Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept
Hae Young Chung1,*, Dae Hyun Kim1, Eun Kyeong Lee1,2, Ki Wung Chung1, Sangwoon Chung3, Bonggi Lee4, Arnold Y. Seo5, Jae Heun Chung6, Young Suk Jung1, Eunok Im1, Jaewon Lee1, Nam Deuk Kim1, Yeon Ja Choi7, Dong Soon Im1,*, Byung Pal Yu8,*
1Molecular Inflammation Research Center for Aging Intervention (MRCA), Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 609-735, Korea. 2Pathological and Analytical Center, Korea Institute of Toxicology, Daejeon 34114, Korea. 3Department of Internal Medicine, Pulmonary, Allergy, Critical Care & Sleep Medicine, The Ohio State University, Columbus, OH 43210, USA. 4Korean Medicine (KM)-Application Center, Korea Institute of Oriental Medicine (KIOM), Daegu 41062, Republic of Korea. 5Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. 6Department of Internal Medicine, Pusan National University Yangsan Hospital, Yangsan 50612, Korea. 7Department of Biopharmaceutical Engineering, Division of Chemistry and Biotechnology, Dongguk University, Gyeongju 38066, Korea. 8Department of Physiology, The University of Texas Health Science Center at San Antonio, TX 78229, USA.
Age-associated chronic inflammation is characterized by unresolved and uncontrolled inflammation with multivariable low-grade, chronic and systemic responses that exacerbate the aging process and age-related chronic diseases. Currently, there are two major hypotheses related to the involvement of chronic inflammation in the aging process: molecular inflammation of aging and inflammaging. However, neither of these hypotheses satisfactorily addresses age-related chronic inflammation, considering the recent advances that have been made in inflammation research. A more comprehensive view of age-related inflammation, that has a scope beyond the conventional view, is therefore required. In this review, we discuss newly emerging data on multi-phase inflammatory networks and proinflammatory pathways as they relate to aging. We describe the age-related upregulation of nuclear factor (NF)-κB signaling, cytokines/chemokines, endoplasmic reticulum (ER) stress, inflammasome, and lipid accumulation. The later sections of this review present our expanded view of age-related senescent inflammation, a process we term “senoinflammation”, that we propose here as a novel concept. As described in the discussion, senoinflammation provides a schema highlighting the important and ever-increasing roles of proinflammatory senescence-associated secretome, inflammasome, ER stress, TLRs, and microRNAs, which support the senoinflammation concept. It is hoped that this new concept of senoinflammation opens wider and deeper avenues for basic inflammation research and provides new insights into the anti-inflammatory therapeutic strategies targeting the multiple proinflammatory pathways and mediators and mediators that underlie the pathophysiological aging process.
Hae Young Chung,Dae Hyun Kim,Eun Kyeong Lee, et al. Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept[J]. Aging and disease,
2019, 10(2): 367-382.
Figure 1. Schematic representation of the senoinflammation concept. MMP, matrix metalloproteinase; Infla-genes, proinflammatory genes; ER, endoplasmic reticulum; TLRs, Toll-like receptors; HMGB1, high-mobility group box 1; RAGE, receptor for advanced glycation end product.
Cytokines, chemokines, and regulators
Other proinflammatory factors
TCGA data base
Table 1 Proinflammatory SA secretome in senescent cells, aged tissues, and human tissues.
Age-related inflammation/molecular inflammation
Sirt1, PPAR, FOXOs, SOD, CAT, PTK/PTP
FOXOs, SOD, CAT, LCK, SRC, PTK/PTP
COX-2, iNOS, TNFα, IL-1,6, AMs
COX-2, iNOS, TNFα, IL-1,6
IL-7, IL-2RA, CXCL1,2,3, MCP-1, CCL3
TGFβ, IL-8, TNFα
cytokines, chemokines, MMPs, GFs, IGFBPs
p53, p21, Bax
leptin, adiponectin, anabolism, catabolism
IRE, PERK, ATF4,6
10, 11, 54
6-9, 12-15, 23-25, 42, 125
Table 2 Comparison of major key features defining age-related chronic inflammation.
Freire MO, Van Dyke TE (2013). Natural resolution of inflammation. Periodontol 2000, 63: 149-164.
Chen M, Xu H (2015). Parainflammation, chronic inflammation, and age-related macular degeneration. J Leukoc Biol, 98:713-725.
Chung HY, Sung B, Jung KJ, Zou Y, Yu BP (2006). The molecular inflammatory process in aging. Antioxid Redox Signal, 8: 572-581.
Bruunsgaard H, Ladelund S, Pedersen AN, Schroll M, Jørgensen T, Pedersen BK (2003). Predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people. Clin Exp Immunol, 132: 24-31.
Gordon CJ, Rowsey PJ, Bishop BL, Ward WO, Macphail RC (2011). Serum biomarkers of aging in the Brown Norway rat. Exp Gerontol, 46: 953-957.
Kim HJ, Kim KW, Yu BP, Chung HY (2000). The effect of age on cyclooxygenase-2 gene expression: NF-kappaB activation and IkappaBalpha degradation. Free Radic Biol Med, 28: 683-692.
Chung HY, Kim HJ, Shim KH, Kim KW (1999). Dietary modulation of prostanoid synthesis in the aging process: role of cyclooxygenase-2. Mech Ageing Dev, 111: 97-106.
Kim JW, Baek BS, Kim YK, Herlihy JT, Ikeno Y, Yu BP, et al. (2001). Gene expression of cyclooxygenase in the aging heart. J Gerontol A Biol Sci Med Sci, 56: B350-355.
Kwon HJ, Sung BK, Kim JW, Lee JH, Kim ND, Yoo MA, et al. (2001). The effect of lipopolysaccharide on enhanced inflammatory process with age: Modulation of NF-κB. J Am Aging Assoc, 24: 163-171.
Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. (2000). Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci, 908: 244-254.
Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, 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.
Chung HY, Kim HJ, Jung KJ, Yoon JS, Yoo MA, Kim KW, et al. (2000). The inflammatory process in aging. Rev Clin Gerontol, 10: 207-222.
Chung HY, Kim HJ, Kim JW, Yu BP (2001). The inflammation hypothesis of aging: molecular modulation by calorie restriction. Ann N Y Acad Sci, 928: 327-335.
Chung HY, Kim HJ, Kim KW, Choi JS, Yu BP (2002). Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction. Microsc Res Tech, 59: 264-272.
Chung HY, Lee EK, Choi YJ, Kim JM, Kim DH, Zou Y, et al. (2011). Molecular inflammation as an underlying mechanism of the aging process and age-related diseases. J Dent Res, 90: 830-840.
Zou Y, Jung KJ, Kim JW, Yu BP, Chung HY (2004). Alteration of soluble adhesion molecules during aging and their modulation by calorie restriction. FASEB J, 18: 320-322.
Adler AS, Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY (2007). Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes Dev, 21: 3244-3257.
Korhonen P, Helenius M, Salminen A (1997). Age-related changes in the regulation of transcription factor NF-kappa B in rat brain. Neurosci Lett, 225: 61-64.
Helenius M, Hanninen M, Lehtinen SK, Salminen A (1996). Changes associated with aging and replicative senescence in the regulation of transcription factor nuclear factor-kappa B. Biochem J, 318: 603-608.
Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, et al. (2013). Hypothalamic programming of systemic ageing involving IKK-beta, NF-kappaB and GnRH. Nature, 497: 211-216.
Tilstra JS, Robinson AR, Wang J, Gregg SQ, Clauson CL, Reay DP, et al. (2012). NF-kappaB inhibition delays DNA damage-induced senescence and aging in mice. J Clin Invest, 122: 2601-2612.
Haigis MC, Yankner BA (2010). The aging stress response. Mol Cell, 40: 333-344.
Kim CH, Lee EK, Choi YJ, An HJ, Chung HO, Park DE, et al. (2016). Shory-term calorie restriction ameliorates genomewide, age-related alterations in DNA methylation. Aging Cell, 15: 1074-1081.
Park D, Lee EK, Jang EJ, Jeong HO, Kim BC, Ha YM, et al. (2013). Identification of the dichotomous role of age-related LCK in calorie restriction revealed by integrative analysis of cDNA microarray and interactome. Age, 35: 1045-1060.
Jung KJ, Lee EK, Yu BP, Chung HY (2009). Significance of protein tyrosine kinase/protein tyrosine phosphatase balance in the regulation of NF-kappaB signaling in the inflammatory process and aging. Free Radic Biol Med, 47: 983-991.
Linehan E, Fitzgerald DC (2015). Ageing and the immune system: focus on macrophages. Eur J Microbiol Immunol (Bp), 5: 14-24.
Herrero C, Marques L, Lloberas J, Celada A (2001). IFN-gamma-dependent transcription of MHC class II IA is impaired in macrophages from aged mice. J Clin Invest, 107: 485-493.
Ponnappan S, Ponnappan U (2011). Aging and immune function: molecular mechanisms to interventions. Antioxid Redox Signal, 14: 1551-1585.
Solana R, Pawelec G, Tarazona R (2006). Aging and innate immunity. Immunity, 24: 491-494.
van Deursen JM (2014). The role of senescent cells in ageing. Nature, 509: 439-446.
Singh P, Coskun ZZ, Goode C, Dean A, Thompson-Snipes L, Darlington G (2008). Lymphoid neogenesis and immune infiltration in aged liver. Hepatology, 47: 1680-1690.
Deleidi M, Jaggle M, Rubino G (2015). Immune aging, dysmetabolism, and inflammation in neurological diseases. Front Neurosci, 9: 172.
Finkin S, Yuan D, Stein I, Taniguchi K, Weber A, Unger K, et al. (2015). Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma. Nat Immunol, 16: 1235-1244.
Lumeng CN, Liu J, Geletka L, Delaney C, Delproposto J, Desai A, et al. (2011). Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue. J Immunol, 187: 6208-6216.
Rawji KS, Mishra MK, Michaels NJ, Rivest S, Stys PK, Yong VW (2016). Immunosenescence of microglia and macrophages: impact on the ageing central nervous system. Brain, 139(Pt 3): 653-661.
Oishi Y, Manabe I (2016). Macrophages in age-related chronic inflammatory diseases. NPJ Aging Mech Dis, 2: 16018.
Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, et al. (2009). Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev, 8: 18-30.
Tabas I, Glass CK (2013). Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science, 339: 166-172.
Palmer AK, Kirkland JL (2016). Aging and adipose tissue: potential interventions for diabetes and regenerative medicine. Exp Gerontol, 86: 97-105.
Bruunsgaard H, Pedersen BK (2003). Age-related inflammatory cytokines and disease. Immunol Allergy Clin North Am, 23: 15-39.
Soysal P, Stubbs B, Lucato P, Luchini C, Solmi M, Peluso R, et al. (2016). Inflammation and frailty in the elderly: A systematic review and meta-analysis. Ageing Res Rev, 31: 1-8.
Arai Y, Martin-Ruiz CM, Takayama M, Abe Y, Takebayashi T, Koyasu S, et al. (2015). Inflammation, But Not Telomere Length, Predicts Successful Ageing at Extreme Old Age: A Longitudinal Study of Semi-supercentenarian. EBioMedicine, 2: 1549-1558.
Michaud M, Balardy L, Moulis G, Gaudin C, Peyrot C, Vellas B, et al. (2013). Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc, 14: 877-882.
Ferrucci L, Corsi A, Lauretani F, Bandinelli S, Bartali B, Taub DD, et al. (2005). The origins of age-related proinflammatory state. Blood, 105: 2294-2299.
Roubenoff R, Harris TB, Abad LW, Wilson PW, Dallal GE, Dinarello CA (1998). Monocyte cytokine production in an elderly population: effect of age and inflammation. J Gerontol A Biol Sci Med Sci, 53: M20-26.
Semba RD, Nicklett EJ, Ferrucci L (2010). Does accumulation of advanced glycation end products contribute to the aging phenotype? J Gerontol A Biol Sci Med Sci, 65: 963-975.
Fonken LK, Frank MG, Kitt MM, D'Angelo HM, Norden DM, Weber MD, et al. (2016). The Alarmin HMGB1 Mediates Age-Induced Neuroinflammatory Priming. J Neurosci, 36: 7946-7956.
Maya EK, Ruslan M (2015). Inflammation, and disease susceptibility. Cell, 160: 816-827.
Franceschi C, Campisi J (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci, 69: S4-9.
Hotamisligil GS (2006). Inflammation and metabolic disorders. Nature, 444: 860-867.
Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N (2014). Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract, 105: 141-150.
Monteiro R, Azevedo I (2010). Chronic inflammation in obesity and the metabolic syndrome. Mediators Inflamm, 2010.
Bluher M (2016). Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance? Clin Sci (Lond), 130: 1603-1614.
Tilg H, Moschen AR (2010). Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology, 52: 1836-1846.
Hansson GK (2005). Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med, 352: 1685-1695.
Libby P (2006). Inflammation and cardiovascular disease mechanisms. Am J Clin Nutr, 83: 456S-460S.
Libby P (2012). Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol, 32: 2045-2051.
Biasucci LM, Rosa GL, Pdicini D, D’Aiello1 A, Galli M, Liuzzo G (2017). Where does inflammation fit? Current Cardiology Reports, 19: 84-94.
Leonard BE (2007). Inflammation, depression and dementia: are they connected? Neurochem Res, 32: 1749-1756.
Solito E, Sastre M (2012). Microglia function in Alzheimer's disease. Front Pharmacol, 3: 14.
Wyss-Coray T, Rogers J (2012). Inflammation in Alzheimer disease-a brief review of the basic science and clinical literature. Cold Spring Harb Perspect Med, 2: a006346.
Coussens LM, Werb Z (2002). Inflammation and cancer. Nature, 420: 860-867.
Shalapour S, Karin M (2015). Immunity, inflammation, and cancer: an eternal fight between good and evil. J Clin Invest, 125: 3347-3355.
Rakoff-Nahoum S (2006). Why cancer and inflammation? Yale J Biol Med, 79: 123-130.
Hoesel B, Schmid JA (2013). The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer, 12: 86.
Grivennikov SI, Karin M (2010). Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer. Cytokine Growth Factor Rev, 21: 11-19.
Webster GA, Perkins ND (1999). Transcriptional cross talk between NF-kappaB and p53. Mol Cell Biol, 19: 3485-3495.
Serhan CN, Chiang N, Dalli J (2015). The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution. Semin Immunol, 27: 200-215.
Arnardottir HH, Dalli J, Colas RA, Shinohara M, Serhan CN (2014). Aging delays resolution of acute inflammation in mice: reprogramming the host response with novel nano-proresolving medicines. J Immunol, 193: 4235-4244.
Carragher DM, Rangel-Moreno J, Randall TD (2008). Ectopic lymphoid tissues and local immunity. Semin Immunol, 20: 26-42.
Salminen A, Kauppinen A, Kaarniranta K (2012). Emerging role of NF-kappaB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal, 24: 835-845.
Franceschi C, Campisi J (2014). Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci, 7: e48978.
Baylis D, Bartlett DB, Patel HP, Roberts HC (2013). Understanding how we age: insights into inflammaging. Longev Healthspan, 2: 8.
Fagiolo U, Cossarizza A, Scala E, Fanales-Belasio E, Ortolani C, Cozzi E, et al. (1993). Increased cytokine production in mononuclear cells of healthy elderly people. Eur J Immunol, 23: 2375-2378.
Bauer ME, Fuente Mde L (2016). The role of oxidative and inflammatory stress and persistent viral infections in immunosenescence. Mech Ageing Dev, 158: 27-37.
Salminen A, Kaarniranta K, Kauppinen A (2012). Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging (Albany NY), 4: 166-175.
Chung KW, Kim KM, Choi YJ, An HJ, Lee B, Kim DH, et al. (2017). The critical role played by endotoxin-induced liver autophagy in the maintenance of lipid metabolism during sepsis. Autophagy, 13: 1113-1129.
Mancuso P (2016). The role of adipokines in chronic inflammation. Immunotargets Ther, 5: 47-56.
Vitale G, Salvioli S, Franceschi C (2013). Oxidative stress and the ageing endocrine system. Nat Rev Endocrinol, 9: 228-240.
Alasiri G, Fan LY, Zona S, Goldsbrough IG, Ke HL, Auner HW, et al. (2018). ER stress and cancer: The FOXO forkhead transcription factor link. Mol Cell Endocrinol, 462(Pt B): 67-81.
Jiao P, Chen Q, Shah S, Du J, Tao B, Tzameli I, et al. (2009). Obesity-related upregulation of monocyte chemotactic factors in adipocytes: involvement of nuclear factor-kappaB and c-Jun NH2-terminal kinase pathways. Diabetes, 58: 104-115.
Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, et al. (2004). Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science, 306: 457-461.
Ren LP, Chan SM, Zeng XY, Laybutt DR, Iseli TJ, Sun RQ, et al. (2012). Differing endoplasmic reticulum stress response to excess lipogenesis versus lipid oversupply in relation to hepatic steatosis and insulin resistance. PLoS One, 7: e30816.
Brown MR, Clark KD, Gulia M, Zhao Z, Garczynski SF, Crim JW, et al. (2008). An insulin-like peptide regulates egg maturation and metabolism in the mosquito Aedes aegypti. Proc Natl Acad Sci USA, 105: 5716-5721.
Sprenkle NT, Sims SG, Sánchez CL, Meares GP (2017). Endoplasmic reticulum stress and inflammation in the central nervous system. Molecular Neurodegeneration, 12: 42.
Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, et al. (2002). A central role for JNK in obesity and insulin resistance. Nature, 420: 333-336.
Tereshina EV (2009). Metabolic abnormalities as a basis for age-dependent diseases and aging? State of the art. Adv Gerontol, 22:129-138.
Goldberg EL, Dixit VD (2015). Drivers of age-related inflammation and strategies for healthspan extension. Immunol Rev, 265: 63-74.
Zhang K, Kaufman RJ (2008). From endoplasmic-reticulum stress to the inflammatory response. Nature, 454: 455-462.
Lerner AG, Upton JP, Praveen PV, Ghosh R, Nakagawa Y, Igbaria A, et al. (2012). IRE1α induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metab, 16: 250-264.
Mills KH, Dunne A (2009). Immune modulation: IL-1, master mediator or initiator of inflammation. Nat Med, 15: 1363-1364.
Schroder K, Zhou R, Tschopp J (2010). The NLRP3 inflammasome: a sensor for metabolic danger? Science, 327: 296-300.
Strowig T, Henao-Mejia J, Elinav E, Flavell R (2012). Inflammasomes in health and disease. Nature, 481: 278-286.
Stienstra R, van Diepen JA, Tack CJ, Zaki MH, van de Veerdonk FL, Perera D, et al. (2004). Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol, 76: 509-513.
Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, et al. (2011). The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med, 17: 179-188.
Hanouna G, Mesnard L, Vandermeersch S, Perez J, Placier S, Haymann JP, et al. (2017). Specific calpain inhibition protects kidney against inflammaging. Sci Rep, 7: 8016.
Youm YH, Grant RW, Mccabe LR, Albarado DC, Nguyen KY, Ravussin A, et al. (2013). Canonical Nlrp3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metabolism, 18: 519-532.
Xi Y, Shao F, Bai XY, Cai G, Lv Y, Chen X (2014). Changes in the expression of the Toll-like receptor system in the aging rat kidneys. PLoS One, 9: e96351.
Magna M, Pisetsky DS (2014). The role of HMGB1 in the pathogenesis of inflammatory and autoimmune diseases. Mol Med, 20: 138-146.
Nogueira-Machado JA, Volpe CM, Veloso CA, Chaves MM (2011). HMGB1, TLR and RAGE: a functional tripod that leads to diabetic inflammation. Expert Opin Ther Targets, 15: 1023-1035.
Tsoyi K, Nizamutdinova IT, Jang HJ, Mun L, Kim HJ, Seo HG, et al. (2010). Carbon monoxide from CORM-2 reduces HMGB1 release through regulation of IFN-β/JAK2/STAT-1/INOS/NO signaling but not COX-2 in TLR-activated macrophages. Shock, 34: 608-614.
van Beijnum JR, Buurman WA, Griffioen AW (2008). Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis, 11: 91-99.
Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, et al. (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.
Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, et al. (2005). Understanding RAGE, the receptor for advanced glycation end products. J Mol Med, 83: 876-886.
Ott C, Jacobs K, Haucke E, Navarrete Santos A, Grune T, Simm A (2014). Role of advanced glycation end products in cellular signaling. Redox Biol, 9: 411-429.
Jhun J, Lee S, Kim H, Her YM, Byun JK, Kim EK, et al. (2005). HMGB1/RAGE induces IL-17 expression to exaggerate inflammation in peripheral blood cells of hepatitis B patients. J Transl Med, 21: 310.
Ferhani N, Letuve S, Kozhich A, Thibaudeau O, Grandsaigne M, Maret M, et al. (2010). Expression of high-mobility group box 1 and of receptor for advanced glycation end products in chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 181: 917-927.
Davalos AR, Kawahara M, Malhotra GK, Schaum N, Huang J, Ved U, et al. (2013). p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. Cell Biol, 13: 613-629.
Sabroe I, Parker LC, Dower SK, Whyte MK (2008). The role of TLR activation in inflammation. J Pathol, 214: 126-135.
Rehli M (2002). Of mice and men: species variations of Toll-like receptor expression. Trends Immunol, 23: 375-378.
Mahla RS, Reddy MC, Prasad DV, Kumar H (2013). Sweeten PAMPs: Role of Sugar Complexed PAMPs in Innate Immunity and Vaccine Biology. Front Immunol, 4: 248.
Qian F, Wang X, Zhang L, Chen S, Piecychna M, Allore H, et al. (2012). Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly. Aging Cell, 1: 104-110.
Ghosh S, Lertwattanarak R, Garduño JJ, Galeana JJ, Li J, Zamarripa F, et al. (2015). Elevated muscle TLR4 expression and metabolic endotoxemia in human aging. J Gerontol A Biol Sci Med Sci, 70: 232-246.
Park D, Kim BC, Kim CH, Choi YJ, Jeong HO, Kim ME, et al. (2016). RNA-Seq analysis reveals new evidence for inflammation-related changes in aged kidney. Oncotarget, 7: 30037-30048.
Shaw AC, Panda A, Joshi SR, Qian F, Allore HG, Montgomery RR (2011). Dysregulation of human Toll-like receptor function in aging. Ageing Res Rev, 10: 346-353.
Boehmer ED, Goral J, Faunce DE, Kovacs EJ (2004). Age-dependent decrease in Toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression. J Leukoc Biol, 75: 342-349.
Yiu WH, Lin M, Tang SC (2014). Toll-like receptor activation: from renal inflammation to fibrosis. Kidney Int, Suppl 4: 20-25.
Quinn SR, O'Neill LA (2011). A trio of microRNAs that control Toll-like receptor signalling. Int Immunol, 23: 421-425.
Olivieri F, Spazzafumo L, Santini G, Lazzarini R, Albertini MC, Rippo MR, et al. (2012). Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging. Mech Ageing Dev, 133: 675-685.
Olivieri F, Capri M, Bonafè M, Morsiani C, Jung HJ, Spazzafumo L, et al. (2017). Circulating miRNAs and miRNA shuttles as biomarkers: Perspective trajectories of healthy and unhealthy aging. Mech Ageing Dev, 165: 162-170.
Sredni ST, Gadd S, Jafari N, Huang CC (2011). A parallel study of mRNA and microRNA profiling of peripheral blood in young adult women. Front Genet, 2: 49.
Oerlemans MI, Mosterd A, Dekker MS, de Vrey EA, van Mil A, Pasterkamp G, et al. (2012). Early assessment of acute coronary syndromes in the emergency department: the potential diagnostic value of circulating microRNAs. EMBO Mol Med, 4: 1176-1185.
Dong H, Li J, Huang L, Chen X, Li D, Wang T, et al. (2015). Serum MicroRNA Profiles Serve as Novel Biomarkers for the Diagnosis of Alzheimer's Disease. Dis Markers, 2015: 625-659.
Dhahbi JM (2014). Circulating small noncoding RNAs as biomarkers of aging. Ageing Res Rev, 17: 86-98.
Smith-Vikos T, Slack FJ (2012). MicroRNAs and their roles in aging. J Cell Sci, 125: 7-17.
Rippo MR, Olivieri F, Monsurrò V, Prattichizzo F, Albertini MC, Procopio AD (2014). MitomiRs in human inflamm-aging: a hypothesis involving miR-181a, miR-34a and miR-146a. Exp Gerontol, 56: 154-163.
Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, et al. (2012). MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci USA, 109: E2110-E2116.
Bernard JJ, Cowing-Zitron C, Nakatsuji T, Muehleisen B, Muto J, Borkowski AW, et al. (2012). Ultraviolet radiation damages self noncoding RNA and is detected by TLR3. Nat Med, 18: 1286-1290.
Chen C, Feng Y, Zou L, Wang L, Chen HH, Cai JY, et al. (2014). Role of extracellular RNA and TLR3-Trif signaling in myocardial ischemia-reperfusion injury. J Am Heart Assoc, 3: e000683.
Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, et al. (2016). Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature, 530: 184-189.
Young AR, Narita M (2009). SASP reflects senescence. EMBO Rep, 10: 228-230.
Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, et al. (2008). Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol, 6: 2853-2868.
Freund A, Orjalo AV, Desprez PY, Campisi J (2010). Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med, 16: 238-246.
Kim YM, Byun HO, Jee BA, Cho H, Seo YH, Kim YS, et al. (2013). Implications of time-series gene expression profiles of replicative senescence. Aging Cell, 12: 622-634.
Fougère B, Boulanger E, Nourhashémi F, Guyonnet S, Cesari M (2017). Chronic Inflammation: Accelerator of Biological Aging. J Gerontol A Biol Sci Med Sci, 72: 1218-1225.
Bektas A, Schurman SH, Sen R, Ferrucci L (2017). Aging, inflammation and the environment. Exp Gerontol, in press.
Fulop T, Larbi A, Dupuis G, Le Page A, Frost EH, Cohen AA, et al. (2018). Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes? Front Immunol, 8: 1960.
Chhetri JK, de Souto Barreto P, Fougère B, Rolland Y, Vellas B, Cesari M (2018). Chronic inflammation and sarcopenia: A regenerative cell therapy perspective. Exp Gerontol, 103: 115-123.
Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S (2017). Inflammaging and 'Garb-aging'. Trends Endocrinol Metab, 28: 199-212.