Regulators of Detoxification Genes Extend Life Span in Nematode Worms
Researchers here note that the stress response to the presence of toxic molecules can, like other stress responses, be upregulated to slow aging in short-lived species such as the nematode worms used in this study. Detoxification is arguably not as well studied as the response to heat shock or low nutrient availability. Like those items, upregulation of the detoxification response will likely only produce a usefully large slowing of aging in short-lived species. As species life span increases, the effects of the increased operation of stress response mechanisms remain similar in the short term, but the degree of slowed aging over the long term diminishes. Mice live as much as 40% longer when calorie intake is limited, but humans likely gain only a few years from the long term practice of calorie restriction.
Recently, increasing evidence shows that the expression of detoxification genes is enhanced in long-lived animals. The increase in the expression of detoxification genes was identified in several long-lived mice. For example, in genetic long-lived growth hormone-releasing hormone receptor knockout Little mice and growth hormone deficient Ames dwarf mice, the livers' detoxification genes were increased and showed more resistance to liver toxins. Similar observation was found in the pituitary abnormal Snell dwarf mice and growth hormone receptor knockout mice. A recent study has found that the transcription levels of detoxification enzymes, cytochrome P450s (Cyps) and glutathione-S-transferases (Gsts), were increased in the livers of mice with lifespan-extending interventions. Enhancing detoxification functions is a common transcriptome marker of all long-lived mice, suggesting that the upregulation of detoxification enzymes may be a potential anti-aging therapy.
Here, we show that farnesoid X receptor (FXR) agonist obeticholic acid (OCA), a marketed drug for the treatment of cholestasis, may extend the lifespan and healthspan both in C. elegans and chemical-induced early senescent mice. Furthermore, OCA increased the resistance of worms to toxicants and activated the expression of detoxification genes in both mice and C. elegans. The longevity effects of OCA were attenuated in Fxr-/- mice and Fxr homologous nhr-8 and daf-12 mutant C. elegans. In addition, metabolome analysis revealed that OCA increased the endogenous agonist levels of the pregnane X receptor (PXR), a major nuclear receptor for detoxification regulation, in the liver of mice. Together, our findings suggest that OCA has the potential to lengthen lifespan and healthspan by activating nuclear receptor-mediated detoxification functions, thus, targeting FXR may offer to promote longevity.