Enoxacin Modestly Extends Life in Nematodes via Mitochondrial Hormesis

Many methods demonstrated to slow aging in short-lived species, such as the nematode worm Caenorhabditis elegans, involve hormesis. This is the induction of mild cellular stress and damage, through heat, or lack of nutrients, or raised levels of oxidative molecules generated by mitochondria, that leads to an enhanced cellular maintenance response. The net result is a gain in health and tissue function. The open access paper here discusses some of the known hormetic mechanisms in nematodes, those involving alterations in mitochondrial function, and illustrates one of many methods of triggering mitochondrial hormesis in that species. The degree to which longevity is enhanced in this case is not large at all when considering the plasticity of life span in nematodes; life spans in this species have been extended by a factor of ten by some research groups. Sadly, we know that these approaches have nowhere near the same outcome in mammals.

Alterations in microRNA (miRNA) processing have been previously linked to aging. Here we used the small molecule enoxacin to pharmacologically interfere with miRNA biogenesis and study how it affects aging in C. elegans. Enoxacin extended worm lifespan and promoted survival under normal and oxidative stress conditions. Enoxacin-induced longevity required the transcription factor SKN-1/Nrf2 and was blunted by the antioxidant N-acetyl-cysteine, suggesting a prooxidant-mediated mitohormetic response. The longevity effects of enoxacin were also dependent on the miRNA pathway, consistent with changes in miRNA expression elicited by the drug. Among these differentially expressed miRNAs, the widely conserved miR-34-5p was found to play an important role in enoxacin-mediated longevity.

And how does miR-34-5p down-regulation affect lifespan? Mir-34 has been previously associated with lifespan and the onset of age-related diseases in model organisms, but the directionality and the mechanisms underlying its effects have been a matter of debate. A previous study demonstrated that mir-34 loss-of-function significantly extends lifespan through activation of autophagy, but other studies did not see an effect on survival or even found the opposite. Here we show that both enoxacin and mir-34 loss-of-function extend lifespan via a mechanism that requires a prooxidative effect. Different types of food (e.g., dead bacteria here versus live bacteria in the previous studies) and slightly different experimental conditions could have created different thresholds of sensitivity to prooxidant agents or a different redox balance which in turn could explain the apparent discrepancies in reports associating mir-34 with longevity.

Sub-lethal levels of mitochondrial reactive oxygen species (ROS) are usually associated with beneficial effects and lifespan extension, while elevated ROS can be toxic - a phenomenon often referred to as mitohormesis. Mitochondrial ROS requires the transcription factor SKN-1/Nrf2 to increase lifespan and confer their beneficial effects, and so does enoxacin. Together, these results indicate that enoxacin promotes non-toxic levels of ROS through inhibition of miR-34-5p, which in turn activates stress response pathways mediated by SKN-1 and autophagy. In addition to its beneficial outcomes, there is a toxic effect caused by enoxacin treatment. Consistent with this notion, enoxacin-mediated miR-34-5p inhibition confers a lesser lifespan extension than deletion of the mir-34 gene.

Link: https://doi.org/10.1016/j.redox.2018.06.006

Comments

Hi Chris,
This study sheets that damaged, disfunctional or outright missing mitochondria can cause age related damage. So mitochondria repair is a good target.

For the moment we don't have many good options.
Urolutin supplements, calorie restriction and fasting followed by high intensity training could help cycle damaged mitochondria.

I am not sure how to handle the fact that someone's damaged mitochondria outcome the good ones. Probably by senolitics...

I have heard a few stories where fasting over 30 days reversed gray hair, wrinkles and even scarring. So, fast alone will not help 100%.

If I muster the will power I will try to do 14 days and share personal results

Posted by: Cuberat at July 20th, 2018 2:08 PM

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