Review

Recent developments and future perspectives in aging and macrophage immunometabolism

  • Received: 14 July 2021 Accepted: 24 August 2021 Published: 26 August 2021
  • Aging is the strongest contributor to the development and severity of many chronic and infectious diseases, primarily through age-related increases in low-grade inflammation (inflammaging) and decreases in immune function (immunosenescence). Metabolic reprogramming in immune cells is a significant contributor to functional and phenotypic changes in these cells, but little is known about the direct effect of aging on immunometabolism. This review highlights several recent advances in this field, focusing on mitochondrial dysfunction, NAD+ metabolism, and therapeutic reprogramming in aged monocytes and macrophages. Perspectives on opportunities for future research in this area are also provided. Targeting immunometabolism is a promising strategy for designing therapeutics for a wide variety of age-related diseases.

    Citation: Brandt D. Pence. Recent developments and future perspectives in aging and macrophage immunometabolism[J]. AIMS Molecular Science, 2021, 8(3): 193-201. doi: 10.3934/molsci.2021015

    Related Papers:

  • Aging is the strongest contributor to the development and severity of many chronic and infectious diseases, primarily through age-related increases in low-grade inflammation (inflammaging) and decreases in immune function (immunosenescence). Metabolic reprogramming in immune cells is a significant contributor to functional and phenotypic changes in these cells, but little is known about the direct effect of aging on immunometabolism. This review highlights several recent advances in this field, focusing on mitochondrial dysfunction, NAD+ metabolism, and therapeutic reprogramming in aged monocytes and macrophages. Perspectives on opportunities for future research in this area are also provided. Targeting immunometabolism is a promising strategy for designing therapeutics for a wide variety of age-related diseases.



    加载中

    Acknowledgments



    BDP is funded by American Heart Association award 19TPA34910232 and a Collaborative Research Network (CORNET) award from the University of Memphis and the University of Tennessee Health Science Center.

    Conflict of interest



    The author declares no conflict of interest in this paper.

    [1] Niccoli T, Partridge L (2012) Ageing as a risk factor for disease. Curr Biol 22: R741-R752. doi: 10.1016/j.cub.2012.07.024
    [2] Franceschi C, Garagnani P, Parini P, et al. (2018) Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14: 576-590. doi: 10.1038/s41574-018-0059-4
    [3] Williamson EJ, Walker AJ, Bhaskaran K, et al. (2020) Factors associated with COVID-19-related death using OpenSAFELY. Nature 584: 430-436. doi: 10.1038/s41586-020-2521-4
    [4] Pence BD (2020) Severe COVID-19 and aging: are monocytes the key? GeroScience 42: 1051-1061. doi: 10.1007/s11357-020-00213-0
    [5] Viboud C, Boëlle P, Cauchemez S, et al. (2004) Risk factors of influenza transmission in households. Br J Gen Pract 54: 684-689.
    [6] Hernandez-Vargas EA, Wilk E, Canini L, et al. (2014) Effects of aging on influenza virus infection dynamics. J Virol 88: 4123-4131. doi: 10.1128/JVI.03644-13
    [7] Falsey AR, Walsh EE (2000) Respiratory syncytial virus infection in adults. Clin Microbiol Rev 13: 371-384. doi: 10.1128/CMR.13.3.371
    [8] Franceschi C, Capri M, Monti D, et al. (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128: 92-105. doi: 10.1016/j.mad.2006.11.016
    [9] Nikolich-Žugich J (2018) The twilight of immunity: Emerging concepts in aging of the immune system review-article. Nat Immunol 19: 10-19. doi: 10.1038/s41590-017-0006-x
    [10] O'Neill LAJ, Kishton RJ, Rathmell J (2016) A guide to immunometabolism for immunologists. Nat Rev Immunol 16: 553-565. doi: 10.1038/nri.2016.70
    [11] Mills EL, Kelly B, Logan A, et al. (2016) Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167: 457-470.e13. doi: 10.1016/j.cell.2016.08.064
    [12] Tannahill GM, Curtis AM, Adamik J, et al. (2013) Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496: 238-242. doi: 10.1038/nature11986
    [13] Arts RJW, Novakovic B, Horst RT, et al. (2016) Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab 24: 807-819. doi: 10.1016/j.cmet.2016.10.008
    [14] Lampropoulou V, Sergushichev A, Bambouskova M, et al. (2016) Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab 24: 158-166. doi: 10.1016/j.cmet.2016.06.004
    [15] Domínguez-Andrés J, Novakovic B, Li Y, et al. (2019) The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metab 29: 211-220.e5. doi: 10.1016/j.cmet.2018.09.003
    [16] Yarbro JR, Emmons RS, Pence BD (2020) Macrophage immunometabolism and inflammaging: roles of mitochondrial dysfunction, cellular senescence, CD38, and NAD. Immunometabolism 2: e200026.
    [17] Zasłona Z, O'Neill LAJ (2020) Cytokine-like roles for metabolites in immunity. Mol Cell 78: 814-823. doi: 10.1016/j.molcel.2020.04.002
    [18] Makowski L, Chaib M, Rathmell JC (2020) Immunometabolism: from basic mechanisms to translation. Immunol Rev 295: 5-14. doi: 10.1111/imr.12858
    [19] Wang A, Luan HH, Medzhitov R (2019) An evolutionary perspective on immunometabolism. Science 363: eaar3932. doi: 10.1126/science.aar3932
    [20] Lee KA, Robbins PD, Camell CD (2021) Intersection of immunometabolism and immunosenescence during aging. Curr Opin Pharmacol 57: 107-116. doi: 10.1016/j.coph.2021.01.003
    [21] Murphy MP, O'Neill LAJ (2018) Krebs cycle reimagined: the emerging roles of succinate and itaconate as signal transducers. Cell 174: 780-784. doi: 10.1016/j.cell.2018.07.030
    [22] López-Otín C, Blasco MA, Partridge L, et al. (2013) The hallmarks of aging. Cell 153: 1194-1217. doi: 10.1016/j.cell.2013.05.039
    [23] Pence BD, Yarbro JR (2018) Aging impairs mitochondrial respiratory capacity in classical monocytes. Exp Gerontol 108: 112-117. doi: 10.1016/j.exger.2018.04.008
    [24] Saare M, Tserel L, Haljasmägi L, et al. (2020) Monocytes present age-related changes in phospholipid concentration and decreased energy metabolism. Aging Cell 19: e13127. doi: 10.1111/acel.13127
    [25] Gon Y, Hashimoto S, Hayashi S, et al. (1996) Lower serum concentrations of cytokines in elderly patients with pneumonia and the impaired production of cytokines by peripheral blood monocytes in the elderly. Clin Exp Immunol 106: 120-126.
    [26] McLachlan JA, Serkin CD, Morrey KM, et al. (1995) Antitumoral properties of aged human monocytes. J Immunol 154: 832-843.
    [27] Pence BD, Yarbro JR (2019) Classical monocytes maintain ex vivo glycolytic metabolism and early but not later inflammatory responses in older adults. Immun Ageing 16: 3. doi: 10.1186/s12979-019-0143-1
    [28] Renshaw M, Rockwell J, Engleman C, et al. (2002) Cutting edge: impaired toll-like receptor expression and function in aging. J Immunol 169: 4697-4701. doi: 10.4049/jimmunol.169.9.4697
    [29] Sinclair L V, Barthelemy C, Cantrell DA (2020) Single cell glucose uptake assays: a cautionary tale. Immunometabolism 2: e200029.
    [30] Reinfeld BI, Madden MZ, Wolf MM, et al. (2021) Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 593: 282-288. doi: 10.1038/s41586-021-03442-1
    [31] Yoshino J, Baur JA, Imai S (2018) NAD+ intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab 27: 513-528. doi: 10.1016/j.cmet.2017.11.002
    [32] Cameron AM, Castoldi A, Sanin DE, et al. (2019) Inflammatory macrophage dependence on NAD+ salvage is a consequence of reactive oxygen species–mediated DNA damage. Nat Immunol 20: 420-432. doi: 10.1038/s41590-019-0336-y
    [33] Verdin E (2015) NAD+ in aging, metabolism, and neurodegeneration. Science 350: 1208-1213. doi: 10.1126/science.aac4854
    [34] Minhas PS, Liu L, Moon PK, et al. (2019) Macrophage de novo NAD+ synthesis specifies immune function in aging and inflammation. Nat Immunol 20: 50-63. doi: 10.1038/s41590-018-0255-3
    [35] Covarrubias AJ, Kale A, Perrone R, et al. (2020) Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages. Nat Metab 2: 1265-1283. doi: 10.1038/s42255-020-00305-3
    [36] Minhas PS, Latif-Hernandez A, McReynolds MR, et al. (2021) Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature 590: 122-128. doi: 10.1038/s41586-020-03160-0
    [37] Vats D, Mukundan L, Odegaard JI, et al. (2006) Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 4: 13-24. doi: 10.1016/j.cmet.2006.05.011
    [38] Van den Bossche J, Baardman J, Otto NA, et al. (2016) Mitochondrial dysfunction prevents repolarization of inflammatory macrophages. Cell Rep 17: 684-696. doi: 10.1016/j.celrep.2016.09.008
    [39] Liang Y, Piao C, Beuschel CB, et al. (2021) eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction. Cell Rep 35: 108941. doi: 10.1016/j.celrep.2021.108941
    [40] Zhang H, Alsaleh G, Feltham J, et al. (2019) Polyamines control eIF5A hypusination, TFEB translation, and autophagy to reverse B cell senescence. Mol Cell 76: 110-125.e9. doi: 10.1016/j.molcel.2019.08.005
    [41] Puleston DJ, Buck MD, Klein Geltink RI, et al. (2019) Polyamines and eIF5A hypusination modulate mitochondrial respiration and macrophage activation. Cell Metab 30: 352-363.e8. doi: 10.1016/j.cmet.2019.05.003
    [42] Pence BD (2021) Aging and monocyte immunometabolism in COVID-19. Aging 13: 9154-9155. doi: 10.18632/aging.202918
    [43] Codo AC, Davanzo GG, de Brito Monteiro L, et al. (2020) Elevated glucose levels favor SARS-CoV-2 infection and monocyte response through a HIF-1α/glycolysis-dependent axis. Cell Metab 3: 437-446.e5. doi: 10.1016/j.cmet.2020.07.007
    [44] Ketelhuth DFJ, Lutgens E, Bäck M, et al. (2019) Immunometabolism and atherosclerosis: perspectives and clinical significance: a position paper from the Working Group on Atherosclerosis and Vascular Biology of the European Society of Cardiology. Cardiovasc Res 115: 1385-1392. doi: 10.1093/cvr/cvz166
    [45] Roy DG, Kaymak I, Williams KS, et al. (2020) Immunometabolism in the tumor microenvironment. Annu Rev Cancer Biol 5: 137-159.
    [46] O'Sullivan D, Sanin DE, Pearce EJ, et al. (2019) Metabolic interventions in the immune response to cancer. Nat Rev Immunol 19: 324-335. doi: 10.1038/s41577-019-0140-9
    [47] Hearps AC, Martin GE, Angelovich TA, et al. (2012) Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 11: 867-875. doi: 10.1111/j.1474-9726.2012.00851.x
    [48] Ong SM, Hadadi E, Dang T, et al. (2018) The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence. Cell Death Dis 9: 266. doi: 10.1038/s41419-018-0327-1
    [49] Ma EH, Verway MJ, Johnson RM, et al. (2019) Metabolic profiling using stable isotope tracing reveals distinct patterns of glucose utilization by physiologically activated CD8+ T cells. Immunity 51: 856-870.e5. doi: 10.1016/j.immuni.2019.09.003
    [50] Artyomov MN, Van den Bossche J (2020) Immunometabolism in the single-cell era. Cell Metab 32: 710-725. doi: 10.1016/j.cmet.2020.09.013
    [51] Tabula Muris Consortium (2020) A single-cell transcriptomic atlas characterizes ageing tissues in the mouse. Nature 583: 590-595.
    [52] Wagner A, Wang C, Fessler J, et al. (2021) Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell 184: 4168-4185. doi: 10.1016/j.cell.2021.05.045
    [53] Argüello RJ, Combes AJ, Char R, et al. (2020) SCENITH: A flow cytometry-based method to functionally profile energy metabolism with single-cell resolution. Cell Metab 32: 1063-1075.e7. doi: 10.1016/j.cmet.2020.11.007
    [54] Rappez L, Stadler M, Triana S, et al. (2021) SpaceM reveals metabolic states of single cells. Nat Methods 18: 799-805. doi: 10.1038/s41592-021-01198-0
    [55] Zhang D, Tang Z, Huang H, et al. (2019) Metabolic regulation of gene expression by histone lactylation. Nature 574: 575-580. doi: 10.1038/s41586-019-1678-1
    [56] Tanaka T, Biancotto A, Moaddel R, et al. (2018) Plasma proteomic signature of age in healthy humans. Aging Cell 17: e12799. doi: 10.1111/acel.12799
    [57] Ackermann K, Bonaterra GA, Kinscherf R, et al. (2019) Growth differentiation factor-15 regulates oxLDL-induced lipid homeostasis and autophagy in human macrophages. Atherosclerosis 281: 128-136. doi: 10.1016/j.atherosclerosis.2018.12.009
    [58] Pence BD, Yarbro JR, Emmons RS (2021) Growth differentiation factor-15 is associated with age-related monocyte dysfunction. Aging Med 4: 47-52. doi: 10.1002/agm2.12128
  • Reader Comments
  • © 2021 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(2210) PDF downloads(149) Cited by(0)

Article outline

Other Articles By Authors

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog