Have you ever looked at side-by-side photos of a person before and after a particularly trying time in his or her life, for instance, before and a few years after starting a highly demanding job? The person likely appears much older in the later photo. The stress of the job is thought to contribute to the prematurely aged appearance. You might feel stress from work or other aspects of your daily life, too. Stress is everywhere. Even when you feel relaxed, your body is still experiencing considerable stress—biological stress. And, it is this type of stress that is widely studied by gerontologists for its effects on aging and longevity.
Biological stress begins with the very basic processes in the body that produce and use energy. We eat foods and we breathe, and our body uses those two vital elements (glucose from food and oxygen from the air) to produce energy, in a process known as metabolism. You may already think of metabolism as it pertains to eating—“My metabolism is fast, so I can eat dessert," or “My metabolism has slowed down over the years, so I’m gaining weight.” Since metabolism is all about energy, it also encompasses breathing, circulating blood, eliminating waste, controlling body temperature, contracting muscles, operating the brain and nerves, and just about every other activity associated with living.
These everyday metabolic activities that sustain life also create “metabolic stress,” which, over time, results in damage to our bodies. Take breathing—obviously, we could not survive without oxygen, but oxygen is a catalyst for much of the damage associated with aging because of the way it is metabolized inside our cells. Tiny parts of the cell, called mitochondria, use oxygen to convert food into energy. While mitochondria are extremely efficient in doing this, they produce potentially harmful by-products called oxygen free radicals.
Free Radicals: Oxidation Chain Reaction
A variety of environmental factors, including tobacco smoke and sun exposure, can produce them, too. The oxygen free radicals react with and create instability in surrounding molecules. This process, called oxidation, occurs as a chain reaction: the oxygen free radical reacts with molecule “A” causing molecule “A” to become unstable; molecule “A” attempts to stabilize itself by reacting with neighboring molecule “B”; then molecule “B” is unstable and attempts to become stable by reacting with neighboring molecule “C”; and so on. This process repeats itself until one of the molecules becomes stable by breaking or rearranging itself, instead of passing the instability on to another molecule.
Some free radicals are beneficial. The immune system, for instance, uses oxygen free radicals to destroy bacteria and other harmful organisms. Oxidation and its by-products also help nerve cells in the brain communicate. But, in general, the outcome of free radicals is damage (breaks or rearrangements) to other molecules, including proteins and DNA. Because mitochondria metabolize oxygen, they are particularly prone to free radical damage. As damage mounts, mitochondria may become less efficient, progressively generating less energy and more free radicals.
Scientists study whether the accumulation of oxidative (free radical) damage in our cells and tissues over time might be responsible for many of the changes we associate with aging. Free radicals are already implicated in many disorders linked with advancing age, including cancer, atherosclerosis, cataracts, and neurodegeneration.
Fortunately, free radicals in the body do not go unchecked. Cells use substances called antioxidants to counteract them. Antioxidants include nutrients, such as vitamins C and E, as well as enzyme proteins produced naturally in the cell, such as superoxide dismutase (SOD), catalase, and glutathione peroxidase.
Many scientists are taking the idea that antioxidants counter the negative effects of oxygen free radicals a step further. Studies have tested whether altering the antioxidant defenses of the cell can affect the lifespan of animal models. These experiments have had conflicting results. NIA-supported researchers found that inserting extra copies of the SOD gene into fruit flies extended the fruit flies’ average lifespan by as much as 30 percent. Other researchers found that immersing roundworms in a synthetic form of SOD and catalase extended their lifespan by 44 percent. However, in a comprehensive set of experiments, increasing or decreasing antioxidant enzymes in laboratory mice had no effect on lifespan. Results from a limited number of human clinical trials involving antioxidants generally have not supported the premise that adding antioxidants to the diet will support longer life. Antioxidant supplementation remains a topic of continuing investigation.
Heat Shock Proteins
In the early 1960s, scientists discovered that fruit flies exposed to a burst of heat produced proteins that helped their cells survive the temperature change. Over the years, scientists have found these “heat shock proteins” in virtually every living organism, including plants, bacteria, worms, mice, and even humans. Scientists have learned that, despite their name, heat shock proteins are produced when cells are exposed to a variety of stresses, not just heat. The proteins can be triggered by oxidative stress and by exposure to toxic substances (for example, some chemicals). When heat shock proteins are produced, they help cells dismantle and dispose of damaged proteins and help other proteins keep their structure and not become unraveled by stress. They also facilitate making and transporting new proteins in the body.
Heat shock response to stress changes with age. Older animals have a higher everyday level of heat shock proteins, indicating that their bodies are under more biological stress than younger animals. On the other hand, older animals are unable to produce an adequate amount of heat shock proteins to cope with fleeting bouts of stress from the environment.
Heat shock proteins are being considered as a possible aging biomarker—something that could predict lifespan or development of age-related problems—in animal models like worms and fruit flies. However, the exact role heat shock proteins play in the human aging process is not yet clear.
The Future of Aging Research: Stress
The first C. elegans worm genetically manipulated to have a longer lifespan was resistant to stress caused by heat. Subsequently, researchers learned that a common thread among all long-lived animals is that their cells (and in some cases the animals as a whole) are more resistant to a variety of stresses, compared to animals with an average or shorter lifespan.
Scientists also found that age-related damage to DNA and proteins is often reversible and does not cause problems until the damage evokes a stress response. This suggests that the stress response, rather than the damage itself, is partially responsible for age-related deterioration.
Some biologists have started looking at stress resistance when choosing animal models to study as examples of successful aging. Researchers can test stress resistance in young animals and then continue studying only those animals demonstrating high resistance. Ongoing studies will determine if there is a direct cause-effect relationship between stress resistance and longevity, and if these longer-lived animals are resistant to all or only certain sources of stress.
In addition, researchers are studying the relationship between psychological stress and aging. In one study, mothers of severely and chronically sick children had shorter telomeres, relative to other women. In other research, caregivers of people with Alzheimer’s disease were found to have shortened telomeres. These findings could suggest that emotional or psychological stress might affect the aging process. More research on the mechanisms involved is needed before scientists can make any conclusions about clinical implications.