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Novel small molecule inhibition of IKK/NF-κB activation reduces markers of senescence and improves healthspan in mouse models of aging.

ABSTRACT: Constitutive NF-κB activation is associated with cellular senescence and stem cell dysfunction and rare variants in NF-κB family members are enriched in centenarians. We recently identified a novel small molecule (SR12343) that inhibits IKK/NF-κB activation by disrupting the association between IKKβ and NEMO. Here we investigated the therapeutic effects of SR12343 on senescence and aging in three different mouse models. SR12343 reduced senescence-associated beta-galactosidase (SA-β-gal) activity in oxidative stress-induced senescent mouse embryonic fibroblasts as well as in etoposide-induced senescent human IMR90 cells. Chronic administration of SR12343 to the Ercc1^-/ ^∆ and Zmpste24^-/- mouse models of accelerated aging reduced markers of cellular senescence and SASP and improved multiple parameters of aging. SR12343 also reduced markers of senescence and increased muscle fiber size in 2-year-old WT mice. Taken together, these results demonstrate that IKK/NF-κB signaling pathway represents a promising target for reducing markers of cellular senescence, extending healthspan and treating age-related diseases.

SUBMITTER: Zhang L

PROVIDER: S-EPMC8672781 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Novel small molecule inhibition of IKK/NF-κB activation reduces markers of senescence and improves healthspan in mouse models of aging.

Zhang Lei L Zhao Jing J Mu Xiaodong X McGowan Sara J SJ Angelini Luise L O'Kelly Ryan D RD Yousefzadeh Matthew J MJ Sakamoto Ayumi A Aversa Zaira Z LeBrasseur Nathan K NK Suh Yousin Y Huard Johnny J Kamenecka Theodore M TM Niedernhofer Laura J LJ Robbins Paul D PD

Aging cell 20211103 12

Constitutive NF-κB activation is associated with cellular senescence and stem cell dysfunction and rare variants in NF-κB family members are enriched in centenarians. We recently identified a novel small molecule (SR12343) that inhibits IKK/NF-κB activation by disrupting the association between IKKβ and NEMO. Here we investigated the therapeutic effects of SR12343 on senescence and aging in three different mouse models. SR12343 reduced senescence-associated beta-galactosidase (SA-β-gal) activity ...[more]

PMID: 34734460

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Project description:BackgroundIncreasing evidence indicates that neuroinflammation is a critical factor contributing to the progression of various neurodegenerative diseases. The IKK/NF-κB signalling system is a central regulator of inflammation, but it also affects neuronal survival and differentiation. A complex interplay between different CNS resident cells and infiltrating immune cells, which produce and respond to various inflammatory mediators, determines whether neuroinflammation is beneficial or detrimental. The IKK/NF-κB system is involved in both production of and responses to these mediators, although the precise contribution depends on the cell type as well as the cellular context, and is only partially understood. Here we investigated the specific contribution of neuronal IKK/NF-κB signalling on the regulation of neuroinflammatory processes and its consequences. To address this issue, we established and analysed a conditional gain-of-function mouse model that expresses a constitutively active allele of IKK2 in principal forebrain neurons (IKK2nCA). Proinflammatory gene and growth factor expression, histopathology, microgliosis, astrogliosis, immune cell infiltration and spatial learning were assessed at different timepoints after persistent canonical IKK2/NF-κB activation.ResultsIn contrast to other cell types and organ systems, chronic IKK2/NF-κB signalling in forebrain neurons of adult IKK2nCA animals did not cause a full-blown inflammatory response including infiltration of immune cells. Instead, we found a selective inflammatory response in the dentate gyrus characterized by astrogliosis, microgliosis and Tnf-α upregulation. Furthermore, downregulation of the neurotrophic factor Bdnf correlated with a selective and progressive atrophy of the dentate gyrus and a decline in hippocampus-dependent spatial learning. Neuronal degeneration was associated with increased Fluoro-jade staining, but lacked activation of apoptosis. Remarkably, neuronal loss could be partially reversed when chronic IKK2/NF-κB signalling was turned off and Bdnf expression was restored.ConclusionOur results demonstrate that persistent IKK2/NF-κB signalling in forebrain neurons does not induce overall neuroinflammation, but elicits a selective inflammatory response in the dentate gyrus accompanied by decreased neuronal survival and impaired learning and memory. Our findings further suggest that chronic activation of neuronal IKK2/NF-κB signalling, possibly as a consequence of neuroinflammatory conditions, is able to induce apoptosis-independent neurodegeneration via paracrine suppression of Bdnf synthesis.

Project description:BackgroundAirway hyperresponsiveness (AHR) is characterized by excessive contraction of airway smooth muscle, leading to airflow limitation, increasing perioperative airway spasm and even triggering the defense of silent lungs, which can lead to delayed surgery. Stellate ganglion blockade (SGB) has gained attention for its immunomodulatory and anti-inflammatory effects; however, its impact on AHR and the underlying mechanisms remain unexplored. This study aims to evaluate whether SGB reduces AHR and if this effect is related to inflammation.MethodsThe experimental groups included Control, OVA (ovalbumin-induced AHR), OVA + SGB2, OVA + SGB4, OVA + SGB5, OVA + SGB6, OVA + SGB8, OVA + 4PBA, Tm, and Tm + SGB6. Mice underwent varying numbers of SGB interventions over 17 days. On day 18, lung function tests were performed, followed by ELISA of IL-4, IL-5, and IL-13 levels in alveolar lavage fluid from the right lung, and finally, tissue from the right lung was extracted for transcriptome analysis, and tissue from the left lung (without lavage fluid) was stained with HE staining to assess histopathological changes.ResultsCompared to the Control group, the OVA group exhibited increased overall respiratory resistance (Rrs), overall respiratory elasticity (Ers), central airway resistance (Rn), peripheral tissue elasticity (H), and tissue damage (G), alongside decreased overall respiratory compliance (Crs) (P < 0.05). SGB significantly improved lung function parameters, with the OVA + SGB6 group showing the most pronounced improvement (P < 0.05). The Tm group displayed elevated Rrs compared to Control (P < 0.05), while the OVA + 4PBA group demonstrated significant improvement in Rrs (P < 0.05). The Tm + SGB6 group also showed significant improvement in Rrs compared to the Tm group (P < 0.05). The expression of IRE1β-IKK/NF-κB genes was upregulated in the OVA group and downregulated in the OVA + SGB6 group. Furthermore, ER stress inhibitors reduced the expression of these key genes in OVA-induced AHR. Notably, the expression of ER stress-related genes was elevated in the OVA group, with a significant decrease in Agr2 (a promoter of ER stress IRE1β) observed in the OVA + SGB6 group compared to the OVA group (114 vs. 16).ConclusionSGB effectively reduced AHR while down-regulating the expression of key genes in the IKK/NF-κB/IL-4/IL-5/IL-13 signaling pathway, which may be related to IRE1β-mediated endoplasmic reticulum stress. However, further studies are needed to confirm the exact mechanism.

Dataset Information

Novel small molecule inhibition of IKK/NF-κB activation reduces markers of senescence and improves healthspan in mouse models of aging.

Publications

Novel small molecule inhibition of IKK/NF-κB activation reduces markers of senescence and improves healthspan in mouse models of aging.

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