Skip to main content
SpringerLink
Log in

The Role of Metaflammation in the Development of Senescence-Associated Secretory Phenotype and Cognitive Dysfunction in Aging Mice

  • Experimental Papers
  • Published:
Journal of Evolutionary Biochemistry and Physiology Aims and scope Submit manuscript

Abstract

Aging is accompanied by the triggering of numerous pathophysiological events, which include inflammation, cellular senescence and the development of the senescence-associated secretory phenotype (SASP), altered glucose tolerance, and insulin resistance (IR). Neuroinflammation significantly contributes to the development of brain IR due to the activation of the multiprotein oligomeric complex, NLRP3 inflammasome. The aim of the present study was to explore the impairment of the mechanisms underlying insulin signaling and metabolic inflammation in the brain of aging C57BL/6 mice. We found that aging in these mice is accompanied by an increase both in the number of senescent cells in brain slices, as well as neuron–astrocyte co-culture, and in the expression of phosphorylated protein kinases PKR and IKKβ, metaflammasome components. Another metaflammasome component, whose expression increased in the hippocampus during aging, was IKKβ. We demonstrated that constitutive IKKβ activation is related with cell senescence and aging, as well as overactivation of the NLRP3 inflammasome and increased lactate production in aging mice. Changes in NLRP3 expression in the brain are reflected in changes in complex behaviors. Here, we documented the impairment of contextual memory, but not the acquisition process and cued memory, in aging mice. Nevertheless, aging in mice did not led to a change in the expression of insulin receptors, insulin receptor substrate 1 (IRS1phospho-S312), suggesting that during physiological aging, without signs of neurodegeneration (e.g., reactive astrogliosis), insulin signaling is not yet impaired, but the manifestations of metabolic inflammation are already observed. Thus, modulation of the activity of PKR and IKKβ metaflammasome components may represent a new pathogenetically substantiated strategy for managing the mechanisms of metabolic inflammation and SASP development in the brain, aimed at improving age-related cognitive dysfunctions.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.
Fig. 3.
Fig. 4.
Fig. 5.
Fig. 6.

Similar content being viewed by others

REFERENCES

  1. Costantini E, D’Angelo C, Reale M (2018) The Role of Immunosenescence in Neurodegenerative Diseases. Mediat Inflammat 2018: 6039171. https://doi.org/10.1155/2018/6039171

    Article  CAS  Google Scholar 

  2. Khan SS, Singer BD, Vaughan DE (2017) Molecular and physiological manifestations and measurement of aging in humans. Aging Cell 16(4): 624–633. https://doi.org/10.1111/acel.12601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. de Souto Barreto P, Guyonnet S, Ader I, Andrieu S, Casteilla L, Davezac N, Rolland Y (2020) The INSPIRE research initiative: a program for GeroScience and healthy aging research going from animal models to humans and the healthcare system. J Frailty Aging 10: 86–93. https://doi.org/10.14283/jfa.2020.18

    Article  Google Scholar 

  4. Komleva Y, Chernykh A, Lopatina O, Gorina Y, Lokteva I, Salmina A, Gollasch M (2021) Inflamm-Aging and Brain Insulin Resistance: New Insights and Role of Life-style Strategies on Cognitive and Social Determinants in Aging and Neurodegeneration. Front Neurosci 14: 618395. https://doi.org/10.3389/fnins.2020.618395

    Article  PubMed  PubMed Central  Google Scholar 

  5. Spinelli M, Fusco S, Grassi C (2019) Brain Insulin Resistance and Hippocampal Plasticity: Mechanisms and Biomarkers of Cognitive Decline. Front Neurosci 13: 788. https://doi.org/10.3389/fnins.2019.00788

    Article  PubMed  PubMed Central  Google Scholar 

  6. Komleva YK, Lopatina OL, Gorina YV, Shuvaev AN, Chernykh AI, Potapenko IV, Salmina AB (2021) NLRP3 deficiency-induced hippocampal dysfunction and anxiety-like behavior in mice. Brain Res 1752: 147220. https://doi.org/10.1016/j.brainres.2020.147220

    Article  CAS  PubMed  Google Scholar 

  7. Komleva YK, Potapenko IV, Lopatina OL, Gorina YV, Chernykh AI, Khilazheva ED, Shuvaev AN (2021) NLRP3 Inflammasome Blocking as a Potential Treatment of Central Insulin Resistance in Early-Stage Alzheimer’s Disease. Int J Mol Sci 22(21): 11588. https://doi.org/10.3390/ijms222111588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Komleva YK, Lopatina OL, Gorina YV, Chernykh AI, Shuvaev AN, Salmina AB (2018) Early changes in hyppocampal neurogenesis induced by soluble Ab1-42 oligomers. Biomed Chem 64(4): 326–333. https://doi.org/10.18097/PBMC20186404326

    Article  CAS  Google Scholar 

  9. Heneka MT, McManus RM, Latz E (2018) Inflammasome signalling in brain function and neurodegenerative disease. Nature Rev Neurosci 19(10): 610–621. https://doi.org/10.1038/s41583-018-0055-7

    Article  CAS  Google Scholar 

  10. Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, Ross OA (2018) Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines. Front Immunol 9: 586. https://doi.org/10.3389/fimmu.2018.00586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Barra NG, Henriksbo BD, Anhê FF, Schertzer JD (2020) The NLRP3 inflammasome regulates adipose tissue metabolism. Biochem J 477(6): 1089–1107. https://doi.org/10.1042/BCJ20190472

    Article  CAS  PubMed  Google Scholar 

  12. Meyers AK, Zhu X (2020) The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging. Cells 9(8): 1808. https://doi.org/10.3390/cells9081808

    Article  CAS  PubMed Central  Google Scholar 

  13. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2006) Inflamm-aging: An Evolutionary Perspective on Immunosenescence. Ann NY Acad Sci 908(1): 244–254. https://doi.org/10.1111/j.1749-6632.2000.tb06651.x

    Article  Google Scholar 

  14. Litwiniuk A, Bik W, Kalisz M, Baranowska-Bik A (2021) Inflammasome NLRP3 Potentially Links Obesity-Associated Low-Grade Systemic Inflammation and Insulin Resistance with Alzheimer’s Disease. Int J Mol Sci 22(11): 5603. https://doi.org/10.3390/ijms22115603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kelley N, Jeltema D, Duan Y, He Y (2019) The NLRP3 Inflammasome: An Overview of Mechanisms of Activation and Regulation. Int J Mol Sci 20(13): 3328. https://doi.org/10.3390/ijms20133328

    Article  CAS  PubMed Central  Google Scholar 

  16. Zahid A, Li B, Kombe AJK, Jin T, Tao J (2019) Pharmacological Inhibitors of the NLRP3 Inflammasome. Front Immunol 10: 2538. https://doi.org/10.3389/fimmu.2019.02538

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kanbay M, Yerlikaya A, Sag AA, Ortiz A, Kuwabara M, Covic A, Afsar B (2019) A journey from microenvironment to macroenvironment: the role of metaflammation and epigenetic changes in cardiorenal disease. Clin Kidney J 12(6): 861–870. https://doi.org/10.1093/ckj/sfz106

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kuryłowicz A, Koźniewski K (2020) Anti-Inflammatory Strategies Targeting Metaflammation in Type 2 Diabetes. Molecules 25(9): 2224. https://doi.org/10.3390/molecules25092224

    Article  CAS  PubMed Central  Google Scholar 

  19. Taga M, Minett T, Classey J, Matthews FE, Brayne C, Ince PG, MRC CFAS (2017) Metaflammasome components in the human brain: a role in dementia with Alzheimer’s pathology?: Metaflammasome Proteins in Alzheimer’s Disease. Brain Pathol 27(3): 266–275. https://doi.org/10.1111/bpa.12388

    Article  CAS  PubMed  Google Scholar 

  20. Gritsenko A, Green JP, Brough D, Lopez-Castejon G (2020) Mechanisms of NLRP3 priming in inflammaging and age related diseases. Cytokine Growth Factor Rev 55: 15–25. https://doi.org/10.1016/j.cytogfr.2020.08.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gorina YV, Komleva YK, Lopatina OL, Volkova VV, Chernykh AI, Shabalova AA, Salmina AB (2017) Battery of tests for behavioral phenotyping of aging animals in experiment. Advances Gerontol 1: 49–55. (In Russ).

    Google Scholar 

  22. Shoji H, Takao K, Hattori S, Miyakawa T (2014) Contextual and Cued Fear Conditioning Test Using a Video Analyzing System in Mice. J Visual Exp 85: e50871. https://doi.org/10.3791/50871

    Article  Google Scholar 

  23. Morimura N, Yasuda H, Yamaguchi K, Katayama K, Hatayama M, Tomioka NH, Aruga J (2017) Autism-like behaviours and enhanced memory formation and synaptic plasticity in Lrfn2/SALM1-deficient mice. Nature Communicat 8: 15800. https://doi.org/10.1038/ncomms15800

    Article  CAS  Google Scholar 

  24. Paxinos G, Franklin KBJ (2004) The mouse brain in stereotaxic coordinates (Compact 2nd ed.). Elsevier Acad Press, Amsterdam-Boston.

    Google Scholar 

  25. Pai CS, Sharma PK, Huang HT, Loganathan S, Lin H, Hsu Y-L, Liu IY (2018) The Activating Transcription Factor 3 (Atf3) Homozygous Knockout Mice Exhibit Enhanced Conditioned Fear and Down Regulation of Hippocampal GELSOLIN. Front Mol Neurosci 11: 37. https://doi.org/10.3389/fnmol.2018.00037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zhang M, Cheng X, Dang R, Zhang W, Zhang J, Yao Z (2018) Lactate Deficit in an Alzheimer Disease Mouse Model: The Relationship With Neuronal Damage. J Neuropathol Exp Neurol 77(12): 1163–1176. https://doi.org/10.1093/jnen/nly102

    Article  CAS  PubMed  Google Scholar 

  27. Scapagnini G, Caruso C, Spera G (2016) Preventive Medicine and Healthy Longevity: Basis for Sustainable Anti-Aging Strategies. In: Scuderi N, Toth BA (Eds) International Textbook of Aesthetic Surgery. Springer, Berlin-Heidelberg. https://doi.org/10.1007/978-3-662-46599-8_82

    Chapter  Google Scholar 

  28. Martínez-Zamudio RI, Dewald HK, Vasilopoulos T, Gittens-Williams L, Fitzgerald-Bocarsly P, Herbig U (2021) Senescence-associated β-galactosidase reveals the abundance of senescent CD8+ T cells in aging humans. Aging Cell 20(5): e13344. https://doi.org/10.1111/acel.13344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Papadopoulos D, Magliozzi R, Mitsikostas DD, Gorgoulis VG, Nicholas RS (2020) Aging, Cellular Senescence, and Progressive Multiple Sclerosis. Front Cell Neurosci 14: 178. https://doi.org/10.3389/fncel.2020.00178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang L, Zhao J, Mu X, McGowan SJ, Angelini L, O’Kelly RD, Robbins PD (2021) Novel small molecule inhibition of IKK/NF-κB activation reduces markers of senescence and improves healthspan in mouse models of aging. Aging Cell 20(12): e13486. https://doi.org/10.1111/acel.13486

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. de Tredern E, Rabah Y, Pasquer L, Minatchy J, Plaçais PY, Preat T (2021) Glial glucose fuels the neuronal pentose phosphate pathway for long-term memory. Cell Reports 36(8): 109620. https://doi.org/10.1016/j.celrep.2021.109620

    Article  CAS  PubMed  Google Scholar 

  32. Diniz BS, Vieira EM, Mendes-Silva AP, Bowie CR, Butters MA, Fischer CE on behalf of the PACt-MD Study Group (2021) Mild cognitive impairment and major depressive disorder are associated with molecular senescence abnormalities in older adults. Alzheimer’s & Dementia: Translational Res Clin Intervent 7(1): e12129. https://doi.org/10.1002/trc2.12129

    Article  Google Scholar 

  33. Taga M, Mouton-Liger F, Sadoune M, Gourmaud S, Norman J, Tible M, Hugon J (2018) PKR modulates abnormal brain signaling in experimental obesity. PLOS One 13(5): e0196983. https://doi.org/10.1371/journal.pone.0196983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Arnold SE, Arvanitakis Z, Macauley-Rambach SL, Koenig AM, Wang H-Y, Ahima RS, Nathan DM (2018) Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nature Rev Neurol 14(3): 168–181. https://doi.org/10.1038/nrneurol.2017.185

    Article  CAS  Google Scholar 

  35. Hugon J, Mouton-Liger F, Dumurgier J, Paquet C (2017) PKR involvement in Alzheimer’s disease. Alzheimer’s Res & Therapy 9(1): 83. https://doi.org/10.1186/s13195-017-0308-0

    Article  CAS  Google Scholar 

  36. Stunnenberg M, Hamme JL, Trimp M, Gringhuis SI, Geijtenbeek TBH (2021) Abortive HIV-1 RNA induces pro-IL-1β maturation via protein kinase PKR and inflammasome activation in humans. Eur J Immunol 51(10): 2464–2477. https://doi.org/10.1002/eji.202149275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dresselhaus EC, Meffert MK (2019) Cellular Specificity of NF-κB Function in the Nervous System. Front Immunol 10: 1043. https://doi.org/10.3389/fimmu.2019.01043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Komleva YK, Lopatina OL, Gorina YV, Chernykh AI, Trufanova LV, Vais EF, Salmina AB (2022) Expression of NLRP3 Inflammasomes in Neurogenic Niche Contributes to the Effect of Spatial Learning in Physiological Conditions but Not in Alzheimer’s Type Neurodegeneration. Cell Mol Neurobiol 42(5): 1355–1371. https://doi.org/10.1007/s10571-020-01021-y

    Article  CAS  PubMed  Google Scholar 

  39. Li Q, Liu S, Zhu X, Mi W, Maoying Q, Wang J, Wang Y (2019) Hippocampal PKR/NLRP1 Inflammasome Pathway Is Required for the Depression-Like Behaviors in Rats with Neuropathic Pain. Neuroscience 412: 16–28. https://doi.org/10.1016/j.neuroscience.2019.05.025

    Article  CAS  PubMed  Google Scholar 

  40. Lin H-C, Chen Y-J, Wei Y-H, Lin H-A, Chen C-C, Liu T-F, Chen L-C (2021) Lactic Acid Fermentation Is Required for NLRP3 Inflammasome Activation. Front Immunol 12: 630380. https://doi.org/10.3389/fimmu.2021.630380

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Subramaniapillai S, Rajagopal S, Elshiekh A, Pasvanis S, Ankudowich E, Rajah MN (2019) Sex Differences in the Neural Correlates of Spatial Context Memory Decline in Healthy Aging. J Cogn Neurosci 31(12): 1895–1916. https://doi.org/10.1162/jocn_a_01455

    Article  PubMed  Google Scholar 

  42. Bouton ME, Maren S, McNally GP (2021) Behavioral and neurobiological mechanisms of pavlovian and instrumental extinction learning. Physiol Rev 101(2): 611–681. https://doi.org/10.1152/physrev.00016.2020

    Article  PubMed  Google Scholar 

  43. Tran T, Tobin KE, Block SH, Puliyadi V, Gallagher M, Bakker A (2021) Effect of aging differs for memory of object identity and object position within a spatial context. Learning & Memory 28(7): 239–247. https://doi.org/10.1101/lm.053181.120

    Article  Google Scholar 

  44. Battaglia S, Garofalo S, di Pellegrino G (2018) Context-dependent extinction of threat memories: influences of healthy aging. Sci Rep 8(1): 12592. https://doi.org/10.1038/s41598-018-31000-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bernier BE, Lacagnina AF, Ayoub A, Shue F, Zemelman BV, Krasne FB, Drew MR (2017) Dentate Gyrus Contributes to Retrieval as well as Encoding: Evidence from Context Fear Conditioning, Recall, and Extinction. J Neurosci 37(26): 6359–6371. https://doi.org/10.1523/JNEUROSCI.3029-16.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

ACKNOWLEDGMENT

The study was carried out using the equipment of the Molecular and Cell Technologies Center for Collective Use at the Voino-Yasenetsky Krasnoyarsk State Medical University of the Ministry of Health of the Russian Federation.

Funding

This work was supported by the grant of the President of the Russian Federation for the state support of young Russian scientists, candidates and doctors of science (MD-2368.2022.3).

Author information

Authors and Affiliations

  1. Voino-Yasenetsky Krasnoyarsk State Medical University of the Ministry of Health of the Russian Federation, Krasnoyarsk, Russia

    E. D. Khilazheva, O. S. Belozor, Yu. A. Panina, Ya. V. Gorina, A. I. Mosyagina, A. V. Vasiliev, N. A. Malinovskaya & Yu. K. Komleva

Authors
  1. E. D. Khilazheva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. O. S. Belozor
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yu. A. Panina
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ya. V. Gorina
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. I. Mosyagina
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. V. Vasiliev
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. N. A. Malinovskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu. K. Komleva
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization and experimental design (Yu.K.K., E.D.Kh.); data collection (Yu.K.K., E.D.Kh., O.S.B., Yu.A.P., A.I.M., A.V.V.); data processing, preparing of illustrative materials (Yu.K.K., E.D.Kh., O.S.B., N.A.M); writing and editing of the manuscript (Yu.K.K., E.D.Kh.).

Corresponding author

Correspondence to Yu. K. Komleva.

Ethics declarations

CONFLICT OF INTEREST

The authors declare that they have neither evident nor potential conflict of interest associated with the publication of this article.

Additional information

Translated by A. Polyanovsky

Russian Text © The Author(s), 2022, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2022, Vol. 108, No. 9, pp. 1200–1221https://doi.org/10.31857/S0869813922090072.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Khilazheva, E.D., Belozor, O.S., Panina, Y.A. et al. The Role of Metaflammation in the Development of Senescence-Associated Secretory Phenotype and Cognitive Dysfunction in Aging Mice. J Evol Biochem Phys 58, 1523–1539 (2022). https://doi.org/10.1134/S0022093022050222

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0022093022050222

Keywords:

Search

Navigation