Nematode worms are one of the most studied types of organism, and many genetic alterations known to extend healthy life span by slowing aging were first demonstrated in the nematode species C. elegans. Numerous important low-level cellular processes and components are very similar in all animals, so studying the aging of worms is in fact a very cost-effective way to obtain insight into mammal biochemistry. Nematodes are very short-lived and comparatively cheap to maintain, and so much of the exploratory work in the aging research community takes place in these and other lower animals.
Over the course of recent decades it has become clear that mitochondria, the power plants of the cell, play an important role in degenerative aging. They emit damaging reactive oxygen species (ROS) in the course of turning food into chemical energy stores for the cell, and by a complicated process this starting point leads to the creation of a small population of dysfunctional cells that export toxic, broken proteins into their surroundings. This is one of the causes of aging.
Many of the ways of extending life in laboratory animals change the degree to which mitochondria generate reactive oxygen species, such as by disabling some portions of the intricate assembly of proteins inside each mitochondrion known as the electron transport chain. Interestingly in nematode worms there are examples of genetic and other changes that either lower or raise ROS output but in both cases induce life extension. The high level theory here is that less in the way of ROS emission means less damage to clean up, but modestly greater ROS production can boost the performance of cellular maintenance processes and thus more than offset the additional damage. The situation is probably more complex than this, however. The path between two points in a biological system is rarely a straight line.
Here researchers are tracing the mechanisms that connect increased ROS levels to greater life span in nematode worms, and joining more of the dots along the way:
Programmed cell death, or apoptosis, is a process by which damaged cells commit suicide in a variety of situations: to avoid becoming cancerous, to avoid inducing auto-immune disease, or to kill off viruses that have invaded the cell. The main molecular mechanism by which this happens is well conserved in all animals, but was first discovered in C. elegans.
[Researchers] found that this same mechanism, when stimulated in the right way by free radicals, actually reinforces the cell's defenses and increases its lifespan. The findings have important implications. "Showing the actual molecular mechanisms by which free radicals can have a pro-longevity effect provides strong new evidence of their beneficial effects as signaling molecules. It also means that apoptosis signaling can be used to stimulate mechanisms that slow down aging. Since the mechanism of apoptosis has been extensively studied in people, because of its medical importance in immunity and in cancer, a lot of pharmacological tools already exist to manipulate apoptotic signaling. But that doesn't mean it will be easy."
The increased longevity of the C. elegans electron transport chain mutants isp-1 and nuo-6 is mediated by mitochondrial ROS (mtROS) signaling. Here we show that the mtROS signal is relayed by the conserved, mitochondria-associated, intrinsic apoptosis signaling pathway (CED-9/Bcl2, CED-4/Apaf1, and CED-3/Casp9) triggered by CED-13, an alternative BH3-only protein.
Activation of the pathway by an elevation of mtROS does not affect apoptosis but protects from the consequences of mitochondrial dysfunction by triggering a unique pattern of gene expression that modulates stress sensitivity and promotes survival. In vertebrates, mtROS induce apoptosis through the intrinsic pathway to protect from severely damaged cells.
Our observations in nematodes demonstrate that sensing of mtROS by the apoptotic pathway can, independently of apoptosis, elicit protective mechanisms that keep the organism alive under stressful conditions. This results in extended longevity when mtROS generation is inappropriately elevated. These findings clarify the relationships between mitochondria, ROS, apoptosis, and aging.