Sci. Aging Knowl. Environ., 29 June 2005
Vol. 2005, Issue 26, p. nf49
[DOI: 10.1126/sageke.2005.26.nf49]


How Can We Use Moderate Stresses to Fortify Humans and Slow Aging?

Science's 125th anniversary special issue

Mitch Leslie

Toss out the Prozac. Shelve that DVD of relaxation techniques. Give the yoga mat to the dog. The secret to a long, healthy life lies not in cultivating inner peace but in embracing stress. That's the lesson some researchers draw from more than a century of work on the counterintuitive phenomenon called hormesis, in which moderate doses of radiation, noxious compounds, and other hazards prove beneficial rather than harmful. Hormesis intrigues gerontologists because lab organisms often survive longer after exposure to stress, and researchers are eager to learn whether they can harness this response to strengthen our bodies as we age. But before patients start lining up for a salubrious blast of radiation or an invigorating injection of poison, scientists need to address a slew of issues, from what stresses are most effective to how to make treatments palatable to a discomfort-averse population. Most important, researchers need to tackle the biggest question of all: Will hormesis work in humans?

It certainly pays off for lab organisms from worms to flies to rats. A stack of studies has documented salutary effects from moderate doses of heavy metals, radiation, high temperatures, stronger-than-normal gravity, and other torturous stimuli (see "Stress for Success"). For example, heating a dish of nematodes to 30°C, 10° above their favored temperature, for only 6 hours prolongs their lives by 12%. Stress hardens the body by rousing some of the same protective pathways as do longevity-promoting mutations. Toasting nematodes, for instance, activates their heat shock proteins, which prevent other proteins from unfolding at high temperatures. Worms with life-stretching mutations in the daf-2 gene also ramp up heat shock proteins (see Longo Perspective).

That modest stress benefits a range of organisms suggests that it will work for people, too. But so far the evidence remains circumstantial. Human studies rely on individuals exposed accidentally or for another purpose, such as shipyard workers irradiated on the job, who suffered fewer cancers than did unexposed workers. Building a stronger case will require long-term trials in which subjects receive controlled amounts of stress. Such studies face huge ethical obstacles today--although hormesis researchers question the traditional toxicology approach of minimizing exposure. By their logic, not stressing people almost becomes unethical. Putting hormesis to the test also raises many practical problems. For instance, hormesis experts suspect that stress will not provide a huge boost in life span. Rather, it might help us age more gracefully. So researchers will have to select measures that indicate whether exposure is helping--such as whether it lets oldsters retain muscle strength or trims their risk of heart disease.

If investigators do detect an effect, new questions pop up, such as how to tailor the dose to produce the largest benefit. Animal studies show that although modest stress can be a boon, overdoing it can negate a potentially helpful stimulus. For instance, male fruit flies last 15% longer than normal if they're spun in a centrifuge for 2 weeks. Remaining in the centrifuge for about 6 weeks, their entire existence, slightly shortens their lives, however. Several factors complicate the task of defining a helpful amount of stress. For one, people will probably respond differently to the same dose. Moreover, even the most prudent and well-adjusted person is always under some physical and psychological pressure, but the degree of stress varies from person to person. So researchers will have to gauge each individual's stress exposure and determine how much extra will provide a benefit. The effective dose might also change over time--the elderly might have to curtail their exposures because aging increases sensitivity to the ill effects of stress. In some lab animals, for example, older individuals die from stresses that prolong the lives of youngsters.

The elderly might not be the only ones to suffer. Another obvious question is whether hormesis can induce long-term damage. Evolutionary theory argues that organisms must pay a price for their increased vigor. Otherwise, the world would teem with creatures that perpetually activate their stress defenses. That these defenses switch on only when organisms feel pressure suggests that they exact a cost. Researchers predict that reduced fertility is the most likely downside of hormesis. Reduced reproduction might not be such a drawback today, however, because most people voluntarily limit their family size. However, scientists don't know whether stress "treatments" will provoke other health problems.

Even if we can overcome these challenges, another obstacle looms: convincing residents of the modern world, who are increasingly loath to put down their burgers and cake, that therapeutic suffering has value. Experts note that the body has to sense that it's under duress for hormesis to work. However, researchers might be able to bundle hormetic compounds into a drug that would trigger cellular responses without sparking bodywide agony. In the future, health-conscious folks might pop a stress pill every morning the way many people today down a multivitamin, some scientists predict.

Solving all these questions might allow us to convert stress into an ally. Still, researchers have a lot to do before they can say they've transformed hormesis from a lab curiosity into a clinical standby.

June 29, 2005 Citation: M. Leslie, How Can We Use Moderate Stresses to Fortify Humans and Slow Aging? Sci. Aging Knowl. Environ. 2005 (26), nf49 (2005).

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