Please wait a minute...
 Home  About the Journal Editorial Board Aims & Scope Peer Review Policy Subscription Contact us
Early Edition  //  Current Issue  //  Open Special Issues  //  Archives  //  Most Read  //  Most Downloaded  //  Most Cited
Aging and Disease    2017, Vol. 8 Issue (5) : 611-627     DOI: 10.14336/AD.2016.1230
Review |
Cancer and Aging - the Inflammatory Connection
Adar Zinger1,William C Cho2,Arie Ben-Yehuda1,*
1Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
2Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong
Download: PDF(852 KB)   HTML
Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks    

Aging and cancer are highly correlated biological phenomena. Various cellular processes such as DNA damage responses and cellular senescence that serve as tumor suppressing mechanisms throughout life result in degenerative changes and contribute to the aging phenotype. In turn, aging is considered a pro-tumorigenic state, and constitutes the single most important risk factor for cancer development. However, the causative relations between aging and cancer is not straight forward, as these processes carry contradictory hallmarks; While aging is characterized by tissue degeneration and organ loss of function, cancer is a state of sustained cellular proliferation and gain of new functions. Here, we review the molecular and cellular pathways that stand in the base of aging related cancer. Specifically, we deal with the inflammatory perspective that link these two processes, and suggest possible molecular targets that may be exploited to modify their courses.

Keywords aging      cancer      senescence      inflammation      immunosenescence      autophagy     
Corresponding Authors: Arie Ben-Yehuda   
Just Accepted Date: 08 January 2017   Issue Date: 27 September 2017
E-mail this article
E-mail Alert
Articles by authors
Adar Zinger
William C Cho
Arie Ben-Yehuda
Cite this article:   
Adar Zinger,William C Cho,Arie Ben-Yehuda. Cancer and Aging - the Inflammatory Connection[J]. A&D, 2017, 8(5): 611-627.
URL:     OR
Figure 1.  Aging-related cancer

Exposure to various endogenous and exogenous stressors throughout life results in multiple cellular and tissue function changes. Accumulation of senescent cells in the tissue is associated with tissue degeneration and SASP-related changes of the microenvironment. Functional changes in aging immune system along with DAMPs-associated immune responses contribute to the ensemble of inflammatory processes that accompanies the aging process, so-called “inflammaging”. This unique inflammatory network joins intracellular processes including changes in chromatin function and reduction in autophagy capacity, and to changes in the microbiome and intestinal barrier dysfunction, to create a pro-tumorigenic environment.

Figure 2.  SASP regulation

SASP is under a regulation of multifactorial singaling networks. The DDR effectors NBS1, ATM and CHK2 upregulate SASP. Importantly, p53 is a negative regulator of SASP and serves to restrain it upon DDR activation. mTOR positively regulates SASP via activation of the MAPK p38 pathway, and upregulation of IL-1α. Chromatin reorganization in senescent cells involves newly activated super enhancer (SE) elements. BRD4 is recruited to the SE and participate in the regulation of key SASP genes. NOTCH1 was indentified as a modulator of SASP composition in oncogene-induced senescent cells.

[1] Hsu T (2016). Educational initiatives in geriatric oncology - Who, why, and how?. J Geriatr Oncol, 7: 390-396
[2] Siegel RL, Miller KD, Jemal A (2015). Cancer statistics, 2015. CA Cancer J Clin, 65: 5-29
[3] Granger A, Mott R, Emambokus N (2016). Is Aging as Inevitable as Death and Taxes?. Cell Metab, 23: 947-948
[4] Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013). The hallmarks of aging. Cell, 153: 1194-1217
[5] Hanahan D, Weinberg RA (2000). The hallmarks of cancer. Cell, 100: 57-70
[6] Campisi J (2013). Aging, cellular senescence, and cancer. Annu Rev Physiol, 75: 685-705
[7] Williams PD, Day T (2003). Antagonistic pleiotropy, mortality source interactions, and the evolutionary theory of senescence. Evolution, 57: 1478-1488
[8] Ungewitter E, Scrable H (2009). Antagonistic pleiotropy and p53. Mech Ageing Dev, 130: 10-17
[9] Munoz-Espin D, Canamero M, Maraver A, Gomez-Lopez G, Contreras J, Murillo-Cuesta S, et al. (2013). Programmed cell senescence during mammalian embryonic development. Cell, 155: 1104-1118
[10] Campisi J (2001). Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol, 11: S27-31
[11] Campisi J, d’Adda di Fagagna F (2007). Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol, 8: 729-740
[12] Ovadya Y, Krizhanovsky V (2014). Senescent cells: SASPected drivers of age-related pathologies. Biogerontology, 15: 627-642
[13] Coppe JP, Desprez PY, Krtolica A, Campisi J (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol, 5: 99-118
[14] Franceschi C, Bonafe 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
[15] Lasry A, Zinger A, Ben-Neriah Y (2016). Inflammatory networks underlying colorectal cancer. Nat Immunol, 17: 230-240
[16] 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
[17] Cho WC, Kwan CK, Yau S, So PP, Poon PC, Au JS (2011). The role of inflammation in the pathogenesis of lung cancer. Expert Opin Ther Targets, 15: 1127-1137
[18] Turke PW (1994). Microbial parasites versus developing T cells: an evolutionary ’arms race’ with implications for the timing of thymic involution and HIV pathogenesis. Thymus, 24: 29-40
[19] Shanley DP, Aw D, Manley NR, Palmer DB (2009). An evolutionary perspective on the mechanisms of immunosenescence. Trends Immunol, 30: 374-381
[20] Aw D, Silva AB, Palmer DB (2007). Immunosenescence: emerging challenges for an ageing population. Immunology, 120: 435-446
[21] Pawelec G, Adibzadeh M, Pohla H, Schaudt K (1995). Immunosenescence: ageing of the immune system. Immunol Today, 16: 420-422
[22] Pawelec G, Derhovanessian E, Larbi A (2010). Immunosenescence and cancer. Crit Rev Oncol Hematol, 75: 165-172
[23] Halazonetis TD, Gorgoulis VG, Bartek J (2008). An oncogene-induced DNA damage model for cancer development. Science, 319: 1352-1355
[24] Jackson SP, Bartek J (2009). The DNA-damage response in human biology and disease. Nature, 461: 1071-1078
[25] Sinha RP, Hader DP (2002). UV-induced DNA damage and repair: a review. Photochem Photobiol Sci, 1: 225-236
[26] Iliakis G, Wang Y, Guan J, Wang H (2003). DNA damage checkpoint control in cells exposed to ionizing radiation. Oncogene, 22: 5834-5847
[27] Kumaravel TS, Jha AN (2006). Reliable Comet assay measurements for detecting DNA damage induced by ionising radiation and chemicals. Mutat Res, 605: 7-16
[28] Valko M, Izakovic M, Mazur M, Rhodes CJ, Telser J (2004). Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem, 266: 37-56
[29] Hoeijmakers JH (2001). Genome maintenance mechanisms for preventing cancer. Nature, 411: 366-374
[30] d’Adda di Fagagna F, Reaper PM, Clay-Farrace L, Fiegler H, Carr P, Von Zglinicki T, et al. (2003). A DNA damage checkpoint response in telomere-initiated senescence. Nature, 426: 194-198
[31] Ribezzo F, Shiloh Y, Schumacher B (2016). Systemic DNA damage responses in aging and diseases. Semin Cancer Biol, 37-38: 26-35
[32] Bartkova J, Horejsi Z, Koed K, Kramer A, Tort F, Zieger K, et al. (2005). DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature, 434: 864-870
[33] Sirbu BM, Cortez D (2013). DNA damage response: three levels of DNA repair regulation. Cold Spring Harb Perspect Biol, 5: a012724
[34] Brooks CL, Gu W (2010). New insights into p53 activation. Cell Res, 20: 614-621
[35] Chang BD, Watanabe K, Broude EV, Fang J, Poole JC, Kalinichenko TV, et al. (2000). Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. Proc Natl Acad Sci U S A, 97: 4291-4296
[36] Haupt S, Berger M, Goldberg Z, Haupt Y (2003). Apoptosis - the p53 network. J Cell Sci, 116: 4077-4085
[37] Signer RA, Morrison SJ (2013). Mechanisms that regulate stem cell aging and life span. Cell Stem Cell, 12: 152-165
[38] Maier B, Gluba W, Bernier B, Turner T, Mohammad K, Guise T, et al. (2004). Modulation of mammalian life span by the short isoform of p53. Genes Dev, 18: 306-319
[39] Dumble M, Moore L, Chambers SM, Geiger H, Van Zant G, Goodell MA, et al. (2007). The impact of altered p53 dosage on hematopoietic stem cell dynamics during aging. Blood, 109: 1736-1742
[40] Garcia-Cao I, Garcia-Cao M, Martin-Caballero J, Criado LM, Klatt P, Flores JM, et al. (2002). "Super p53" mice exhibit enhanced DNA damage response, are tumor resistant and age normally. EMBO J, 21: 6225-6235
[41] Reinhardt HC, Schumacher B (2012). The p53 network: cellular and systemic DNA damage responses in aging and cancer. Trends Genet, 28: 128-136
[42] Abegglen LM, Caulin AF, Chan A, Lee K, Robinson R, Campbell MS, et al. (2015). Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA, 314: 1850-1860
[43] Rossi DJ, Jamieson CH, Weissman IL (2008). Stems cells and the pathways to aging and cancer. Cell, 132: 681-696
[44] Sperka T, Wang J, Rudolph KL (2012). DNA damage checkpoints in stem cells, ageing and cancer. Nat Rev Mol Cell Biol, 13: 579-590
[45] Hayflick L, Moorhead PS (1961). The serial cultivation of human diploid cell strains. Exp Cell Res, 25: 585-621
[46] Campisi J, Robert L (2014). Cell senescence: role in aging and age-related diseases. Interdiscip Top Gerontol, 39: 45-61
[47] Kipling D (2001). Telomeres, replicative senescence and human ageing. Maturitas, 38: 25-37; discussion 37-28
[48] Colavitti R, Finkel T (2005). Reactive oxygen species as mediators of cellular senescence. IUBMB Life, 57: 277-281
[49] Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, et al. (2006). Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature, 444: 633-637
[50] Munro J, Barr NI, Ireland H, Morrison V, Parkinson EK (2004). Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock. Exp Cell Res, 295: 525-538
[51] Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, 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
[52] Naylor RM, Baker DJ, van Deursen JM (2013). Senescent cells: a novel therapeutic target for aging and age-related diseases. Clin Pharmacol Ther, 93: 105-116
[53] Baker DJ, Perez-Terzic C, Jin F, Pitel KS, Niederlander NJ, Jeganathan K, et al. (2008). Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol, 10: 825-836
[54] Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, et al. (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 479: 232-236
[55] 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
[56] Klapper W, Kuhne K, Singh KK, Heidorn K, Parwaresch R, Krupp G (1998). Longevity of lobsters is linked to ubiquitous telomerase expression. FEBS Lett, 439: 143-146
[57] Lasry A, Ben-Neriah Y (2015). Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol, 36: 217-228
[58] Shelton DN, Chang E, Whittier PS, Choi D, Funk WD (1999). Microarray analysis of replicative senescence. Curr Biol, 9: 939-945
[59] van Deursen JM (2014). The role of senescent cells in ageing. Nature, 509: 439-446
[60] Coppe JP, Patil CK, Rodier F, Sun Y, Munoz 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
[61] Freund A, Orjalo AV, Desprez PY, Campisi J (2010). Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med, 16: 238-246
[62] Rodier F, Munoz DP, Teachenor R, Chu V, Le O, Bhaumik D, et al. (2011). DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J Cell Sci, 124: 68-81
[63] 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
[64] Ben-Neriah Y, Karin M (2011). Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol, 12: 715-723
[65] Herranz N, Gallage S, Mellone M, Wuestefeld T, Klotz S, Hanley CJ, et al. (2015). mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nat Cell Biol, 17: 1205-1217
[66] Laberge RM, Sun Y, Orjalo AV, Patil CK, Freund A, Zhou L, et al. (2015). MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol, 17: 1049-1061
[67] Sims JE, Smith DE (2010). The IL-1 family: regulators of immunity. Nat Rev Immunol, 10: 89-102
[68] Serrano M (2015). The InflammTORy Powers of Senescence. Trends Cell Biol, 25: 634-636
[69] Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, et al. (2013). Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell, 153: 307-319
[70] Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, et al. (2013). Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell, 153: 320-334
[71] Shi J, Whyte WA, Zepeda-Mendoza CJ, Milazzo JP, Shen C, Roe JS, et al. (2013). Role of SWI/SNF in acute leukemia maintenance and enhancer-mediated Myc regulation. Genes Dev, 27: 2648-2662
[72] Tasdemir N, Banito A, Roe JS, Alonso-Curbelo D, Camiolo M, Tschaharganeh DF, et al. (2016). BRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance. Cancer Discov, 6: 612-629
[73] Guruharsha KG, Kankel MW, Artavanis-Tsakonas S (2012). The Notch signalling system: recent insights into the complexity of a conserved pathway. Nat Rev Genet, 13: 654-666
[74] Hoare M, Ito Y, Kang TW, Weekes MP, Matheson NJ, Patten DA, et al. (2016). NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat Cell Biol, 18: 979-992
[75] Collado M, Serrano M (2010). Senescence in tumours: evidence from mice and humans. Nat Rev Cancer, 10: 51-57
[76] Collado M, Gil J, Efeyan A, Guerra C, Schuhmacher AJ, Barradas M, et al. (2005). Tumour biology: senescence in premalignant tumours. Nature, 436: 642
[77] Michaloglou C, Vredeveld LC, Soengas MS, Denoyelle C, Kuilman T, van der Horst CM, et al. (2005). BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature, 436: 720-724
[78] Paul PJ, Raghu D, Chan AL, Gulati T, Lambeth L, Takano E, et al. (2016). Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP. Oncogene
[79] Loaiza N, Demaria M (2016). Cellular senescence and tumor promotion: Is aging the key?. Biochim Biophys Acta, 1865: 155-167
[80] Lecot P, Alimirah F, Desprez PY, Campisi J, Wiley C (2016). Context-dependent effects of cellular senescence in cancer development. Br J Cancer, 114: 1180-1184
[81] Krtolica A, Parrinello S, Lockett S, Desprez PY, Campisi J (2001). Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging. Proc Natl Acad Sci U S A, 98: 12072-12077
[82] Lujambio A, Akkari L, Simon J, Grace D, Tschaharganeh DF, Bolden JE, et al. (2013). Non-cell-autonomous tumor suppression by p53. Cell, 153: 449-460
[83] Krizhanovsky V, Yon M, Dickins RA, Hearn S, Simon J, Miething C, et al. (2008). Senescence of activated stellate cells limits liver fibrosis. Cell, 134: 657-667
[84] Jun JI, Lau LF (2010). Cellular senescence controls fibrosis in wound healing. Aging (Albany NY), 2: 627-631
[85] Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, et al. (2007). Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature, 445: 656-660
[86] Kang TW, Yevsa T, Woller N, Hoenicke L, Wuestefeld T, Dauch D, et al. (2011). Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature, 479: 547-551
[87] Pribluda A, Elyada E, Wiener Z, Hamza H, Goldstein RE, Biton M, et al. (2013). A senescence-inflammatory switch from cancer-inhibitory to cancer-promoting mechanism. Cancer Cell, 24: 242-256
[88] 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): S4-9
[89] 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
[90] Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser R (2003). Chronic stress and age-related increases in the proinflammatory cytokine IL-6. Proc Natl Acad Sci U S A, 100: 9090-9095
[91] Ershler WB, Keller ET (2000). Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med, 51: 245-270
[92] Pasparakis M (2009). Regulation of tissue homeostasis by NF-kappaB signalling: implications for inflammatory diseases. Nat Rev Immunol, 9: 778-788
[93] Medzhitov R (2010). Inflammation 2010: new adventures of an old flame. Cell, 140: 771-776
[94] Medzhitov R (2008). Origin and physiological roles of inflammation. Nature, 454: 428-435
[95] Coussens LM, Werb Z (2002). Inflammation and cancer. Nature, 420: 860-867
[96] Rodier F, Campisi J (2011). Four faces of cellular senescence. J Cell Biol, 192: 547-556
[97] Vasto S, Carruba G, Lio D, Colonna-Romano G, Di Bona D, Candore G, et al. (2009). Inflammation, ageing and cancer. Mech Ageing Dev, 130: 40-45
[98] Oishi Y, Manabe I (2016). Macrophages in age-related chronic inflammatory diseases. Npj Aging And Mechanisms Of Disease, 2: 16018
[99] Rubartelli A, Lotze MT (2007). Inside, outside, upside down: damage-associated molecular-pattern molecules (DAMPs) and redox. Trends Immunol, 28: 429-436
[100] Feldman N, Rotter-Maskowitz A, Okun E (2015). DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res Rev, 24: 29-39
[101] Piccinini AM, Midwood KS (2010). DAMPening inflammation by modulating TLR signalling. Mediators Inflamm, 2010
[102] Tschopp J, Schroder K (2010). NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production?. Nat Rev Immunol, 10: 210-215
[103] Strowig T, Henao-Mejia J, Elinav E, Flavell R (2012). Inflammasomes in health and disease. Nature, 481: 278-286
[104] Keating SE, Baran M, Bowie AG (2011). Cytosolic DNA sensors regulating type I interferon induction. Trends Immunol, 32: 574-581
[105] Meyer C, Sevko A, Ramacher M, Bazhin AV, Falk CS, Osen W, et al. (2011). Chronic inflammation promotes myeloid-derived suppressor cell activation blocking antitumor immunity in transgenic mouse melanoma model. Proc Natl Acad Sci U S A, 108: 17111-17116
[106] Bonafe 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: 40-49
[107] Knupfer H, Preiss R (2007). Significance of interleukin-6 (IL-6) in breast cancer (review). Breast Cancer Res Treat, 102: 129-135
[108] Sansone P, Storci G, Tavolari S, Guarnieri T, Giovannini C, Taffurelli M, et al. (2007). IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest, 117: 3988-4002
[109] Jordan CT, Guzman ML, Noble M (2006). Cancer stem cells. N Engl J Med, 355: 1253-1261
[110] Magee JA, Piskounova E, Morrison SJ (2012). Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell, 21: 283-296
[111] Marotta LL, Almendro V, Marusyk A, Shipitsin M, Schemme J, Walker SR, et al. (2011). The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(-) stem cell-like breast cancer cells in human tumors. J Clin Invest, 121: 2723-2735
[112] Iliopoulos D, Hirsch HA, Wang G, Struhl K (2011). Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci U S A, 108: 1397-1402
[113] Hanahan D, Weinberg RA (2011). Hallmarks of cancer: the next generation. Cell, 144: 646-674
[114] Gruver AL, Hudson LL, Sempowski GD (2007). Immunosenescence of ageing. J Pathol, 211: 144-156
[115] Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, et al. (2009). Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol, 30: 325-333
[116] Maue AC, Yager EJ, Swain SL, Woodland DL, Blackman MA, Haynes L (2009). T-cell immunosenescence: lessons learned from mouse models of aging. Trends Immunol, 30: 301-305
[117] Lynch HE, Goldberg GL, Chidgey A, Van den Brink MR, Boyd R, Sempowski GD (2009). Thymic involution and immune reconstitution. Trends Immunol, 30: 366-373
[118] Koch S, Solana R, Dela Rosa O, Pawelec G (2006). Human cytomegalovirus infection and T cell immunosenescence: a mini review. Mech Ageing Dev, 127: 538-543
[119] Gayoso I, Sanchez-Correa B, Campos C, Alonso C, Pera A, Casado JG, et al. (2011). Immunosenescence of human natural killer cells. J Innate Immun, 3: 337-343
[120] Colonna-Romano G, Aquino A, Bulati M, Lio D, Candore G, Oddo G, et al. (2004). Impairment of gamma/delta T lymphocytes in elderly: implications for immunosenescence. Exp Gerontol, 39: 1439-1446
[121] Golomb L, Sagiv A, Pateras IS, Maly A, Krizhanovsky V, Gorgoulis VG, et al. (2015). Age-associated inflammation connects RAS-induced senescence to stem cell dysfunction and epidermal malignancy. Cell Death Differ, 22: 1764-1774
[122] Rosenberg SA (2014). Decade in review-cancer immunotherapy: entering the mainstream of cancer treatment. Nat Rev Clin Oncol, 11: 630-632
[123] Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD, et al. (2006). Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med, 355: 1018-1028
[124] Clair EWSt (2008). The calm after the cytokine storm: lessons from the TGN1412 trial. J Clin Invest, 118: 1344-1347
[125] June CH (2007). Adoptive T cell therapy for cancer in the clinic. J Clin Invest, 117: 1466-1476
[126] Lipowska-Bhalla G, Gilham DE, Hawkins RE, Rothwell DG (2012). Targeted immunotherapy of cancer with CAR T cells: achievements and challenges. Cancer Immunol Immunother, 61: 953-962
[127] Topalian SL, Taube JM, Anders RA, Pardoll DM (2016). Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer, 16: 275-287
[128] Bouchlaka MN, Sckisel GD, Chen M, Mirsoian A, Zamora AE, Maverakis E, et al. (2013). Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. J Exp Med, 210: 2223-2237
[129] Nishijima TF, Muss HB, Shachar SS, Moschos SJ (2016). Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: A systematic review and meta-analysis. Cancer Treat Rev, 45: 30-37
[130] Martinez-Lopez N, Athonvarangkul D, Singh R (2015). Autophagy and aging. Adv Exp Med Biol, 847: 73-87
[131] Glick D, Barth S, Macleod KF (2010). Autophagy: cellular and molecular mechanisms. J Pathol, 221: 3-12
[132] Zhong Z, Sanchez-Lopez E, Karin M (2016). Autophagy, Inflammation, and Immunity: A Troika Governing Cancer and Its Treatment. Cell, 166: 288-298
[133] Cuervo AM (2010). Chaperone-mediated autophagy: selectivity pays off. Trends Endocrinol Metab, 21: 142-150
[134] Rubinsztein DC, Marino G, Kroemer G (2011). Autophagy and aging. Cell, 146: 682-695
[135] Klionsky DJ, Abdelmohsen K, Abe A, Abedin MJ, Abeliovich H, Acevedo Arozena A, et al. (2016). Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy, 12: 1-222
[136] Choi AM, Ryter SW, Levine B (2013). Autophagy in human health and disease. N Engl J Med, 368: 1845-1846
[137] Carames B, Taniguchi N, Otsuki S, Blanco FJ, Lotz M (2010). Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum, 62: 791-801
[138] de Kreutzenberg SV, Ceolotto G, Papparella I, Bortoluzzi A, Semplicini A, Dalla Man C, et al. (2010). Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms. Diabetes, 59: 1006-1015
[139] Shirakabe A, Ikeda Y, Sciarretta S, Zablocki DK, Sadoshima J (2016). Aging and Autophagy in the Heart. Circ Res, 118: 1563-1576
[140] Lipinski MM, Zheng B, Lu T, Yan Z, Py BF, Ng A, et al. (2010). Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer’s disease. Proc Natl Acad Sci U S A, 107: 14164-14169
[141] Madeo F, Pietrocola F, Eisenberg T, Kroemer G (2014). Caloric restriction mimetics: towards a molecular definition. Nat Rev Drug Discov, 13: 727-740
[142] Jung CH, Ro SH, Cao J, Otto NM, Kim DH (2010). mTOR regulation of autophagy. FEBS Lett, 584: 1287-1295
[143] Madeo F, Tavernarakis N, Kroemer G (2010). Can autophagy promote longevity?. Nat Cell Biol, 12: 842-846
[144] Mah LY, Ryan KM (2012). Autophagy and cancer. Cold Spring Harb Perspect Biol, 4: a008821
[145] White E (2015). The role for autophagy in cancer. J Clin Invest, 125: 42-46
[146] Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, et al. (2016). NF-kappaB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell, 164: 896-910
[147] Shibutani ST, Saitoh T, Nowag H, Munz C, Yoshimori T (2015). Autophagy and autophagy-related proteins in the immune system. Nat Immunol, 16: 1014-1024
[148] Kroemer G, Galluzzi L, Kepp O, Zitvogel L (2013). Immunogenic cell death in cancer therapy. Annu Rev Immunol, 31: 51-72
[149] Shalapour S, Font-Burgada J, Di Caro G, Zhong Z, Sanchez-Lopez E, Dhar D, et al. (2015). Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy. Nature, 521: 94-98
[150] Zhang YJ, Li S, Gan RY, Zhou T, Xu DP, Li HB (2015). Impacts of gut bacteria on human health and diseases. Int J Mol Sci, 16: 7493-7519
[151] O’Hara AM, Shanahan F (2006). The gut flora as a forgotten organ. EMBO Rep, 7: 688-693
[152] Collins SM, Surette M, Bercik P (2012). The interplay between the intestinal microbiota and the brain. Nat Rev Microbiol, 10: 735-742
[153] Simren M, Barbara G, Flint HJ, Spiegel BM, Spiller RC, Vanner S, et al. (2013). Intestinal microbiota in functional bowel disorders: a Rome foundation report. Gut, 62: 159-176
[154] Delzenne NM, Neyrinck AM, Backhed F, Cani PD (2011). Targeting gut microbiota in obesity: effects of prebiotics and probiotics. Nat Rev Endocrinol, 7: 639-646
[155] Nicoletti C (2015). Age-associated changes of the intestinal epithelial barrier: local and systemic implications. Expert Rev Gastroenterol Hepatol, 9: 1467-1469
[156] Rera M, Clark RI, Walker DW (2012). Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proc Natl Acad Sci U S A, 109: 21528-21533
[157] Heintz C, Mair W (2014). You are what you host: microbiome modulation of the aging process. Cell, 156: 408-411
[158] Zapata HJ, Quagliarello VJ (2015). The microbiota and microbiome in aging: potential implications in health and age-related diseases. J Am Geriatr Soc, 63: 776-781
[159] Sandek A, Rauchhaus M, Anker SD, von Haehling S (2008). The emerging role of the gut in chronic heart failure. Curr Opin Clin Nutr Metab Care, 11: 632-639
[160] Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, et al. (2011). Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A, 108 (Suppl 1): 4586-4591
[161] Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, et al. (2012). Gut microbiota composition correlates with diet and health in the elderly. Nature, 488: 178-184
[162] Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, et al. (2013). Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe, 14: 207-215
[163] Gur C, Ibrahim Y, Isaacson B, Yamin R, Abed J, Gamliel M, et al. (2015). Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity, 42: 344-355
[164] Wu N, Yang X, Zhang R, Li J, Xiao X, Hu Y, et al. (2013). Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb Ecol, 66: 462-470
[165] Park K, Kim KB (2013). miRTar Hunter: a prediction system for identifying human microRNA target sites. Mol Cells, 35: 195-201
[166] Olivieri F, Rippo MR, Monsurro V, Salvioli S, Capri M, Procopio AD, et al. (2013). MicroRNAs linking inflamm-aging, cellular senescence and cancer. Ageing Res Rev, 12: 1056-1068
[167] Bartel DP (2009). MicroRNAs: target recognition and regulatory functions. Cell, 136: 215-233
[168] Schroen B, Heymans S (2012). Small but smart--microRNAs in the centre of inflammatory processes during cardiovascular diseases, the metabolic syndrome, and ageing. Cardiovasc Res, 93: 605-613
[169] Schwarzenbach H, Nishida N, Calin GA, Pantel K (2014). Clinical relevance of circulating cell-free microRNAs in cancer. Nat Rev Clin Oncol, 11: 145-156
[170] Kumarswamy R, Volkmann I, Thum T (2011). Regulation and function of miRNA-21 in health and disease. RNA Biol, 8: 706-713
[171] Cingarlini S, Bonomi M, Corbo V, Scarpa A, Tortora G (2012). Profiling mTOR pathway in neuroendocrine tumors. Target Oncol, 7: 183-188
[172] Liu LZ, Li C, Chen Q, Jing Y, Carpenter R, Jiang Y, et al. (2011). MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1alpha expression. PLoS One, 6: e19139
[173] Ma X, Becker Buscaglia LE, Barker JR, Li Y (2011). MicroRNAs in NF-kappaB signaling. J Mol Cell Biol, 3: 159-166
[174] Merline R, Moreth K, Beckmann J, Nastase MV, Zeng-Brouwers J, Tralhao JG, et al. (2011). Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and MicroRNA-21. Sci Signal, 4: ra75
[175] 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
[176] Yu HW, Cho WC (2015). The emerging role of miRNAs in combined cancer therapy. Expert Opin Biol Ther, 15: 923-925
[177] Bonafe M, Barbi C, Storci G, Salvioli S, Capri M, Olivieri F, et al. (2002). What studies on human longevity tell us about the risk for cancer in the oldest old: data and hypotheses on the genetics and immunology of centenarians. Exp Gerontol, 37: 1263-1271
[178] Salvioli S, Capri M, Bucci L, Lanni C, Racchi M, Uberti D, et al. (2009). Why do centenarians escape or postpone cancer? The role of IGF-1, inflammation and p53. Cancer Immunol Immunother, 58: 1909-1917
[179] Pavlidis N, Stanta G, Audisio RA (2012). Cancer prevalence and mortality in centenarians: a systematic review. Crit Rev Oncol Hematol, 83: 145-152
[180] Bonafe M, Valensin S, Gianni W, Marigliano V, Franceschi C (2001). The unexpected contribution of immunosenescence to the leveling off of cancer incidence and mortality in the oldest old. Crit Rev Oncol Hematol, 39: 227-233
[181] Serna E, Gambini J, Borras C, Abdelaziz KM, Belenguer A, Sanchis P, et al. (2012). Centenarians, but not octogenarians, up-regulate the expression of microRNAs. Sci Rep, 2: 961
[182] Thun MJ, Jacobs EJ, Patrono C (2012). The role of aspirin in cancer prevention. Nat Rev Clin Oncol, 9: 259-267
[183] Baron JA, Sandler RS (2000). Nonsteroidal anti-inflammatory drugs and cancer prevention. Annu Rev Med, 51: 511-523
[1] Ulises Urzua,Carlos Chacon,Luis Lizama,Sebastián Sarmiento,Pía Villalobos,Belén Kroxato,Katherine Marcelain,María-Julieta Gonzalez. Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice[J]. A&D, 2017, 8(5): 546-557.
[2] Ilia Stambler. Recognizing Degenerative Aging as a Treatable Medical Condition: Methodology and Policy[J]. A&D, 2017, 8(5): 583-589.
[3] Xianglai Xu,Brian Wang,Changhong Ren,Jiangnan Hu,David A. Greenberg,Tianxiang Chen,Liping Xie,Kunlin Jin. Age-related Impairment of Vascular Structure and Functions[J]. A&D, 2017, 8(5): 590-610.
[4] Mariaelena Occhipinti,Anna Rita Larici,Lorenzo Bonomo,Raffaele Antonelli Incalzi. Aging Airways: between Normal and Disease. A Multidimensional Diagnostic Approach by Combining Clinical, Functional, and Imaging Data[J]. A&D, 2017, 8(4): 471-485.
[5] Marta K. Zamroziewicz,Erick J. Paul,Chris E. Zwilling,Aron K. Barbey. Predictors of Memory in Healthy Aging: Polyunsaturated Fatty Acid Balance and Fornix White Matter Integrity[J]. A&D, 2017, 8(4): 372-383.
[6] Xianglai Xu,Brian Wang,Changhong Ren,Jiangnan Hu,David A. Greenberg,Tianxiang Chen,Liping Xie,Kunlin Jin. Recent Progress in Vascular Aging: Mechanisms and Its Role in Age-related Diseases[J]. A&D, 2017, 8(4): 486-505.
[7] Alexey Moskalev,Elizaveta Chernyagina,Anna Kudryavtseva,Mikhail Shaposhnikov. Geroprotectors: A Unified Concept and Screening Approaches[J]. A&D, 2017, 8(3): 354-363.
[8] Alan R. Hipkiss. On the Relationship between Energy Metabolism, Proteostasis, Aging and Parkinson’s Disease: Possible Causative Role of Methylglyoxal and Alleviative Potential of Carnosine[J]. A&D, 2017, 8(3): 334-345.
[9] Minwen Xu,Olga Sizova,Liefeng Wang,Dong-Ming Su. A Fine-Tune Role of Mir-125a-5p on Foxn1 During Age-Associated Changes in the Thymus[J]. A&D, 2017, 8(3): 277-286.
[10] Guangxian Zhao,Xian W. Cheng,Limei Piao,Lina Hu,Yanna Lei,Guang Yang,Aiko Inoue,Shinyu Ogasawara,Hongxian Wu,Chang-Ning Hao,Kenji Okumura,Masafumi Kuzuya. The Soluble VEGF Receptor sFlt-1 Contributes to Impaired Neovascularization in Aged Mice[J]. A&D, 2017, 8(3): 287-300.
[11] A.R. Ghanam,Qianlan Xu,Shengwei Ke,Muhammad Azhar,Qingyu Cheng,Xiaoyuan Song. Shining the Light on Senescence Associated LncRNAs[J]. A&D, 2017, 8(2): 149-161.
[12] Zohara Sternberg,Zihua Hu,Daniel Sternberg,Shayan Waseh,Joseph F. Quinn,Katharine Wild,Kaye Jeffrey,Lin Zhao,Michael Garrick. Serum Hepcidin Levels, Iron Dyshomeostasis and Cognitive Loss in Alzheimer’s Disease[J]. A&D, 2017, 8(2): 215-227.
[13] Massimo De Martinis,Maria Maddalena Sirufo,Lia Ginaldi. Allergy and Aging: An Old/New Emerging Health Issue[J]. A&D, 2017, 8(2): 162-175.
[14] Hongxia Zhang,Fen Sun,Jixian Wang,Luokun Xie,Chenqi Yang,Mengxiong Pan,Bei Shao,Guo-Yuan Yang,Shao-Hua Yang,Qichuan ZhuGe,Kunlin Jin. Combining Injectable Plasma Scaffold with Mesenchymal Stem/Stromal Cells for Repairing Infarct Cavity after Ischemic Stroke[J]. A&D, 2017, 8(2): 203-214.
[15] Jue Wang,Bin Cao,Dong Han,Miao Sun,Juan Feng. Long Non-coding RNA H19 Induces Cerebral Ischemia Reperfusion Injury via Activation of Autophagy[J]. A&D, 2017, 8(1): 71-84.
Full text



Copyright © 2014 Aging and Disease, All Rights Reserved.
Address: Aging and Disease Editorial Office 3400 Camp Bowie Boulevard Fort Worth, TX76106 USA
Fax: (817) 735-0408 E-mail:
Powered by Beijing Magtech Co. Ltd