Delaying the aging process is one of the main goals of modern biomedical research. In animal models, modulation of multiple signaling pathways or diet restriction has been shown to delay aging and extend lifespan, but these approaches are either impractical or cannot be simply applied to the general population.
There is growing evidence that expression of detoxification enzyme genes and resistance to toxins are increased in long-lived fruit flies, nematodes and rodents.
Recent studies have also found increased expression of drug metabolism and detoxification genes such as cytochrome P450 enzymes (CYPs) and glutathione-s -transferases (GSTs) in the livers of mice receiving 17 interventions known to extend lifespan, suggesting that targeting detoxification processes may be a useful longevity intervention therapy.
Nomilin is a natural compound found in citrus fruits such as lemons, grapefruits, and oranges, as well as in orange seeds and peels.
Nomilin has a variety of pharmacological effects, including anticancer, anti-inflammatory, anti-obesity, anti-viral, antioxidant, immunomodulatory and neuroprotective effects, but its role in life extension and specific mechanisms are not yet known.
Huang Cheng's team from Shanghai University of Traditional Chinese Medicine, Cao Yu's team from Shanghai Jiao Tong University and Zhu Huanhu's team from Shanghai University of Science and Technology published in Nature Communications a paper entitled "Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions".
The study found that nomilin extends lifespan and healthspan in preclinical models through detoxification functions mediated by activation of the pregnane X receptor (PXR).
Normillin is thought to have certain health-promoting and disease-preventing properties, and studies have found that it prolongs the lifespan of WT N2 nematodes in a dose-dependent manner. Treatment with 25, 50 and 100 μM normulin increased mean lifespan by 9.4%, 24% and 24%, respectively.
In addition, accumulation of lipofuscin, a biomarker of aging in Cryptobacterium hidradenum, was significantly reduced with nomenclatural supplementation. The locomotor behavior of aged nematodes, such as body flexion, head bobbing, and pharyngeal pumping, was also significantly improved under nemerine treatment. In conclusion, these data suggest that nomeline may slow down the aging process and extend the lifespan and health span of Cryptobacterium hidradenum.
To test whether nomaline could improve the health status of aging mice, researchers used D-galactose-induced mice to mimic the symptoms of human aging and found that nomaline improved the aging status and prolonged the healthy life span of D-galactose-induced premature aging mice, and confirmed that nomaline improved toxin-induced aging by activating the detoxification function of mice.
The researchers then analyzed the health span prolonging effect of nomilin in PXR knockout mice treated with D-galactose. As a result of D-galactose treatment, mice showed a decrease in dwell time in the rotarod test and an increase in the number of falls from the rotarod. In the gait test, D-gal-treated PXR hind limb stance width was increased, while the intervention of normilin did not improve gait instability in PXR -/- mice.
D-gal also resulted in neuronal death in hippocampal CA1 and CA3 and inflammatory infiltration in the liver of PXR-/- mice. These data suggest that nortriptyline does not ameliorate impaired motility, neuronal death, and liver inflammation in D-galactose-induced aging mPXR-deficient mice, further demonstrating that the health span prolonging effects of nortriptyline occur through mPXR activation.
In conclusion, this study found that nortriptyline prolongs healthy lifespan in nematodes and mice and regulates the gene expression of detoxification enzymes through activation of nuclear hormone receptors. The detoxification function of nemaline may be linked to IIS longevity signaling, and thus targeting PXR may be a viable strategy to promote longevity and health.
