Mutual antagonism between aryl hydrocarbon receptor and hypoxia-inducible factor-1α (AhR/HIF-1α) signaling: Impact on the aging process

The ambient oxygen level, many environmental toxins, and the rays of ultraviolet light (UV) provide a significant risk for the maintenance of organismal homeostasis. The aryl hydrocarbon receptors (AhR) represent a complex sensor system not only for environmental toxins and UV radiation but also for many endogenous ligands, e.g., L-tryptophan metabolites. The AhR signaling system is evolutionarily conserved and AhR homologs existed as many as 600 million years ago. The ancient atmosphere demanded the evolution of an oxygen-sensing system, i.e., hypoxia-inducible transcription factors (HIF) and their prolyl hydroxylase regulators (PHD). Given that both signaling systems have important roles in embryogenesis, it seems that they have been involved in the evolution of multicellular organisms. The evolutionary origin of the aging process is unknown although it is most likely associated with the evolution of multicellularity. Intriguingly, there is compelling evidence that while HIF-1α signaling extends the lifespan, that of AhR promotes many age-related degenerative processes, e.g., it increases oxidative stress, inhibits autophagy, promotes cellular senescence, and aggravates extracellular matrix degeneration. In contrast, HIF-1α signaling stimulates autophagy, inhibits cellular senescence, and enhances cell proliferation. Interestingly, there is a clear antagonism between the AhR and HIF-1α signaling pathways. For instance, (i) AhR and HIF-1α factors heterodimerize with the same factor, ARNT/HIF-1β, leading to their competition for DNA-binding, (ii) AhR and HIF-1α signaling exert antagonistic effects on autophagy, and (iii) co-chaperone p23 exhibits specific functions in the signaling of AhR and HIF-1α factors. One might speculate that it is the competition between the AhR and HIF-1α signaling pathways that is a driving force in the aging process.