Xenobiotic Detoxifying Enzymes are Critical to the Hormetic Increase in Life Span via Mitochondrial Oxidative Stress

Researchers have for many years demonstrated that short-lived organisms such as the nematode worms C. elegans live longer when there is some increase in damaging reactive oxygen species released by mitochondria. This is a hormetic mechanism: processes of cell maintenance are triggered into greater activity, and the net result is improved tissue function and increased longevity. Unfortunately we know that these mechanisms do not have the same sizable effect on life span in long-lived species such as our own, even though they appear quite beneficial to short term measures of health.

Establishing the fine details of exactly which stress responses are important, and to what degree, is a work in progress. Metabolism is enormously complex, and there are only so many scientists and so much funding for ongoing investigations. Researchers here identify xenobiotic detoxifying enzymes as an important component of stress responses, and in this context it is interesting to look back at other recent research showing correlation between genetic variants of xenobiotic metabolizing enzymes and human longevity.

Lifespan extension in different species can be achieved by various genetic manipulations and treatments, such as disruption of insulin/IGF1 signalling, decrease in mitochondrial respiration, suppression of translation or caloric restriction. Despite very different origins of these longevity programmes, they all warrant increased resistance to various stresses like heat, oxidative stress or radiation. Although the concept that lifespan might depend on the capacity to withstand external stress cues is very old, little is currently known about signalling pathways underlying these cytoprotective responses and their ability to affect lifespan. Furthermore, how much an individual cytoprotective mechanism contributes to the lifespan extension induced by different manipulations is a key question that remains to be answered.

Transcription profiling of many long-lived mutants from worm to mouse has recently revealed that upregulation of a number of genes involved in xenobiotic detoxification is common to longevity-assurance pathways across different phyla. Xenobiotic detoxification includes activation of drug-metabolizing enzymes (DMEs), which are classified in two main groups: phase I, mainly cytochrome P450 oxidases (CYPs), and phase II, mainly UDP-glucuronosyltransferases (UGTs), glutathione-S-transferases (GSTs), sulfotransferases, and acetyltransferases, coupled to the activity of phase III transporters that mediate the efflux of metabolic end products out of the cells after the completion of phase II.

Interestingly, analyses of expression profiles from long-lived mice, including calorically restricted mice, different dwarf mice, or mice treated with rapamycin, revealed that many CYPs are upregulated and positively correlate with increased longevity. Moreover, increased expression of multiple cyp genes was reported in diverse long-lived C. elegans models, including mitochondrial mutants. Although interesting, these findings provided just a correlative connection to longevity.

Here we identify Kr├╝ppel-like factor 1 (KLF-1) as a mediator of a cytoprotective response that dictates longevity induced by reduced mitochondrial function. A redox-regulated KLF-1 activation and transfer to the nucleus coincides with the peak of somatic mitochondrial biogenesis that occurs around a transition from larval stage. We further show that KLF-1 activates genes involved in the xenobiotic detoxification programme and identified cytochrome P450 oxidases, the KLF-1 main effectors, as longevity-assurance factors of mitochondrial mutants. Collectively, these findings underline the importance of the xenobiotic detoxification in the mitohormetic, longevity assurance pathway and identify KLF-1 as a central factor in orchestrating this response.

Link: https://doi.org/10.1038/s41467-019-11275-w

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