Skip to main content
SpringerLink
Log in

Inflammaging

  • Living reference work entry
  • First Online:
Handbook of Immunosenescence

Abstract

Inflammaging is a theory of aging based on the evidence that the evolutionary unpredicted persistent/increasing exposure to a variety of external and internal stressors occurring beyond the age of reproduction activates innate and adaptive immunity pathways involved in inflammatory response. Seventeen years after this theory was launched, it is now recognized that this phenomenon also involves non-immune cells, including adipocytes, fibroblasts, muscle, endothelial, and senescent cells. Recent data suggest that besides classical stimuli, such as cytomegalovirus persistent infection (non-self), inflammging is fueled by a variety of stimuli derived from the gut microbiota (quasi-self) and by the continuous production of potentially inflammatory molecules released/secreted as a consequence of cell death and organelle dysfunction (self). All these products (alarmins) are sensed by a small number of evolutionary-selected sensors, and eventually activate few basic inflammatory pathways such as NF-κB, inflammasomes, and cGAS. These phenomena are physiological and crucial for survival, but they undergo a progressive increase with age, sometimes reaching a threshold over which age-related pathologies ensue, thus representing an example of antagonist pleiotropy. Inflammaging is a dynamic phenomenon, and its final clinical outcome is highly “personalized” depending on what we propose to call “immunobiography,” i.e., the lifelong immunological experiences and stimuli each individual has been exposed to. Finally, a particular attention is devoted to antiaging strategies, showing that most of them have a direct or indirect impact on inflammaging itself.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

References

  • Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, Pascual G, Morris KJ, Khan S, Jin H, Dharmalingam G, Snijders AP, Carroll T, Capper D, Pritchard C, Inman GJ, Longerich T, Sansom OJ, Benitah SA, Zender L, Gil J (2013) A complex secretory program orches-trated by the inflammasome controls paracrine senescence. Nat Cell Biol 15:978–990

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akunuru S, Geiger H (2016) Aging, Clonality, and rejuvenation of hematopoietic stem cells. Trends Mol Med 22(8):701–712

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anderson OA, Finkelstein A, Shima DT (2013) A2E induces IL-1ß production in retinal pigment epithelial cells via the NLRP3 inflammasome. PLoS One 8(6):e67263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Andreeva L, Hiller B, Kostrewa D, Lässig C, de Oliveira Mann CC, Jan Drexler D, Maiser A, Gaidt M, Leonhardt H, Hornung V, Hopfner KP (2017) cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders. Nature 549(7672):394–398

    Article  CAS  PubMed  Google Scholar 

  • Arai Y, Hirose N, Nakazawa S, Yamamura K, Shimizu K, Takayama M, Ebihara Y, Osono Y, Homma S (2001) Lipoprotein metabolism in Japanese centenarians: effects of apolipoprotein E polymorphism and nutritional status. J Am Geriatr Soc 49(11):1434–1441

    Article  CAS  PubMed  Google Scholar 

  • Ayyadevara S, Bharill P, Dandapat A, Hu C, Khaidakov M, Mitra S, Shmookler Reis RJ, Mehta JL (2013) Aspirin inhibits oxidant stress, reduces age-associated functional declines, and extends lifespan of Caenorhabditis Elegans. Antioxid Redox Signal 18:481–490

    Article  CAS  PubMed  Google Scholar 

  • Balaj L, Lessard R, Dai L, Cho YJ, Pomeroy SL, Breakefield XO, Skog J (2011) Tumour microvesicles contain retrotransposon elements and amplified oncogene sequences. Nat Commun 2:180

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Basso N, Cini R, Pietrelli A, Ferder L, Terragno NA, Inserra F (2007) Protective effect of long-term angiotensin II inhibition. Am J Physiol Heart Circ Physiol 293:H1351–H1358

    Article  CAS  PubMed  Google Scholar 

  • Bellavista E, Martucci M, Vasuri F, Santoro A, Mishto M, Kloss A, Capizzi E, Degiovanni A, Lanzarini C, Remondini D, Dazzi A, Pellegrini S, Cescon M, Capri M, Salvioli S, D’Errico-Grigioni A, Dahlmann B, Grazi GL, Franceschi C (2014) Lifelong maintenance of composition, function and cellular/subcellular distribution of proteasomes in human liver. Mech Ageing Dev 141-142:26–34

    Article  CAS  PubMed  Google Scholar 

  • Benigni A, Corna D, Zoja C, Sonzogni A, Latini R, Salio M, Conti S, Rottoli D, Longaretti L, Cassis P, Morigi M, Coffman TM, Remuzzi G (2009) Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest 119:524–530

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bewicke-Copley F, Mulcahy LA, Jacobs LA, Samuel P, Akbar N, Pink RC, Carter DRF (2017) Extracellular vesicles released following heat stress induce bystander effect in unstressed populations. J Extracell Vesicles 6(1):1340746

    Article  PubMed  PubMed Central  Google Scholar 

  • Biagi E, Candela M, Fairweather-Tait S, Franceschi C, Brigidi P (2012) Aging of the human metaorganism: the microbial counterpart. Age (Dordr) 34:247–267

    Article  Google Scholar 

  • Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S, Consolandi C, Quercia S, Scurti M, Monti D, Capri M, Brigidi P, Candela M (2016) Gut microbiota and extreme longevity. Curr Biol 26(11):1480–1485

    Article  CAS  PubMed  Google Scholar 

  • Biagi E, Nylund L, Candela M, Ostan R, Bucci L, Pini E, Nikkïla J, Monti D, Satokari R, Franceschi C, Brigidi P, De Vos W (2010) Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One 5(5):e10667

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Blagosklonny MV (2017) From rapalogs to anti-aging formula. Oncotarget 8(22):35492–35507

    Article  PubMed  PubMed Central  Google Scholar 

  • Bonaccio M, Di Castelnuovo A, De Curtis A, Costanzo S, Persichillo M, Donati MB, Cerletti C, Iacoviello L, de Gaetano G, Investigators M-s P (2014) Adherence to the Mediterranean diet is associated with lower platelet and leukocyte counts: results from the Moli-sani study. Blood 123(19):3037–3044

    Article  CAS  PubMed  Google Scholar 

  • Bonaccio M, Cerletti C, Iacoviello L, de Gaetano G (2015) Mediterranean diet and low-grade subclinical inflammation: the Moli-sani study. Endocr Metab Immune Disord Drug Targets 15(1):18–24

    Article  CAS  PubMed  Google Scholar 

  • Bonafè M, Storci G, Franceschi C (2012) Inflamm-aging of the stem cell niche: breast cancer as a paradigmatic example: breakdown of the multi-shell cytokine network fuels cancer in aged people. BioEssays 34(1):40–49

    Article  PubMed  CAS  Google Scholar 

  • Bravo-San Pedro JM, Senovilla L (2013) Immunostimulatory activity of lifespan-extending agents. Aging (Albany NY) 5(11):793–801

    Article  CAS  Google Scholar 

  • Brenner C, Galluzzi L, Kepp O, Kroemer G (2013) Decoding cell death signals in liver inflammation. J Hepatol 59(3):583–594

    Article  CAS  PubMed  Google Scholar 

  • Bruunsgaard H, Andersen-Ranberg K, Jeune B, Pedersen AN, Skinhøj P, Pedersen BK (1999) A high plasma concentration of TNF-alpha is associated with dementia in centenarians. J Gerontol A Biol Sci Med Sci 54(7):M357–M364

    Article  CAS  PubMed  Google Scholar 

  • Cabreiro F, Au C, Leung KY, Vergara-Irigaray N, Cocheme HM, Noori T, Weinkove D, Schuster E, Greene ND, Gems D (2013) Metformin retards aging in C. Elegans by altering microbial folate and methionine metabolism. Cell 153:228–239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cabrera AJR (2016) Inflammatory oxidative aging: a new theory of aging. MOJ Immunol 3(5):00103

    Article  Google Scholar 

  • Campbell JM, Bellman SM, Stephenson MD, Lisy K (2017) Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. Ageing Res Rev 40:31–44

    Article  CAS  PubMed  Google Scholar 

  • Campisi J, Andersen JK, Kapahi P, Melov S (2011) Cellular senescence: a link between cancer and age-related degenerative disease? Semin Cancer Biol 21(6):354–359

    CAS  PubMed  PubMed Central  Google Scholar 

  • Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8(9):729–740

    Article  CAS  PubMed  Google Scholar 

  • Campisi J (2011) Cellular senescence: putting the paradoxes in perspective. Curr Opin Genet Dev 21:107–112

    Article  CAS  PubMed  Google Scholar 

  • Capasso S, Alessio N, Squillaro T, Di Bernardo G, Melone MA, Cipollaro M, Peluso G, Galderisi U (2015) Changes in autophagy, proteasome activity and metabolism to determine a specific signature for acute and chronic senescent mesenchymal stromal cells. Oncotarget 6(37):39457–39468

    PubMed  PubMed Central  Google Scholar 

  • Carrieri G, Marzi E, Olivieri F, Marchegiani F, Cavallone L, Cardelli M, Giovagnetti S, Stecconi R, Molendini C, Trapassi C, De Benedictis G, Kletsas D, Franceschi C (2004) The G/C915 polymorphism of transforming growth factor beta1 is associated with human longevity: a study in Italian centenarians. Aging Cell 3(6):443–448

    Article  CAS  PubMed  Google Scholar 

  • Cevenini E, Monti D, Franceschi C (2013) Inflamm-ageing. Curr Opin Clin Nutr Metab Care 16(1):14–20

    Article  CAS  PubMed  Google Scholar 

  • Chan AT, Giovannucci EL, Meyerhardt JA, Schernhammer ES, Curhan GC, Fuchs CS (2005) Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer. JAMA 294:914–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Childs BG, Gluscevic M, Baker DJ, Laberge RM, Marquess D, Dananberg J, van Deursen JM (2017) Senescent cells: an emerging target for diseases of ageing. Nat Rev Drug Discov 16(10):718–735

    Article  CAS  PubMed  Google Scholar 

  • Chirumbolo S (2012) Plant phytochemicals as new potential drugs for immune disorders and cancer therapy: really a promising path? J Sci Food Agric 92(8):1573–1577

    Article  CAS  PubMed  Google Scholar 

  • Chondrogianni N, Gonos ES (2010) Proteasome function determines cellular homeostasis and the rate of aging. Adv Exp Med Biol 694:38–46

    Article  CAS  PubMed  Google Scholar 

  • Chondrogianni N, Petropoulos I, Franceschi C, Friguet B, Gonos ES (2000) Fibroblast cultures from healthy centenarians have an active proteasome. Exp Gerontol 35(6–7):721–728

    Article  CAS  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, JR FD, Dinan T, Fitzgerald G, Stanton C, van Sinderen D, O’Connor M, Harnedy N, O’Connor K, Henry C, O’Mahony D, Fitzgerald AP, Shanahan F, Twomey C, Hill C, Ross RP, O’Toole PW (2011) Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci 108:4586–4591

    Article  CAS  PubMed  Google Scholar 

  • Clarke G, Stilling RM, Kennedy PJ, Stanton C, Cryan JF, Dinan TG (2014) Minireview: gut microbiota: the neglected endocrine organ. Mol Endocrinol 28:1221–1238

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Collado MC, Rautava S, Aakko J, Isolauri E, Salminen S (2016) Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep 6:23129

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • 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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Coppé J-P, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008) Senescence-associated secretory phenotypes reveal cell non autonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868

    Article  PubMed  CAS  Google Scholar 

  • Criscione SW, De Cecco M, Siranosian B, Zhang Y, Kreiling JA, Sedivy JM, Neretti N (2016) Reorganization of chromosome architecture in replicative cellular senescence. Sci Adv 2(2):e1500882

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cuervo AM, Bergamini E, Brunk UT, Dröge W, French M, Terman A (2005) Autophagy and aging: the importance of maintaining “clean” cells. Autophagy 1(3):131–140

    Article  PubMed  Google Scholar 

  • Cuervo AM, Wong E (2014) Chaperone-mediated autophagy: roles in disease and aging. Cell Res 24(1):92–104

    Article  CAS  PubMed  Google Scholar 

  • Cuzick J, Thorat MA, Bosetti C, Brown PH, Burn J, Cook NR, Ford LG, Jacobs EJ, Jankowski JA, La Vecchia C, Law M, Meyskens F, Rothwell PM et al (2015) Estimates of benefits and harms of prophylactic use of aspirin in the general population. Ann Oncol 26:47–57

    Article  CAS  PubMed  Google Scholar 

  • Dall’Olio F, Vanhooren V, Chen CC, Slagboom PE, Wuhrer M, Franceschi C (2013) N-glycomic biomarkers of biological aging and longevity: a link with inflammaging. Ageing Res Rev 12(2):685–698

    Article  PubMed  CAS  Google Scholar 

  • Danilov A, Shaposhnikov M, Shevchenko O, Zemskaya N, Zhavoronkov A, Moskalev A (2015) Influence of non-steroidal anti-inflammatory drugs on Drosophila Melanogaster longevity. Oncotarget 6:19428–19444

    Article  PubMed  PubMed Central  Google Scholar 

  • Davalos AR, Kawahara M, Malhotra GK, Schaum N, Huang J, Ved U, Beausejour CM, Coppe JP, Rodier F, Campisi J (2013) p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes. J Cell Biol 201(4):613–629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Davis BK, Wen H, Ting JP (2011) The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol 29:707–735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Lorgeril M, Salen P (2012) New insights into the health effects of dietary saturated and omega-6 and omega-3 polyunsaturated fatty acids. BMC Med 10:50

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • De Martinis M, Franceschi C, Monti D, Ginaldi L (2005) Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 579(10):2035–2039

    Article  PubMed  CAS  Google Scholar 

  • Dethlefsen L, Eckburg PB, Bik EM, Relman DA (2006) Assembly of the human intestinal microbiota. Trends Ecol Evol 21:517–523

    Article  PubMed  Google Scholar 

  • DiGiulio DB, Romero R, Kusanovic JP, Gomez R, Kim CJ, Seok KS, Gotsch F, Mazaki-Tovi S, Vaisbuch E, Sanders K, Bik EM, Chaiworapongsa T, Oyarzún E, Relman DA (2010) Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol 64:38e57

    Google Scholar 

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92:9363–9367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98–107

    Article  CAS  PubMed  Google Scholar 

  • Durieux J, Wolff S, Dillin A (2011) The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144(1):79–91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA (2005) Diversity of the human intestinal microbial Flora. Science 308:1635–1638

    Article  PubMed  PubMed Central  Google Scholar 

  • Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305

    Article  PubMed  PubMed Central  Google Scholar 

  • Fabbri E, An Y, Zoli M, Simonsick EM, Guralnik JM, Bandinelli S, Boyd CM, Ferrucci L (2015) Aging and the burden of multimorbidity: associations with inflammatory and anabolic hormonal biomarkers. J Gerontol A Biol Sci Med Sci 70(1):63–70

    Article  CAS  PubMed  Google Scholar 

  • 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(9):2375–2378

    Article  CAS  PubMed  Google Scholar 

  • Fang F, Lue LF, Yan S, Xu H, Luddy JS, Chen D, Walker DG, Stern DM, Yan S, Schmidt AM, Chen JX, Yan SS (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(4):1043–1055

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feldstein CA (2010) Statins in hypertension: are they a new class of antihypertensive agents? Am J Ther 17:255–262

    Article  PubMed  Google Scholar 

  • Ferrucci L, Corsi A, Lauretani F, Bandinelli S, Bartali B, Taub DD, Guralnik JM, Longo DL (2005) The origins of age-related pro-inflammatory state. Blood 105(6):2294–2299

    Article  CAS  PubMed  Google Scholar 

  • Fontana L, Klein S, Holloszy JO (2010) Effects of long-term calorie restriction and endurance exercise on glucose tolerance, insulin action, and adipokines production. Age (Dordr) 32(1):97–108

    Article  CAS  Google Scholar 

  • Forsey RJ, Thompson JM, Ernerudh J, Hurst TL, Strindhall J, Johansson B, Nilsson BO, Wikby A (2003) Plasma cytokine profiles in elderly humans. Mech Ageing Dev 124(4):487–493

    Article  CAS  PubMed  Google Scholar 

  • Franceschi C (2017) Healthy ageing in 2016: obesity in geroscience – is cellular senescence the culprit? Nat Rev Endocrinol 13(2):76–78

    Article  CAS  PubMed  Google Scholar 

  • Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000a) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254

    Article  CAS  PubMed  Google Scholar 

  • Franceschi C, Bonafè M, Valensin S (2000b) Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine 18:1717–1720

    Article  CAS  PubMed  Google Scholar 

  • Franceschi C, Campisi J (2014) Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci 69(Suppl 1):S4–S9

    Article  PubMed  Google Scholar 

  • Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128(1):92–105

    Article  CAS  PubMed  Google Scholar 

  • Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S (2017a) Inflammaging and ‘Garb-aging’. Trends Endocrinol Metab 28(3):199–212

    Article  CAS  PubMed  Google Scholar 

  • Franceschi C, Monti D, Sansoni P, Cossarizza A (1995) The immunology of exceptional individuals: the lesson of centenarians. Immunol Today 16(1):12–16

    Article  CAS  PubMed  Google Scholar 

  • Franceschi C, Salvioli S, Garagnani P, de Eguileor M, Monti D, Capri M (2017b) Immunobiography and the heterogeneity of immune responses in the elderly: a focus on inflammaging and trained immunity. Front Immunol 8:982

    Article  PubMed  PubMed Central  Google Scholar 

  • Fuhrmann-Stroissnigg H, Ling YY, Zhao J, McGowan SJ, Zhu Y, Brooks RW, Grassi D, Gregg SQ, Stripay JL, Dorronsoro A, Corbo L, Tang P, Bukata C, Ring N, Giacca M, Li X, Tchkonia T, Kirkland JL, Niedernhofer LJ, Robbins PD (2017) Identification of HSP90 inhibitors as a novel class of senolytics. Nat Commun 8(1):422

    Article  PubMed  PubMed Central  Google Scholar 

  • Gallenga CE, Parmeggiani F, Costagliola C, Sebastiani A, Gallenga PE (2014) Inflammaging: should this term be suitable for age related macular degeneration too? Inflamm Res 63:105–107

    Article  CAS  PubMed  Google Scholar 

  • Gallucci S, Maffei ME (2017) DNA sensing across the tree of life. Trends Immunol 38(10):719–732

    Article  CAS  PubMed  Google Scholar 

  • Gangemi S, Basile G, Merendino RA, Minciullo PL, Novick D, Rubinstein M, Dinarello CA, Lo Balbo C, Franceschi C, Basili S, D’Urbano E, Daví G, Nicita-Mauro V, Romano M (2003) Increased circulating Interleukin-18 levels in centenarians with no signs of vascular disease: another paradox of longevity? Exp Gerontol 38(6):669–672

    Article  CAS  PubMed  Google Scholar 

  • Gangemi S, Basile G, Monti D, Merendino RA, Di Pasquale G, Bisignano U, Nicita-Mauro V, Franceschi C (2005) Age-related modifications in circulating IL-15 levels in humans. Mediat Inflamm 2005(4):245–247

    Article  Google Scholar 

  • Garatachea N, Pareja-Galeano H, Sanchis-Gomar F, Santos-Lozano A, Fiuza-Luces C, Morán M, Emanuele E, Joyner MJ, Lucia A (2015) Exercise attenuates the major hallmarks of aging. Rejuvenation Res 18(1):57–89

    Article  PubMed  PubMed Central  Google Scholar 

  • García-Prat L, Martínez-Vicente M, Perdiguero E, Ortet L, Rodríguez-Ubreva J, Rebollo E, Ruiz-Bonilla V, Gutarra S, Ballestar E, Serrano AL, Sandri M, Muñoz-Cánoves P (2016) Autophagy maintains stemness by preventing senescence. Nature 529(7584):37–42

    Article  PubMed  CAS  Google Scholar 

  • Geiger H (2016) Depleting senescent cells to combat aging. Nat Med 22:23–24

    Article  CAS  PubMed  Google Scholar 

  • Gerli R, Monti D, Bistoni O, Mazzone AM, Peri G, Cossarizza A, Di Gioacchino M, Cesarotti ME, Doni A, Mantovani A, Franceschi C, Paganelli R (2000) Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians. Mech Ageing Dev 121(1–3):37–46

    CAS  PubMed  Google Scholar 

  • Giuliani N, Sansoni P, Girasole G, Vescovini R, Passeri G, Passeri M, Pedrazzoni M (2001) Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes. Exp Gerontol 36(3):547–557

    Article  CAS  PubMed  Google Scholar 

  • Goldberg EL, Dixit VD (2015) Drivers of age-related inflammation and strategies for healthspan extension. Immunol Rev 265:63–74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gómez M, Moles L, Melgar A, Ureta N, Bustos G, Fernández L, Rodríguez JM, Jiménez E (2016) Early gut colonization of preterm infants: effect of enteral feeding tubes. J Pediatr Gastroenterol Nutr 62(6):893–900

    Article  PubMed  Google Scholar 

  • Gravina S, Sedivy JM, Vijg J (2016) The dark side of circulating nucleic acids. Aging Cell 15(3):398–399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445

    Article  CAS  PubMed  Google Scholar 

  • Grignolio A, Mishto M, Faria AM, Garagnani P, Franceschi C, Tieri P (2014) Towards a liquid self: how time, geography, and life experiences reshape the biological identity. Front Immunol 5:153

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Grootjans J, Kaser A, Kaufman RJ, Blumberg RS (2016) The unfolded protein response in immunity and inflammation. Nat Rev Immunol 16(8):469–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gurung P, Lukens JR, Kanneganti T-D (2015) Mitochondria: diversity in the regulation of the NLRP3 inflammasome. Trends Mol Med 21(3):193–201

    Article  CAS  PubMed  Google Scholar 

  • Hall BM, Balan V, Gleiberman AS, Strom E, Krasnov P, Virtuoso LP, Rydkina E, Vujcic S, Balan K, Gitlin I, Leonova K, Polinsky A, Chernova OB, Gudkov AV (2016) Aging of mice is associated with p16(Ink4a)- and β-galactosidase-positive macrophage accumulation that can be induced in young mice by senescent cells. Aging (Albany NY) 8(7):1294–1315

    Article  Google Scholar 

  • Hansson GK, Hermansson A (2011) The immune system in atherosclerosis. Nat Immunol 12(3):204–212

    Article  CAS  PubMed  Google Scholar 

  • Hoare M, Ito Y, Kang TW, Weekes MP, Matheson NJ, Patten DA, Shetty S, Parry AJ, Menon S, Salama R, Antrobus R, Tomimatsu K, Howat W, Lehner PJ, Zender L, Narita M (2016) NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat Cell Biol 18(9):979–992

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Howcroft TK, Campisi J, Louis GB, Smith MT, Wise B, Wyss-Coray T, Augustine AD, McElhaney JE, Kohanski R, Sierra F (2013) The role of inflammation in age-related disease. Aging (Albany NY) 5(1):84–93

    Article  CAS  Google Scholar 

  • Jacobs JM, Cohen A, Ein-Mor E, Stessman J (2013) Cholesterol, statins, and longevity from age 70 to 90 years. J Am Med Dir Assoc 14:883–888

    Article  PubMed  Google Scholar 

  • Jylhä M, Paavilainen P, Lehtimäki T, Goebeler S, Karhunen PJ, Hervonen A, Hurme M (2007) Interleukin-1 receptor antagonist, interleukin-6, and C-reactive protein as predictors of mortality in nonagenarians: the vitality 90+ study. J Gerontol A Biol Sci Med Sci 62(9):1016–1021

    Article  PubMed  Google Scholar 

  • Jylhävä J, Jylhä M, Lehtimäki T, Hervonen A, Hurme M (2012) Circulating cell-free DNA is associated with mortality and inflammatory markers in nonagenarians: the vitality 90+ study. Exp Gerontol 47(5):372–378

    Article  PubMed  CAS  Google Scholar 

  • Jylhävä J, Kotipelto T, Raitala A, Jylhä M, Hervonen A, Hurme M (2011) Aging is associated with quantitative and qualitative changes in circulating cell-free DNA: the vitality 90+ study. Mech Ageing Dev 132(1–2):20–26

    Article  PubMed  CAS  Google Scholar 

  • Jylhävä J, Lehtimäki T, Jula A, Moilanen L, Kesäniemi YA, Nieminen MS, Kähönen M, Hurme M (2014) Circulating cell-free DNA is associated with cardiometabolic risk factors: the health 2000 survey. Atherosclerosis 233(1):268–271

    Article  PubMed  CAS  Google Scholar 

  • Jylhävä J, Nevalainen T, Marttila S, Jylhä M, Hervonen A, Hurme M (2013) Characterization of the role of distinct plasma cell-free DNA species in age-associated inflammation and frailty. Aging Cell 12(3):388–397

    Article  PubMed  CAS  Google Scholar 

  • Kahlert C, Melo SA, Protopopov A, Tang J, Seth S, Koch M, Zhang J, Weitz J, Chin L, Futreal A, Kalluri R (2014) Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem 289:3869–3875

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kalinkovich A, Livshits G (2017) Sarcopenic obesity or obese sarcopenia: a cross talk between age associated adipose tissue and skeletal muscle inflammation as a main mechanism of the pathogenesis. Ageing Res Rev 35:200–221

    Article  CAS  PubMed  Google Scholar 

  • Khan N, Syed DN, Ahmad N, Mukhtar H (2013) Fisetin: a dietary antioxidant for health promotion. Antioxid Redox Signal 19(2):151–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koch L (2010) Cancer: long-term use of metformin could protect against breast cancer. Nat Rev Endocrinol 6:356

    Article  PubMed  Google Scholar 

  • Kong F, Hua Y, Zeng B, Ning R, Li Y, Zhao J (2016) Gut microbiota signatures of longevity. Curr Biol 26(18):R832–R833

    Article  CAS  PubMed  Google Scholar 

  • Korre M, Tsoukas MA, Frantzeskou E, Yang J, Kales SN (2014) Mediterranean diet and workplace health promotion. Curr Cardiovasc Risk Rep 8(12):416

    Article  PubMed  PubMed Central  Google Scholar 

  • Kuilman T, Michaloglou C, Mooi WJ, Peeper DS (2010) The essence of senescence. Genes Dev 24:2463–2479

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuilman T, Peeper DS (2009) Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer 9:81–94

    Article  CAS  PubMed  Google Scholar 

  • Lee MS (2015) Effect of mitochondrial stress on systemic metabolism. Ann N Y Acad Sci 1350:61–65

    Article  CAS  PubMed  Google Scholar 

  • Lee YK, Mazmanian SK (2010) Has the microbiota played a critical role in the evolution of the adaptive immune system? Science 330:1768–1773

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liang X, FitzGerald GA (2017) Timing the microbes: the circadian rhythm of the gut microbiome. J Biol Rhythm. https://doi.org/10.1177/0748730417729066

  • Liang X, Bushman FD, FitzGerald GA (2015) Rhythmicity of the intestinal microbiota is regulated by gender and the host circadian clock. Proc Natl Acad Sci U S A 112(33):10479–10484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin L, Park S, Lakatta EG (2009) RAGE signaling in inflammation and arterial aging. Front Biosci (Landmark Ed) 14:1403–1413

    Article  CAS  Google Scholar 

  • Lin T, Walker GB, Kurji K, Fang E, Law G, Prasad SS, Kojic L, Cao S, White V, Cui JZ, Matsubara JA (2013) Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: implications for age-related degenerative diseases of the eye. Cytokine 62(3):369–381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Linz W, Jessen T, Becker RH, Scholkens BA, Wiemer G (1997) Long-term ACE inhibition doubles lifespan of hypertensive rats. Circulation 96:3164–3172

    Article  CAS  PubMed  Google Scholar 

  • Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, Fontana L (2015) Interventions to slow aging in humans: are we ready? Aging Cell 14(4):497–510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lozupone CA, Stombaugh JI, Gordon JI, Jansson JK, Knight R (2012) Diversity, stability and resilience of the human gut microbiota. Nature 489:220–230

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright R, Prigaro BJ, Wood JL, Bhanot S, MacDonald MJ, Jurczak MJ, Camporez JP, Lee HY, Cline GW, Samuel VT, Kibbey RG, Shulman GI (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510(7506):542–546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Malavolta M, Pierpaoli E, Giacconi R, Costarelli L, Piacenza F, Basso A, Cardelli M, Provinciali M (2016) Pleiotropic effects of Tocotrienols and quercetin on cellular senescence: introducing the perspective of Senolytic effects of phytochemicals. Curr Drug Targets 17(4):447–459

    Article  CAS  PubMed  Google Scholar 

  • Mari D, Coppola R, Provenzano R (2008) Hemostasis factors and aging. Exp Gerontol 43:66–73

    Article  CAS  PubMed  Google Scholar 

  • Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4:2192

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Martucci M, Ostan R, Biondi F, Bellavista E, Fabbri C, Bertarelli C, Salvioli S, Capri M, Franceschi C, Santoro A (2017) Mediterranean diet and inflammaging within the hormesis paradigm. Nutr Rev 75(6):442–455

    Article  PubMed  Google Scholar 

  • McElhaney JE, Effros B (2009) Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol 21:418–424

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mehta JL, Bursac Z, Hauer-Jensen M, Fort C, Fink LM (2006) Comparison of mortality rates in statin users versus nonstatin users in a United States veteran population. Am J Cardiol 98:923–928

    Article  CAS  PubMed  Google Scholar 

  • Meydani SN, Das SK, Pieper CF, Lewis MR, Klein S, Dixit VD, Gupta AK, Villareal DT, Bhapkar M, Huang M, Fuss PJ, Roberts SB, Holloszy JO, Fontana L (2016) Long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans. Aging (Albany NY) 8(7):1416–1431

    Article  Google Scholar 

  • Mikkelsen UR, Couppé C, Karlsen A, Grosset JF, Schjerling P, Mackey AL, Klausen HH, Magnusson SP, Kjær M (2013) Life-long endurance exercise in humans: circulating levels of inflammatory markers and leg muscle size. Mech Ageing Dev 134(11–12):531–540

    Article  CAS  PubMed  Google Scholar 

  • Monti D, Ostan R, Borelli V, Castellani G, Franceschi C (2017) Inflammaging and human longevity in the omics era. Mech Ageing Dev 165(Pt B):129–138

    Article  PubMed  Google Scholar 

  • 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

    Article  CAS  PubMed  Google Scholar 

  • Muñoz-Cánoves P, Scheele C, Pedersen BK, Serrano AL (2013) Interleukin-6 myokine signaling in skeletal muscle: a double-edged sword? FEBS J 280(17):4131–4148

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Murakami N, Riella LV, Funakoshi T (2014) Risk of metabolic complications in kidney transplantation after conversion to mTOR inhibitor: a systematic review and meta-analysis. Am J Transplant 14:2317–2327

    Article  CAS  PubMed  Google Scholar 

  • Nakahira K, Haspel JA, Rathinam VA, Lee S-J, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AM (2011) Autophagy proteins regulate innate immune response by inhibiting NALP3 inflammasome-mediated mitochondrial DNA release. Nat Immunol 12:222–230

    Article  CAS  PubMed  Google Scholar 

  • Nakajima K, Takeoka M, Mori M, Hashimoto S, Sakurai A, Nose H, Higuchi K, Itano N, Shiohara M, Oh T, Taniguchi S (2010) Exercise effects on methylation of ASC gene. Int J Sports Med 31:671–675

    Article  CAS  PubMed  Google Scholar 

  • Nelson G, Wordsworth J, Wang C, Jurk D, Lawless C, Martin-Ruiz C, von Zglinicki T (2012) A senescent cell bystander effect: senescence induced senescence. Aging Cell 11:345–349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • O’Toole PW, Jeffery IB (2015) Gut microbiota and aging. Science 350(6265):1214–1216

    Article  PubMed  CAS  Google Scholar 

  • Olivieri F, Capri M, Bonafè M, Morsiani C, Jung HJ, Spazzafumo L, Viña J, Suh Y (2017) Circulating miRNAs and miRNA shuttles as biomarkers: perspective trajectories of healthy and unhealthy aging. Mech Ageing Dev 165(Pt B):162–170

    Article  CAS  PubMed  Google Scholar 

  • Olivieri F, Lazzarini R, Recchioni R, Marcheselli F, Rippo MR, Di Nuzzo S, Albertini MC, Graciotti L, Babini L, Mariotti S, Spada G, Abbatecola AM, Antonicelli R, Franceschi C, Procopio AD (2013a) MiR-146a as marker of senescence-associated pro-inflammatory status in cells involved in vascular remodelling. Age (Dordr) 35(4):1157–1172

    Article  CAS  Google Scholar 

  • Olivieri F, Rippo MR, Monsurrò V, Salvioli S, Capri M, Procopio AD, Franceschi C (2013b) MicroRNAs linking inflamm-aging, cellular senescence and cancer. Ageing Res Rev 12(4):1056–1068

    Article  CAS  PubMed  Google Scholar 

  • Olivieri F, Spazzafumo L, Santini G, Lazzarini R, Albertini MC, Rippo MR, Galeazzi R, Abbatecola AM, Marcheselli F, Monti D, Ostan R, Cevenini E, Antonicelli R, Franceschi C, Procopio AD (2012) Age-related differences in the expression of circulating microRNAs: miR-21 as a new circulating marker of inflammaging. Mech Ageing Dev 133(11–12):675–685

    Article  CAS  PubMed  Google Scholar 

  • Onken B, Driscoll M (2010) Metformin induces a dietary restriction-like state and the oxidative stress response to extend C. Elegans Healthspan via AMPK, LKB1, and SKN. PLoS One 5(1):e8758

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ottaviani E, Franceschi C (1998) A new theory on the common evolutionary origin of natural immunity, inflammation and stress response: the invertebrate phagocytic immunocyte as an eye witness. Domest Anim Endocrinol 15:291–296

    Article  CAS  PubMed  Google Scholar 

  • Ottaviani E, Franceschi C (1997) The invertebrate phagocytic immunocyte: clues to a common evolution of immune and neuroendocrine systems. Immunol Today 18(4):169–174

    Article  CAS  PubMed  Google Scholar 

  • Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Görgün C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306(5695):457–461

    Article  PubMed  CAS  Google Scholar 

  • Pedersen BK, Febbraio MA (2008) Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol Rev 88:1379–1406

    Article  CAS  PubMed  Google Scholar 

  • Pedersen BK (2013) Muscle as a secretory organ. Compr Physiol 3:1337–1362

    PubMed  Google Scholar 

  • Pedersen BK (2012) Muscular interleukin-6 and its role as an energy sensor. Med Sci Sports Exerc 44:392–396

    Article  CAS  PubMed  Google Scholar 

  • Petersen KS, Smith C (2016) Ageing-associated oxidative stress and inflammation are alleviated by products from grapes. Oxidative Med Cell Longev 2016:6236309

    Article  CAS  Google Scholar 

  • Pinti M, Cevenini E, Nasi M, De Biasi S, Salvioli S, Monti D, Benatti S, Gibellini L, Cotichini R, Stazi MA, Trenti T, Franceschi C, Cossarizza A (2014) Circulating mitochondrial DNA increases with age and is a familiar trait: implications for “inflamm-aging”. Eur J Immunol 44(5):1552–1562

    Article  CAS  PubMed  Google Scholar 

  • Pounis G, Bonaccio M, Di Castelnuovo A, Costanzo S, de Curtis A, Persichillo M, Sieri S, Donati MB, Cerletti C, de Gaetano G, Iacoviello L (2016) Polyphenol intake is associated with low-grade inflammation, using a novel data analysis from the Moli-sani study. Thromb Haemost 115(2):344–352

    Article  PubMed  Google Scholar 

  • Prattichizzo F, Giuliani A, Recchioni R, Bonafè M, Marcheselli F, De Carolis S, Campanati A, Giuliodori K, Rippo MR, Brugè F, Tiano L, Micucci C, Ceriello A, Offidani A, Procopio AD, Olivieri F (2016) Anti-TNF-α treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells. Oncotarget 7(11):11945–11958

    Article  PubMed  PubMed Central  Google Scholar 

  • Rajilić-Stojanović M, de Vos WM (2014) The first 1000 cultured species of the human gastrointestinal microbiota. FEMS Microbiol Rev 38:996–1047

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ravussin E, Redman LM, Rochon J, Das SK, Fontana L, Kraus WE, Romashkan S, Williamson DA, Meydani SN, Villareal DT, Smith SR, Stein RI, Scott TM, Stewart TM, Saltzman E, Klein S, Bhapkar M, Martin CK, Gilhooly CH, Holloszy JO, Hadley EC, Roberts SB (2015) A 2-year randomized controlled trial of human caloric restriction: feasibility and effects on predictors of health span and longevity. J Gerontol Ser A Biol Sci Med Sci 70:1097–1104

    Article  Google Scholar 

  • Rena G, Pearson ER, Sakamo K (2013) Molecular mechanism of action of metformin: old or new insights? Diabetologia 56:1898–1906

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robbesyn F, Salvayre R, Negre-Salvayre A (2004) Dual role of oxidized LDL on the NF-kappaB signaling pathway. Free Radic Res 38:541–551

    Article  CAS  PubMed  Google Scholar 

  • Round JL, Mazmanian SK (2009) The gut microbiota shapes intestinal immune responses during health and disease. Nat Rev Immunol 9:313–323

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Safdar A, Saleem A, Tarnopolsky MA (2016) The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat Rev Endocrinol 12(9):504–517

    Article  CAS  PubMed  Google Scholar 

  • Salminen A, Kaarniranta K, Kauppinen A (2017) Integrated stress response stimulates FGF21 expression: systemic enhancer of longevity. Cell Signal 40:10–21

    Article  CAS  PubMed  Google Scholar 

  • Salvioli S, Monti D, Lanzarini C, Conte M, Pirazzini C, Bacalini MG, Garagnani P, Giuliani C, Fontanesi E, Ostan R, Bucci L, Sevini F, Yani SL, Barbieri A, Lomartire L, Borelli V, Vianello D, Bellavista E, Martucci M, Cevenini E, Pini E, Scurti M, Biondi F, Santoro A, Capri M, Franceschi C (2013) Immune system, cell senescence, aging and longevity--inflamm-aging reappraised. Curr Pharm Des 19(9):1675–1679

    CAS  PubMed  Google Scholar 

  • Sansonetti PJ, Di Santo JP (2007) Debugging how bacteria manipulate the immune response. Immunity 26:149–161

    Article  CAS  PubMed  Google Scholar 

  • Sansoni P, Vescovini R, Fagnoni FF, Akbar A, Arens R, Chiu Y-L, Čičin-Šain L, Dechanet-Merville J, Derhovanessian E, Ferrando-Martinez S, Franceschi C, Frasca D, Fulöp T, Furman D, Gkrania-Klotsas E, Goodrum F, Grubeck-Loebenstein B, Hurme M, Kern F, Lilleri D, López-Botet M, Maier AB, Marandu T, Marchant A, Matheï C, Moss P, Muntasell A, Remmerswaal EBM, Riddell NE, Rothe K, Sauce D, Shin E-C, Simanek AM, Smithey MJ, Söderberg-Nauclér C, Solana R, Thomas PG, Van Lier AR, Pawelec G, Nikolich-Zugich J, Sansoni P (2014) New advances in CMV and immunosenescence. Exp Cell Res 55:54–62

    Google Scholar 

  • Santoro A, Ostan R, Candela M, Biagi E, Brigidi P, Capri M, Franceschi C (2017) Gut microbiota changes in the extreme decades of human life: a focus on centenarians. Cell Mol Life Sci. https://doi.org/10.1007/s00018-017-2674-y. (epub ahead of print)

  • Santos EL, de Picoli Souza K, da Silva ED, Batista EC, Martins PJ, D’Almeida V, Pesquero JB (2009) Long term treatment with ACE inhibitor enalapril decreases body weight gain and increases life span in rats. Biochem Pharmacol 78:951–958

    Article  CAS  PubMed  Google Scholar 

  • Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602

    Article  CAS  PubMed  Google Scholar 

  • Shaw AC, Joshi S, Greenwood H, Panda A, Lord JM (2010) Aging of the innate immune system. Curr Opin Immunol 22:507–513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shirakabe A, Ikeda Y, Sciarretta S, Zablocki DK, Sadoshima J (2016) Aging and autophagy in the heart. Circ Res 118(10):1563–1576

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sierra A, Gottfried-Blackmore AC, McEwen BS, Bulloch K (2007) Microglia derived from aging mice exhibit an altered inflammatory profile. Glia 55(4):412–424

    Article  PubMed  Google Scholar 

  • Snodgrass RG, Huang S, Choi IW, Rutledge JC, Hwang DH (2013) Inflammasome-mediated secretion of IL-1β in human monocytes through TLR2 activation; modulation bydietary fatty acids. J Immunol 191(8):4337–4347

    Article  CAS  PubMed  Google Scholar 

  • Sochocka M, Diniz BS, Leszek J (2016) Inflammatory response in the CNS: friend or foe? Mol Neurobiol 54:8071–8089. [Epub ahead of print]

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Spazzafumo L, Olivieri F, Abbatecola AM, Castellani G, Monti D, Lisa R, Galeazzi R, Sirolla C, Testa R, Ostan R, Scurti M, Caruso C, Vasto S, Vescovini R, Ogliari G, Mari D, Lattanzio F, Franceschi C (2013) Remodelling of biological parameters during human ageing: evidence for complex regulation in longevity and in type 2 diabetes. Age (Dordr) 35(2):419–429

    Article  CAS  Google Scholar 

  • Strong R, Miller RA, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E, Nadon NL, Warner HR, Harrison DE (2008) Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 7:641–650

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun L, Wu J, Du F, Chen X, Chen ZJ (2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339:786–791

    Article  CAS  PubMed  Google Scholar 

  • Swindell WR, Johnston A, Xing X, Little A, Robichaud P, Voorhees JJ, Fisher G, Gudjonsson JE (2013) Robust shifts in S100a9 expression with aging: a novel mechanism for chronic inflammation. Sci Rep 3:1215

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Takai S, Jin D, Sakaguchi M, Miyazaki M (2004) Significant target organs for hypertension and cardiac hypertrophy by angiotensin-converting enzyme inhibitors. Hypertens Res 27:213–219

    Article  CAS  PubMed  Google Scholar 

  • Thakur BK, Zhang H, Becker A, Matei I, Huang Y, Costa-Silva B, Zheng Y, Hoshino A, Brazier H, Xiang J, Williams C, Rodriguez-Barrueco R, Silva JM, Zhang W, Hearn S, Elemento O, Paknejad N, Manova-Todorova K, Welte K, Bromberg J, Peinado H, Lyden D (2014) Double-stranded DNA in exosomes: a novel biomarker in cancer detection. Cell Res 24:766–769

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Thaiss CA, Zeevi D, Levy M, Zilberman-Schapira G, Suez J, Tengeler AC, Abramson L, Katz MN, Korem T, Zmora N, Kuperman Y, Biton I, Gilad S, Harmelin A, Shapiro H, Halpern Z, Segal E, Elinav E (2014) Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Cell 159(3):514–529

    Article  CAS  PubMed  Google Scholar 

  • Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, Loukov D, Schenck LP, Jury J, Foley KP, Schertzer JD, Larché MJ, Davidson DJ, Verdú EF, Surette MG, Bowdish DM (2017) Age-associated microbial Dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe 21:455–466.e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tóbon-Velasco JC, Cuevas E, Torres-Ramos MA (2014) Receptor for AGEs (RAGE) as mediator of NF-kB pathway activation in neuroinflammation and oxidative stress. CNS Neurol Disord Drug Targets 13(9):1615–1626

    Article  PubMed  CAS  Google Scholar 

  • Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17(2):179–188

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vescovini R, Telera A, Fagnoni FF, Biasini C, Medici MC, Valcavi P, di Pede P, Lucchini G, Zanlari L, Passeri G, Zanni F, Chezzi C, Franceschi C, Sansoni P (2004) Different contribution of EBV and CMV infections in very long-term carriers to age-related alterations of CD8+ T cells. Exp Gerontol 39(8):1233–1243

    Article  PubMed  Google Scholar 

  • Vitale G, Salvioli S, Franceschi C (2013) Oxidative stress and the ageing endocrine system. Nat Rev Endocrinol 9:228–240

    Article  CAS  PubMed  Google Scholar 

  • Walford RL, Mock D, Verdery R, MacCallum T (2002) Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. J Gerontol A Biol Sci Med Sci 57(6):B211–B224

    Article  PubMed  Google Scholar 

  • Wan QL, Zheng SQ, GS W, Luo HR (2013) Aspirin extends the lifespan of Caenorhabditis Elegans via AMPK and DAF-16/ FOXO in dietary restriction pathway. Exp Gerontol 48:499–506

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Chang J, Liu X, Zhang X, Zhang S, Zhang X, Zhou D, Zheng G (2016) Discovery of piperlongumine as a potential novel lead for the development of senolytic agents. Aging (Albany NY) 8(11):2915–2926

    Article  Google Scholar 

  • Wellen KE, Fucho R, Gregor MF, Furuhashi M, Morgan C, Lindstad T, Vaillancourt E, Gorgun CZ, Saatcioglu F, Hotamisligil GS (2007) Coordinated regulation of nutrient and inflammatory responses by STAMP2 is essential for metabolic homeostasis. Cell 129(3):537–548

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu H, Esteve E, Tremaroli V, Khan MT, Caesar R, Mannerås-Holm L, Ståhlman M, Olsson LM, Serino M, Planas-Fèlix M, Xifra G, Mercader JM, Torrents D, Burcelin R, Ricart W, Perkins R, Fernàndez-Real JM, Bäckhed F (2017) Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat Med 23(7):850–858

    Article  CAS  PubMed  Google Scholar 

  • Wu J, Sun L, Chen X, Du F, Shi H, Chen C, Chen ZJ (2013) Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339:826–830

    Article  CAS  PubMed  Google Scholar 

  • Yan Y, Jiang W, Spinetti T, Tardivel A, Castillo R, Bourquin C, Guarda G, Tian Z, Tschopp J, Zhou R (2013) Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 38(6):1154–1163

    Article  CAS  PubMed  Google Scholar 

  • Yang H, Wang H, Ren J, Chen Q, Chen ZJ (2017) cGAS is essential for cellular senescence. Proc Natl Acad Sci U S A 114(23):E4612–E4620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Youm Y-H, Grant RW, Mccabe LR, Albarado DC, Nguyen KY, Ravussin A, Pistell P, Newman S, Carter R, Laque A, Mü H, Rosen CJ, Ingram DK, Salbaum JM, Dixit VD (2013) Canonical NLRP3 Inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab 18:519–532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zarrinpar A, Chaix A, Yooseph S, Panda S (2014) Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab 20(6):1006–1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang J, Wang X, Vikash V, Ye Q, Wu D, Liu Y, Dong W (2016) ROS and ROS-mediated cellular Signaling. Oxidative Med Cell Longev 2016:4350965

    Google Scholar 

  • Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464(7285):104–107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, He F, Boassa D, Perkins G, Ali SR, McGeough MD, Ellisman MH, Seki E, Gustafsson AB, Hoffman HM, Diaz-Meco MT, Moscat J, Karin M (2016) NF-κB restricts Inflammasome activation via elimination of damaged mitochondria. Cell 164(5):896–910

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 475:122–122

    Article  CAS  Google Scholar 

  • Zhu J, Woods D, McMahon M, Bishop JM (1998) Senescence of human fibroblasts induced by oncogenic Raf. Genes Dev 12:2997–3007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhu Y, Doornebal EJ, Pirtskhalava T, Giorgadze N, Wentworth M, Fuhrmann-Stroissnigg H, Niedernhofer LJ, Robbins PD, Tchkonia T, Kirkland JL (2017) New agents that target senescent cells: the flavone, fisetin, and the BCL-XL inhibitors, A1331852 and A1155463. Aging (Albany NY) 9(3):955–963

    Google Scholar 

Download references

Acknowledgements

This work was partly supported by CARIPLO - Fondazione Cassa di Risparmio delle Province Lombarde- (Rif. 2015-0564) to CF and CARIPLO (Rif 2016-0835); by EU JPND ‘Adage’ to CF; and by EU H2020 Project ‘Propag-ageing’ (grant agreement no. 634821) to CF and PG.

Author information

Authors and Affiliations

  1. IRCCS, Institute of Neurological Sciences of Bologna, Bologna, Italy

    Claudio Franceschi

  2. Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy

    Miriam Capri, Paolo Garagnani, Rita Ostan, Aurelia Santoro & Stefano Salvioli

  3. Interdepartmental Centre ‘L. Galvani’ (CIG), University of Bologna, Bologna, Italy

    Miriam Capri, Paolo Garagnani, Aurelia Santoro & Stefano Salvioli

  4. Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy

    Daniela Monti

Authors
  1. Claudio Franceschi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Miriam Capri
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paolo Garagnani
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rita Ostan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aurelia Santoro
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniela Monti
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stefano Salvioli
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claudio Franceschi .

Editor information

Editors and Affiliations

  1. Division of Geriatrics Research Center on Aging, University of Sherbrooke Dept. of Medicine, Sherbrooke, Québec, Canada

    Tamas Fulop

  2. Dept of Experimental Pathology, University of Bologna, Bologna, Italy

    Claudio Franceschi

  3. Institute for Health and Life Sciences, Tokyo, Japan

    Katsuiku Hirokawa

  4. Center for Medical Research, University of Tübingen, Tübingen, Germany

    Graham Pawelec

Section Editor information

  1. Research Center on Aging, Department of Medicine, Immunology Graduate Programme, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Quebec, Canada

    Tamas Fulop

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Franceschi, C. et al. (2018). Inflammaging. In: Fulop, T., Franceschi, C., Hirokawa, K., Pawelec, G. (eds) Handbook of Immunosenescence. Springer, Cham. https://doi.org/10.1007/978-3-319-64597-1_45-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-64597-1_45-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-64597-1

  • Online ISBN: 978-3-319-64597-1

  • eBook Packages: Springer Reference Biomedicine and Life SciencesReference Module Biomedical and Life Sciences

Publish with us

Policies and ethics

Search

Navigation