] Ruiz Pérez M,Maueröder C,Steels W,et al.TL1 A and IL-18 synergy promotes GM-CSF-dependent thymic granulopoiesis in mice[J].Cell Mol Immunol,2024,21(8):807-825.
[31] Wang H,Divaris K,Pan B,et al.Clonal hematopoiesis driven by mutated DNMT3A promotes inflammatory bone loss[J].Cell,2024,187(14):3690-3711.e19.
[32] Gladow N,Hollmann C,Weirather J,et al.Role of CD4⁺T-cells for regulating splenic myelopoiesis and monocyte differentiation after experimental myocardial infarction[J].Basic Res Cardiol,2024,119(2):261-275.
[33] Fulop T,Dupuis G,Baehl S,et al.From inflamm-aging to immune-paralysis:A slippery slope during aging for immune-adaptation[J].Biogerontology,2016,17(1):147-157.
[34] Frasca D,Diaz A,Romero M,et al.High TNF-α levels in resting B cells negatively correlate with their response[J].Exp Gerontol,2014,54:116-122.
[35] de Punder K,Heim C,Wadhwa P D,et al.Stress and immunosenescence:The role of telomerase[J].Psychoneuroendocrinology,2019,101:87-100.
[36] Wang Y,Dong C,Han Y,et al.Immunosenescence,aging and successful aging[J].Front Immunol,2022,13:942796.
[37] Li P H,Zhang R,Cheng L Q,et al.Metabolic regulation of immune cells in proinflammatory microenvironments and diseases during ageing[J].Aging Res Rev,2020,64:101165.
[38] Lee K A,Robbins P D,Camell C D.Intersection of immunometabolism and immunosenescence during aging[J].Curr Opin Pharmacol,2021,57:107-116.
[39] 张沛雯,马小彤.稳态及衰老情况下骨髓微环境对造血干细胞的调控作用[J].中国细胞生物学学报,2021,43(2):420-427.
Zhang P W,Ma X T.Regulation of bone marrow microenvironment on hematopoietic stem cells under steady state and aging[J].Chinese Journal of Cell Biology,2021,43(2):420-427.
[40] Ganguly P,Toghill B,Pathak S.Aging,bone marrow and next-generation sequencing(NGS):Recent advances and future perspectives[J].Int J Mol Sci,2021,22(22):12225.
[41] Saxena P,Srivastava J,Rai B,et al.Elevated senescence in the bone marrow mesenchymal stem cells of acquired aplastic anemia patients:A possible implication of DNA damage responses and telomere attrition[J].Biochim Biophys Acta Mol Basis Dis,2024,1870(3):167025.
[42] Gnani D,Crippa S,Della Volpe L,et al.An early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program[J].Aging Cell,2019,18(3):e12933.
[43] Lee B C,Yu K R.Impact of mesenchymal stem cell senescence on inflammaging[J].BMB Rep,2020,53(2):65-73.
[44] Lefterova M I,Zhang Y,Steger D J,et al.PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale[J].Genes Dev,2008,22(21):2941-2952.
[45] Xu R,Shen X,Si Y,et al.MicroRNA-31a-5p from aging BMSCs links bone formation and resorption in the aged bone marrow microenvironment[J].Aging Cell,2018,17(4):e12794.
[46] Cheng H C,Liu S W,Li W,et al.Arsenic trioxide regulates adipogenic and osteogenic differentiation in bone marrow MSCs of aplastic anemia patients through BMP4 gene[J].Acta Biochim Biophys Sin,2015,47(9):673-679.
[47] Naveiras O,Nardi V,Wenzel P L,et al.Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment[J].Nature,2009,460(7252):259-263.
[48] van den Berg S M,Seijkens T T P,Kusters P J H,et al.Diet-induced obesity in mice diminishes hematopoietic stem and progenitor cells in the bone marrow[J].FASEB J,2016,30(5):1779-1788.
[49] Groleau J,Dussault S,Haddad P,et al.Essential role of copper-zinc superoxide dismutase for ischemia-induced neovascularization via modulation of bone marrow-derived endothelial progenitor cells[J].Arterioscler Thromb Vasc Biol,2010,30(11):2173-2181.
[50] Tang S Q,Xing T,Lyu Z S,et al.Repair of dysfunctional bone marrow endothelial cells alleviates aplastic anemia[J].Sci China Life Sci,2023,66(11):2553-2570.
[51] Luu N T,McGettrick H M,Buckley C D,et al.Crosstalk between mesenchymal stem cells and endothelial cells leads to downregulation of cytokine-induced leukocyte recruitment[J].Stem Cells,2013,31(12):2690-2702.
[52] Shevyrev D,Tereshchenko V,Berezina T N,et al.Hematopoietic stem cells and the immune system in development and aging[J].Int J Mol Sci,2023,24(6):5862.
[53] Xiao M,Zhou P,Wang Z,et al.Dynamic biological characteristics of human bone marrow hematopoietic stem cell senescence[J].Sci Rep,2022,12(1):17071.
[54] Yang D,de Haan G.Inflammation and aging of hematopoietic stem cells in their niche[J].Cells,2021,10(8):1849.
[55] Sorimachi Y,Karigane D,Ootomo Y,et al.p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts[J].J Biol Chem,2021,296:100563.
[56] Mann M,Mehta A,de Boer C G,et al.Heterogeneous responses of hematopoietic stem cells to inflammatory stimuli are altered with age[J].Cell Rep,2018,25(11):2992-3005.e5.
[57] Chen Z,Amro E M,Becker F,et al.Cohesin-mediated NF-κB signaling limits hematopoietic stem cell self-renewal in aging and inflammation[J].J Exp Med,2019,216(1):152-175.
[58] Chen C,Liu Y,Liu R,et al.TSC-mTOR maintains quiescence and function of hematopoietic stem cells by repressing mitochondrial biogenesis and reactive oxygen species[J].J Exp Med,2008,205(10):2397-2408.
[59] Pietras E M.Inflammation:A key regulator of hematopoietic stem cell fate in health and disease[J].Blood,2017,130(15):1693-1698.
[60] Zeng X,Li X,Li X,et al.Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation[J].Blood,2023,141(14):1691-1707.
[61] Mohrin M,Shin J,Liu Y,et al.Stem cell aging.A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging[J].Science,2015,347(6228):1374-1377.
[62] 周郁鸿.中医药治疗慢性再生障碍性贫血研究述评[J].北京中医药大学学报,2023,46(10):1461-1466.
Zhou Y H.Comment on the research of chronic aplastic anemia treatment with traditional Chinese medicine[J].Journal of Beijing University of Traditional Chinese Medicine,2023,46(10):1461-1466.
[63] 鲍晓敏,史晓,沈雁,等.基于“肾虚致衰”理论的“杞鹿健肾颗粒”对老年衰弱综合征肾气虚证的二阶段交叉对照研究[J].现代中西医结合杂志,2023,32(17):2388-2392.
Bao X M,Shi X,Shen Y,et al.“Qilu Jianshen granules”based on the theory of“kidney-qi deficiency causing weakness”on senile debilitating syndrome of kidney-qi deficiency type:A two-stage cross-over controlled study[J].Modern Journal of Integrated Traditional Chinese and Western Medicine,2023,32(17):2388-2392.
[64] 李少康,赵赟,高娜,等.补肾类方药及中药有效成分抗衰老的作用机制研究进展[J].天津中医药,2023,40(4):537-544.
Li S K,Zhao B,Gao N,et al.Research progress of kidney-tonifying herbs and anti-aging mechanism of traditional Chinese medicine active ingredients[J].Tianjin Journal of Traditional Chinese Medicine,2023,40(4):537-544.