Sci. Aging Knowl. Environ., 12 February 2003
Stress for Success
Too much stress is bad, but the right amount can prolong life and bring other benefits
Abstract: Researchers in aging and other fields are warming to hormesis, the idea that moderate doses of heat, toxicants, radiation, or other stresses are helpful. The notion fell into disrepute because of early supporters' belief in homeopathy, but a plethora of data supports it. Experts on aging are now trying to dissect the molecular pathways behind hormesis to find out how they increase life-span and bestow other benefits. The small amount investigators have learned suggests that hormesis might erect some of the same defenses as do life-extending mutations, such as increased amounts of heat shock proteins that prevent other proteins from unfolding. Further research might allow doctors to use hormesis to aid aging patients.
A tennis player might feel only elation after driving a match-winning forehand down the line, but hours later she'll be babying tender muscles and icing achy joints. Exercise tortures our bodies. It cranks up production of noxious oxidants, mars proteins, hikes temperature, and starves some cells of oxygen and glucose. At first glance, "there is nothing good about exercise biochemically," says biogerontologist Suresh Rattan of Aarhus University in Denmark.
But even sluggards know that a vigorous workout is a boon for the body, unless a person overdoes it. The same is true for a multitude of seemingly harmful cellular assaults that provoke moderate stress. Low concentrations of toxicants such as cadmium, brief exposure to nuclear radiation, or short bouts of high temperature can hasten reproduction, lengthen life, and elicit other salutary effects. The notion that radiation, poisons, or harsh treatments such as overheating can be beneficial at low doses yet harmful at high doses is called hormesis. It might be tough to swallow, but stacks of papers confirm this paradoxical idea in organisms ranging from paramecia to humans. "Twenty years ago, people didn't believe you could have longevity genes; until 5 years ago, people didn't believe hormesis was real," says geneticist Thomas Johnson of the University of Colorado, Boulder.
The study of hormesis at first attracted mainly pharmacologists working to establish more potent drug dosages and toxicologists seeking to refine pollution standards, but it has also infiltrated the field of aging research. Mild stress prolongs life-span in a menagerie of creatures. Scientists are just beginning to untangle the molecular events behind stress-induced increases in longevity, but the mechanisms might overlap with those of life-extending mutations. The findings so far bolster the view that stress resistance helps dictate longevity, says molecular biologist Gordon Lithgow of the Buck Institute for Age Research in Novato, California. Further probing will help us better understand the mechanics of aging, some researchers assert, and it might even lead to therapies. Just as we learned to harness the body's natural defenses against pathogens through vaccination, they say, we might someday know enough to tweak the body's stress responses to improve health or extend life.
The notion that some poisons might be salubrious at low doses dates back at least to the ancient Greeks. The first scientist to experiment systematically on hormesis was Hugo Schulz, an obscure 19th century microbiologist laboring at the backwater University of Greifswald in Germany. Schulz noticed that at low concentrations, nasties such as mercury and phenol fired up yeast metabolism instead of slaying the cells. The results got Schulz noticed by some of the big shots of the day, including a protégé of eminent bacteriologist Robert Koch, but they never got him a more prestigious job. Although he and other early researchers gathered batches of supporting evidence, they also argued that hormesis was the mechanism for homeopathy: the fanciful idea that multiple dilutions increase the power of a solution. Their advocacy of this quack therapy is one reason that hormesis fell from favor in the early 1900s, says toxicologist Edward Calabrese of the University of Massachusetts, Amherst. It's also probably the reason that Schulz's career stagnated, Calabrese adds.
Johnson and Rattan agree that Calabrese deserves the lion's share of credit for recovering hormesis from the intellectual junk heap and making it respectable. He scoured the toxicology literature for studies measuring everything from the effect of methanol on fruit fly longevity to the connection between gamma ray exposure and lung cancer incidence in mice. After comparing the results of many studies, Calabrese noticed that hormesis usually brings only modest improvement in the measured parameter, averaging about 30% to 60% greater than measurements in untreated controls. Previous researchers had assumed that the amount of damage increased proportionally with dose or that there was a threshold exposure. Instead, says Calabrese, the relation between dose and effect often looks roughly like an upside-down U (see figure below), with optimal benefits at low doses and injury at high doses.
The rediscovery of hormesis is already having an impact on toxicology and pharmacology. For example, drug designers need to be aware that compounds that kill cancer cells at high concentrations might encourage growth at low concentrations. In addition, state and federal regulatory agencies are interested in applying the new data on the effects of low doses to rejigger pollution standards and acceptable workplace exposures, which today are often set at 10% of the lowest harmful dose. Bumping that up to 20% might allow us to accrue the advantages of hormesis without endangering health, Calabrese writes.
Along with calorie restriction (see "Hungry for Science") and mutations in genes such as those in the insulin and insulin-like growth factor-1 (IGF-1) pathway (see "One for All"), mild stress is the only manipulation that extends life in multiple organisms. Some scientists classify calorie restriction as a type of hormesis. For instance, physiologist Edward Masoro, a professor emeritus at the University of Texas Health Science Center in San Antonio, points out that this drastic diet seems to fortify resistance to other stresses, such as heat and surgery. However, other researchers think that we know too little about the biochemical details of hormesis and calorie restriction to link the two.
Whether calorie restriction qualifies or not, a long list of chemicals, kinds of radiation, and other stimuli can stretch life-span or confer other benefits, such as heightened cancer resistance, that might increase survival (see examples in table below). In a study published last year in the Journal of Gerontology, for instance, Johnson and graduate student James Cypser (now at Brown University in Providence, Rhode Island) forced nematodes to endure temperatures above their preferred 20 degrees C. Toasting the worms for 2 hours at 35 degrees C hardened them to future hardship. They were 25% more likely to survive a subsequent bout of high temperature than were controls, and they lived about 25% longer overall. By contrast, a 4-hour heat bath reduced future temperature tolerance and shrank life-span by almost a quarter.
Ecologist James Curtsinger of the University of Minnesota, Twin Cities, and colleagues observed much smaller improvements when they baked fruit flies for 70 minutes at 36 degrees C--only about a 6% rise in longevity. However, as their 1997 paper in the Journal of Gerontology revealed, the heated flies not only showed increased resistance to high temperatures, they had a lower mortality rate throughout their remaining 4 weeks of life. Other studies have uncovered similar changes, suggesting that mild stress toughens organisms permanently and thus must somehow revamp many aspects of their biochemistry.
Even gravity can be stressful in a good way. Three years ago, French researchers whirled male fruit flies in a centrifuge for 2 to 4 weeks. The flies weren't all shook up: They outlived unspun flies and retained their climbing ability longer as they grew old.
Humans also reap the benefits of hormesis. British patients who received radiation treatment for a swollen thyroid showed a 17% lower risk of cancer later in life, according to a study published 4 years ago in The Lancet. And several papers argue that survivors of the atomic blasts at Nagasaki and Hiroshima might be outlasting residents who lived farther from ground zero and therefore absorbed little radiation. For example, a 1990 paper published in the International Journal of Radiation Biology found a 10% lower death rate among men with moderate radiation exposure, compared with men who were more than 3 kilometers from the Nagasaki blast. The result remains controversial: A 2000 review in The Lancet assails this conclusion.
Whether a particular stress evokes a response depends on the species. Heat, for instance, affects almost every organism, from bacteria to blue whales, but other stresses aren't universal. "Your ecological niche definitely determines how well you can respond to particular stresses," says Lithgow. For example, Cypser and Johnson saw no life extension from ultraviolet light, which the subterranean worms would rarely encounter in nature.
They did notice that dousing worms with juglone, a chemical that spurs release of destructive oxidants, protected the animals from damage caused by an atmosphere of pure oxygen, which also induces oxidant production. The result jibes with other work showing that one stress can induce resistance to another one; moreover, the two insults can be very different. Spinning flies in the centrifuge increases their tolerance to heat, for instance. "What we see is that there are certain genes that are induced by lots of stresses," says Cypser, which suggests "a common stress response."
Forging a Hard Body
Stress is an attack on the cell, says Rattan, and "the cell's response against any stress is to defend itself." Hormesis is the byproduct of these defenses. Researchers are just beginning to categorize the changes that "harden" an organism. Heat and many other stresses induce the production of heat shock proteins. These molecular guardians sidle up to other proteins and prevent them from misfolding or, if they're irreparably damaged, speed their destruction. Another defense system that swings into action is antioxidant enzymes. For example, 2 years ago, Lithgow and colleagues showed that modest amounts of cadmium, which is toxic at high concentrations, induce worms to make extra metallothioneins, proteins that squelch oxidants.
What intrigues experts on aging is the mechanistic connection between hormesis and mutations that confer long life. A 1995 paper by Lithgow, Johnson, and colleagues forged the link, revealing that heat-treated worms and animals with mutations in the age-1 gene were resistant to high temperatures. Subsequent work has shown that many long-lived worms and flies with mutations in the insulin/IGF-1 pathway pump out prodigious amounts of heat shock proteins and antioxidant enzymes. Researchers don't know whether hormesis and life-stretching mutations activate the same molecular pathways, but both evoke some of the same defensive mechanisms--including heat shock proteins and antioxidant enzymes--suggesting that stress resistance is crucial to long life, says Lithgow. Using gene chips, scientists will get a clearer picture of the genes and proteins activated by stress, Lithgow says, although researchers will still have to work out the details of how these molecules prolong life.
Although heat shock proteins and antioxidant enzymes are the bedrock of stress resistance, they don't persist. Ecologist Martin Feder of the University of Chicago showed that in flies, the amounts of proteins fall back to normal within a few hours after a blast of heat, so they can't confer lifelong resistance to stress. What does is a mystery. However, one recent study identified a cellular messenger that might evoke some of these long-term changes. Stress forces an organism to make an economic decision between allocating resources to its defense budget or to future reproduction. Johnson and his colleague Steve Henderson tagged a protein known as daf-16 with a glowing marker so they could follow its peregrinations. When a cell is under duress, daf-16, a gene regulator that is normally incarcerated in the cytoplasm, rushes to the nucleus. Because worms engineered to carry extra daf-16 are stress resistant but breed slowly, Johnson and Henderson concluded that the protein might shift the balance from reproduction toward stress resistance by turning on particular genes.
An Evolutionary Mistake?
At first glance, switching on stress defenses only when under attack seems like a bad solution, because organisms are vulnerable to sudden environmental changes. "Why in the world wouldn't natural selection make an animal as stress resistant as possible?" Lithgow asks. It sounds as foolish as building a castle with a drawbridge that doesn't close until after the attackers have already crossed.
One possible reason is that defenses are costly. Heat shock proteins that prevent proteins from unraveling in an adult might block other proteins from folding properly during embryonic development, Lithgow speculates. Evolutionary theory also predicts that you can't get stronger for free. Shifting resources to protection diverts them from making offspring: Stressed worms halt reproduction for a few days, Cypser notes. Although it might seem that lengthening life would increase fitness by giving organisms more time to reproduce, that isn't so either, says Johnson. Wild creatures usually perish from predation, disease, or other causes long before reaching advanced age, he says, so a few days tacked onto the end of life are irrelevant to reproduction.
Better Living Through Suffering?
It might be hard to imagine old folks lining up for a blast of radiation or a dose of cadmium. However, in the past, "therapeutic" stress was a fairly common medical technique, says Lithgow. To speed healing, for example, surgeons would irritate the tissue they planned to operate on.
That was before the boom in malpractice lawsuits. However, studying hormesis could bring medical payoffs that lawyers would countenance. It should help us deconstruct the molecular changes behind aging and focus on the most important ones, says Rattan: "Hormesis will tell us what are the most likely pathways to have beneficial effects." Lithgow is less sanguine, believing that we can probably learn more from age-extending mutations that involve only one gene; hormesis likely recruits hundreds of genes, which will make the process harder to untangle. Still, he agrees that by discovering the molecular tricks that underlie hormesis, researchers might allow patients to get the gain without the pain. Rattan says he's confident that we will be able to use hormesis to help the very old--if not extending life, then perhaps improving it. Take an elderly woman with osteoporosis who is confined to a wheelchair. Boosting her muscle strength so she could stand up would be an enormous benefit, he says: "You don't need too much biological improvement to make a significant impact on health." The payoffs aren't limited to the old. After a soak in the whirlpool and a few days' rest, our tennis champion will bound back on the court ready for an even longer match.
February 12, 2003
Mitch Leslie, a science writer in New Mexico, should live an extra decade, given the stress he's been under lately.
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