PATHOGENETIC SIGNIFICANCE AND BENEFITS OF MACROPHAGE TARGETING IN AGING-ASSOCIATED CHRONIC INFLAMMATION
Keywords:
inflammaging, macrophages, polarization, cellular senescence, SASP, phagocytosis, efferocytosis, targeted therapy
Abstract
The review is devoted to the analysis of the pathogenetic significance of macrophages in the development of chronic inflammation associated with aging (inflammaging) and the substantiation of the prospects for targeting macrophages for the correction of age-associated diseases. The authors performed a non-systematic review of the scientific literature, including 176 sources from the international databases Lens, PubMed, Medline, Cochrane on the topic under consideration, with a search depth of 15 years (2010-2024). Macrophages play a key role in the pathogenesis of inflammation, interacting with senescent cells through the mechanisms of the secretory phenotype associated with aging (SASP). It was revealed that SASP components (IL-6, IL-10, TNF-α, TGF-β) modulate macrophage polarization via STAT3/NF-κB pathways, contributing to the formation of a functional continuum of macrophage phenotypes, including special senescence-associated phenotypes. It was established that senescent cells alter key functions of macrophages that ensure body homeostasis (phagocytosis, efferocytosis, autophagy) via expression of CD47, CD24 and activation of the JAK/STAT3 cascade, which forms a "vicious circle" of inflammaging. Promising therapeutic strategies for targeting macrophages have been identified: polarization modulation, cell therapy (autologous macrophage transplantation, CAR macrophages), effects on mitochondrial metabolism and redox signaling. Thus, participation in the regulation of inflammatory processes and high phenotypic plasticity of cells allow us to consider macrophages as a key pathogenetic target in inflammaging. Therapeutic approaches aimed at correcting impaired functions of macrophages open up new prospects for the prevention and treatment of age-associated diseases.
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References
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4.Nicolas-Avila J.A., Lechuga-Vieco A.V., Esteban-Martinez L., et al. A Network of Macrophages Supports Mitochondrial Homeostasis in the Heart. Cell. 2020;183:94–109. doi: 10.1016/j.cell.2020.08.031.
5.Li X., Li C., Zhang W., et al. Inflammation and aging: signaling pathways and intervention therapies. Sig Transduct Target Ther. 2023;8:239. https://doi.org/10.1038/s41392-023-01502-8.
6.Reynolds L.E., Maallin S., Haston S., et al. Effects of senescence on the tumour microenvironment and response to therapy. FEBS J. 2024;291(11):2306-2319. doi: 10.1111/febs.16984.
7.Xiong J., Dong L., Lv Q., et al. Targeting senescence-associated secretory phenotypes to remodel the tumour microenvironment and modulate tumour outcomes. Clin Transl Med. 2024;14(9):e1772. doi: 10.1002/ctm2.1772.
8.Wang Y., Li T., Wang F., et al. The Dual Role of Cellular Senescence in Macrophages: Unveiling the Hidden Driver of Age-Related Inflammation in Kidney Disease. Int J Biol Sci. 2025;21(2):632-657. doi:10.7150/ijbs.104404.
10.Korolnek T., Hamza I. Macrophages and iron trafficking at the birth and death of red cells. Blood. 2015;125:2893–2897. doi:10.1182/blood-2014-12-567776.
11.Egashira, M., Hirota Y., Shimizu-Hirota R., et al. F4/80+ Macrophages Contribute to Clearance of Senescent Cells in the Mouse Postpartum Uterus. Endocrinology. 2017;158:2344–2353. doi:10.1210/en.2016-1886.
12.Oishi Y., Manabe I. Macrophages in age-related chronic inflammatory diseases. NPJ Aging Mech. Dis. 2016;2:16018. doi:10.1038/npjamd.2016.18.
13.Murano I., Barbatelli G., Parisani V., et al. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. J. Lipid Res. 2008;49:1562–1568. doi:10.1194/jlr.M800019-JLR200.
14.Sturmlechner I., Zhang C., Sine C.C., et al. P21 produces a bioactive secretome that places stressed cells under immunosurveillance. Science. 2021.374(6567):eabb3420. doi:10.1126/science.abb3420.
15.Mau T., O’Brien M., Ghosh A.K., et al. Life-span Extension Drug Interventions Affect Adipose Tissue Inflammation in Aging. J. Gerontol. Ser. A-Biol. Sci. Med. Sci. 2020;75(1):89–98. doi: 10.1093/gerona/glz177.
16.Wu Y., Hu S.S., Zhang R., et al. Single cell RNA sequencing unravels mechanisms underlying senescence-like phenotypes of alveolar macrophages. 2023; 26(7):107197. doi:10.1016/j.isci.2023.107197.
17.Chakarov S., Lim H.Y., Tan L., et al. Two distinct interstitial macrophage populations coexist across tissues in specific subtissular niches. Science. 2019.363(6432):eaau0964. doi:10.1126/science.aau0964.
18.Li C.M., Shapiro H., Tsiobikas C., et al. Aging-associated alterations in mammary epithelia and stroma revealed by single-cell RNA sequencing. Cell Rep. 2020. 33(13):108566.doi: 10.1016/j.celrep.2020.108566.
19.Campbell R.A., Docherty M.-H., Ferenbach D.A., Mylonas K.J. The role of ageing and parenchymal senescence on macrophage function and fibrosis. Front. Immunol. 2021;12:700790. doi: 10.3389/fimmu.2021.700790.
20.Behmoaras J., Gil J. Similarities and interplay between senescent cells and macrophages. J Cell Biol. 2021;220(2):e202010162. doi: 10.1083/jcb.202010162.
21.Jiang Q., Zhou J., Chen Q., et al. Construction and experimental validation of a macrophage cell senescence-related gene signature to evaluate the prognosis, immunotherapeutic sensitivity, and chemotherapy response in bladder cancer. Funct. Integr. Genom. 2023;23(3):228. doi: 10.1007/s10142-023-01163-4.
22.Datta I., Bangi E. Senescent cells and macrophages cooperate through a multi-kinase signaling network to promote intestinal transformation in Drosophila. bioRxiv. 2023;18:2023.05.15.540869. doi: 10.1101/2023.05.15.540869.
23.Xia T., Zhang M., Lei W., et al. Advances in the role of STAT3 in macrophage polarization. Front Immunol. 2023;14:1160719. doi: 10.3389/fimmu.2023.1160719.
24.Peng N., Kang H.H., Feng Y., et al. Autophagy inhibition signals through senescence to promote tumor suppression. Autophagy. 2023;19(6):1764-1780. doi:10.1080/15548627.2022.2155794.
25.Yan H., Liu Y., Li X., et al. Leucine alleviates cytokine storm syndrome by regulating macrophage polarization via the mTORC1/LXRα signaling pathway. Elife. 2024;12:RP89750.doi: 10.7554/eLife.89750.
26.Wang P., Li Z., Song Y., et al. Resveratrol-driven macrophage polarization: unveiling mechanisms and therapeutic potential. Front Pharmacol. 2025;15:1516609. doi:10.3389/fphar.2024.1516609.
27.Wang G., Xu B., Shi F., et al. Protective Effect of Methane-Rich Saline on Acetic Acid-Induced Ulcerative Colitis via Blocking the TLR4/NF-κB/MAPK Pathway and Promoting IL-10/JAK1/STAT3-Mediated Anti-inflammatory Response. Oxid Med Cell Longev. 2019;2019:7850324. doi: 10.1155/2019/7850324.
28.Geiß C., Salas E., Guevara-Coto J., et al. Multistability in Macrophage Activation Pathways and Metabolic Implications. Cells. 2022;11(3):404. doi: 10.3390/cells11030404.
29.Joshi P., Joshi S., Semwal D., et al. Curcumin: An Insight into Molecular Pathways Involved in Anticancer Activity. Mini Rev Med Chem. 2021;21(17):2420-2457. doi:10.2174/1389557521666210122153823.
30.Omer A., Barrera M.C., Moran J.L., et al. G3BP1 controls the senescence-associated secretome and its impact on cancer progression. Nat Commun. 2020;11(1):4979. doi:10.1038/s41467-020-18734-9.
31.Lox D. Preserving cell homeostasis as an aging modultation strategy. Innov Aging. 2024;8(1):910. doi: 10.1093/geroni/igae098.2938.
32.Rana M.N., Lu J., Xue E., et al. PDE9 Inhibitor PF-04447943 Attenuates DSS-Induced Colitis by Suppressing Oxidative Stress, Inflammation, and Regulating T-Cell Polarization. Front Pharmacol. 2021;12:643215. doi: 10.3389/fphar.2021.643215.
33.Laliberté C., Bossé B., Bourdeau V., et al. Senescent Macrophages Release Inflammatory Cytokines and RNA-Loaded Extracellular Vesicles to Circumvent Fibroblast Senescence. Biomedicines. 2024;12(5):1089. doi: 10.3390/biomedicines12051089.
34.Rana T., Jiang C., Liu G., et al. PAI-1 Regulation of TGF-β1-induced Alveolar Type II Cell Senescence, SASP Secretion, and SASP-mediated Activation of Alveolar Macrophages. Am J Respir Cell Mol Biol. 2020;62(3):319-330. doi: 10.1165/rcmb.2019-0071OC.
35.Huna A., Martin N., Bernard D. The senescence-associated secretory phenotype induces neuroendocrine transdifferentiation. Aging. 2023;15(8):2819-2821. doi: 10.18632/aging.204669.
36.Schloesser D., Lindenthal L., Sauer J., et al. Senescent cells suppress macrophage-mediated corpse removal via upregulation of the CD47-QPCT/L axis. J Cell Biol. 2023;222(2):e202207097. doi: 10.1083/jcb.202207097.
37.Ogata Y., Yamada T., Hasegawa S., et al. SASP-induced macrophage dysfunction may contribute to accelerated senescent fibroblast accumulation in the dermis. Exp. Dermatol. 2021;30:84–91. doi: 10.1111/exd.14205.
39.Razi S., Yaghmoorian Khojini J., Kargarijam F., et al. Macrophage efferocytosis in health and disease. Cell Biochem Funct. 2023;41(2):152-165. doi: 10.1002/cbf.3780.
40.Gerlach B.D., Ampomah P.B., Yurdagul A., et al. Efferocytosis induces macrophage proliferation to help resolve tissue injury. Cell Metab. 2021;33(12):2445-2463.e8. doi: 10.1016/j.cmet.2021.10.015.
41.Martinez-Zamudio R.I., Dewald H.K., Vasilopoulos T., et al. Senescence-associated beta-galactosidase reveals the abundance of senescent CD8+T cells in aging humans. Aging Cell. 2021;20(5):e13344. doi: 10.1111/acel.13344.
42.Xiao J., Li H.S., Satyanarayanan S.K., et al. Advancements in Targeting Macrophage Senescence for Age-Associated Conditions. Aging Dis. 2024. doi: 10.14336/AD.2024.0720.
43.Chen W., Xiao W., Liu X., et al. Pharmacological manipulation of macrophage autophagy effectively rejuvenates the regenerative potential of biodegrading vascular graft in aging body. Bioact. Mater. 2024;11:283–299. doi: 10.1016/j.bioactmat.2021.09.027.
44.Tai H., Wang Z., Gong H., et al. Autophagy impairment with lysosomal and mitochondrial dysfunction is an important characteristic of oxidative stress-induced senescence. Autophagy. 2017;13:99–113. doi: 10.1080/15548627.2016.1247143.
45.Covarrubias A.J., 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. doi: 10.1038/s42255-020-00305-3.
46.Vizioli M.G., Liu T., Miller K.N., et al. Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence. Genes Dev. 34, 428–445. doi: 10.1101/gad.331272.119.
47.Seegren Ph., Harper L., Downs T., et al. Reduced mitochondrial calcium uptake in macrophages is a major driver of inflammaging. Nature Aging. 2023;3(7):796-812. doi: 10.1038/s43587-023-00436-8.
48.Minhas P.S., Latif-Hernandez A., McReynolds M.R., et al. Restoring metabolism of myeloid cells reverses cognitive decline in aging. Nature. 2021;590:122-128. doi: 10.1038/s41586-020-03160-0.
49.Qu L., Matz A.J., Karlinsey K., et al. Macrophages at the Crossroad of Meta-Inflammation and Inflammaging. Genes (Basel). 2022;13(11):2074. doi: 10.3390/genes13112074.
50.Horiba S., Kami R., Tsutsui T., Hosoi J. IL-34 Downregulation‒Associated M1/M2 Macrophage Imbalance Is Related to Inflammaging in Sun-Exposed Human Skin. JID Innov. 2022;2(3):100112. doi: 10.1016/j.xjidi.2022.100112.
51.Das P., Jana S., Kumar Nandi S. Biomaterial-Based Therapeutic Approaches to Osteoarthritis and Cartilage Repair Through Macrophage Polarization. Chem Rec. 2022;22(9):e202200077. doi: 10.1002/tcr.202200077.
52.Brennan P.N., MacMillan M., Manship T., et al. Study protocol: a multicentre, open-label, parallel-group, phase 2, randomised controlled trial of autologous macrophage therapy for liver cirrhosis (MATCH). BMJ Open. 2021;11(11):e053190. doi: 10.1136/bmjopen-2021-053190.
53.Arumugam P., Carey B.C., Wikenheiser-Brokamp K.A., et al. A toxicology study of Csf2ra complementation and pulmonary macrophage transplantation therapy of hereditary PAP in mice. Mol Ther Methods Clin Dev. 2024;32(2):101213. doi: 10.1016/j.omtm.2024.101213.
54.Pan K., Farrukh H., Chittepu V.C.S.R, et al. CAR race to cancer immunotherapy: from CAR T, CAR NK to CAR macrophage therapy. J Exp Clin Cancer Res. 2022;41(1):119. doi: 10.1186/s13046-022-02327-z.
55.Yegorov Y.E., Poznyak A.V., Nikiforov N.G., et al. The Link between Chronic Stress and Accelerated Aging. Biomedicines. 2020;8(7):198. doi: 10.3390/biomedicines8070198.
56.Sołdacka D., Podgórska M., Barańska-Rybak W. Unique retinol therapy with antioxidant and anti-inflammaging complex for naturally reborn skin: the clinical case series study. Dermatologic Therapy. 2023;(7):1-9. https://doi.org/10.1155/2023/5588525C.
57.Wu L., Du Z., Li L., et al. Camouflaging attenuated Salmonella by cryo-shocked macrophages for tumor-targeted therapy. Signal Transduct Target Ther. 2024;9(1):14. doi: 10.1038/s41392-023-01703-1.
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Published
21-10-2025
How to Cite
Lyamina S. V., Kalish S. V., Kozhevnikova E. O. PATHOGENETIC SIGNIFICANCE AND BENEFITS OF MACROPHAGE TARGETING IN AGING-ASSOCIATED CHRONIC INFLAMMATION // Patologicheskaya Fiziologiya i Eksperimental’naya Terapiya (Pathological physiology and experimental therapy). 2025. VOL. 69. № 4. PP. 168–181.
Issue
Section
Reviews
