IKK/NF-κB Activation as a Target for Senotherapeutics

The accumulation of senescent cells in later life is a contributing cause of aging. While these errant cells never amount to more than a tiny fraction of all cells in a tissue, their inflammatory signaling is harmful. Researchers here describe an approach to diminish that inflammatory signaling, thereby reducing the ability of senescent cells to force nearby cells to also adopt a senescent state. This could shift the balance between the pace of creation and pace of clearance of senescent cells, allowing the burden of senescent cells in aged tissues to fall to more youthful levels. The result is improved function and a reduction in inflammatory markers of aging.

NF-κB is an inducible transcription factor capable of regulating diverse biological processes, including inflammation, immunity, stress responses, cell proliferation, differentiation, and survival. A wide range of external, internal, and environmental inducers can activate the NF-κB signaling including growth factors, viral or pathogenic assaults, tissue injury, genotoxic, oxidative, and inflammatory stresses. Subsequent signaling cascades in most cases converge on the IKK complex formed by two catalytic subunits, IKKα and IKKβ, and a regulatory subunit IKKγ (NEMO). Activated IKK complex phosphorylates IκB proteins, leading to its subsequent degradation. As a result, the NF-κB dimer sequestered in the cytoplasm is liberated and translocated to the nucleus to activate specific transcriptional machinery.

Normal activation of NF-κB is required to maintain many physiological functions, whereas its abnormal or chronic activation have been linked to many inflammatory and age-related diseases. NF-κB also plays key roles in cellular senescence and the aging process. Chronic inflammation, a hallmark of aging, also induces cellular senescence and promotes tissue aging. Bioinformatics studies demonstrated that NF-κB is the transcription factor most associated with mammalian aging. Furthermore, constitutive NF-κB activation drives senescence and mammalian aging, conferring expression of senescence-associated secretory phenotype (SASP) factors including pro-inflammatory cytokines and chemokines.

Acute genetic blockade of NF-κB signaling in epidermis of old mice reduced the expression of age-associated genes and reverted many features of aging to that observed in young mice. We and others also demonstrated that inhibition of NF-κB by genetic depletion of one allele of the p65 subunit of NF-κB delayed the onset of aging-related symptoms and extended healthspan in progeroid mice.

Given its key role in senescence and aging, the NF-κB signaling pathway presents a therapeutic target for extending healthspan. Previously, we developed the small molecule SR12343 capable of inhibiting NF-κB activation by disrupting the association between IKKβ and NEMO. SR12343 was developed to act as a mimetic of the NEMO Binding Domain (NBD) peptide shown previously to improve pathology in many pre-clinical models as well as to reduce senescence and improve healthspan in a mouse model of accelerated aging. Treatment with SR12343 demonstrated positive effects in murine models of acute inflammation. Here, we examined the therapeutic potential of SR12343 in reducing cellular senescence and extending healthspan using both cell-based models and mouse models of accelerated and naturally aging.

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 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 wild-type mice. Taken together, these results demonstrate that the IKK/NF-κB signaling pathway represents a promising target for reducing markers of cellular senescence, extending healthspan, and treating age-related diseases.

Link: https://doi.org/10.1111/acel.13486


Naturally Occurring NF-κB Inhibitors

'These plant-derived substances include several distinct classes of compounds such as
phenols and polyphenols (curcumin, resveratrol, caffeic acid phenethyl ester (CAPE), quercetin, epigenin, epigallocatechin-3-gallate), lignans (manassantins, (+)-saucernetin, (-)-saucerneol methyl ether), sesquiterpenes (costunolide, parthenolide), diterpenes (helenalin, excisanin, kamebakaurin), triterpenes (avicin, oleandrin), etc. The majority of these compounds are anti-oxidants and act by blocking the protein kinase-mediated IκB degradation, thereby preventing NF-κB activation. In this mini-review we will discuss briefly the medicinal chemistry of these compounds with regards to the NF-κB inhibition. '

Posted by: Jones at November 17th, 2021 6:08 AM
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