Small, short doses of damaging cellular stress, such as that achieved through the application of heat, toxins, lack of nutrients, or raised levels of oxidative molecules, produce a net benefit to cell and tissue function. This is called hormesis. It occurs because cells react to short periods of stress with a lasting upregulation of maintenance activities and other altered behavior. Hormetic behaviors are the basis for many of the benefits of exercise, calorie restriction, and other related interventions shown to slow aging to some degree in animal studies.
In the research noted here, scientists report on an investigation into the way in which mitochondrial activity changes in response to cellular stress. Mitochondria are the power plants of the cell, and their function is central to cellular health. With age, mitochondria become dysfunctional in a number of different ways. Periodic hormetic stress may slow down or attenuate this progressive decline by, for example, increasing the housekeeping processes of mitophagy, responsible for recycling damaged mitochondria. Other signaling processes that more directly determine mitochondrial function are also likely involved, however.
Researchers report that brief exposures to stressors can be beneficial by prompting the cell to trigger sustained production of antioxidants, molecules that help get rid of toxic cellular buildup related to normal metabolism. Short-term stress to cells leads to remodeling mitochondria, the powerhouses of the cell that deteriorate with age, so they generate fewer toxic byproducts. The findings could lead to new approaches to counter the cellular effects of aging, possibly even extending lifespan.
"The novelty of this study is that we've generated a model in which we can turn off antioxidant production in mitochondria but in a reversible way. So we were able to induce this stress for specific time windows and see how cells responded." In the process of converting food into chemical energy, mitochondria produce a chemical called superoxide, which has a critical role in cells but is toxic if it builds up. For this reason, mitochondria also produce an enzyme - superoxide dismutase, or SOD - to convert superoxide to a less toxic form.
In a group of genetically identical mice in utero, half with a molecular "off" switch for SOD experienced brief stress when the enzyme was deactivated. After the mice were born and continued to grow to adulthood, the two groups looked very similar. But liver samples taken when they were four weeks old told a strikingly different story: the mice whose SOD enzyme had been turned off briefly to trigger stress in mitochondria had - surprisingly - higher levels of antioxidants, more mitochondria and less superoxide buildup than the mice who had not experienced stress.
When the team analyzed which genes were being activated in both the lab dishes and the liver samples of all the mice, they found unexpected molecular pathways at work in the SOD group that were reprogramming mitochondria to produce fewer toxic molecules while simultaneously increaseing the cells' antioxidant capacity. The work suggests that short-term mitochondrial stress may lead to long-term adaptations (a concept called "mitohormesis") that could keep cells healthy longer, staving off aging and disease. Researchers next plan to study whether the mechanism elucidated here can delay the effects of aging in mammals.