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RESEARCH BRIEFSResistance to Food Poisoning Seems Factor in Worm LongevityStudies on C. elegans have shown that an insulinlike signaling pathway helps control the nematode's lifespan. A study in the June 20 Science led by Fred Ausubel, HMS professor of genetics at Massachusetts General Hospital, now suggests that a hardier immune system may account for part of the pathway's effect on longevity. Worms with mutations in the pathway are resistant to pathogenic bacteria and live much longer when fed a diet of these bad bugs than do wild type strains. Staphylococcus aureus (in green) piles up in the gut of a worm, shortening its life span. (Image courtesy of Jake Begun) Ausubel's lab has been using C. elegansas a model for studying bacterial and fungal pathogenesis for several years. In the course of their studies, his team encountered a surprising phenomenon; not only did known pathogens kill the worms early, but E. coli, the standard fare of worms in the lab, was mildly pathogenic as well. When worms were fed a relatively harmless type of bacteria that they were more likely to encounter in the wild, Bacillus subtilis, they lived surprisingly longer. That diet could have such a profound effect on lifespan poses some interesting problems. For one, the lifespan extension enjoyed by these Bacillus-feeders is comparable to that seen in some mutant worms that have been studied for longevity. It is plausible that these mutations have little to do with longevity per se, but instead may be giving the nematodes a resistance to pathogenic factors in E. coli. Ausubel's team, led by Danielle Garsin, tested this theory in a pair of well-known longevity mutants, in collaboration with the lab of Gary Ruvkun, HMS professor of genetics at MGH. They fed B. subtilisto the long-lived daf-2 and age-1 mutants, which have a defect in the pathway analogous to the one that responds to insulin and insulinlike growth factors in mammals. The mutants still outlived wild type worms on the new diet--showing that the longevity was not simply the result of resistance to E. coli pathogenesis--but the extension in survival was slightly less pronounced than it was on E. coli. Furthermore, when the team gave the long-lived daf-2 and age-1 mutants more virulent foods--three different strains of highly pathogenic bacteria--the mutants lived much longer than their wild type peers. Daf-2 mutants, which outlive normal worms by a factor of two when fed E. coli, survived up to six times longer than normal worms on an infectious diet of Staphylococcus aureus. While other factors are involved, "a component of the long-lived phenotype can be attributed to pathogen resistance," Ausubel said. The theory is supported by a study in the June 29 Nature led by Cynthia Kenyon, the Herbert Boyer professor of biochemistry and biophysics at the University of California, San Francisco. Kenyon's group used DNA microarrays to identify genes that were activated downstream of DAF-2 and its transcription factor DAF-16. In addition to genes involved in stress response and metabolism, her team found several antimicrobial genes in the mix. Bacteria have also been observed to build up in the nematodes' digestive tracts as they age. How the bacterial build-up and pathogenesis is related to aging is still unclear, though it may shed light on why humans become susceptible to infection when they are elderly. "The bottom line is that pathogen resistance is intrinsically related to longevity," said Ausubel. "And that relationship may be more subtle than simply dying of an infection." Another implication of the work may be harder for researchers to address: is a change in diet warranted for C. elegans? "It's a bit of an indictment of what we're doing in the worm," said Ruvkun. When Sydney Brenner launched the laboratory career of C. elegans, E. coli was a convenient choice for the worms' diet, since he and other researchers were already studying it. But Ausubel believes that if E. coliis making the worms sick, the effects of a bad diet may be creating a confounding effect.
Immune Cells Deal Death Blow to Damaged NeuronsCatching a common cold may take an additional toll on people with Alzheimer's disease, ALS, and other neurodegenerative diseases--producing accelerated neuronal loss along with sneezes, coughs, and fever. Systemic infections can injure or kill neurons in people with a host of central nervous system diseases. "The general question of how infection can cause neuronal injury is not very well understood," said Timothy Vartanian, HMS associate professor of neurology at Beth Israel Deaconess Medical Center. But Vartanian, Seija Lehnardt, and their colleagues may have hit upon an explanation. They believe that the microglia--macrophagelike cells that are part of the brain's first line of defense against invaders--may be responsible. Normally, these cells protect neurons by digesting pathogens and secreting other inflammatory molecules. Healthy neurons can better withstand the microglia's assault than those affected by neurodegeneration. "In those diseases, you have neurons that have died, are dying, or are on the threshold of death, but still functioning," said Vartanian. Activating the inflammatory response could push these weakened neurons past that threshold, essentially killing them. To test their hypothesis, Vartanian; Lehnardt, visiting research fellow in neurology; and colleagues simulated an infection in cultured brain cells. They did this by adding the bacterial endotoxin lipopolysaccharide (LPS), known to activate the toll-like 4 receptor on microglia. Neurons in the culture were damaged, but only when microglia with an intact toll-like 4 receptor were also present. To see exactly how the microglia were provoking neuronal loss--and specifically whether they were acting as part of a two-step process by killing already weakened neurons--the researchers created temporary ischemic attacks in mice. Normally, mice recover from ischemic insults of 30 minutes or less. However, when exposed to LPS as well, the mice exhibited irreversible brain damage. The findings appear in the June 20 online edition of the Proceedings of the National Academy of Sciences. "This tells us that activation of innate immunity can convert reversible neuronal injury in vivo to irreversible injury," Vartanian said. --Misia Landau
Molecular Timekeeper Keeps Up Speed Through PrecisionImagine if it took 30 seconds for our eyes to catch up with every change of scene in our daily lives. We are saved from such excruciatingly slow transitions by a strict timekeeper in the light-sensing pathway. New research from the lab of Vadim Arshavsky, HMS associate professor of ophthalmology at the Massachusetts Eye and Ear Infirmary, shows that this timekeeper works at a split-second pace because of a domain that helps it perform with high precision in the retina. The findings are reported in the June 19 Neuron. Signals from light and other input turn on a common type of pathway that starts with a receptor and travels through a G protein to its true target in the cell. G proteins can turn up a weak signal, such as light from stars, and they can turn it off, in case we want to look at Mars instead. The problem is, G proteins by themselves can be very slow in ending a signal. The job of keeping the signaling pathways on time and in sync falls to a family known as RGS proteins. But in the crowded cell, how do these timekeepers find the right G proteins within milliseconds? It turns out they need to have the right glue. Led by postdoctoral fellow Kirill Martemyanov, the researchers identified specialized protein domains whose sole function is to ensure rapid mutual recognition between RGS proteins and the G proteins they need to inactivate. The researchers call their newfound specialized molecular glue "affinity adaptors." In the retina's rod and cone cells, the affinity adaptor domain is nestled into the downstream target of the G protein and tightly binds the RSG9-1 shut-down switch. A longer version of the protein, RSG9-2, contains a homologous sticky domain that works the same way on its target G protein signaling complex and may be evolutionarily derived from the same gene. --Carol Cruzan Morton |
