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

• Published in: Journal of evolutionary biochemistry and physiology 2022-09, Vol.58 (5), p.1523-1539
• Main Authors: Khilazheva, E. D., Belozor, O. S., Panina, Yu. A., Gorina, Ya. V., Mosyagina, A. I., Vasiliev, A. V., Malinovskaya, N. A., Komleva, Yu. K.
• Format: Article
• Language: English
• Subjects: Aging; Animal Physiology; Biochemistry; Biomedical and Life Sciences; Brain slice preparation; Cell activation; Cell culture; Cognitive ability; eIF-2 kinase; Evolutionary Biology; Experimental Papers; Gliosis; Glucose tolerance; Inflammasomes; Inflammation; Insulin; Insulin receptor substrate 1; Insulin receptors; Insulin resistance; Lactic acid; Life Sciences; Memory; Metabolism; Neurodegeneration; Phenotypes; Protein kinase; Senescence
• ISSN: 0022-0930; 1608-3202
• DOI: 10.1134/S0022093022050222

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.