Sci. Aging Knowl. Environ., 19 December 2001
Understanding how animals brace for the worst might provide clues to life extension
Abstract: Plants, animals, and bacteria boast varied mechanisms to resist extreme environmental conditions. Many of these strategies seal an organism in an inactive form: The creature diverts energy from routine life activities to build robust defenses. But emerging evidence suggests that parts of these survival pathways can lengthen life-span without also triggering hibernation.
As far as survivors go, it's hard to beat Sir Ernest Shackleton. After spending two winters stranded on the Antarctic ice, the British explorer led his entire crew to safety. Such endurance didn't help Shackleton lead an exceptionally long life, however: He died of a heart attack at age 48. But hope is not lost for a link between survival and longevity. Although hints of such a biological connection have lurked for decades, recent work brings the idea to the forefront and suggests that it might apply throughout the living world.
Researchers are discovering how natural survivors, from the sacred lotus to the Monarch butterfly, can shield themselves against adverse environmental conditions. Executing some of these survival mechanisms to their fullest extent puts animals in "cold storage": The creatures assume an alternate, sleeplike form that protects them from the elements. Harnessing only parts of these preservation pathways, however, allows some long-lived organisms to extend their normal, active lives. These survival tactics might help plants and animals stave off the most adverse condition of all: old age.
"Organisms in dormancy have mechanisms to prevent damage by metabolic byproducts, reactive oxygen species [free radicals], and radiation," says biogerontologist Richard Miller of the University of Michigan, Ann Arbor. "Maybe these same mechanisms have a role in aging and longevity."
Making the Connection
At first glance, hunkering down against an onslaught might seem unrelated to living longer under normal conditions. But studies of life-span in the roundworm Caenorhabditis elegans illustrate the connection. The tiny nematodes usually live for 3 weeks, but when starved or overcrowded during early development they enter a so-called dauer larval state for up to several months: Dauer larvae cease eating and reproducing until conditions improve, at which time they grow into adults.
Dauer worms don't gain active life-span when they reawaken; they mature and die at rates similar to those of animals that never entered the inactive state. But some mutant animals use dauer tricks to live longer: An insulin/insulin-like growth factor-1 (IGF-1) signaling pathway that regulates dauer formation also controls life-span. Some mutations that turn down pathway activity enable worms to live twice as long as normal, without entering the dauer state (see "Growing Old Together"). The worms might be co-opting dauer stress-resistance strategies: Long-lived mutants defy environmental menaces such as harsh temperatures, chemicals, and radiation better than normal worms do. Mice, yeast, and flies with extended life-spans similarly fight off such threats with unusual aplomb, and mechanistic commonalities might exist. For example, yeast that carry a defect in the Sch9 gene--which shows similarity to a gene in the C. elegans insulin/IGF-1 signaling pathway--resist chemical stress better and live longer than do normal yeast, according to work published last spring by molecular geneticist Valter Longo of the University of Southern California in Los Angeles (see Fabrizio Science article).
"It's a highly conserved system," says molecular biologist Cynthia Kenyon of the University of California, San Francisco. "We want to see whether the same thing happens in higher animals." People wouldn't want to live longer by sleeping away their extra years, but worms show that it's possible to adapt survival techniques to counteract normal aging. Although musings of such a connection between survival and longevity have floated around for years, says geneticist Tom Johnson of the University of Colorado, Boulder, now the concept is stepping into the spotlight. And the idea extends beyond nematodes in a lab dish.
Recent work on Monarch butterflies provides another clear example of the connection between survival and longevity and also illustrates the sacrifices organisms must make to persist. Monarchs breed several times per year; generations that mature in fall fly as far as 5000 kilometers to spend the winter in southern Mexico and avoid freezing to death. These butterflies live six times longer than do their nonmigratory relatives that develop during the summer. Monarch caterpillars that hatch in late fall undergo physiological changes that help them endure the journey and the coming winter. For example, they stock up on fat reserves and put reproduction on hold--a state called reproductive diapause--to focus their energies on survival.
Many of these changes are controlled by juvenile hormone: JH concentrations decrease in fall then rise in winter, and high JH concentrations impel the butterflies to fly north and lay eggs. The butterflies die soon afterward, having fulfilled their reproductive destiny. Although JH ensures fecundity, it appears to limit life-span. Adult Monarchs whose JH-producing endocrine glands have been removed live twice as long as do normal Monarchs, according to work published in the 22 December Proceedings: Biological Sciences by entomologist William Herman of the University of Minnesota, Twin Cities, and geneticist Marc Tatar of Brown University in Providence, Rhode Island.
Like worms, long-lived insects are especially equipped to resist stress. Drosophila with low JH concentrations resist heat and oxidizing chemicals such as paraquat. "[Paraquat] doesn't touch them," says Tatar. In contrast, flies treated with JH succumb readily to the compound. Flies in diapause also flout the harmful effects of heat shock, perhaps because they accumulate an as-yet-unidentified chaperone protein, Tatar says. Studies in C. elegans support the idea that supplementary portions of chaperones--which help other proteins assume and maintain proper structure--can contribute to extended life-span. A particular long-lived C. elegans mutant stalls aging because of extra chaperone proteins, reported worm researcher Gordon Lithgow of the Buck Institute in Novato, California, and colleagues. Many aging-related problems--such as Alzheimer's disease and cataracts--are associated with unfolded or misfolded proteins, so understanding how chaperones affect life-span in other animals could help scientists devise methods to overcome these human afflictions.
But like with Monarch butterflies, stress resistance comes at a cost, which is why insects aren't always pumped up with chaperones, says Tatar. Flies with abnormally low concentrations of the hsp70 chaperone enjoy greater fertility but age faster than normal flies do. Flies with extra hsp70, meanwhile, lay fewer healthy eggs. Clarifying the role of JH and chaperone proteins in survival and life-span is likely to help scientists gain a better understanding of how--and when--survivors make the choice between self-preservation and procreation. This trade-off, says Tatar, is a "key problem in current research." Because some long-lived lab animals don't appear to compromise reproductive fitness in exchange for longer lives, controversy is raging about whether the swap is obligatory (see "Aging Research Grows Up"). Conclusions from this debate might reveal sacrifices that humans who want to extend their life-spans will face.
On the outermost branches of the tree of life perch the freaks of survival--and even these creatures that are unrelated to humans might teach us something about our own aging. The prize for longest (and most controversial) biological survivor goes to a tiny bacterium with the unassuming moniker Bacillus strain 2-9-3. The microbe hid inside salt crystals in the 250-million-year-old Permian Salado salt beds near Carlsbad, New Mexico, until Russell Vreeland, a microbiologist at West Chester University in Pennsylvania, found it. He discovered that the burrowed bacilli could still grow in the lab--albeit very slowly at first, because of their long dormancy. The extent of the bacterium's survival capabilities remains controversial: Some scientists question whether the culture arose from a 250-million-year-old spore or a contaminant that is merely tens of thousands of years old. Still, spores seem capable of endurance feats that humans would envy.
Perhaps Bacillus owes its survival to the molecular armor it pulls on under adverse conditions, such as starvation. When the environment turns unfriendly, many bacteria tighten the links in the cell walls that surround them--a skill especially refined by Bacillus, says Vreeland.
The wall fends against some enemies, but small molecules and destructive temperature changes can penetrate this shield; when the bacterium transforms into its hardy form--or sporulates--it prepares for a time of hardship in other ways as well. The microbe dehydrates, thus rendering itself resistant to heat and chemicals, and brings its metabolism to a halt. In addition, spore-forming bacteria coat their DNA with small acid-soluble proteins, which protect against the DNA breakage that heat and ultraviolet (UV) radiation can induce.
When spores reawaken--a process known as germination--they don't just blink their eyes and jump out of bed. During the first hour of germination, the bacteria metabolize only prepackaged materials that reside in the spore. In that hour they also repair DNA damage that occurred while they slept. The longer a spore has slumbered, the longer it takes to germinate. Several-week-old spores germinate in about 24 hours; 1-year-old spores require 48 hours. Vreeland's spores took 2 months.
Although the mechanism of spore formation is not fully fleshed out, genetic studies from a variety of bacterial species implicate about 130 genes in the process. Many resemble eukaryotic genes, but it remains to be seen whether any of these genes from more complex organisms confer life-extending capabilities. Although humans would shrivel after millions of years in a salt bed, they face many of the same threats as a salt-embedded spore does, to less dire extremes. Subtle variations on mechanisms that toughen spore defenses might help us withstand chemical or radiation insults over less geologic lengths of time.
Durability isn't restricted to the animal kingdom: The Chinese sacred lotus wins the award for the second-longest survivor. Aquatic lotus plants, one of which can cover an entire lake, have been cultivated as a food crop in Asia for more than 5000 years. After radiocarbon dating revealed 1300-year-old lotus seeds, plant biologist Jane Shen-Miller of the University of California, Los Angeles, wondered whether the ancient seeds would still sprout. She sowed 67 of them; 80% germinated.
What's the secret of the lotus? The seed's outer fruit coat is very hard, reminiscent of Bacillus's spore wall. The many layers of lignin and cellulose--polymers that compose plant cell walls--prevent the entry of water and oxygen, two culprits in the breakdown of any tissue. "These cells are impervious," says Shen-Miller. Furthermore, several lotus chaperone proteins boast unusual heat resistance: They remain properly folded at temperatures that fry normal proteins, including most other chaperones. Two of the tenacious molecules can withstand 110 degrees C, and a third one keeps its shape at 80 degrees C.
Lotus seeds are far from perfect survival machines, however. Old seeds lose their outer layer of lignin and cellulose protection over time. Plants from old seeds grow rapidly after germination but are small and droopy. They also have abnormally small, thick, curled leaves. Furthermore, their dormant phase ends earlier in the year--in January rather than March--which can expose them to intolerably severe weather. But perfection is a lot to ask from something that's been out of circulation for more than a millennium, and Shen-Miller suggests that the lotus has plenty to teach us about staving off the ravages of aging. Understanding the lotus chaperones' unique properties might reveal how the Asian plant has taken survival to an extreme and how we could shore up our own defenses.
A Human Connection?
Whether humans can learn from an ancient plant or a salt-encrusted bacterium remains to be seen. Humans don't store their seeds for thousands of years, form spores, or otherwise assume an altered state that helps them survive. But all organisms must withstand a variety of threats: temperature extremes, harmful chemicals, UV radiation, and lack of food. The survivors have relinquished normal, active lives for especially robust defenses. Perhaps by understanding their molecular exploits, we can adapt some of them to increase our own vitality.
December 19, 2001
Sibylle Hechtel writes about science from Boulder, Colorado. She's survived numerous climbing trips and hopes that those experiences will help her live longer.
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