Abstract
The receptor for advanced glycation end-products (RAGE) was initially characterized and named for its ability to bind to advanced glycation end-products (AGEs) that form upon the irreversible and non-enzymatic interaction between nucleophiles, such as lysine, and carbonyl compounds, such as reducing sugars. The concentrations of AGEs are known to increase in conditions such as diabetes, as well as during ageing. However, it is now widely accepted that RAGE binds with numerous ligands, many of which can be defined as pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs). The interaction between RAGE and its ligands mainly results in a pro-inflammatory response, and can lead to stress events often favouring mitochondrial dysfunction or cellular senescence. Thus, RAGE should be considered as a pattern recognition receptor (PRR), similar to those that regulate innate immunity. Innate immunity itself plays a central role in inflammaging, the chronic low-grade and sterile inflammation that increases with age and is a potentially important contributory factor in ageing. Consequently, and in addition to the age-related accumulation of PAMPs and DAMPs and increases in pro-inflammatory cytokines from senescent cells and damaged cells, PRRs are therefore important in inflammaging. We suggest here that, through its interconnection with immunity, senescence, mitochondrial dysfunction and inflammasome activation, RAGE is a key contributor to inflammaging and that the pro-longevity effects seen upon blocking RAGE, or upon its deletion, are thus the result of reduced inflammaging.
Similar content being viewed by others
References
Abedini A, Cao P, Plesner A, Zhang J, He M, Derk J, Patil SA, Rosario R, Lonier J, Song F et al (2018) RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity. J Clin Invest 128:682–698
Akchurin OM, Kaskel F (2015) Update on inflammation in chronic kidney disease. Blood Purif 39:84–92
Akirav EM, Preston-Hurlburt P, Garyu J, Henegariu O, Clynes R, Schmidt AM, Herold KC (2012) RAGE expression in human T cells: a link between environmental factors and adaptive immune responses. PLoS ONE 7:e34698
Aquilano K, Vigilanza P, Baldelli S, Pagliei B, Rotilio G, Ciriolo MR (2010) Peroxisome proliferator-activated receptor γ Co-activator 1α (PGC-1α) and Sirtuin 1 (SIRT1) reside in mitochondria possible direct function in mitochondrial biogenesis. J Biol Chem 285:21590–21599
Arai Y, Martin-Ruiz CM, Takayama M, Abe Y, Takebayashi T, Koyasu S, Suematsu M, Hirose N, von Zglinicki T (2015) Inflammation, but not telomere length, predicts successful ageing at extreme old age: a longitudinal study of semi-supercentenarians. EBioMedicine 2:1549–1558
Austin S, St-Pierre J (2012) PGC1α and mitochondrial metabolism—emerging concepts and relevance in ageing and neurodegenerative disorders. J Cell Sci 125:4963–4971
Barile GR, Schmidt AM (2007) RAGE and its ligands in retinal disease. Curr Mol Med 7:758–765
Barlovic DP, Thomas MC, Jandeleit-Dahm K (2010) Cardiovascular disease: what’s all the AGE/RAGE about? Cardiovasc Hematol Disord 10:7–15
Bartling B, Hofmann H-S, Weigle B, Silber R-E, Simm A (2005) Down-regulation of the receptor for advanced glycation end-products (RAGE) supports non-small cell lung carcinoma. Carcinogenesis 26:293–301
Batkulwar K, Godbole R, Banarjee R, Kassaar O, Williams RJ, Kulkarni MJ (2018) Advanced glycation end products modulate amyloidogenic APP processing and tau phosphorylation: a mechanistic link between glycation and the development of Alzheimer’s disease. ACS Chem Neurosci 9:988–1000
Biagi E, Nylund L, Candela M, Ostan R, Bucci L, Pini E, Nikkïla J, Monti D, Satokari R, Franceschi C et al (2010) Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS ONE 5:e10667
Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S, Consolandi C, Quercia S, Scurti M, Monti D et al (2016) Gut microbiota and extreme longevity. Curr Biol CB 26:1480–1485
Bianchi ME, Agresti A (2005) HMG proteins: dynamic players in gene regulation and differentiation. Curr Opin Genet Dev 15:496–506
Bianchi R, Giambanco I, Donato R (2010) S100B/RAGE-dependent activation of microglia via NF-kappaB and AP-1 Co-regulation of COX-2 expression by S100B, IL-1beta and TNF-alpha. Neurobiol Aging 31:665–677
Bierhaus A, Stern DM, Nawroth PP (2006) RAGE in inflammation: a new therapeutic target? Curr Opin Investig Drugs Lond Engl 2000(7):985–991
Body-Malapel M, Djouina M, Waxin C, Langlois A, Gower-Rousseau C, Zerbib P, Schmidt A-M, Desreumaux P, Boulanger E, Vignal C (2019) The RAGE signaling pathway is involved in intestinal inflammation and represents a promising therapeutic target for Inflammatory Bowel Diseases. Mucosal Immunol 12:468–478
Bongarzone S, Savickas V, Luzi F, Gee AD (2017) Targeting the receptor for advanced glycation endproducts (RAGE): a medicinal chemistry perspective. J Med Chem 60:7213–7232
Boulanger E, Wautier M-P, Wautier J-L, Boval B, Panis Y, Wernert N, Danze P-M, Dequiedt P (2002) AGEs bind to mesothelial cells via RAGE and stimulate VCAM-1 expression. Kidney Int 61:148–156
Boulanger E, Grossin N, Wautier M-P, Taamma R, Wautier J-L (2007) Mesothelial RAGE activation by AGEs enhances VEGF release and potentiates capillary tube formation. Kidney Int 71:126–133
Bresnick AR, Weber DJ, Zimmer DB (2015) S100 proteins in cancer. Nat Rev Cancer 15:96–109
Brett J, Schmidt AM, Yan SD, Zou YS, Weidman E, Pinsky D, Nowygrod R, Neeper M, Przysiecki C, Shaw A et al (1993) Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues. Am J Pathol 143:1699–1712
Buckley ST, Ehrhardt C (2010) The receptor for advanced glycation end products (RAGE) and the lung. J Biomed Corp 3:3. https://doi.org/10.1155/2010/917108
Burstein AH, Sabbagh M, Andrews R, Valcarce C, Dunn I, Altstiel L (2018) Development of Azeliragon, an oral small molecule antagonist of the receptor for advanced glycation endproducts, for the potential slowing of loss of cognition in mild Alzheimer’s disease. J Prev Alzheimers Dis 5:149–154
Burton DGA, Stolzing A (2018) Cellular senescence: immunosurveillance and future immunotherapy. Ageing Res Rev 43:17–25
Cai W, He JC, Zhu L, Chen X, Wallenstein S, Striker GE, Vlassara H (2007) Reduced oxidant stress and extended lifespan in mice exposed to a low glycotoxin diet: association with increased AGER1 expression. Am J Pathol 170:1893–1902
Cai Z, Liu N, Wang C, Qin B, Zhou Y, Xiao M, Chang L, Yan L-J, Zhao B (2016) Role of RAGE in Alzheimer’s disease. Cell Mol Neurobiol 36:483–495
Candela P, Gosselet F, Saint-Pol J, Sevin E, Boucau M-C, Boulanger E, Cecchelli R, Fenart L (2010) Apical-to-basolateral transport of amyloid-β peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein. J Alzheimers Dis 22:849–859
Chavakis T, Bierhaus A, Al-Fakhri N, Schneider D, Witte S, Linn T, Nagashima M, Morser J, Arnold B, Preissner KT et al (2003) The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins. J Exp Med 198:1507–1515
Chen Y, Akirav EM, Chen W, Henegariu O, Moser B, Desai D, Shen JM, Webster JC, Andrews RC, Mjalli AM et al (2008) RAGE ligation affects T cell activation and controls T cell differentiation. J Immunol Baltim Md 1950(181):4272–4278
Chen J, Sun Z, Jin M, Tu Y, Wang S, Yang X, Chen Q, Zhang X, Han Y, Pi R (2017) Inhibition of AGEs/RAGE/Rho/ROCK pathway suppresses non-specific neuroinflammation by regulating BV2 microglial M1/M2 polarization through the NF-κB pathway. J Neuroimmunol 305:108–114
Cheng C, Tsuneyama K, Kominami R, Shinohara H, Sakurai S, Yonekura H, Watanabe T, Takano Y, Yamamoto H, Yamamoto Y (2005) Expression profiling of endogenous secretory receptor for advanced glycation end products in human organs. Mod Pathol 18:1385–1396
Comenzo RL (2000) Primary systemic amyloidosis. Curr Treat Opt Oncol 1:83–89
Coppé J-P, Desprez P-Y, Krtolica A, Campisi J (2010) The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol 5:99–118
Correia-Melo C, Marques FDM, Anderson R, Hewitt G, Hewitt R, Cole J, Carroll BM, Miwa S, Birch J, Merz A et al (2016) Mitochondria are required for pro-ageing features of the senescent phenotype. EMBO J 35:724–742
Coughlan MT, Thorburn DR, Penfold SA, Laskowski A, Harcourt BE, Sourris KC, Tan ALY, Fukami K, Thallas-Bonke V, Nawroth PP et al (2009) RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J Am Soc Nephrol JASN 20:742–752
Crow YJ, Manel N (2015) Aicardi-Goutières syndrome and the type I interferonopathies. Nat Rev Immunol 15:429–440
Daroux M, Prévost G, Maillard-Lefebvre H, Gaxatte C, D’Agati VD, Schmidt AM, Boulanger E (2010) Advanced glycation end-products: implications for diabetic and non-diabetic nephropathies. Diabetes Metab 36:1–10
Davalos AR, Kawahara M, Malhotra GK, Schaum N, Huang J, Ved U, Beausejour CM, Coppe J-P, Rodier F, Campisi J (2013) p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J Cell Biol 201:613–629
de Gonzalo-Calvo D, Neitzert K, Fernández M, Vega-Naredo I, Caballero B, García-Macía M, Suárez FM, Rodríguez-Colunga MJ, Solano JJ, Coto-Montes A (2010) Differential inflammatory responses in aging and disease: TNF-alpha and IL-6 as possible biomarkers. Free Radic Biol Med 49:733–737
Deane R, Singh I, Sagare AP, Bell RD, Ross NT, LaRue B, Love R, Perry S, Paquette N, Deane RJ et al (2012) A multimodal RAGE-specific inhibitor reduces amyloid β-mediated brain disorder in a mouse model of Alzheimer disease. J Clin Invest 122:1377–1392
Del Rio D, Stewart AJ, Pellegrini N (2005) A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr Metab Cardiovasc Dis NMCD 15:316–328
Demling N, Ehrhardt C, Kasper M, Laue M, Knels L, Rieber EP (2006) Promotion of cell adherence and spreading: a novel function of RAGE, the highly selective differentiation marker of human alveolar epithelial type I cells. Cell Tissue Res 323:475–488
Dinarello CA (2006) Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr 83:447S–455S
Ding Q, Keller JN (2005a) Splice variants of the receptor for advanced glycosylation end products (RAGE) in human brain. Neurosci Lett 373:67–72
Ding Q, Keller JN (2005b) Evaluation of rage isoforms, ligands, and signaling in the brain. Biochim Biophys. Acta BBA 1746:18–27
Dou Z, Ghosh K, Vizioli MG, Zhu J, Sen P, Wangensteen KJ, Simithy J, Lan Y, Lin Y, Zhou Z et al (2017) Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550:402–406
Emanuele E, D’Angelo A, Tomaino C, Binetti G, Ghidoni R, Politi P, Bernardi L, Maletta R, Bruni AC, Geroldi D (2005) Circulating levels of soluble receptor for advanced glycation end products in Alzheimer disease and vascular dementia. Arch Neurol 62:1734–1736
Evankovich J, Cho SW, Zhang R, Cardinal J, Dhupar R, Zhang L, Klune JR, Zlotnicki J, Billiar T, Tsung A (2010) High mobility group box 1 release from hepatocytes during ischemia and reperfusion injury is mediated by decreased histone deacetylase activity. J Biol Chem 285:39888–39897
Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, Monti D, Franceschi C, Paganelli R (1993) Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol 23:2375–2378
Fang F, Lue L-F, Yan S, Xu H, Luddy JS, Chen D, Walker DG, Stern DM, Yan S, Schmidt AM et al (2010) RAGE-dependent signaling in microglia contributes to neuroinflammation, Abeta accumulation, and impaired learning/memory in a mouse model of Alzheimer’s disease. FASEB J 24:1043–1055
Fatchiyah F, Hardiyanti F, Widodo N (2015) Selective inhibition on RAGE-binding AGEs required by bioactive peptide alpha-S2 case in protein from goat Ethawah breed milk: study of biological modeling. Acta Inform Med 23:90–96
Ferrucci L, Guralnik JM, Woodman RC, Bandinelli S, Lauretani F, Corsi AM, Chaves PHM, Ershler WB, Longo DL (2005a) Proinflammatory state and circulating erythropoietin in persons with and without anemia. Am J Med 118:1288
Ferrucci L, Corsi A, Lauretani F, Bandinelli S, Bartali B, Taub DD, Guralnik JM, Longo DL (2005b) The origins of age-related proinflammatory state. Blood 105:2294–2299
Forbes JM, Cooper ME, Oldfield MD, Thomas MC (2003) Role of advanced glycation end products in diabetic nephropathy. J Am Soc Nephrol JASN 14:S254–S258
Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol Ser A 69:S4–S9
Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254
Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S (2017) Inflammaging and ‘Garb-aging’. Trends Endocrinol Metab 28:199–212
Franchi L, Muñoz-Planillo R, Núñez G (2012) Sensing and reacting to microbes through the inflammasomes. Nat Immunol 13:325–332
Fransen F, van Beek AA, Borghuis T, Aidy SE, Hugenholtz F, van der Gaast-de Jongh C, Savelkoul HFJ, De Jonge MI, Boekschoten MV, Smidt H et al (2017) Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol 8:1385
Fukami K, Yamagishi S-I, Okuda S (2014) Role of AGEs-RAGE system in cardiovascular disease. Curr Pharm Des 20:2395–2402
Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, Witkowski JM, Franceschi C (2018) Immunosenescence and inflamm-aging as two sides of the same coin: friends or foes?. Front, Immunol, p 8
Gao ZQ, Yang C, Wang YY, Wang P, Chen HL, Zhang XD, Liu R, Li WL, Qin XJ, Liang X et al (2008) RAGE upregulation and nuclear factor-kappaB activation associated with ageing rat cardiomyocyte dysfunction. Gen Physiol Biophys 27:152–158
Gardella S, Andrei C, Ferrera D, Lotti LV, Torrisi MR, Bianchi ME, Rubartelli A (2002) The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep 3:995–1001
Gerli R, Monti D, Bistoni O, Mazzone AM, Peri G, Cossarizza A, Di Gioacchino M, Cesarotti ME, Doni A, Mantovani A et al (2000) Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians. Mech Ageing Dev 121:37–46
Geroldi D, Falcone C, Minoretti P, Emanuele E, Arra M, D’Angelo A (2006) High levels of soluble receptor for advanced glycation end products may be a marker of extreme longevity in humans. J Am Geriatr Soc 54:1149–1150
Ghidoni R, Benussi L, Glionna M, Franzoni M, Geroldi D, Emanuele E, Binetti G (2008) Decreased plasma levels of soluble receptor for advanced glycation end products in mild cognitive impairment. J Neural Transm 1996(115):1047–1050
Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120:885–890
Goldin A, Beckman JA, Schmidt AM, Creager MA (2006) Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114:597–605
Grossin N, Auger F, Niquet-Leridon C, Durieux N, Montaigne D, Schmidt AM, Susen S, Jacolot P, Beuscart J-B, Tessier FJ et al (2015) Dietary CML-enriched protein induces functional arterial aging in a RAGE-dependent manner in mice. Mol Nutr Food Res 59:927–938
Gu Q, Wang B, Zhang X-F, Ma Y-P, Liu J-D, Wang X-Z (2014) Contribution of receptor for advanced glycation end products to vasculature-protecting effects of exercise training in aged rats. Eur J Pharmacol 741:186–194
Guo ZJ, Niu HX, Hou FF, Zhang L, Fu N, Nagai R, Lu X, Chen BH, Shan YX, Tian JW et al (2008) Advanced oxidation protein products activate vascular endothelial cells via a RAGE-mediated signaling pathway. Antioxid Redox Signal 10:1699–1712
Gursky O (2014) Hot spots in apolipoprotein A-II misfolding and amyloidosis in mice and men. FEBS Lett 588:845–850
Hallam KM, Li Q, Ananthakrishnan R, Kalea A, Zou YS, Vedantham S, Schmidt AM, Yan SF, Ramasamy R (2010) Aldose Reductase and AGE–RAGE pathways: central roles in the pathogenesis of vascular dysfunction in aging rats. Aging Cell 9:776–784
Harris HE, Andersson U (2004) Mini-review: the nuclear protein HMGB1 as a proinflammatory mediator. Eur J Immunol 34:1503–1512
Hauptmann G, Bahram S (2004) Genetics of the central MHC. Curr Opin Immunol 16:668–672
He Q, Liang CH, Lippard SJ (2000) Steroid hormones induce HMG1 overexpression and sensitize breast cancer cells to cisplatin and carboplatin. Proc Natl Acad Sci USA 97:5768–5772
He M, Kubo H, Morimoto K, Fujino N, Suzuki T, Takahasi T, Yamada M, Yamaya M, Maekawa T, Yamamoto Y et al (2011) Receptor for advanced glycation end products binds to phosphatidylserine and assists in the clearance of apoptotic cells. EMBO Rep 12:358–364
Hearps AC, Martin GE, Angelovich TA, Cheng W-J, Maisa A, Landay AL, Jaworowski A, Crowe SM (2012) Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 11:867–875
Higuchi K, Kitagawa K, Naiki H, Hanada K, Hosokawa M, Takeda T (1991) Polymorphism of apolipoprotein A-II (apoA-II) among inbred strains of mice. Relationship between the molecular type of apoA-II and mouse senile amyloidosis. Biochem J 279(2):427–433
Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, Avila C, Kambham N, Bierhaus A, Nawroth P et al (1999) RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell 97:889–901
Hopkins MJ, Macfarlane GT (2002) Changes in predominant bacterial populations in human faeces with age and with Clostridium difficile infection. J Med Microbiol 51:448–454
Hopkins MJ, Sharp R, Macfarlane GT (2001) Age and disease related changes in intestinal bacterial populations assessed by cell culture, 16S rRNA abundance, and community cellular fatty acid profiles. Gut 48:198–205
Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, Nagashima M, Lundh ER, Vijay S, Nitecki D (1995) The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 270:25752–25761
Howes KA, Liu Y, Dunaief JL, Milam A, Frederick JM, Marks A, Baehr W (2004) Receptor for advanced glycation end products and age-related macular degeneration. Invest Ophthalmol Vis Sci 45:3713–3720
Huang JS, Guh JY, Chen HC, Hung WC, Lai YH, Chuang LY (2001) Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells. J Cell Biochem 81:102–113
Hudson BI, Carter AM, Harja E, Kalea AZ, Arriero M, Yang H, Grant PJ, Schmidt AM (2008a) Identification, classification, and expression of RAGE gene splice variants. FASEB J 22:1572–1580
Hudson BI, Kalea AZ, Del Mar Arriero M, Harja E, Boulanger E, D’Agati V, Schmidt AM (2008b) Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J Biol Chem 283:34457–34468
Iannuzzi C, Irace G, Sirangelo I (2014) Differential effects of glycation on protein aggregation and amyloid formation. Front Mol Biosci 1:9
Ito H, Fujita K, Tagawa K, Chen X, Homma H, Sasabe T, Shimizu J, Shimizu S, Tamura T, Muramatsu S et al (2015) HMGB1 facilitates repair of mitochondrial DNA damage and extends the lifespan of mutant ataxin-1 knock-in mice. EMBO Mol Med 7:78–101
Ivanov A, Pawlikowski J, Manoharan I, van Tuyn J, Nelson DM, Rai TS, Shah PP, Hewitt G, Korolchuk VI, Passos JF et al (2013) Lysosome-mediated processing of chromatin in senescence. J Cell Biol 202:129–143
Jastroch M, Divakaruni AS, Mookerjee S, Treberg JR, Brand MD (2010) Mitochondrial proton and electron leaks. Essays Biochem 47:53–67
Jeon OH, David N, Campisi J, Elisseeff JH (2018) Senescent cells and osteoarthritis: a painful connection. J Clin Invest 128:1229–1237
Jules J, Maiguel D, Hudson BI (2013) Alternative splicing of the RAGE cytoplasmic domain regulates cell signaling and function. PLoS ONE 8:e78267
Jurk D, Wilson C, Passos JF, Oakley F, Correia-Melo C, Greaves L, Saretzki G, Fox C, Lawless C, Anderson R et al (2014) Chronic inflammation induces telomere dysfunction and accelerates ageing in mice. Nat Commun 5:4172
Kalea AZ, Reiniger N, Yang H, Arriero M, Schmidt AM, Hudson BI (2009) Alternative splicing of the murine receptor for advanced glycation end-products (RAGE) gene. FASEB J 23:1766–1774
Kang P, Tian C, Jia C (2012) Association of RAGE gene polymorphisms with type 2 diabetes mellitus, diabetic retinopathy and diabetic nephropathy. Gene 500:1–9
Kang R, Chen R, Xie M, Cao L, Lotze MT, Tang D, Zeh HJ (2016) The receptor for advanced glycation endproducts (RAGE) activates the AIM2 inflammasome in acute pancreatitis. J Immunol Baltim Md 1950(196):4331–4337
Kaufmann SHE, Dorhoi A (2016) Molecular determinants in phagocyte-bacteria interactions. Immunity 44:476–491
Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, Franceschi C, Lithgow GJ, Morimoto RI, Pessin JE et al (2014a) Geroscience. Cell 159:709–713
Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, Franceschi C, Lithgow GJ, Morimoto RI, Pessin JE et al (2014b) Aging: a common driver of chronic diseases and a target for novel interventions. Cell 159:709–713
Keri KC, Samji NS, Blumenthal S (2018) Diabetic nephropathy: newer therapeutic perspectives. J Community Hosp Intern Med Perspect 8:200–207
Kierdorf K, Fritz G (2013) RAGE regulation and signaling in inflammation and beyond. J Leukoc Biol 94:55–68
Kim H-R, Won SJ, Fabian C, Kang M-G, Szardenings M, Shin M-G (2015) Mitochondrial DNA aberrations and pathophysiological implications in hematopoietic diseases, chronic inflammatory diseases, and cancers. Ann Lab Med 35:1–14
Kim EJ, Park SY, Baek SE, Jang MA, Lee WS, Bae SS, Kim K, Kim CD (2018) HMGB1 increases IL-1β production in vascular smooth muscle cells via NLRP3 inflammasome. Front Physiol 9:313
Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern D et al (1999) N(epsilon)-(carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem 274:31740–31749
Kitagawa K, Wang J, Mastushita T, Kogishi K, Hosokawa M, Fu X, Guo Z, Mori M, Higuchi K (2003) Polymorphisms of mouse apolipoprotein A-II: seven alleles found among 41 inbred strains of mice. Amyloid 10:207–214
Kuhla A, Hettwer C, Menger MD, Vollmar B (2010) Oxidative stress-associated rise of hepatic protein glycation increases inflammatory liver injury in uncoupling protein-2 deficient mice. Lab. Investig. J. Tech. Methods Pathol. 90:1189–1198
Kuhla A, Hauke M, Sempert K, Vollmar B, Zechner D (2013) Senescence-dependent impact of anti-RAGE antibody on endotoxemic liver failure. Age 35:2153–2163
Kumar V, Fleming T, Terjung S, Gorzelanny C, Gebhardt C, Agrawal R, Mall MA, Ranzinger J, Zeier M, Madhusudhan T et al (2017) Homeostatic nuclear RAGE-ATM interaction is essential for efficient DNA repair. Nucleic Acids Res 45:10595–10613
Laforge M, Rodrigues V, Silvestre R, Gautier C, Weil R, Corti O, Estaquier J (2016) NF-κB pathway controls mitochondrial dynamics. Cell Death Differ 23:89–98
Lange SS, Vasquez KM (2009) HMGB1: the jack-of-all-trades protein is a master DNA repair mechanic. Mol Carcinog 48:571–580
Lange SS, Mitchell DL, Vasquez KM (2008) High mobility group protein B1 enhances DNA repair and chromatin modification after DNA damage. Proc Natl Acad Sci USA 105:10320–10325
Larkin DJ, Kartchner JZ, Doxey AS, Hollis WR, Rees JL, Wilhelm SK, Draper CS, Peterson DM, Jackson GG, Ingersoll C et al (2013) Inflammatory markers associated with osteoarthritis after destabilization surgery in young mice with and without receptor for advanced glycation end-products (RAGE). Front Physiol 4:121
Leclerc E, Vetter SW (2015) The role of S100 proteins and their receptor RAGE in pancreatic cancer. Biochim Biophys Acta 1852:2706–2711
Leclerc E, Fritz G, Vetter SW, Heizmann CW (2009) Binding of S100 proteins to RAGE: an update. Biochim Biophys Acta 1793:993–1007
Li J, Schmidt AM (1997) Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J Biol Chem 272:16498–16506
Li L, Liu X, Glassman AB, Keating MJ, Stros M, Plunkett W, Yang L-Y (1997) Fludarabine triphosphate inhibits nucleotide excision repair of cisplatin-induced DNA adducts in vitro. Cancer Res 57:1487–1494
Li Y, Wu R, Tian Y, Yu M, Tang Y, Cheng H, Tian Z (2015) RAGE/NF-κB signaling mediates lipopolysaccharide induced acute lung injury in neonate rat model. Int J Clin Exp Med 8:13371–13376
Liliensiek B, Weigand MA, Bierhaus A, Nicklas W, Kasper M, Hofer S, Plachky J, Gröne H-J, Kurschus FC, Schmidt AM et al (2004) Receptor for advanced glycation end products (RAGE) regulates sepsis but not the adaptive immune response. J Clin Invest 113:1641–1650
Lin L (2006) RAGE on the Toll Road? Cell Mol Immunol 3:351–358
Lin L, Park S, Lakatta EG (2009) RAGE signaling in inflammation and arterial aging. Front Biosci 14:1403–1413
Liu Y, Liang C, Liu X, Liao B, Pan X, Ren Y, Fan M, Li M, He Z, Wu J et al (2010) AGEs increased migration and inflammatory responses of adventitial fibroblasts via RAGE, MAPK and NF-kappaB pathways. Atherosclerosis 208:34–42
Liu J, Huang K, Cai G-Y, Chen X-M, Yang J-R, Lin L-R, Yang J, Huo B-G, Zhan J, He Y-N (2014) Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling. Cell Signal 26:110–121
Lo M-C, Chen M-H, Lee W-S, Lu C-I, Chang C-R, Kao S-H, Lee H-M (2015) Nε-(carboxymethyl) lysine-induced mitochondrial fission and mitophagy cause decreased insulin secretion from β-cells. Am J Physiol Endocrinol Metab 309:E829–E839
Loeser RF, Yammani RR, Carlson CS, Chen H, Cole A, Im H-J, Bursch LS, Yan SD (2005) Articular chondrocytes express the receptor for advanced glycation end products: potential role in osteoarthritis. Arthritis Rheum 52:2376–2385
Lopetuso LR, Scaldaferri F, Petito V, Gasbarrini A (2013) Commensal Clostridia: leading players in the maintenance of gut homeostasis. Gut Pathog 5:23
López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217
Ma W, Rai V, Hudson BI, Song F, Schmidt AM, Barile GR (2012) RAGE binds C1q and enhances C1q-mediated phagocytosis. Cell Immunol 274:72–82
Magna M, Pisetsky DS (2014) The role of HMGB1 in the pathogenesis of inflammatory and autoimmune diseases. Mol Med 20:138–146
Maillard-Lefebvre H, Boulanger E, Daroux M, Gaxatte C, Hudson BI, Lambert M (2009) Soluble receptor for advanced glycation end products: a new biomarker in diagnosis and prognosis of chronic inflammatory diseases. Rheumatol Oxf Engl 48:1190–1196
Malaquin N, Martinez A, Rodier F (2016) Keeping the senescence secretome under control: molecular reins on the senescence-associated secretory phenotype. Exp Gerontol 82:39–49
Man SM, Kanneganti T-D (2015) Regulation of inflammasome activation. Immunol Rev 265:6–21
Manfredi AA, Capobianco A, Esposito A, De Cobelli F, Canu T, Monno A, Raucci A, Sanvito F, Doglioni C, Nawroth PP et al (2008) Maturing dendritic cells depend on RAGE for in vivo homing to lymph nodes. J Immunol Baltim Md 1950(180):2270–2275
Manigrasso MB, Pan J, Rai V, Zhang J, Reverdatto S, Quadri N, DeVita RJ, Ramasamy R, Shekhtman A, Schmidt AM (2016) Small molecule inhibition of ligand-stimulated RAGE-DIAPH1 signal transduction. Sci Rep 6:22450
Mankan AK, Schmidt T, Chauhan D, Goldeck M, Höning K, Gaidt M, Kubarenko AV, Andreeva L, Hopfner K-P, Hornung V (2014) Cytosolic RNA:DNA hybrids activate the cGAS–STING axis. EMBO J 33:2937–2946
Mao YX, Cai WJ, Sun XY, Dai PP, Li XM, Wang Q, Huang XL, He B, Wang PP, Wu G et al (2018) RAGE-dependent mitochondria pathway: a novel target of silibinin against apoptosis of osteoblastic cells induced by advanced glycation end products. Cell Death Dis 9:674
Mariani E, Cattini L, Neri S, Malavolta M, Mocchegiani E, Ravaglia G, Facchini A (2006) Simultaneous evaluation of circulating chemokine and cytokine profiles in elderly subjects by multiplex technology: relationship with zinc status. Biogerontology 7:449–459
Masters PM, Bada JL, Zigler JS (1977) Aspartic acid racemisation in the human lens during ageing and in cataract formation. Nature 268:71–73
Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K (1985a) Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci USA 82:4245–4249
Masters CL, Multhaup G, Simms G, Pottgiesser J, Martins RN, Beyreuther K (1985b) Neuronal origin of a cerebral amyloid: neurofibrillary tangles of Alzheimer’s disease contain the same protein as the amyloid of plaque cores and blood vessels. EMBO J 4:2757–2763
Minciullo PL, Catalano A, Mandraffino G, Casciaro M, Crucitti A, Maltese G, Morabito N, Lasco A, Gangemi S, Basile G (2016) Inflammaging and anti-inflammaging: the role of cytokines in extreme longevity. Arch Immunol Ther Exp (Warsz) 64:111–126
Misur I, Zarković K, Barada A, Batelja L, Milicević Z, Turk Z (2004) Advanced glycation endproducts in peripheral nerve in type 2 diabetes with neuropathy. Acta Diabetol 41:158–166
Monnier VM, Cerami A (1981) Nonenzymatic browning in vivo: possible process for aging of long-lived proteins. Science 211:491–493
Morizane R, Monkawa T, Konishi K, Hashiguchi A, Ueda M, Ando Y, Tokuyama H, Hayashi K, Hayashi M, Itoh H (2011) Renal amyloidosis caused by apolipoprotein A-II without a genetic mutation in the coding sequence. Clin Exp Nephrol 15:774–779
Morrisette-Thomas V, Cohen AA, Fülöp T, Riesco É, Legault V, Li Q, Milot E, Dusseault-Bélanger F, Ferrucci L (2014) Inflamm-aging does not simply reflect increases in pro-inflammatory markers. Mech Ageing Dev 139:49–57
Moser B, Desai DD, Downie MP, Chen Y, Yan SF, Herold K, Schmidt AM, Clynes R (2007) Receptor for advanced glycation end products expression on T cells contributes to antigen-specific cellular expansion in vivo. J Immunol Baltim Md 1950(179):8051–8058
Most P, Seifert H, Gao E, Funakoshi H, Völkers M, Heierhorst J, Remppis A, Pleger ST, DeGeorge BR, Eckhart AD et al (2006) Cardiac S100A1 protein levels determine contractile performance and propensity toward heart failure after myocardial infarction. Circulation 114:1258–1268
Narumi K, Miyakawa R, Ueda R, Hashimoto H, Yamamoto Y, Yoshida T, Aoki K (2015) Proinflammatory proteins S100A8/S100A9 activate NK cells via interaction with RAGE. J Immunol Baltim Md 1950(194):5539–5548
Navarrete Santos A, Jacobs K, Simm A, Glaubitz N, Horstkorte R, Hofmann B (2017) Dicarbonyls induce senescence of human vascular endothelial cells. Mech Ageing Dev 166:24–32
Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, Elliston K, Stern D, Shaw A (1992) Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J Biol Chem 267:14998–15004
Neviere R, Yu Y, Wang L, Tessier F, Boulanger E (2016) Implication of advanced glycation end products (Ages) and their receptor (Rage) on myocardial contractile and mitochondrial functions. Glycoconj J 33:607–617
Nguyen THO, Sant S, Bird NL, Grant EJ, Clemens EB, Koutsakos M, Valkenburg SA, Gras S, Lappas M, Jaworowski A et al (2018) Perturbed CD8+ T cell immunity across universal influenza epitopes in the elderly. J Leukoc Biol 103:321–339
Oczypok EA, Perkins TN, Oury TD (2017) All the “RAGE” in lung disease: the receptor for advanced glycation endproducts (RAGE) is a major mediator of pulmonary inflammatory responses. Paediatr Respir Rev 23:40–49
Olejarz W, Łacheta D, Głuszko A, Migacz E, Kukwa W, Szczepański MJ, Tomaszewski P, Nowicka G (2018) RAGE and TLRs as key targets for antiatherosclerotic therapy. Biomed Res Int. https://doi.org/10.1155/2018/7675286
Oliveira JB, Soares AASM, Sposito AC (2018) Inflammatory response during myocardial infarction. Adv Clin Chem 84:39–79
Ostendorp T, Leclerc E, Galichet A, Koch M, Demling N, Weigle B, Heizmann CW, Kroneck PMH, Fritz G (2007) Structural and functional insights into RAGE activation by multimeric S100B. EMBO J 26:3868–3878
Park H, Adsit FG, Boyington JC (2010) The 1.5 Å crystal structure of human receptor for advanced glycation endproducts (RAGE) ectodomains reveals unique features determining ligand binding. J Biol Chem 285:40762–40770
Park S, Yoon S-J, Tae H-J, Shim CY (2011) RAGE and cardiovascular disease. Front Biosci Landmark Ed 16:486–497
Pawelec G (2017) Immunosenescence and cancer. Biogerontology 18:717–721
Pelucchi C, Galeone C, Levi F, Negri E, Franceschi S, Talamini R, Bosetti C, Giacosa A, La Vecchia C (2006) Dietary acrylamide and human cancer. Int J Cancer 118:467–471
Peng Q, Li K, Sacks SH, Zhou W (2009) The role of anaphylatoxins C3a and C5a in regulating innate and adaptive immune responses. Inflamm Allergy Drug Targets 8:236–246
Peng Y, Park H-S, Tang LA, Horwitz N, Lin L (2019) Generation of sRAGEhigh transgenic mice to study inflammaging. Front Biosci Landmark Ed 24:555–563
Pettersson-Fernholm K, Forsblom C, Hudson BI, Perola M, Grant PJ, Groop P-H (2003) The functional —374 T/A RAGE gene polymorphism is associated with proteinuria and cardiovascular disease in type 1 diabetic patients. Diabetes 52:891–894
Porcel JM, Ordi J, Castro-Salomo A, Vilardell M, Rodrigo MJ, Gene T, Warburton F, Kraus M, Vergani D (1995) The value of complement activation products in the assessment of systemic lupus erythematosus flares. Clin Immunol Immunopathol 74:283–288
Prusiner SB (1982) Novel proteinaceous infectious particles cause scrapie. Science 216:136–144
Prusiner SB (1991) Molecular biology of prion diseases. Science 252:1515–1522
Rai V, Maldonado AY, Burz DS, Reverdatto S, Yan SF, Schmidt AM, Shekhtman A (2012a) Signal transduction in receptor for advanced glycation end products (RAGE): solution structure of C-terminal rage (ctRAGE) and its binding to mDia1. J Biol Chem 287:5133–5144
Rai V, Touré F, Chitayat S, Pei R, Song F, Li Q, Zhang J, Rosario R, Ramasamy R, Chazin WJ et al (2012b) Lysophosphatidic acid targets vascular and oncogenic pathways via RAGE signaling. J Exp Med 209:2339–2350
Rainone V, Schneider L, Saulle I, Ricci C, Biasin M, Al-Daghri NM, Giani E, Zuccotti GV, Clerici M, Trabattoni D (2016) Upregulation of inflammasome activity and increased gut permeability are associated with obesity in children and adolescents. Int J Obes 2005(40):1026–1033
Rambaran RN, Serpell LC (2008) Amyloid fibrils. Prion 2:112–117
Rampelli S, Candela M, Turroni S, Biagi E, Collino S, Franceschi C, O’Toole PW, Brigidi P (2013) Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging 5:902–912
Raucci A, Cugusi S, Antonelli A, Barabino SM, Monti L, Bierhaus A, Reiss K, Saftig P, Bianchi ME (2008) A soluble form of the receptor for advanced glycation endproducts (RAGE) is produced by proteolytic cleavage of the membrane-bound form by the sheddase a disintegrin and metalloprotease 10 (ADAM10). FASEB J Off Publ Fed Am Soc Exp Biol 22:3716–3727
Ray R, Juranek JK, Rai V (2016) RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis. Neurosci Biobehav Rev 62:48–55
Rivera A, Siracusa MC, Yap GS, Gause WC (2016) Innate cell communication kick-starts pathogen-specific immunity. Nat Immunol 17:356–363
Ruan BH, Li X, Winkler AR, Cunningham KM, Kuai J, Greco RM, Nocka KH, Fitz LJ, Wright JF, Pittman DD et al (2010) Complement C3a, CpG oligos, and DNA/C3a complex stimulate IFN-α production in a receptor for advanced glycation end product-dependent manner. J Immunol Baltim Md 1950(185):4213–4222
Sakaguchi M, Murata H, Yamamoto K, Ono T, Sakaguchi Y, Motoyama A, Hibino T, Kataoka K, Huh N (2011) TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding. PLoS ONE 6(8):e23132
Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195
Schmidt AM (2017) RAGE and implications for the pathogenesis and treatment of cardiometabolic disorders—spotlight on the macrophage. Arterioscler Thromb Vasc Biol 37:613–621
Schmidt AM, Vianna M, Gerlach M, Brett J, Ryan J, Kao J, Esposito C, Hegarty H, Hurley W, Clauss M (1992) Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface. J Biol Chem 267:14987–14997
Seidler S, Zimmermann HW, Bartneck M, Trautwein C, Tacke F (2010) Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults. BMC Immunol 11:30
Sell DR, Lane MA, Johnson WA, Masoro EJ, Mock OB, Reiser KM, Fogarty JF, Cutler RG, Ingram DK, Roth GS et al (1996) Longevity and the genetic determination of collagen glycoxidation kinetics in mammalian senescence. Proc Natl Acad Sci USA 93:485–490
Sellier C, Boulanger E, Maladry F, Tessier FJ, Lorenzi R, Nevière R, Desreumaux P, Beuscart J-B, Puisieux F, Grossin N (2015) Acrylamide induces accelerated endothelial aging in a human cell model. Food Chem Toxicol Int J Publ Br Ind Biol Res Assoc 83:140–145
Senatus LM, Schmidt AM (2017) The AGE-RAGE axis: implications for age-associated arterial diseases. Front, Genet, p 8
Serratos IN, Castellanos P, Pastor N, Millán-Pacheco C, Rembao D, Pérez-Montfort R, Cabrera N, Reyes-Espinosa F, Díaz-Garrido P, López-Macay A et al (2015) Modeling the Interaction between Quinolinate and the Receptor for Advanced Glycation End Products (RAGE): relevance for Early Neuropathological Processes. PLoS ONE 10(3):120221
Sessa L, Gatti E, Zeni F, Antonelli A, Catucci A, Koch M, Pompilio G, Fritz G, Raucci A, Bianchi ME (2014) The receptor for advanced glycation end-products (RAGE) is only present in mammals, and belongs to a family of cell adhesion molecules (CAMs). PLoS ONE 9:e86903
Shahab U, Ahmad MK, Mahdi AA, Waseem M, Arif B, Moinuddin, Ahmad S (2018) The receptor for advanced glycation end products: a fuel to pancreatic cancer. Semin Cancer Biol 49:37–43
Shahzad K, Bock F, Dong W, Wang H, Kopf S, Kohli S, Al-Dabet MM, Ranjan S, Wolter J, Wacker C et al (2015) Nlrp3-inflammasome activation in non-myeloid-derived cells aggravates diabetic nephropathy. Kidney Int 87:74–84
Shen YJ, Le Bert N, Chitre AA, Koo CX, Nga XH, Ho SSW, Khatoo M, Tan NY, Ishii KJ, Gasser S (2015) Genome-derived cytosolic DNA mediates type I interferon-dependent rejection of B cell lymphoma cells. Cell Rep 11:460–473
Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM et al (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36:401–414
Shirasawa M, Fujiwara N, Hirabayashi S, Ohno H, Iida J, Makita K, Hata Y (2004) Receptor for advanced glycation end-products is a marker of type I lung alveolar cells. Genes Cells 9:165–174
Shuvaev VV, Laffont I, Serot JM, Fujii J, Taniguchi N, Siest G (2001) Increased protein glycation in cerebrospinal fluid of Alzheimer’s disease. Neurobiol Aging 22:397–402
Silverstein DM (2009) Inflammation in chronic kidney disease: role in the progression of renal and cardiovascular disease. Pediatr. Nephrol. Berl. Ger. 24:1445–1452
Simm A, Casselmann C, Schubert A, Hofmann S, Reimann A, Silber R-E (2004) Age associated changes of AGE-receptor expression: RAGE upregulation is associated with human heart dysfunction. Exp Gerontol 39:407–413
Somensi N, Brum PO, de Miranda Ramos V, Gasparotto J, Zanotto-Filho A, Rostirolla DC, da Silva Morrone M, Moreira JCF, Pens Gelain D (2017) Extracellular HSP70 activates ERK1/2, NF-kB and pro-inflammatory gene transcription through binding with RAGE in A549 human lung cancer cells. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 42:2507–2522
Son M, Chung W-J, Oh S, Ahn H, Choi CH, Hong S, Park KY, Son KH, Byun K (2017) Age dependent accumulation patterns of advanced glycation end product receptor (RAGE) ligands and binding intensities between RAGE and its ligands differ in the liver, kidney, and skeletal muscle. Immun Ageing A 14:12
Song Y, Wang Y, Zhang Y, Geng W, Liu W, Gao Y, Li S, Wang K, Wu X, Kang L et al (2017) Advanced glycation end products regulate anabolic and catabolic activities via NLRP3-inflammasome activation in human nucleus pulposus cells. J Cell Mol Med 21:1373–1387
Sorci G, Riuzzi F, Giambanco I, Donato R (2013) RAGE in tissue homeostasis, repair and regeneration. Biochim Biophys Acta 1833:101–109
Sousa MM, Yan SD, Stern D, Saraiva MJ (2000) Interaction of the receptor for advanced glycation end products (RAGE) with transthyretin triggers nuclear transcription factor kB (NF-kB) activation. Lab Invest 80:1101–1110
Sparvero LJ, Asafu-Adjei D, Kang R, Tang D, Amin N, Im J, Rutledge R, Lin B, Amoscato AA, Zeh HJ et al (2009) RAGE (receptor for advanced glycation endproducts), RAGE ligands, and their role in cancer and inflammation. J Transl Med 7:17
Sugaya K, Fukagawa T, Matsumoto K, Mita K, Takahashi E, Ando A, Inoko H, Ikemura T (1994) Three genes in the human MHC class III region near the junction with the class II: gene for receptor of advanced glycosylation end products, PBX2 homeobox gene and a notch homolog, human counterpart of mouse mammary tumor gene int-3. Genomics 23:408–419
Sugimoto K, Yasujima M, Yagihashi S (2008) Role of advanced glycation end products in diabetic neuropathy. Curr Pharm Des 14:953–961
Sun X-H, Liu Y, Han Y, Wang J (2016) Expression and significance of high-mobility group protein B1 (HMGB1) and the receptor for advanced glycation end-product (RAGE) in knee osteoarthritis. Med Sci Monit Int Med J Exp Clin Res 22:2105–2112
Suski JM, Lebiedzinska M, Bonora M, Pinton P, Duszynski J, Wieckowski MR (2012) Relation between mitochondrial membrane potential and ROS formation. Methods Mol Biol Clifton NJ 810:183–205
Tan ALY, Sourris KC, Harcourt BE, Thallas-Bonke V, Penfold S, Andrikopoulos S, Thomas MC, O’Brien RC, Bierhaus A, Cooper ME et al (2009) Disparate effects on renal and oxidative parameters following RAGE deletion, AGE accumulation inhibition, or dietary AGE control in experimental diabetic nephropathy. Am J Physiol Ren Physiol 298:F763–F770
Tanaka N, Yonekura H, Yamagishi S, Fujimori H, Yamamoto Y, Yamamoto H (2000) The receptor for advanced glycation end products is induced by the glycation products themselves and tumor necrosis factor-alpha through nuclear factor-kappa B, and by 17beta-estradiol through Sp-1 in human vascular endothelial cells. J Biol Chem 275:25781–25790
Teh BK, Yeo JG, Chern LM, Lu J (2011) C1q regulation of dendritic cell development from monocytes with distinct cytokine production and T cell stimulation. Mol Immunol 48:1128–1138
Teissier T, Quersin V, Gnemmi V, Daroux M, Howsam M, Delguste F, Lemoine C, Fradin C, Schmidt A-M, Cauffiez C et al (2019) Knockout of receptor for advanced glycation end-products attenuates age-related renal lesions. Aging Cell 18:e12850
Tessier FJ, Niquet-Léridon C, Jacolot P, Jouquand C, Genin M, Schmidt A-M, Grossin N, Boulanger E (2016) Quantitative assessment of organ distribution of dietary protein-bound (13) C-labeled N(ɛ)-carboxymethyllysine after a chronic oral exposure in mice. Mol Nutr Food Res 60(11):2446–2456
Thankam FG, Roesch ZK, Dilisio MF, Radwan MM, Kovilam A, Gross RM, Agrawal DK (2018) Association of inflammatory responses and ECM disorganization with HMGB1 upregulation and NLRP3 inflammasome activation in the injured rotator cuff tendon. Sci Rep 8:8918
Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, Loukov D, Schenck LP, Jury J, Foley KP et al (2017) Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21:455.e4–466.e4
Thornalley PJ, Battah S, Ahmed N, Karachalias N, Agalou S, Babaei-Jadidi R, Dawnay A (2003) Quantitative screening of advanced glycation endproducts in cellular and extracellular proteins by tandem mass spectrometry. Biochem J 375:581–592
Tian J, Avalos AM, Mao S-Y, Chen B, Senthil K, Wu H, Parroche P, Drabic S, Golenbock D, Sirois C et al (2007) Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 8:487–496
Tran L, Greenwood-Van Meerveld B (2013) Age-associated remodeling of the intestinal epithelial barrier. J Gerontol A 68:1045–1056
Tsung A, Tohme S, Billiar TR (2014) High-mobility group box-1 in sterile inflammation. J Intern Med 276:425–443
Tulkens J, Vergauwen G, Van Deun J, Geeurickx E, Dhondt B, Lippens L, De Scheerder M-A, Miinalainen I, Rappu P, De Geest BG et al (2018) Increased levels of systemic LPS-positive bacterial extracellular vesicles in patients with intestinal barrier dysfunction. Gut. https://doi.org/10.1136/gutjnl-2018-317726
Tuppen HAL, Blakely EL, Turnbull DM, Taylor RW (2010) Mitochondrial DNA mutations and human disease. Biochim Biophys Acta 1797:113–128
Turner DP (2015) Advanced glycation end-products: a biological consequence of lifestyle contributing to cancer disparity. Cancer Res 75:1925–1929
van Hout GPJ, Arslan F, Pasterkamp G, Hoefer IE (2016) Targeting danger-associated molecular patterns after myocardial infarction. Expert Opin Ther Targets 20:223–239
van Zoelen MAD, Schouten M, de Vos AF, Florquin S, Meijers JCM, Nawroth PP, Bierhaus A, van der Poll T (2009) The receptor for advanced glycation end products impairs host defense in pneumococcal pneumonia. J Immunol Baltim Md 1950(182):4349–4356
van Zoelen MAD, Wieland CW, van der Windt GJW, Florquin S, Nawroth PP, Bierhaus A, van der Poll T (2012) Receptor for advanced glycation end products is protective during murine tuberculosis. Mol Immunol 52:183–189
Venereau E, Schiraldi M, Uguccioni M, Bianchi ME (2013) HMGB1 and leukocyte migration during trauma and sterile inflammation. Mol Immunol 55:76–82
Verzijl N, DeGroot J, Thorpe SR, Bank RA, Shaw JN, Lyons TJ, Bijlsma JW, Lafeber FP, Baynes JW, TeKoppele JM (2000) Effect of collagen turnover on the accumulation of advanced glycation end products. J Biol Chem 275:39027–39031
Wada R, Yagihashi S (2005) Role of advanced glycation end products and their receptors in development of diabetic neuropathy. Ann N Y Acad Sci 1043:598–604
Walton GE, van den Heuvel EGHM, Kosters MHW, Rastall RA, Tuohy KM, Gibson GR (2012) A randomised crossover study investigating the effects of galacto-oligosaccharides on the faecal microbiota in men and women over 50 years of age. Br J Nutr 107:1466–1475
Wang JQ, Jeelall YS, Ferguson LL, Horikawa K (2014) Toll-like receptors and cancer: MYD88 mutation and inflammation. Front, Immunol, p 5
Wang J, Zeng J, Wang H, Ye S, Bi Y, Zhou Y, Li K, Zhou Y (2016) Genetic polymorphisms of RAGE and risk of ulcerative colitis in a Chinese population. Immunol Lett 170:88–94
Ward MS, Fortheringham AK, Cooper ME, Forbes JM (2013) Targeting advanced glycation endproducts and mitochondrial dysfunction in cardiovascular disease. Curr Opin Pharmacol 13:654–661
Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL (2001) Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab 280:E685–E694
Wendt TM, Tanji N, Guo J, Kislinger TR, Qu W, Lu Y, Bucciarelli LG, Rong LL, Moser B, Markowitz GS et al (2003) RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol 162:1123–1137
Wolf L, Herr C, Niederstraßer J, Beisswenger C, Bals R (2017) Receptor for advanced glycation endproducts (RAGE) maintains pulmonary structure and regulates the response to cigarette smoke. PLoS ONE 12:e0180092
Xie J, Burz DS, He W, Bronstein IB, Lednev I, Shekhtman A (2007) Hexameric calgranulin C (S100A12) binds to the receptor for advanced glycated end products (RAGE) using symmetric hydrophobic target-binding patches. J Biol Chem 282:4218–4231
Xie J, Reverdatto S, Frolov A, Hoffmann R, Burz DS, Shekhtman A (2008) Structural basis for pattern recognition by the receptor for advanced glycation end products (RAGE). J Biol Chem 283:27255–27269
Xie J, Méndez JD, Méndez-Valenzuela V, Aguilar-Hernández MM (2013) Cellular signalling of the receptor for advanced glycation end products (RAGE). Cell Signal 25:2185–2197
Xu M, Bradley EW, Weivoda MM, Hwang SM, Pirtskhalava T, Decklever T, Curran GL, Ogrodnik M, Jurk D, Johnson KO et al (2017) Transplanted senescent cells induce an osteoarthritis-like condition in mice. J Gerontol A 72:780–785
Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, Inman CL, Ogrodnik MB, Hachfeld CM, Fraser DG et al (2018) Senolytics improve physical function and increase lifespan in old age. Nat Med 24:1246
Xue J, Rai V, Singer D, Chabierski S, Xie J, Reverdatto S, Burz DS, Schmidt AM, Hoffmann R, Shekhtman A (2011) Advanced glycation end product recognition by the receptor for AGEs. Struct Lond Engl 1993(19):722–732
Xue J, Ray R, Singer D, Böhme D, Burz DS, Rai V, Hoffmann R, Shekhtman A (2014) The receptor for advanced glycation end products (RAGE) specifically recognizes methylglyoxal-derived AGEs. Biochemistry 53:3327–3335
Yamagishi S, Matsui T, Fukami K (2015) Role of receptor for advanced glycation end products (RAGE) and its ligands in cancer risk. Rejuvenation Res 18:48–56
Yamamoto H, Watanabe T, Yamamoto Y, Yonekura H, Munesue S, Harashima A, Ooe K, Hossain S, Saito H, Murakami N (2007) RAGE in diabetic nephropathy. Curr Mol Med 7:752–757
Yamamoto Y, Harashima A, Saito H, Tsuneyama K, Munesue S, Motoyoshi S, Han D, Watanabe T, Asano M, Takasawa S et al (2011) Septic shock is associated with receptor for advanced glycation end products ligation of LPS. J Immunol Baltim Md 1950(186):3248–3257
Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J et al (1996) RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691
Yan SD, Zhu H, Zhu A, Golabek A, Du H, Roher A, Yu J, Soto C, Schmidt AM, Stern D et al (2000) Receptor-dependent cell stress and amyloid accumulation in systemic amyloidosis. Nat Med 6:643–651
Yan SD, Bierhaus A, Nawroth PP, Stern DM (2009a) RAGE and Alzheimer’s disease: a progression factor for amyloid-β-induced cellular perturbation? J Alzheimers Dis JAD 16:833–843
Yan SF, Yan SD, Ramasamy R, Schmidt AM (2009b) Tempering the wrath of RAGE: an emerging therapeutic strategy against diabetic complications, neurodegeneration, and inflammation. Ann Med 41:408–422
Yang HY, Chuang SY, Fang WH, Huang GS, Wang CC, Huang YY, Chu MY, Lin C, Su W, Chen CY et al (2015) Effect of RAGE polymorphisms on susceptibility to and severity of osteoarthritis in a Han Chinese population: a case-control study. Genet Mol Res GMR 14:11362–11370
Yao X, Carlson D, Sun Y, Ma L, Wolf SE, Minei JP, Zang QS (2015) Mitochondrial ROS induces cardiac inflammation via a pathway through mtDNA damage in a pneumonia-related sepsis model. PLoS ONE 10:e0139416
Yatime L, Andersen GR (2013) Structural insights into the oligomerization mode of the human receptor for advanced glycation end-products. FEBS J 280:6556–6568
Yeh CH, Sturgis L, Haidacher J, Zhang XN, Sherwood SJ, Bjercke RJ, Juhasz O, Crow MT, Tilton RG, Denner L (2001) Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. Diabetes 50:1495–1504
Yu Y, Wang L, Delguste F, Durand A, Guilbaud A, Rousselin C, Schmidt AM, Tessier F, Boulanger E, Neviere R (2017) Advanced glycation end products receptor RAGE controls myocardial dysfunction and oxidative stress in high-fat fed mice by sustaining mitochondrial dynamics and autophagy-lysosome pathway. Free Radic Biol Med 112:397–410
Yu W, Tao M, Zhao Y, Hu X, Wang M (2018) 4′-Methoxyresveratrol alleviated AGE-induced inflammation via RAGE-mediated NF-κB and NLRP3 inflammasome pathway. Mol J Synth Chem Nat Prod, Chem, p 23
Zeng S, Zhang QY, Huang J, Vedantham S, Rosario R, Ananthakrishnan R, Yan SF, Ramasamy R, DeMatteo RP, Emond JC et al (2012) Opposing roles of RAGE and Myd88 signaling in extensive liver resection. FASEB J 26:882–893
Zhang L, Bukulin M, Kojro E, Roth A, Metz VV, Fahrenholz F, Nawroth PP, Bierhaus A, Postina R (2008) Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases. J Biol Chem 283:35507–35516
Zhang H, Puleston DJ, Simon AK (2016) Autophagy and Immune Senescence. Trends Mol Med 22:671–686
Zong H, Madden A, Ward M, Mooney MH, Elliott CT, Stitt AW (2010) Homodimerization is essential for the receptor for advanced glycation end products (RAGE)-mediated signal transduction. J Biol Chem 285:23137–23146
Zwielehner J, Liszt K, Handschur M, Lassl C, Lapin A, Haslberger AG (2009) Combined PCR-DGGE fingerprinting and quantitative-PCR indicates shifts in fecal population sizes and diversity of Bacteroides, bifidobacteria and Clostridium cluster IV in institutionalized elderly. Exp Gerontol 44:440–446
Acknowledgements
We are grateful to Mike Howsam for his contribution of editorial assistance and English proofreading.
We thank LES LABORATOIRES SERVIER who have shared, under the creative commons license, some of the graphic elements that were adapted for the figures herein.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Teissier, T., Boulanger, É. The receptor for advanced glycation end-products (RAGE) is an important pattern recognition receptor (PRR) for inflammaging. Biogerontology 20, 279–301 (2019). https://doi.org/10.1007/s10522-019-09808-3
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-019-09808-3