Novel small molecule inhibition of IKK/NF‐κB activation reduces markers of senescence and improves healthspan in mouse models of aging
| Autor: | Zaira Aversa, Yousin Suh, Ayumi Sakamoto, Theodore M. Kamenecka, Johnny Huard, Matthew J. Yousefzadeh, Paul D. Robbins, Luise Angelini, Lei Zhang, Sara J. McGowan, Jing Zhao, Laura J. Niedernhofer, Xiaodong Mu, Nathan K. LeBrasseur, Ryan D. O’Kelly |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Senescence
Aging senescence IκB kinase Oxidative phosphorylation Biology Mice chemistry.chemical_compound NEMO Animals Humans Cellular Senescence NF‐κB NF-kappa B SR12343 NF-κB Cell Biology Original Papers Small molecule Embryonic stem cell I-kappa B Kinase Cell biology Disease Models Animal Gene Expression Regulation chemistry Original Article Stem cell Signal transduction |
| Zdroj: | Aging Cell |
| ISSN: | 1474-9726 1474-9718 |
| DOI: | 10.1111/acel.13486 |
| Popis: | 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. Constitutive IKK/NF‐κB activation is associated with cellular senescence and aging. Here we demonstrate that pharmacological inhibition of IKK/NF‐κB activation by the small molecule SR12343 reduced senescence and SAPS factors in cell culture, improved healthspan in mice with accelerated aging, and reduced markers of senescence and pathology in multiple tissues of both accelerated and naturally aged mice. Therefore, IKK/NF‐κB pathway is a promising target for aging interventions to treat age‐related diseases. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text