Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions

Abstract

Citrus fruit has long been considered a healthy food, but its role and detailed mechanism in lifespan extension are not clear. Here, by using the nematode C. elegans, we identified that nomilin, a bitter-taste limoloid that is enriched in citrus, significantly extended the animals’ lifespan, healthspan, and toxin resistance. Further analyses indicate that this ageing inhibiting activity depended on the insulin-like pathway DAF-2/DAF-16 and nuclear hormone receptors NHR-8/DAF-12. Moreover, the human pregnane X receptor (hPXR) was identified as the mammalian counterpart of NHR-8/DAF-12 and X-ray crystallography showed that nomilin directly binds with hPXR. The hPXR mutations that prevented nomilin binding blocked the activity of nomilin both in mammalian cells and in C. elegans. Finally, dietary nomilin supplementation improved healthspan and lifespan in D-galactose- and doxorubicin-induced senescent mice as well as in male senescence accelerated mice prone 8 (SAMP8) mice, and induced a longevity gene signature similar to that of most longevity interventions in the liver of bile-duct-ligation male mice. Taken together, we identified that nomilin may extend lifespan and healthspan in animals via the activation of PXR mediated detoxification functions.

Nicotinamide Mononucleotide Supplementation Alleviates Doxorubicin-Induced Multi-Organ Fibrosis

“…In previous research, no significant changes were found in EF or FS at 53 and 30 days [26] or EF at 5 weeks following DOX treatment [45]. Most studies on DOX toxicity focused on individual organs [10,14,27,46], and NAD + supplementation was suggested as an effective detoxification approach. Here, multi-organ and NAD + levels were detected in mice exposed to DOX.…”

“…Excessive production of reactive oxygen species (ROS) during DOX metabolism also contributes to cardiomyopathy by causing biomolecular damage and activating pro-apoptotic pathways [7]. In addition to the heart, DOX accumulation [8], oxidative damage [9], inflammatory cell infiltration [10] and cytoplasmic vacuolization are also observed in the liver and kidneys of mice treated with DOX [11].…”

Magnolol extends lifespan and improves age-related neurodegeneration in Caenorhabditis elegans via increase of stress resistance

“…As known, dietary restriction prolongs lifespan in nematodes which are fed with E. coli OP50 (the standard experimental food for nematodes). While, previous studies showed that magnolol has antimicrobial effects 9,38 . To exclude the possibility that the lifespan-extending effect of magnolol was due to a decrease in food intake, we conducted the following experiments.…”

“…Drosophila melanogaster mutant strain methuselah (mth) increased resistance to starvation, heat and paraquat stress 5 . At present, several drugs have been reported to enhance the resistance to stress to prolong the lifespan such as nomilin, tangeretin, apple and blueberry extract [6][7][8][9] . It demonstrates that enhancing the stress resistance of an organism may be a potential anti-aging therapy.Aging studies have been conducting using Caenorhabditis elegans (C. elegans) as a model for the highly conserved longevity genes and signaling pathways 4 .…”

Mulberrin extends lifespan in Caenorhabditis elegans through detoxification function

“…The expression of xenobiotic detoxification enzyme genes is regulated by the transcription of nuclear hormone receptors (NHRs) in mammals, including pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Recently, we identified that targeting PXR extends lifespan and healthspan through the activation of detoxification functions in both C. elegans and mice (Fan et al, 2023). In C. elegans , NHR‐8 and DAF‐12 are the homologue of mammalian nuclear receptors, transcriptionally regulating the expression of detoxification enzymes and ATP‐binding cassette (ABC) transporters.…”