Oxidative stress and inflammation tend to go hand in hand in aging, one causing the other. Cells naturally produce oxidizing molecules, such as via mitochondrial activities, and have evolved a range of antioxidant mechanisms to defend themselves. Upregulation of some of these mechanisms has been shown to suppress age-related chronic inflammation, improve tissue function, and even modestly extend life span in animal studies using short-lived species. The paper noted here is an example of this sort of work, targeting NRF2 as a regulator of antioxidant activities in the cell.
Hematopoietic stem cells (HSCs) possess the remarkable capability for self-renewal and multilineage differentiation, giving rise to a spectrum of mature blood and immune cells essential for physiological functions. Oxidative stress, a critical cellular stressor, is characterized by an elevation in reactive oxygen species (ROS) levels and the consequent accumulation of oxidative stress byproducts. This surge in ROS and oxidative damage can precipitate a cascade of detrimental cellular responses, including DNA damage, cell cycle dysregulation, premature cell senescence, and, ultimately, the impairment of HSC function.
DDO1002, a potent inhibitor of the NRF2-KEAP1 pathway, modulates the expression of antioxidant genes. Yet, the extent to which it mitigates hematopoietic decline post-total body irradiation (TBI) or in the context of aging remains to be elucidated. Our study has elucidated the role of DDO1002 in modulating NRF2 activity, which, in turn, activates the NRF2-driven antioxidant response element (ARE) signaling cascade. This activation can diminish intracellular levels of ROS, thereby attenuating cellular senescence. In addition, DDO1002 has been demonstrated to ameliorate DNA damage and avert HSC apoptosis, underscoring its potential to mitigate hematopoietic injury precipitated by TBI.
Competitive transplantation assay revealed that the administration of DDO1002 can improve the reconstitution and self-renewal capacity of HSCs in aged mice. Single-cell sequencing analysis elucidated that DDO1002 treatment attenuated intracellular inflammatory signaling pathways and mitigated ROS pathway in aged HSCs, suggesting its potential to restore the viability of these cells. Consequently, DDO1002 effectively activated the NRF2-ARE pathway, delaying cellular senescence and ameliorating impaired hematopoiesis, thereby demonstrating its potential as a therapeutic agent for age-related hematopoietic disorders.
Link: https://doi.org/10.1093/lifemedi/lnae043
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