A minuscule roundworm is helping to reverse the bad reputation widely attached to oxygen-free radicals, which have long been associated with the cell damage that promotes aging and degenerative illnesses such as heart disease, dementia and cancer. Now, these oxygen molecules are emerging as triggers of an early-alert and defence system that keeps threatened cells alive under stressful conditions.
Working with the one-millimitre-long nematode C. elegans, McGill University molecular geneticist Siegfried Hekimi has shed light on one mechanism by which oxygen radicals – known to scientists as radical oxygen species, or ROS – actually lengthen the two-to-three-week lifespan of these tiny hermaphrodites. His most recent study appears in the journal Cell (May 8, 2014).
“Our latest research in worms shows that free radicals do not cause aging and, in fact, are involved in a protective mechanism that actually combats aging,” said Dr. Hekimi.
The mechanism in question is the so-called apoptotic pathway, which at its extreme end results in apoptosis. Apoptosis is a genetically self-orchestrated process called programmed cell death, or cell suicide, that gets rid of suspicious cells.
“This pathway triggers cell suicide if a cell is not doing well,” he said. “If it looks as though it might become damaged and turn cancerous or autoimmune, for example, it kills it off.”
But Dr. Hekimi’s team has shown that at earlier stages, this same pathway can be stimulated by ROS to increase cells’ resistance to stressors, thereby increasing the lifespan of the whole organism.
Dr. Hekimi’s lab added a very low dose – 0.1 millimolar, to be precise – of a pro-oxidant herbicide called Paraquat (highly toxic at high doses) to the medium in which the hardy hermaphrodites grow. “We were able to double the lifespan of these worms, and it’s possible to increase their lifespan up to five-fold by mixing different types of manipulations,” said the Swiss-born professor of molecular genetics. The abbreviated lifespan of the ephemeral worms, which in nature feed on bacteria in compost, provides a good practical model for the study of aging.
The low-dose Paraquat speeds up the production of ROS in the worm’s mitochondria, which are tiny membrane-bound organs within cells but outside the cell nuclei that act as energy factories.
In Mexico, high concentrations of Paraquat are used to destroy marijuana plants, and Dr. Hekimi explained the different effects of the herbicide at varying strengths: “When employed at higher doses Paraquat will poison cells, but at very low concentrations it mimics the effect of genetic mutations that increase levels of mitochondrial ROS and prolong lifespan.”
Elucidating this novel pathway to longevity is an important step in the study of aging, according to Gerardo Ferbeyre, an expert in senescent cells and professor in the department of biochemistry in the medical faculty at Université de Montréal.
“Dr. Hekimi took on the challenge of re-evaluating the ROS theory of aging and found that worms under oxidative stress lived longer because ROS trigger adaptive changes protecting their cells from damage, readjusting their metabolisms to spare energy and rerouting energy to repair.” And the good news for humans, he added, is that the ROS effect has its counterpart in mammals.
Dr. Ferbeyre said he thinks these findings may shed light on the life-prolonging effects of physical activity. “Recent research shows that exercise causes oxidative stress, and it’s tempting to speculate that the benefits of physical activity in humans is a manifestation of this ancient molecular mechanism that Dr. Hekimi and colleagues have just uncovered in worms.”
Looking ahead, Dr. Hekimi predicts that the survival-boosting role of ROS may have a particular application in neurodegenerative diseases such as Alzheimer’s. Signalling damaged cells to outright self-destruct is all well and good for easily duplicated cells, but “neurons are much harder to replace because these cells have large and complex interconnections established during brain development,” he said.
Long before neuronal suicide, ROS-based interventions might bolster neurons’ resistance and prevent neurodegeneration. “We might be able to intervene early to stimulate this surveillance pathway and not just when something has already started to go wrong,” noted Dr. Hekimi. But how that could be accomplished is not yet known. “There are a lot of reagents that can modulate the apoptotic pathway that might be useful in regulating the cell stressor system, but we’re not there yet.”
In the meantime, his findings on the ROS effect could prompt some people to re-evaluate the benefit of ingesting expensive, commercial antioxidant supplements, which may be useless and, worse, harmful. “The whole idea of antioxidants as a panacea is wrong,” he asserted. In the longer term, their opposites might prove beneficial in humans, as his worm research suggests.