Activation of Nuclear Receptor CAR: A Pathway to Delay Aging through Enhanced Capacity for Xenobiotic Resistance

Environmental factors are linked to aging and age-related diseases. Emerging evidence suggests that enhancing body's resistance to xenobiotics might be an anti-aging strategy. The constitutive androstane receptor (CAR) regulates drug-metabolizing enzymes and transporters, coordinating metabolism and immune responses to adapt to stress triggered by exogenous exposure. However, the impact of activating CAR on aging remains unknown. In this study, Caenorhabditis elegans (C. elegans), drug-induced premature aging mice, and senescence accelerated P8 (SAMP8) mice are used as models to explore the effects of CAR activation on lifespan and healthspan, along with the underlying mechanisms. The results showed that hCAR agonist CITCO and mCAR agonist TCPOBOP prolonged the lifespan and healthspan in model organism. The longevity effects of CITCO and TCPOBOP were attenuated in CAR homozygous nhr-8/daf-12 mutant C. elegans as well as CAR-/- mice. In C. elegans, CITCO activated both anti-stress and detoxification genes, and increased the resistance to environmental adversities. Additionally, the lifespan-extending and xenobiotic resistant effects of CITCO might be related to the regulation of age-related pathways. Furthermore, CITCO improved age-related neurodegeneration in C. elegans models. Taken together, the results suggest that the longevity effects of CAR agonists may be related to the enhancement of xenobiotic resistance of animals.