New mouse data published in the latest issue of Aging Cell highlights the aging benefits of a novel NF-κB-based drug.
NF-κB in aging and disease
NF-κB is a transcription factor found in nearly all animal cell types. It is activated in response to multiple physiological insults, such as stress, reactive oxygen species (ROS), and viral and bacterial infection. Its dysregulation has been linked to several age-related diseases, including cancer, inflammation, and obesity [1-3].
NF-κB is central to aging as well [4]. It is a key regulator of the senescence-associated secretory phenotype (SASP) [5], and genetically suppressing its activity improves aging phenotypes in mice [6,7]. Human genome studies have also implicated NF-κB in the long-lives of centenarians [8].
NF-κB as a therapeutic target
Scientists at the University of Minnesota have recently developed the drug SR12343 to reduce NF-κB expression. By acting upstream of the NF-κB activation pathway (interfering with the association between IKKß and NEMO), the drug showed positive effects on acute inflammation [9]. In this study, these researchers investigated its potential to reduce cellular senescence and extend healthspan in three different mouse models [10].
Anti-aging benefits in vitro, in premature aging models, and in naturally aged mice
SR12343 reduced multiple senescence markers in human lung fibroblasts, mouse embryonic fibroblasts, and mouse Zmpste24-/- muscle progenitor cells in vitro.
In both male and female Ercc1-/Δ mice (a model of accelerated aging that mimics human XFE progeria), the drug slightly reduced various symptoms of aging and dramatically reduced a composite frailty score that combined multiple symptoms. Various measurements of senescence were reduced in the liver, muscle, fat, and lung. Muscle and metabolic pathologies were also alleviated in these tissues.
In Zmpste24-knockout mice (another accelerated aging model), SR12343 reduced senescence and various pathological features in skeletal muscle and heart tissue.
Lastly, aged (25-month) wild-type mice were treated with SR12343 for 17 weeks and showed reduced senescence in the lung, liver, and muscle. Investigating age-related liver and muscle pathologies also revealed an improvement for SR12343-treated mice.
In summary, we demonstrate the therapeutic activity of chronic treatment with the IKK/NF-κB inhibitor SR12343 in terms of reducing cellular senescence, extending healthspan, attenuating metabolic abnormality and improving tissue pathologies in murine models of premature aging as well as natural aging. Our results suggest that inhibiting the IKK-mediated activation of NF-κB signaling represents a promising target for the development of drug interventions for healthy aging. Moreover, SR12343 is a potential therapeutic compound warranting further development for anti-aging interventions and treating age-related diseases.
Conclusion
In this study, SR12343 showed a wide range of therapeutic benefits for aging phenotypes and cellular senescence. It also improved tissue-specific pathologies, especially in muscle and liver. Confirming these results in human cells in vitro and three different models of mouse aging (including natural aging) is a promising sign for the drug’s future development.
Of course, whether these benefits hold in human patients without burdensome side effects remains to be seen. Side effects in particular may be a challenge in future development, as NF-κB is pervasive in many different cellular functions throughout the body. Additionally, the effects of SR12343 on maximum lifespan are still unknown, as the mice in this study were euthanized at specific time points in order to analyze their tissues.
Literature
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[2] Amiri, K.I. and Richmond, A. Role of nuclear factor-kappa B in melanoma. Cancer and Metastasis Reviews (2005). https://doi.org/10.1007/s10555-005-1579-7
[3] Baker, R.G., Hayden, M. S., and Ghosh, S. NF-kappaB, inflammation, and metabolic disease. Cell Metabolism (2011). https://doi.org/10.1016/j.cmet.2010.12.008
[4] Adler, A.S. et al. Motif module map reveals enforcement of aging by continual NF-kappaB activity. Genes & Development (2007). https://doi.org/10.1101/gad.1588507
[5] Gorgoulis, V. et al. Cellular senescence: Defining a path forward. Cell (2019). https://doi.org/10.1016/j.cell.2019.10.005
[6] Osorio, F.G. et al. Nuclear lamina defects cause ATM-dependent NF-kappaB activation and link accelerated aging to a systemic inflammatory response. Genes & Development (2012). https://doi.org/10.1101/gad.197954.112
[7] Tilstra, J.S. et al. NF-kappaB inhibition delays DNA damage-induced senescence and aging in mice. Journal of Clinical Investigation (2012). https://doi.org/10.1172/jci45785
[8] Ryu, S. et al. Genetic signature of human longevity in PKC and NF-κB signaling. Aging Cell (2021). https://doi.org/10.1111/acel.13362
[9] Zhao, J. et al. Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-kappaB activation. PLoS Biology (2018). https://doi.org/10.1371/journal.pbio.2004663
[10] Zhang, L. et al. Novel small molecule inhibition of IKK/NF-κB activation reduces markers of senescence and improves healthspan in mouse models of aging. Aging Cell (2021). https://doi.org/10.1111/acel.13486
