Many studies have demonstrated that modestly increasing the generation of oxidative molecules by mitochondria slows aging. The prevailing view is that this is a form of hormesis; a slight increase in cell stress produces an overcompensating increase in the activity of cell maintenance processes. The outcome is a better function of cells and tissues than is normally the case, greater resilience to molecular damage characteristic of aging than is normally the case, and thus slowed aging. Interestingly, researchers here show that in nematode worms it is only necessary to stress the intestinal cells in this way to obtain the slowing of aging. Flies are also very centered on their intestines when it comes to aging and mortality, but it is quite unclear as whether this sort of lesson can be applied to mammals.
Reactive oxygen species (ROS) are highly reactive oxygen containing molecules that are generated by normal metabolism. While ROS can cause damage to the building blocks that make up cells, these molecules can also act as intracellular signals that promote longevity. The levels of ROS within the cell can be regulated by antioxidant enzymes, such as superoxide dismutase (SOD), which converts superoxide to hydrogen peroxide. Interestingly, our previous work has shown that disruption of the mitochondrial SOD gene sod-2 results in increased lifespan, suggesting that elevating levels of mitochondrial superoxide can promote longevity. To explore the molecular mechanisms involved, we determined the tissues in which disruption of sod-2 is necessary for lifespan extension and the tissues in which disruption of sod-2 is sufficient to extend lifespan.
We found that tissue-specific restoration of SOD-2 expression in worms lacking SOD-2 could partially revert changes in fertility, embryonic lethality, and resistance to stress, but did not inhibit the effects of sod-2 deletion on lifespan. Knocking down sod-2 expression using RNA interference specifically in the intestine, but not other tissues, was sufficient to extend longevity. Intestine-specific knockdown of sod-2 also increased resistance to heat stress while decreasing resistance to oxidative stress. Combined, these results indicate that disruption of sod-2 in neurons, intestine, germline, or muscle is not required for lifespan extension, but that decreasing sod-2 expression in just the intestine extends lifespan. This work defines the conditions required for disruption of mitochondrial superoxide dismutase to increase longevity.
Link: https://doi.org/10.1016/j.freeradbiomed.2025.01.032
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