Some stress at a young age could actually lead to a longer life, according to the results of research in the roundworm Caenorhabditis elegans. The studies, by University of Michigan (UM) scientists, showed that oxidative stress experienced early in life increased subsequent stress resistance later in life. “Experiencing stress at this early point in life may make you better able to fight stress you might encounter later in life,” commented Daphne Bazopoulou, PhD, research fellow at UM and first author of the team’s published paper in Nature. “The general idea that early life events have such profound, positive effects later in life is truly fascinating,” added corresponding author Ursula Jakob, PhD, a professor of molecular, cellular, and developmental biology. “Given the strong connection between stress, aging, and age-related diseases, it is possible that early events in life might also affect the predisposition for age-associated diseases, such as dementia and Alzheimer’s disease.” The researchers’ published paper is titled “Developmental ROS individualizes organismal stress resistance later in life.”
Researchers have long wondered what determines variability in lifespan, noted Jakob. Genetics do play a partial role, so if your parents are long lived, then you have a good chance of a long life as well. However, as the authors wrote, “Genetic effects are estimated to account for only 10–25% of the observed differences in human lifespan.” Environment is another contributory factor, but this also doesn’t complete the puzzle.
That factors other than genetics and environment might be involved is evident in the case of C. elegans. These short-lived roundworms are a popular model system for research on aging, partly because each hermaphroditic mother produces hundreds of genetically identical offspring. However, even when genetically identical C. elegans worms are cultivated under exactly the same environmental conditions, the lifespan of individuals can vary by more than 50-fold.
“If lifespan was determined solely by genes and environment, we would expect that genetically identical worms grown on the same petri dish would all drop dead at about the same time, but this is not at all what happens,” Jakob said. “Some worms live only three days while others are still happily moving around after 20 days. The question then is, what is it, apart from genetics and environment, that is causing this big difference in lifespan?”
The authors suggested that other, “more stochastic factors” account for variations in lifespan. “We, therefore, focused on the concept that specific fluctuating signals during development might differentially affect processes that determine lifespan,” they commented.
Reactive oxygen species (ROS) are oxidants that every air-breathing organism produces. ROS are closely associated with aging: the oxidative damage they elicit is what many anti-aging creams claim to combat. Oxidative stress happens when cells produce more oxidants and free radicals than they can deal with. And while oxidative stress is part of the aging process, it can also arise from stressful conditions such as exercise and calorie restriction. The UM researchers decided to investigate whether transient changes in reactive oxygen species, might impact on C. elegans lifespan.
The team found that individual C. elegans worms varied substantially in the amount of ROS that they produced. Those worms that produced more ROS during development (L2ox worms) perhaps surprisingly lived longer than those that produced less ROS during early life. “L2ox worms displayed an increase of up to 18% in median lifespan and a 1–4-day increase in maximal lifespan,” the scientists wrote. These animals were also more resistant to subsequent heat shock treatment, or being grown in the presence of oxidants later in life.
Interestingly, when the researchers exposed the whole population of juvenile worms to external ROS during development, they found that the average lifespan of the entire population increased.
The team also carried out studies to determine what processes might be involved in enhancing the lifespan of these worms. To do this, Bazopoulou sorted thousands of C. elegans larvae according to the oxidative stress levels they exhibited during development. By separating worms that produced large amounts of ROS from those that produced little amounts of ROS, she showed that the main difference between the two groups was a histone modifier, whose activity is sensitive to oxidative stress conditions.
The researchers found that the temporary production of ROS during development caused changes in the histone modifier early in the worm’s life. “… transient increase in ROS, which occurs naturally during early development in a subpopulation of synchronized C. elegans, sets processes in motion that increase stress resistance, improve redox homeostasis, and ultimately prolong lifespan in those animals,” the authors concluded. “We find that these effects are linked to the global ROS-mediated decrease in developmental histone H3K4me3 levels.”
How these changes persist throughout life and how they ultimately might affect and extend lifespan is still unknown. What is known, however, is that this specific histone modifier is also sensitive to oxidative stress in mammalian cells. Additionally, early-life interventions have been shown to extend lifespans in mammalian model systems such as mice.
“Further investigation is needed to reveal how the transient downregulation of H3K4me3 levels selectively during development can elicit similarly profound lifespan-altering effects,” the authors stated. “Our ability to change the lifespan of an entire population with a simple 10-h exposure to ROS during development suggests that we have identified a time window and a mechanism that helps to individualize lifespan in animals. This study provides a foundation for future work in mammals, in which very early and transient metabolic events in life seem to have equally profound impacts on lifespan.”
Next, the researchers want to figure out what key changes are triggered by these early-life events. Understanding this might allow scientists to develop lifespan-extending interventions that work at later stages in life.