Aryl hydrocarbon receptor: Linking environment to aging process in elderly patients with asthma

Abstract

Aging is a significant risk factor for various diseases, including asthma, and it often leads to poorer clinical outcomes, particularly in elderly individuals. It is recognized that age-related diseases are due to a time-dependent accumulation of cellular damage, resulting in a progressive decline in cellular and physiological functions and an increased susceptibility to chronic diseases. The effects of aging affect not only the elderly but also those of younger ages, posing significant challenges to global healthcare. Thus, understanding the molecular mechanisms associated with aging in different diseases is essential. One intriguing factor is the aryl hydrocarbon receptor (AhR), which serves as a cytoplasmic receptor and ligand-activated transcription factor and has been linked to the aging process. Here, we review the literature on several major hallmarks of aging, including mitochondrial dysfunction, cellular senescence, autophagy, mitophagy, epigenetic alterations, and microbiome disturbances. Moreover, we provide an overview of the impact of AhR on these hallmarks by mediating responses to environmental exposures, particularly in relation to the immune system. Furthermore, we explore how aging hallmarks affect clinical characteristics, inflammatory features, exacerbations, and the treatment of asthma. It is suggested that AhR signaling may potentially play a role in regulating asthma phenotypes in elderly populations as part of the aging process.

Figure 1

Updated hallmarks of aging.

Figure 2

Mechanisms that can cause mitochondrial dysfunction. These include mitochondrial Ca²⁺ overload, mitochondrial turnover, nutrient signaling, genomic instability, and NAD⁺/NADH imbalance. NAD⁺: Nicotinamide adenine dinucleotide; NADH: Nicotinamide adenine dinucleotide hydrogen.

Figure 3

Model of the AhR signaling pathways. Upon binding to ligands from dioxins, allergens, bacterial-derived compounds, dietary sources, and pharmaceuticals, the AhR is activated and then translocated into nucleus. On one hand, AhR in the nucleus forms a heterodimeric complex with the ARNT and binds to a DRE consensus. This induces the expression of the AhR target genes, such as CYP1A1, CYP1A2, CYP1B1, AHRR, and COX-2, which are involved in a canonical signaling pathway. AhR can also be controlled via nuclear export and subsequent AhR degradation through the ubiquitin–proteasome signaling pathway. On the other hand, AhR in the nucleus can directly interact with other proteins such as the members of the NF-κB protein family or participate in the cross-talk with ER, which is involved in a non-canonical signaling pathway. AhR: Aryl hydrocarbon receptor; AHRR: Aryl hydrocarbon receptor repressor; ARNT: Aryl hydrocarbon receptor nuclear translocator; COX-2: Cyclooxygenase-2; CYP1A1/2: Cytochrome P450 1A1/2; CYP1B1: Cytochrome P450 1B1; DRE: Dioxin responsive elements; ER: Estrogen receptor; HSP90: Heat shock protein 90; NF-κB: Nuclear factor-κB; STAT: Signal transducer and activator of transcription; XAP2: Aryl hydrocarbon receptor interacting protein; XRE: Xenobiotic responsive element.

Figure 4

Association of AhR expression with hallmarks of aging. Bioinformatical analyses were performed on public datasets from GEO databases GSE40732 with microarray data from PBMCs of asthmatic patients and healthy controls. The samples are divided into AhR-High and AhR-Low groups based on the median expression value of AhR. GSEA analysis is performed with DEGs in a ranked manner. The NES are listed on the bottom of each bar. Only those biological processes with statistical significance (adjusted P-value <0.05) were illustrated, including epigenetic regulation, autophagy, immune response, DNA damage, protein destabilization, telomere maintenance, and defense to the bacterium. AhR: Aryl hydrocarbon receptor; DEGs: Differential expressed genes; GEO: Gene expression omnibus; GSEA: Gene set enrichment analysis; NES: Normalized enrichment scores; PBMCs: Peripheral blood mononuclear cells.

Figure 5

Association of asthma with hallmarks of aging. Bioinformatical analyses were performed on public datasets from GEO databases GSE69683 with microarray data from PBMCs of asthmatic patients and healthy controls. The comparison is performed between asthma patients and relative normal control. GSEA is performed with DEGs in a ranked manner. The NES are listed on the bottom of each bar. Only those biological processes with statistical significance (adjusted P-value <0.05) were illustrated, including immune response, DNA damage, epigenetic modification, mitochondria, protein stabilization, and autophagy in asthmatic patients. DEGs: Differential expressed genes; GEO: Gene expression omnibus; GSEA: Gene set enrichment analysis; mRNA: Messenger RNA; NADH: Nicotinamide adenine dinucleotide hydrogen; NES: Normalized enrichment scores; PBMCs: Peripheral blood mononuclear cells.

Figure 6

Overview of AhR signaling, hallmarks of aging, and asthma. AhR signaling as a mechanism regulates hallmarks of aging and subsequently a variety of asthma clinical phenotypes. AhR: Aryl hydrocarbon receptor.