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The potential role of necroptosis in inflammaging and aging

  • Gordon H. Royce
  • Holly M. Brown-Borg
  • Sathyaseelan S. DeepaEmail author


An age-associated increase in chronic, low-grade sterile inflammation termed “inflammaging” is a characteristic feature of mammalian aging that shows a strong association with occurrence of various age-associated diseases. However, the mechanism(s) responsible for inflammaging and its causal role in aging and age-related diseases are not well understood. Age-associated accumulation of damage-associated molecular patterns (DAMPs) is an important trigger in inflammation and has been proposed as a potential driver of inflammaging. DAMPs can initiate an inflammatory response by binding to the cell surface receptors on innate immune cells. Programmed necrosis, termed necroptosis, is one of the pathways that can release DAMPs, and cell death due to necroptosis is known to induce inflammation. Necroptosis-mediated inflammation plays an important role in a variety of age-related diseases such as Alzheimer’s disease, Parkinson’s disease, and atherosclerosis. Recently, it was reported that markers of necroptosis increase with age in mice and that dietary restriction, which retards aging and increases lifespan, reduces necroptosis and inflammation. Genetic manipulations that increase lifespan (Ames Dwarf mice) and reduce lifespan (Sod1−/− mice) are associated with reduced and increased necroptosis and inflammation, respectively. While necroptosis evolved to protect cells/tissues from invading pathogens, e.g., viruses, we propose that the age-related increase in oxidative stress, mTOR signaling, and cell senescence results in cells/tissues in old animals being more prone to undergo necroptosis thereby releasing DAMPs, which contribute to the chronic inflammation observed with age. Approach to decrease DAMPs release by reducing/blocking necroptosis is a potentially new approach to reduce inflammaging, retard aging, and improve healthspan.


Necroptosis Aging Inflammation Oxidative stress Cell senescence mTOR 


Funding information

This work was supported by NIH/NIA R01 AG059718, Oklahoma Center for the Advancement of Science and Technology research grant (HR18-053) and Presbyterian Health Foundation (OUHSC) Seed grant to Dr. Sathyaseelan S Deepa. The research was also supported by grants awarded to Dr. Arlan Richardson from the National Institute on Aging (P01AG020591, R01AG045693).


  1. Afonso MB, Rodrigues PM, Carvalho T, Caridade M, Borralho P, Cortez-Pinto H, Castro RE, Rodrigues CM (2015) Necroptosis is a key pathogenic event in human and experimental murine models of non-alcoholic steatohepatitis. Clin Sci (Lond) 129:721–739. CrossRefGoogle Scholar
  2. Ahmadi-Abhari S, Luben RN, Wareham NJ, Khaw KT (2013) Seventeen year risk of all-cause and cause-specific mortality associated with C-reactive protein, fibrinogen and leukocyte count in men and women: the EPIC-Norfolk study. Eur J Epidemiol 28:541–550. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Albiger B, Dahlberg S, Henriques-Normark B, Normark S (2007) Role of the innate immune system in host defence against bacterial infections: focus on the Toll-like receptors. J Intern Med 261:511–228 ReviewPubMedCrossRefPubMedCentralGoogle Scholar
  4. An WL, Cowburn RF, Li L, Braak H, Alafuzoff I, Iqbal K, Iqbal IG, Winblad B, Pe J (2003) Up-regulation of phosphorylated/activated p70 S6 kinase and its relationship to neurofibrillary pathology in Alzheimer’s disease. Am J Pathol 163:591–607. CrossRefPubMedPubMedCentralGoogle Scholar
  5. Baar EL, Carbajal KA, Ong IM, Lamming DW (2016) Sex- and tissue-specific changes in mTOR signaling with age in C57BL/6J mice. Aging Cell 15:155–166. CrossRefPubMedPubMedCentralGoogle Scholar
  6. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479:232–236. CrossRefPubMedPubMedCentralGoogle Scholar
  7. Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM (2013) A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340:1100–1106. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Biagi E, Candela M, Franceschi C, Brigidi P (2011) The aging gut microbiota: new perspectives. Ageing Res Rev 10:428–429. CrossRefPubMedPubMedCentralGoogle Scholar
  9. Bian P, Zheng X, Wei L, Ye C, Fan H, Cai Y, Zhang Y, Zhang F, Jia Z, Lei Y (2017) MLKL mediated necroptosis accelerates JEV-induced neuroinflammation in mice. Front Microbiol 8:303. CrossRefPubMedPubMedCentralGoogle Scholar
  10. Bjedov I, Toivonen JM, Kerr F, Slack C, Jacobson J, Foley A, Partridge L (2010) Mechanisms of life span extension by rapamycin in the fruit fly Drosophila melanogaster. Cell Metab 11:35–46. CrossRefPubMedPubMedCentralGoogle Scholar
  11. Bokov A, Chaudhuri A, Richardson A (2004) The role of oxidative damage and stress in aging. Mech Ageing Dev 125:811–826PubMedCrossRefGoogle Scholar
  12. Breslow JL (1996) Mouse models of atherosclerosis. Science 272:685–688PubMedCrossRefGoogle Scholar
  13. Brown-Borg HM, Borg KE, Meliska CJ, Bartke A (1996) Dwarf mice and the ageing process. Nature 384:33PubMedCrossRefGoogle Scholar
  14. Brubaker AL, Palmer JL, Kovacs EJ (2011) Age-related dysregulation of inflammation and innate immunity: lessons learned from rodent models. Aging Dis 2:346–360PubMedPubMedCentralGoogle Scholar
  15. Bruns DR, Drake JC, Biela LM, Peelor FF 3rd, Miller BF, Hamilton KL (2015) Nrf2 signaling and the slowed aging phenotype: evidence from long-lived models. Oxidative Med Cell Longev 2015:732596CrossRefGoogle Scholar
  16. 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 132:24–31PubMedPubMedCentralCrossRefGoogle Scholar
  17. Bussian TJ, Aziz A, Meyer CF, Swenson BL, van Deursen JM, Baker DJ (2018) Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature 562:578–582PubMedPubMedCentralCrossRefGoogle Scholar
  18. Caccamo A, Majumder S, Richardson A, Strong R, Oddo S (2010) Molecular interplay between ammalian target of rapamycin (mTOR), amyloid-beta, and tau: effects on cognitive impairments. J Biol Chem 285:13107–13120. CrossRefPubMedPubMedCentralGoogle Scholar
  19. Caccamo A, Branca C, Piras IS, Ferreira E, Huentelman MJ, Liang WS, Readhead B, Dudley JT, Spangenberg EE, Green KN, Belfiore R, Winslow W, Oddo S (2017) Necroptosis activation in Alzheimer’s disease. Nat Neurosci 20:1236–1246. CrossRefPubMedGoogle Scholar
  20. Calvo A, Moglia C, Balma M, Chiò A (2010) Involvement of immune response in the pathogenesis of amyotrophic lateral sclerosis: a therapeutic opportunity? CNS Neurol Disord Drug Targets 9(3):325–330PubMedCrossRefPubMedCentralGoogle Scholar
  21. Campisi J, d'Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8(9):729–740PubMedCrossRefGoogle Scholar
  22. Canli Ö, Alankuş YB, Grootjans S, Vegi N, Hültner L, Hoppe PS, Schroeder T, Vandenabeele P, Bornkamm GW, Greten FR (2016) Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors. Blood 127:139–148. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137:1112–1123. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Coppé JP, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, Nelson PS, Desprez PY, Campisi J (2008) Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 6:2853–2868. CrossRefPubMedGoogle Scholar
  25. Coppé JP, Patil CK, Rodier F, Krtolica A, Beauséjour CM, Parrinello S, Hodgson JG, Chin K, Desprez PY, Campisi J (2010) A human-like senescence-associated secretory phenotype is conserved in mouse cells dependent on physiological oxygen. PLoS One 5(2):e9188. CrossRefPubMedPubMedCentralGoogle Scholar
  26. Cordaro M, Paterniti I, Siracusa R, Impellizzeri D, Esposito E, Cuzzocrea S (2017) KU0063794, a Dual mTORC1 and mTORC2 inhibitor, reduces neural tissue damage and locomotor impairment after spinal cord injury in mice. Mol Neurobiol 54:2415–2427PubMedCrossRefGoogle Scholar
  27. Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ, Cotman CW (2012) Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J Neuroinflammation 9:179PubMedPubMedCentralCrossRefGoogle Scholar
  28. 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 201:613–629. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 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 579:2035–2039PubMedCrossRefGoogle Scholar
  30. Deeks SG (2011) HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med 62:141–155. CrossRefPubMedPubMedCentralGoogle Scholar
  31. Deepa SS, Unnikrishnan A, Matyi S, Hadad N, Richardson A (2018) Necroptosis increases with age and is reduced by dietary restriction. Aging Cell 17:e12770. CrossRefPubMedPubMedCentralGoogle Scholar
  32. Deepa SS, Van Remmen H, Brooks SV, Faulkner JA, Larkin L, McArdle A, Jackson MJ, Vasilaki A, Richardson A (2019) Accelerated sarcopenia in Cu/Zn superoxide dismutase knockout mice. Free Radic Biol Med 132:19–23. CrossRefPubMedPubMedCentralGoogle Scholar
  33. Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, Cuny GD, Mitchison TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112–119PubMedCrossRefPubMedCentralGoogle Scholar
  34. Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4:313–321. CrossRefPubMedPubMedCentralGoogle Scholar
  35. Degterev A, Maki JL, Yuan J (2013) Activity and specificity of necrostatin-1, small-molecule inhibitor of RIP1 kinase. Cell Death Differ 20:366. CrossRefPubMedPubMedCentralGoogle Scholar
  36. Deleidi M, Gasser T (2013) The role of inflammation in sporadic and familial Parkinson's disease. Cell Mol Life Sci 70:4259–4273. CrossRefPubMedPubMedCentralGoogle Scholar
  37. Didier ES, Sugimoto C, Bowers LC, Khan IA, Kuroda MJ (2012) Immune correlates of aging in outdoor-housed captive rhesus macaques (Macaca mulatta). Immun Ageing 9(1):25. CrossRefPubMedPubMedCentralGoogle Scholar
  38. Dondelinger Y, Declercq W, Montessuit S, Roelandt R, Goncalves A, Bruggeman I, Hulpiau P, Weber K, Sehon CA, Marquis RW, Bertin J, Gough PJ, Savvides S, Martinou JC, Bertrand MJ, Vandenabeele P (2014) MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep 7:971–981. CrossRefPubMedPubMedCentralGoogle Scholar
  39. Dondelinger Y, Hulpiau P, Saeys Y, Bertrand MJM, Vandenabeele P (2016) An evolutionary perspective on the necroptotic pathway. Trends Cell Biol 26:721–732. CrossRefPubMedPubMedCentralGoogle Scholar
  40. Duan S, Wang X, Chen G, Quan C, Qu S, Tong J (2018) Inhibiting RIPK1 limits neuroinflammation and alleviates postoperative cognitive impairments in D-galactose-induced aged mice. Front Behav Neurosci 12:138. CrossRefPubMedPubMedCentralGoogle Scholar
  41. Duprez L, Takahashi N, Van Hauwermeiren F, Vandendriessche B, Goossens V, Vanden Berghe T, Declercq W, Libert C, Cauwels A, Vandenabeele P (2011) RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity 35:908–918. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Dvoriantchikova G, Degterev A, Ivanov D (2014) Retinal ganglion cell (RGC) programmed necrosis contributes to ischemia-reperfusion-induced retinal damage. Exp Eye Res 123:1–7. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Elchuri S, Oberley TD, Qi W, Eisenstein RS, Jackson Roberts L, Van Remmen H, Epstein CJ, Huang TT (2005) CuZnSOD deficiency leads to persistent and widespread oxidative damage and hepatocarcinogenesis later in life. Oncogene 24:367–380PubMedCrossRefPubMedCentralGoogle Scholar
  44. Ellis HM, Horvitz HR (1986) Genetic control of programmed cell death in the nematode C. elegans. Cell 44:817–829PubMedCrossRefPubMedCentralGoogle Scholar
  45. Feldman N, Rotter-Maskowitz A, Okun E (2015) DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Res Rev 24:29–39. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Ferrucci L, Corsi A, Lauretani F, Bandinelli S, Bartali B, Taub DD, Guralnik JM, Longo DL (2005) The origins of age-related proinflammatory state. Blood 105:2294–2299PubMedCrossRefPubMedCentralGoogle Scholar
  47. 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. CrossRefPubMedPubMedCentralGoogle Scholar
  48. Franceschi C, Bonafè M, Valensin S (2000) Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space. Vaccine 18:1717–1720PubMedCrossRefPubMedCentralGoogle Scholar
  49. 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 128:92–105PubMedCrossRefPubMedCentralGoogle Scholar
  50. Fransen F, van Beek AA, Borghuis T, Aidy SE, Hugenholtz F, van der Gaast-de Jongh C, Savelkoul HFJ, De Jonge MI, Boekschoten MV, Smidt H, Faas MM, de Vos P (2017) Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol 8:1385. CrossRefPubMedPubMedCentralGoogle Scholar
  51. Galluzzi L, Kepp O, Trojel-Hansen C, Kroemer G (2012) Non-apoptotic functions of apoptosis-regulatory proteins. EMBO Rep 13:322–330. CrossRefPubMedPubMedCentralGoogle Scholar
  52. Goldberg EL, Dixit VD (2015) Drivers of age-related inflammation and strategies for healthspan extension. Immunol Rev 265:63–74. CrossRefPubMedPubMedCentralGoogle Scholar
  53. Goto M (2008) Inflammaging (inflammation + aging): a driving force for human aging based on an evolutionarily antagonistic pleiotropy theory? Biosci Trends 2:218–230PubMedPubMedCentralGoogle Scholar
  54. Grabiner BC, Nardi V, Birsoy K, Possemato R, Shen K, Sinha S, Jordan A, Beck AH, Sabatini DM (2014) A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov 4:554–563. CrossRefPubMedPubMedCentralGoogle Scholar
  55. Hager K, Machein U, Krieger S, Platt D, Seefried G, Bauer J (1994) Interleukin-6 and selected plasma proteins in healthy persons of different ages. Neurobiol Aging 15:771–772PubMedCrossRefPubMedCentralGoogle Scholar
  56. Han CH, Guan ZB, Zhang PX, Fang HL, Li L, Zhang HM, Zhou FJ, Mao YF, Liu WW (2017) Oxidative stress induced necroptosis activation is involved in the pathogenesis of hyperoxic acute lung injury. Biochem Biophys Res Commun 495:2178–2183. CrossRefPubMedPubMedCentralGoogle Scholar
  57. Hanus J, Anderson C, Wang S (2015) RPE necroptosis in response to oxidative stress and in AMD. Ageing Res Rev 24:286–298. CrossRefPubMedPubMedCentralGoogle Scholar
  58. He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X (2009) Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137:1100–1111. CrossRefPubMedPubMedCentralGoogle Scholar
  59. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678. CrossRefPubMedPubMedCentralGoogle Scholar
  60. Holtman IR, Raj DD, Miller JA, Schaafsma W, Yin Z, Brouwer N, Wes PD, Möller T, Orre M, Kamphuis W, Hol EM, Boddeke EW, Eggen BJ (2015) Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: a co-expression meta-analysis. Acta Neuropathol Commun 3:31PubMedPubMedCentralCrossRefGoogle Scholar
  61. Huang Z, Zhou T, Sun X, Zheng Y, Cheng B, Li M, Liu X, He C (2018) Necroptosis in microglia contributes to neuroinflammation and retinal degeneration through TLR4 activation. Cell Death Differ 25:180–189. CrossRefPubMedGoogle Scholar
  62. Hyun DH, Emerson SS, Jo DG, Mattson MP, de Cabo R (2006) Calorie restriction up-regulates the plasma membrane redox system in brain cells and suppresses oxidative stress during aging. Proc Natl Acad Sci U S A 103:19908–19912PubMedPubMedCentralCrossRefGoogle Scholar
  63. Iannielli A, Bido S, Folladori L, Segnali A, Cancellieri C, Maresca A, Massimino L, Rubio A, Morabito G, Caporali L, Tagliavini F, Musumeci O, Gregato G, Bezard E, Carelli V, Tiranti V, Broccoli V (2018) Pharmacological inhibition of necroptosis protects from dopaminergic neuronal cell death in Parkinson’s disease models. Cell Rep 22:2066–2079. CrossRefPubMedPubMedCentralGoogle Scholar
  64. Iantorno M, Campia U, Di Daniele N, Nistico S, Forleo GB, Cardillo C, Tesauro M (2014) Obesity, inflammation and endothelial dysfunction. J Biol Regul Homeost Agents 28:169–176PubMedGoogle Scholar
  65. Inoki K, Mori H, Wang J, Suzuki T, Hong S, Yoshida S, Blattner SM, Ikenoue T, Rüegg MA, Hall MN, Kwiatkowski DJ, Rastaldi MP, Huber TB, Kretzler M, Holzman LB, Wiggins RC, Guan KL (2011) mTORC1 activation in podocytes is a critical step in the development of diabetic nephropathy in mice. J Clin Invest 121:2181–2196. CrossRefPubMedPubMedCentralGoogle Scholar
  66. Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y, Hitomi J, Zhu H, Chen H, Mayo L, Geng J, Amin P, DeWitt JP, Mookhtiar AK, Florez M, Ouchida AT, Fan JB, Pasparakis M, Kelliher MA, Ravits J, Yuan J (2016) RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science 353:603–608. CrossRefPubMedPubMedCentralGoogle Scholar
  67. Kaczmarek A, Vandenabeele P, Krysko DV (2013) Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38:209–223. CrossRefPubMedGoogle Scholar
  68. Katsumoto A, Takeuchi H, Takahashi K, Tanaka F (2018) Microglia in Alzheimer’s disease: risk factors and inflammation. Front Neurol 9:978PubMedPubMedCentralCrossRefGoogle Scholar
  69. Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P (1998) The death domain kinase RIP mediates the TNF-induced NF-kappaB signal. Immunity 8:297–303PubMedCrossRefGoogle Scholar
  70. Kennedy BK, Berger SL, Brunet A, Campisi J, Cuervo AM, Epel ES, Franceschi C, Lithgow GJ, Morimoto RI, Pessin JE, Rando TA, Richardson A, Schadt EE, Wyss-Coray T, Sierra F (2014) Geroscience: linking aging to chronic disease. Cell 159:709–713. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Kirwan JP, Krishnan RK, Weaver JA, Del Aguila LF, Evans WJ (2001) Human aging is associated with altered TNF-alpha production during hyperglycemia and hyperinsulinemia. Am J Physiol Endocrinol Metab 281:E1137–E1143PubMedCrossRefGoogle Scholar
  72. Konopka AR, Laurin JL, Musci RV, Wolff CA, Reid JJ, Biela LM, Zhang Q, Peelor FF 3rd, Melby CL, Hamilton KL, Miller BF (2017) Influence of Nrf2 activators on subcellular skeletal muscle protein and DNA synthesis rates after 6 weeks of milk protein feeding in older adults. Geroscience 39:175–186PubMedPubMedCentralCrossRefGoogle Scholar
  73. Lamming DW, Cummings NE, Rastelli AL, Gao F, Cava E, Bertozzi B, Spelta F, Pili R, Fontana L (2015) Restriction of dietary protein decreases mTORC1 in tumors and somatic tissues of a tumor-bearing mouse xenograft model. Oncotarget 6:31233–31240. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Land WG (2015) The role of damage-associated molecular patterns in human diseases: Part I - Promoting inflammation and immunity. Sultan Qaboos Univ Med J 15:e9–e21PubMedPubMedCentralGoogle Scholar
  75. Laster SM, Wood JG, Gooding LR (1988) Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J Immunol 141:2629–2634PubMedGoogle Scholar
  76. Lee J, Taneja V, Vassallo R (2012) Cigarette smoking and inflammation: cellular and molecular mechanisms. J Dent Res 91:142–149. CrossRefPubMedPubMedCentralGoogle Scholar
  77. Leonardi GC, Accardi G, Monastero R, Nicoletti F, Libra M (2018) Ageing: from inflammation to cancer. Immun Ageing 15:1. CrossRefPubMedPubMedCentralGoogle Scholar
  78. Lewis KN, Wason E, Edrey YH, Kristan DM, Nevo E, Buffenstein R (2015) Regulation of Nrf2 signaling and longevity in naturally long-lived rodents. Proc Natl Acad Sci U S A 112:3722–3727PubMedPubMedCentralGoogle Scholar
  79. Li D, Meng L, Xu T, Su Y, Liu X, Zhang Z, Wang X (2017) RIPK1-RIPK3-MLKL-dependent necrosis promotes the aging of mouse male reproductive system. Elife 6:e27692. CrossRefPubMedPubMedCentralGoogle Scholar
  80. Libby P (2002) Inflammation in atherosclerosis. Nature 420:868–874CrossRefGoogle Scholar
  81. Linkermann A, Green DR (2014) Necroptosis. N Engl J Med 370:455–465. CrossRefPubMedPubMedCentralGoogle Scholar
  82. Liu Q, Qiu J, Liang M, Golinski J, van Leyen K, Jung JE, You Z, Lo EH, Degterev A, Whalen MJ (2014) Akt and mTOR mediate programmed necrosis in neurons. Cell Death Dis 5:e1084. CrossRefPubMedPubMedCentralGoogle Scholar
  83. Liu ZY, Wu B, Guo YS, Zhou YH, Fu ZG, Xu BQ, Li JH, Jing L, Jiang JL, Tang J, Chen ZN (2015) Necrostatin-1 reduces intestinal inflammation and colitis-associated tumorigenesis in mice. Am J Cancer Res 5:3174–3185PubMedPubMedCentralGoogle Scholar
  84. Liu ZM, Chen QX, Chen ZB, Tian DF, Li MC, Wang JM, Wang L, Liu BH, Zhang SQ, Li F, Ye H, Zhou L (2018) RIP3 deficiency protects against traumatic brain injury (TBI) through suppressing oxidative stress, inflammation and apoptosis: Dependent on AMPK pathway. Biochem Biophys Res Commun 499:112–119. CrossRefPubMedGoogle Scholar
  85. Maelfait J, Liverpool L, Bridgeman A, Ragan KB, Upton JW, Rehwinkel J (2017) Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis. EMBO J 36:2529–2543. CrossRefPubMedPubMedCentralGoogle Scholar
  86. Mandrekar-Colucci S, Landreth GE (2010) Microglia and inflammation in Alzheimer’s disease. CNS Neurol Disord Drug Targets 9:156–167PubMedCrossRefPubMedCentralGoogle Scholar
  87. Masternak MM, Bartke A (2012) Growth hormone, inflammation and aging. Pathobiol Aging Age Relat Dis 2. CrossRefGoogle Scholar
  88. McElhaney JE, Effros RB (2009) Immunosenescence: what does it mean to health outcomes in older adults? Curr Opin Immunol 418–424. Scholar
  89. McGeer PL, McGeer EG (2002) Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve 26:459–470PubMedCrossRefPubMedCentralGoogle Scholar
  90. Meng L, Jin W, Wang X (2015) RIP3-mediated necrotic cell death accelerates systematic inflammation and mortality. Proc Natl Acad Sci U S A 112:11007–11012. CrossRefPubMedPubMedCentralGoogle Scholar
  91. Mengke NS, Hu B, Han QP, Deng YY, Fang M, Xie D, Li A, Zeng HK (2016) Rapamycin inhibits lipopolysaccharide-induced neuroinflammation in vitro and in vivo. Mol Med Rep 14:4957–4966PubMedPubMedCentralCrossRefGoogle Scholar
  92. Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R (2011) Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 66:191–201. CrossRefPubMedGoogle Scholar
  93. Miura M, Zhu H, Rotello R, Hartwieg EA, Yuan J (1993) Induction of apoptosis in fibroblasts by IL-1 beta-converting enzyme, a mammalian homolog of the C. elegans cell death gene ced-3. Cell 75:653–660PubMedCrossRefGoogle Scholar
  94. Moreno-Gonzalez G, Vandenabeele P, Krysko DV (2016) Necroptosis: a novel cell death modality and its potential relevance for critical care medicine. Am J Respir Crit Care Med 194:415–428. CrossRefPubMedGoogle Scholar
  95. Muller FL, Song W, Liu Y, Chaudhuri A, Pieke-Dahl S, Strong R, Huang TT, Epstein CJ, Roberts LJ 2nd, Csete M, Faulkner JA, Van Remmen H (2006) Absence of CuZn superoxide dismutase leads to elevated oxidative stress and acceleration of age-dependent skeletal muscle atrophy. Free Radic Biol Med 40:1993–2004PubMedCrossRefGoogle Scholar
  96. Murakami Y, Matsumoto H, Roh M, Giani A, Kataoka K, Morizane Y, Kayama M, Thanos A, Nakatake S, Notomi S, Hisatomi T, Ikeda Y, Ishibashi T, Connor KM, Miller JW, Vavvas DG (2014) Programmed necrosis, not apoptosis, is a key mediator of cell loss and DAMP-mediated inflammation in dsRNA-induced retinal degeneration. Cell Death Differ 21:270–277. CrossRefPubMedGoogle Scholar
  97. Murphy JM, Czabotar PE, Hildebrand JM, Lucet IS, Zhang JG, Alvarez-Diaz S, Lewis R, Lalaoui N, Metcalf D, Webb AI, Young SN, Varghese LN, Tannahill GM, Hatchell EC, Majewski IJ, Okamoto T, Dobson RC, Hilton DJ, Babon JJ, Nicola NA, Strasser A, Silke J, Alexander WS (2013) The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39:443–453. CrossRefPubMedGoogle Scholar
  98. Newton K, Manning G (2016) Necroptosis and inflammation. Annu Rev Biochem 85:743–763. CrossRefPubMedPubMedCentralGoogle Scholar
  99. Newton K, Dugger DL, Wickliffe KE, Kapoor N, de Almagro MC, Vucic D, Komuves L, Ferrando RE, French DM, Webster J, Roose-Girma M, Warming S, Dixit VM (2014) Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343:1357–1360. CrossRefPubMedPubMedCentralGoogle Scholar
  100. Ni HM, Chao X, Kaseff J, Deng F, Wang S, Shi YH, Li T, Ding WX, Jaeschke H (2019) Receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis contributes to ischemia-reperfusion injury of steatotic livers. Am J Pathol 189:1363–1374. CrossRefPubMedPubMedCentralGoogle Scholar
  101. Norden DM, Godbout JP (2013) Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol Appl Neurobiol 39:19–34PubMedPubMedCentralCrossRefGoogle Scholar
  102. Northington FJ, Chavez-Valdez R, Martin LJ (2011) Neuronal cell death in neonatal hypoxia-ischemia. Ann Neurol 69:743–758. CrossRefPubMedPubMedCentralGoogle Scholar
  103. Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, DeWitt JP, Ye J, Zhang X, Chang A, Vakifahmetoglu-Norberg H, Geng J, Py B, Zhou W, Amin P, Berlink Lima J, Qi C, Yu Q, Trapp B, Yuan J (2015) Activation of necroptosis in multiple sclerosis. Cell Rep 10:1836–1849PubMedPubMedCentralCrossRefGoogle Scholar
  104. Ofengeim D, Mazzitelli S, Ito Y, DeWitt JP, Mifflin L, Zou C, Das S, Adiconis X, Chen H, Zhu H, Kelliher MA, Levin JZ, Yuan J (2017) RIPK1 mediates a disease-associated microglial response in Alzheimer’s disease. Proc Natl Acad Sci U S A 114:E8788–E8797. CrossRefPubMedPubMedCentralGoogle Scholar
  105. Pasparakis M, Vandenabeele P (2015) Necroptosis and its role in inflammation. Nature 517:311–320. CrossRefPubMedPubMedCentralGoogle Scholar
  106. Pedersen M, Bruunsgaard H, Weis N, Hendel HW, Andreassen BU, Eldrup E, Dela F, Pedersen BK (2003) Circulating levels of TNF-alpha and IL-6-relation to truncal fat mass and muscle mass in healthy elderly individuals and in patients with type-2 diabetes. Mech Ageing Dev 124:495–502PubMedCrossRefPubMedCentralGoogle Scholar
  107. 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 44:1552–1562. CrossRefPubMedPubMedCentralGoogle Scholar
  108. Polykratis A, Hermance N, Zelic M, Roderick J, Kim C, Van TM, Lee TH, Chan FKM, Pasparakis M, Kelliher MA (2014) Cutting edge: RIPK1 kinase inactive mice are viable and protected from TNF-induced necroptosis in vivo. J Immunol 193:1539–1543. CrossRefPubMedPubMedCentralGoogle Scholar
  109. Pouwels SD, Zijlstra GJ, van der Toorn M, Hesse L, Gras R, Ten Hacken NH, Krysko DV, Vandenabeele P, de Vries M, van Oosterhout AJ, Heijink IH, Nawijn MC (2016) Cigarette smoke-induced necroptosis and DAMP release trigger neutrophilic airway inflammation in mice. Am J Phys Lung Cell Mol Phys 310:L377–L386. CrossRefGoogle Scholar
  110. Powers RW 3rd, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S (2006) Extension of chronological life span in yeast by decreased TOR pathway signaling. Genes Dev 20:174–184PubMedPubMedCentralCrossRefGoogle Scholar
  111. Puzianowska-Kuźnicka M, Owczarz M, Wieczorowska-Tobis K, Nadrowski P, Chudek J, Slusarczyk P, Skalska A, Jonas M, Franek E, Mossakowska M (2016) Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study. Immun Ageing 13:21. CrossRefPubMedPubMedCentralGoogle Scholar
  112. Richardson A, Galvan V, Lin AL, Oddo S (2015) How longevity research can lead to therapies for Alzheimer’s disease: the rapamycin story. Exp Gerontol 68:51–58. CrossRefPubMedGoogle Scholar
  113. Robida-Stubbs S, Glover-Cutter K, Lamming DW, Mizunuma M, Narasimhan SD, Neumann-Haefelin E, Sabatini DM, Blackwell TK (2012) TOR signaling and rapamycin influence longevity by regulating SKN-1/Nrf and DAF-16/FoxO. Cell Metab 15:713–724. CrossRefPubMedPubMedCentralGoogle Scholar
  114. 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–M26PubMedCrossRefGoogle Scholar
  115. Rowland LP, Shneider NA (2001) Amyotrophic lateral sclerosis. N Engl J Med 344:1688–1700CrossRefGoogle Scholar
  116. Roychowdhury S, McMullen MR, Pisano SG, Liu X, Nagy LE (2013) Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury. Hepatology 57:1773–1783. CrossRefPubMedPubMedCentralGoogle Scholar
  117. Saeed WK, Jun DW, Jang K, Oh JH, Chae YJ, Lee JS, Koh DH, Kang HT (2019) Decrease in fat de novo synthesis and chemokine ligand expression in non-alcoholic fatty liver disease caused by inhibition of mixed lineage kinase domain-like pseudokinase. J Gastroenterol Hepatol.
  118. Sarlus H, Heneka MT (2017) Microglia in Alzheimer’s disease. J Clin Invest 127:3240–3249PubMedPubMedCentralCrossRefGoogle Scholar
  119. Schaefer L (2014) Complexity of danger: the diverse nature of damage-associated molecular patterns. J Biol Chem 289:35237–32245. CrossRefPubMedPubMedCentralGoogle Scholar
  120. Schmidlin CJ, Dodson MB, Madhavan L, Zhang DD (2019) Redox regulation by NRF2 in aging and disease. Free Radic Biol Med 134:702–707PubMedCrossRefGoogle Scholar
  121. Seehawer M, Heinzmann F, D’Artista L, Harbig J, Roux PF, Hoenicke L, Dang H, Klotz S, Robinson L, Doré G, Rozenblum N, Kang TW, Chawla R, Buch T, Vucur M, Roth M, Zuber J, Luedde T, Sipos B, Longerich T, Heikenwälder M, Wang XW, Bischof O, Zender L (2018) Author correction: Necroptosis microenvironment directs lineage commitment in liver cancer. Nature 564:E9. CrossRefPubMedGoogle Scholar
  122. Seifert L, Werba G, Tiwari S, Giao Ly NN, Alothman S, Alqunaibit D, Avanzi A, Barilla R, Daley D, Greco SH, Torres-Hernandez A, Pergamo M, Ochi A, Zambirinis CP, Pansari M, Rendon M, Tippens D, Hundeyin M, Mani VR, Hajdu C, Engle D, Miller G (2016) The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 532:245–249. CrossRefPubMedPubMedCentralGoogle Scholar
  123. Seong SY, Matzinger P (2004) Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol 4:469–478PubMedCrossRefGoogle Scholar
  124. Sharp ZD, Bartke A (2005) Evidence for down-regulation of phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR)-dependent translation regulatory signaling pathways in Ames dwarf mice. J Gerontol A Biol Sci Med Sci 60:293–300PubMedCrossRefPubMedCentralGoogle Scholar
  125. Shobin E, Bowley MP, Estrada LI, Heyworth NC, Orczykowski ME, Eldridge SA, Calderazzo SM, Mortazavi F, Moore TL, Rosene DL (2017) Microglia activation and phagocytosis: relationship with aging and cognitive impairment in the rhesus monkey. Geroscience 39:199–220PubMedPubMedCentralCrossRefGoogle Scholar
  126. Solon-Biet SM, McMahon AC, Ballard JW, Ruohonen K, Wu LE, Cogger VC, Warren A, Huang X, Pichaud N, Melvin RG, Gokarn R, Khalil M, Turner N, Cooney GJ, Sinclair DA, Raubenheimer D, Le Couteur DG, Simpson SJ (2014) The ratio of macronutrients, not caloric intake, dictates cardiometabolic health, aging, and longevity in ad libitum-fed mice. Cell Metab 19:418–430. CrossRefPubMedPubMedCentralGoogle Scholar
  127. Spaulding CC, Walford RL, Effros RB (1997) Calorie restriction inhibits the age-related dysregulation of the cytokines TNF-alpha and IL-6 in C3B10RF1 mice. Mech Ageing Dev 93:87–94PubMedCrossRefPubMedCentralGoogle Scholar
  128. Srivastava IN, Shperdheja J, Baybis M, Ferguson T, Crino PB (2016) mTOR pathway inhibition prevents neuroinflammation and neuronal death in a mouse model of cerebral palsy. Neurobiol Dis 85:144–154PubMedCrossRefGoogle Scholar
  129. Strilic B, Yang L, Albarrán-Juárez J, Wachsmuth L, Han K, Müller UC, Pasparakis M, Offermanns S (2016) Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature 536:215–218PubMedCrossRefGoogle Scholar
  130. Takemoto K, Hatano E, Iwaisako K, Takeiri M, Noma N, Ohmae S, Toriguchi K, Tanabe K, Tanaka H, Seo S, Taura K, Machida K, Takeda N, Saji S, Uemoto S, Asagiri M (2014) Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure. FEBS Open Bio 4:777–787. CrossRefPubMedPubMedCentralGoogle Scholar
  131. Upton JW, Kaiser WJ, Mocarski ES (2012) DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA. Cell Host Microbe 11:290–297. CrossRefPubMedPubMedCentralGoogle Scholar
  132. Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714. CrossRefPubMedPubMedCentralGoogle Scholar
  133. Völkers M, Doroudgar S, Nguyen N, Konstandin MH, Quijada P, Din S, Ornelas L, Thuerauf DJ, Gude N, Friedrich K, Herzig S, Glembotski CC, Sussman MA (2014) PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity. EMBO Mol Med 6:57–65. CrossRefPubMedPubMedCentralGoogle Scholar
  134. Wang JC, Bennett M (2012) Aging and atherosclerosis: mechanisms, functional consequences, and potential therapeutics for cellular senescence. Circ Res 111:245–259. CrossRefPubMedPubMedCentralGoogle Scholar
  135. Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, Wang FS, Wang X (2014) Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell 54:133–146. CrossRefPubMedPubMedCentralGoogle Scholar
  136. Wang Y, Chen F, Ye L, Zirkin B, Chen H (2017) Steroidogenesis in Leydig cells: effects of aging and environmental factors. Reproduction 154:R111–R122. CrossRefPubMedPubMedCentralGoogle Scholar
  137. Winkeler A, Boisgard R, Martin A, Tavitian B (2010) Radioisotopic imaging of neuroinflammation. J Nucl Med 51:1–4. CrossRefPubMedPubMedCentralGoogle Scholar
  138. Wu YT, Zhou BP (2009) Inflammation: a driving force speeds cancer metastasis. Cell Cycle 8:3267–3273PubMedPubMedCentralCrossRefGoogle Scholar
  139. Wu YT, Tan HL, Huang Q, Ong CN, Shen HM (2009) Activation of the PI3K-Akt-mTOR signaling pathway promotes necrotic cell death via suppression of autophagy. Autophagy 5:824–834PubMedCrossRefPubMedCentralGoogle Scholar
  140. Xiao H (2018) J Immunol May 1 200(1 Supplement)53.12Google Scholar
  141. Xiao X, Du C, Yan Z, Shi Y, Duan H, Ren Y (2017) Inhibition of necroptosis attenuates kidney inflammation and interstitial fibrosis induced by unilateral ureteral obstruction. Am J Nephrol 46:131–138. CrossRefPubMedPubMedCentralGoogle Scholar
  142. Xie T, Peng W, Liu Y, Yan C, Maki J, Degterev A, Yuan J, Shi Y (2013) Structural basis of RIP1 inhibition by necrostatins. Structure 21:493–499. CrossRefPubMedGoogle Scholar
  143. Xie L, Sun F, Wang J, Mao X, Xie L, Yang SH, Su DM, Simpkins JW, Greenberg DA, Jin K (2014) mTOR signaling inhibition modulates macrophage/microglia-mediated neuroinflammation and secondary injury via regulatory T cells after focal ischemia. J Immunol 192:6009–6019PubMedPubMedCentralCrossRefGoogle Scholar
  144. Yang J, Zhao Y, Zhang L, Fan H, Qi C, Zhang K, Liu X, Fei L, Chen S, Wang M, Kuang F, Wang Y, Wu S (2018) RIPK3/MLKL-mediated neuronal necroptosis modulates the M1/M2 polarization of microglia/macrophages in the ischemic cortex. Cereb Cortex 28:2622–2635. CrossRefPubMedPubMedCentralGoogle Scholar
  145. Youm YH, Adijiang A, Vandanmagsar B, Burk D, Ravussin A, Dixit VD (2011) Elimination of the NLRP3-ASC inflammasome protects against chronic obesity-induced pancreatic damage. Endocrinology 152:4039–4045. CrossRefPubMedPubMedCentralGoogle Scholar
  146. Youm YH, Grant RW, McCabe LR, Albarado DC, Nguyen KY, Ravussin A, Pistell P, Newman S, Carter R, Laque A, Münzberg 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. CrossRefPubMedPubMedCentralGoogle Scholar
  147. Yuan J, Amin P, Ofengeim D (2019) Necroptosis and RIPK1-mediated neuroinflammation in CNS diseases. Nat Rev Neurosci 20:19–33. CrossRefPubMedGoogle Scholar
  148. Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ, Han J (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325:332–336. CrossRefPubMedGoogle Scholar
  149. Zhang G, Li J, Purkayastha S, Tang Y, Zhang H, Yin Y, Li B, Liu G, Cai D (2013a) Hypothalamic programming of systemic ageing involving IKK-β, NF-κB and GnRH. Nature 497:211–216. CrossRefPubMedPubMedCentralGoogle Scholar
  150. Zhang Y, Ikeno Y, Bokov A, Gelfond J, Jaramillo C, Zhang HM, Liu Y, Qi W, Hubbard G, Richardson A, Van Remmen H (2013b) Dietary restriction attenuates the accelerated aging phenotype of Sod1(-/-) mice. Free Radic Biol Med 60:300–306. CrossRefPubMedPubMedCentralGoogle Scholar
  151. Zhang H, Davies KJA, Forman HJ (2015) Oxidative stress response and Nrf2 signaling in aging. Free Radic Biol Med 88:314–336PubMedPubMedCentralCrossRefGoogle Scholar
  152. Zhang S, Wang Y, Li D, Wu J, Si W, Wu Y (2016) Necrostatin-1 attenuates inflammatory response and improves cognitive function in chronic ischemic stroke mice. Medicines (Basel) 3(3):E16. CrossRefGoogle Scholar
  153. Zhang L, Feng Q, Wang T (2018) Necrostatin-1 protects against paraquat-induced cardiac contractile dysfunction via RIP1-RIP3-MLKL-dependent necroptosis pathway. Cardiovasc Toxicol 18:346–355. CrossRefPubMedPubMedCentralGoogle Scholar
  154. Zhang J, Qin D, Yang YJ, Hu GQ, Qin XX, Du CT, Chen W (2019a) MLKL deficiency inhibits DSS-induced colitis independent of intestinal microbiota. Mol Immunol 107:132–141. CrossRefPubMedPubMedCentralGoogle Scholar
  155. Zhang P, Kishimoto Y, Grammatikakis I, Gottimukkala K, Cutler RG, Zhang S, Abdelmohsen K, Bohr VA, Misra Sen J, Gorospe M, Mattson MP (2019b) Senolytic therapy alleviates Aβ-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nat Neurosci 22:719–728PubMedPubMedCentralCrossRefGoogle Scholar
  156. Zirkin BR, Tenover JL (2012) Aging and declining testosterone: past, present, and hopes for the future. J Androl 33:1111–1118. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© American Aging Association 2019

Authors and Affiliations

  1. 1.Stephenson Cancer CenterOklahoma CityUSA
  2. 2.Department of Biomedical Sciences, School of Medicine and Health SciencesUniversity of North DakotaGrand ForksUSA
  3. 3.Department of Biochemistry and Molecular Biology, Reynolds Oklahoma Center on AgingUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

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