Colonies of Bacteria Fight for Resources With Lethal Protein

Rival colonies of bacteria can produce a lethal chemical that keeps competitors at bay, scientists report. By halting the growth of nearby colonies and even killing some of the cells, groups of bacteria preserve scarce resources for themselves, even when the encroaching colony is closely related.

"It supports the notion that each colony is a superorganism, a multicellular organism with it's own identity," said Eshel Ben-Jacob, an adjunct senior scientist at UC San Diego's Center for Theoretical Biological Physics and professor of physics at Tel Aviv University. Ben-Jacob and lead author Avraham Be'er of the University of Texas, Austin, and other colleagues at these institutions report their discovery in the early online edition of the Proceedings of the National Academy of Sciences.

Alone in a dish, colonies of the bacterium Paenibacillus dendritiformis will send branches of cells in all directions. But when forced to share a plate of limited nutrients with another colony, the branching patterns of both colonies become lopsided, leaving a space between the two.

It's not a lack of food that halts the growth. The researchers found nutrients in the gap, but they also found a protein there that wasn't present elsewhere on the dish. When they dabbed a bit of the purified protein on a fresh dish inoculated with P. dendritiformis, the bacteria formed a lopsided colony that shied away from the spot. And the cells at the edge of the colony closest to the suspect protein were dead.

They named the protein "sibling lethal factor," for its ability to kill even closely related colonies derived from a single original colony, and identified its gene. But the gene made a protein that was too large, heavier that the lethal factor by two-thirds and harmless. They concluded that some other factor must be in play.

Rather than guess, or poke about experimentally to figure out what was going on, Ben-Jacob and his colleagues created a model to guide their thinking.

"In physics, we use models to make predictions," Ben-Jacob said, noting that biological models often present what is already understood. The model told them that they should be looking for something that would prune the full-size factor to its smaller lethal form as the colonies began to compete, a factor that might be harmless or even helpful until it reached a certain threshold.

P. dendritiformis also secretes a protein called subtilisin, which promotes growth, except in high concentrations. Subtilisin, which was already known and is available commercially, clipped the full-sized protein to the size of that found between competing colonies. This smaller piece slices the bacteria cells open and spills their contents into the medium, they found.

"Very often, you discover that in order to explain what's going on, you need to imagine mechanisms that are beyond what the biologists have specifically discovered about the system," said Herbert Levine, a physics professor at UC San Diego who co-directs the Center for Theoretical Biological Physics, but was not involved in this study. "In this work, they've succeeded in taking the next step," he said. "They were able find the chemical messenger that is actually playing the role they hypothesized."

Journal Reference:

1. A. Be'er, G. Ariel, O. Kalisman, Y. Helman, A. Sirota-Madi, H.P. Zhang, E.-L. Florin, S. M. Payne, E. Ben-Jacob, H. L. Swinney. Lethal protein produced in response to competition between sibling bacterial colonies. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1001062107

Courtesy: ScienceDaily

Disease Cause Is Pinpointed With Genome

Two research teams have independently decoded the entire genome of patients to find the exact genetic cause of their diseases. The approach may offer a new start in the so far disappointing effort to identify the genetic roots of major killers like heart disease, diabetes and Alzheimer’s.

In the decade since the first full genetic code of a human was sequenced for some $500 million, less than a dozen genomes had been decoded, all of healthy people.

Geneticists said the new research showed it was now possible to sequence the entire genome of a patient at reasonable cost and with sufficient accuracy to be of practical use to medical researchers. One subject’s genome cost just $50,000 to decode.

“We are finally about to turn the corner, and I suspect that in the next few years human genetics will finally begin to systematically deliver clinically meaningful findings,” said David B. Goldstein, a Duke University geneticist who has criticized the current approach to identifying genetic causes of common diseases.

Besides identifying disease genes, one team, in Seattle, was able to make the first direct estimate of the number of mutations, or changes in DNA, that are passed on from parent to child. They calculate that of the three billion units in the human genome, 60 per generation are changed by random mutation — considerably less than previously thought.

The three diseases analyzed in the two reports, published online Wednesday, are caused by single, rare mutations in a gene.

In one case, Richard A. Gibbs of the Baylor College of Medicine sequenced the whole genome of his colleague Dr. James R. Lupski, a prominent medical geneticist who has a nerve disease, Charcot-Marie-Tooth neuropathy.

In the second, Leroy Hood and David J. Galas of the Institute for Systems Biology in Seattle have decoded the genomes of two children with two rare genetic diseases, and their parents.

More common diseases, like cancer, are thought to be caused by mutations in several genes, and finding the causes was the principal goal of the $3 billion human genome project. To that end, medical geneticists have invested heavily over the last eight years in an alluring shortcut.

But the shortcut was based on a premise that is turning out to be incorrect. Scientists thought the mutations that caused common diseases would themselves be common. So they first identified the common mutations in the human population in a $100 million project called the HapMap. Then they compared patients’ genomes with those of healthy genomes. The comparisons relied on ingenious devices called SNP chips, which scan just a tiny portion of the genome. (SNP, pronounced “snip,” stands for single nucleotide polymorphism.) These projects, called genome-wide association studies, each cost around $10 million or more.

The results of this costly international exercise have been disappointing. About 2,000 sites on the human genome have been statistically linked with various diseases, but in many cases the sites are not inside working genes, suggesting there may be some conceptual flaw in the statistics. And in most diseases the culprit DNA was linked to only a small portion of all the cases of the disease. It seemed that natural selection has weeded out any disease-causing mutation before it becomes common.

The finding implies that common diseases, surprisingly, are caused by rare, not common, mutations. In the last few months, researchers have begun to conclude that a new approach is needed, one based on decoding the entire genome of patients.

The new reports, though involving only single-gene diseases, suggest that the whole-genome approach can be developed into a way of exploring the roots of the common multigene diseases.

“We need a way of assessing rare variants better than the genomewide association studies can do, and whole-genome sequencing is the only way to do that,” Dr. Lupski said.

With 10 genomes of healthy humans sequenced, Dr. Gibbs, a specialist in DNA sequencing, decided it was time to decode the genome of someone with a genetic disease and asked his colleague Dr. Lupski to volunteer.

Mutations in any of 39 genes can cause Charcot-Marie-Tooth, a disease that impairs nerves to the hands and feet and causes muscle weakness.

Fifty thousand dollars later, Dr. Lupski turned out to have mutations in an obscure gene called SH3TC2. The copy of the gene he inherited from his father is mutated in one place, and the copy from his mother in a second.

Both his parents had one good copy of the gene in addition to the mutated one. A single good copy can generate enough, or nearly enough, of the gene’s product for the nerves to work properly. Dr. Lupski’s mother was free of the disease and his father had only mild symptoms.

In the genetic lottery that is human procreation, two of their eight children inherited good copies of SH3TC2 from each parent; two inherited the mother’s mutation but the father’s good copy and are free of the disease; and four siblings including Dr. Lupski inherited mutated copies from both parents. These four all have Charcot-Marie-Tooth disease. The results are reported in The New England Journal of Medicine.

In Seattle, Dr. Hood and Dr. Galas have also applied whole-genome sequencing to disease. They analyzed the genome of a family of four, in which the two children each have two single-gene diseases, called Miller syndrome and ciliary dyskinesia. With four related genomes available, the researchers could identify the causative genes. They also improved the accuracy of the sequencing because DNA changes that did not obey Mendel’s rules of inheritance could be classed as errors in the decoding process.

The Seattle team believes whole-genome sequencing can be applied to the study of the common multigene diseases and plans to sequence more than 100 genomes next year, starting with multigenerational families.

The family whose genomes they report in Science were sequenced by a company with a new DNA sequencing method, Complete Genomics of Mountain View, Calif., at a cost of $25,000 each. Clifford Reid, the chief executive, said that the company was scaling up to sequence 500 genomes a month and that for large projects the price per genome would soon drop below $10,000. “We are on our way to the $5,000 genome,” he said.

Dr. Reid said the HapMap and genomewide association studies were not a mistake but “the best we could do at the time.” But they have not yet revolutionized medicine, “which we are on the verge of doing,” he said.

Dr. Goldstein, of Duke University, said the whole-genome sequencing approach that was now possible should allow rapid progress. “I think we are finally headed where we have long wanted to go,” he said.

Courtesy: Newyork Times

Low Levels of Vitamin D Linked to Higher Rates of Asthma in African-American Kids

Researchers at Children's National Medical Center have discovered that African American children with asthma in metropolitan Washington, DC, are significantly more likely to have low levels of vitamin D than healthy African American children. This study supports recent research that suggests vitamin D plays a greater role in the body than just keeping bones healthy. Vitamin D deficiency has been recently linked to a variety of non-bone related diseases including depression, autoimmune disorders, and now asthma.

"It's been well-documented that as a group, African Americans are more likely than other racial groups to have low levels of vitamin D," said Robert Freishtat, MD, MPH, an emergency medicine physician and lead author on the study. "But we were shocked to see that almost all of the African American children with asthma that we tested had low vitamin D levels. After adjusting for differences in age, weight, and the time of year of the testing, the odds of these kids with asthma being vitamin D deficient were nearly twenty times those of healthy kids."

The study took a one-time measurement of vitamin D in the blood of 85 African American children with asthma, who were between 6 and 20 years old. Additionally, the researchers measured the vitamin D levels of 21 healthy African American children between the ages of 6 and 9 years of age. The research team found that 86 percent of the children in the study with asthma had insufficient levels of vitamin D, while only 19 percent of non-asthmatics had these low levels.

These findings may mean that low vitamin D levels have more serious effects on a child's lung health than previously believed. Though more research is needed to establish definitively how vitamin D deficiency can contribute to asthma, parents can ensure that their children receive healthier amounts of vitamin D by following the current USDA guidelines for milk consumption and seeking a doctor's advice about multivitamins.

"The District of Columbia has among the highest rates of pediatric asthma in the United States, and we're working to find out why," says Stephen Teach, MD, MPH, senior author of the study. "For African American kids with asthma, vitamin D testing and ensuring adequate vitamin D intake may need to become necessary steps in their primary care."

Journal Reference:

1. Robert J. Freishtat, Sabah F. Iqbal, Dinesh K. Pillai, Catherine J. Klein, Leticia M. Ryan, Angela S. Benton, Stephen J. Teach. High Prevalence of Vitamin D Deficiency among Inner-City African American Youth with Asthma in Washington, DC. The Journal of Pediatrics, 2010; DOI: 10.1016/j.jpeds.2009.12.033

Courtesy: ScienceDaily

Marine Mr. Mom: Male Pipefish Gives Birth, but Some Are Deadbeat Dads, Study Shows

Male pipefishes and their seahorse cousins are the only males that actually become pregnant and give birth, but pipefishes likely will never win any Father of The Year awards -- their attitude towards their offspring can range from total love to total neglect, according to new findings from Texas A&M University researchers.

Kim Paczolt and Adam Jones, researchers in the Department of Biology, found that the male pipefish can be a nurturing father as it tends its young before giving birth, but later it may not choose to make the effort. The key factor for this attitude: How the male feels about the mother.

The study was funded by the National Science Foundation and the findings are published in the current issue of Nature.

The Texas A&M researchers studied consecutive broods in male Gulf pipefish to understand why some offspring survive while others do not. Their results reveal that the males who were especially fond of the females they had mated with were more likely to show a nurturing attitude toward their offspring. In almost every case, those that were not overly fond of the mother were less nurturing toward their young.

"The bottom line seems to be, if the male likes the mom, the kids are treated better," Paczolt explains.

"Why this occurs, we don't fully understand, but our findings are quite specific about this relationship between the male pipefish and its mate. If the male prefers the female, he treats their mutual offspring better."

Pipefishes are found worldwide and are especially prevalent in tropical and subtropical waters, including the U.S. Gulf Coast. They are 4-5 inches in length and somewhat resemble a stretched-out version of a seahorse.

Like the seahorse, the male pipefish becomes pregnant and gives birth. The Gulf pipefish can carry from 5 to 40 developing offspring at one time in its specialized brood pouch.

Pipefishes and seahorses are part of a family of marine life called syngnathid fishes that have a unique reproductive system in which the male carries developing embryos. The male -- not the female -- provides for the embryo during their development.

Paczolt says the study supports several aspects of the sexual selection theory -- not only do individuals choose their mates based on a variety of traits, but also, this choice can be expressed both before and after mating.

"The one trait in the pipefish that seems to stand out is the size of the female," she adds.

"Mate choice in the Gulf pipefish is related to the size of the female. Males tend to seek out larger females to be their mates. If he really likes his female mate, he makes a greater effort to tend their babies. It's almost as if he is saying, 'Are these babies worth my effort?' If he is not overly fond of the mother, the answer appears to be 'No,' and he invests fewer resources."

Paczolt says by studying male pregnancy in pipefish, it may give researchers a better understanding of how the brood pouch in syngnathid fishes evolved. "The whole phenomenon of male pregnancy is full of conflict and far more complex than we had previously realized," she notes.

Journal Reference:

1. Kimberly A. Paczolt & Adam G. Jones. Post-copulatory sexual selection and sexual conflict in the evolution of male pregnancy. Nature, 2010; 464 (7287): 401 DOI: 10.1038/nature08861

Courtesy: ScienceDaily

Frogs, Foam and Fuel: Solar Energy Converted to Sugars

For decades, farmers have been trying to find ways to get more energy out of the sun. In natural photosynthesis, plants take in solar energy and carbon dioxide and then convert it to oxygen and sugars. The oxygen is released to the air and the sugars are dispersed throughout the plant -- like that sweet corn we look for in the summer. Unfortunately, the allocation of light energy into products we use is not as efficient as we would like. Now engineering researchers at the University of Cincinnati are doing something about that.

The researchers are finding ways to take energy from the sun and carbon from the air to create new forms of biofuels, thanks to a semi-tropical frog species. Their results have just been published online in Nano Letters.

Research Assistant Professor David Wendell, student Jacob Todd and College of Engineering and Applied Science Dean Carlo Montemagno co-authored the paper, based on research in Montemagno's lab in the Department of Biomedical Engineering. Their work focused on making a new artificial photosynthetic material which uses plant, bacterial, frog and fungal enzymes, trapped within a foam housing, to produce sugars from sunlight and carbon dioxide.

Foam was chosen because it can effectively concentrate the reactants but allow very good light and air penetration. The design was based on the foam nests of a semi-tropical frog called the Tungara frog, which creates very long-lived foams for its developing tadpoles.

"The advantage for our system compared to plants and algae is that all of the captured solar energy is converted to sugars, whereas these organisms must divert a great deal of energy to other functions to maintain life and reproduce," says Wendell. "Our foam also uses no soil, so food production would not be interrupted, and it can be used in highly enriched carbon dioxide environments, like the exhaust from coal-burning power plants, unlike many natural photosynthetic systems."

He adds, "In natural plant systems, too much carbon dioxide shuts down photosynthesis, but ours does not have this limitation due to the bacterial-based photo-capture strategy."

There are many benefits to being able to create a plant-like foam.

"You can convert the sugars into many different things, including ethanol and other biofuels," Wendell explains. "And it removes carbon dioxide from the air, but maintains current arable land for food production."

"This new technology establishes an economical way of harnessing the physiology of living systems by creating a new generation of functional materials that intrinsically incorporates life processes into its structure," says Dean Montemagno. "Specifically in this work it presents a new pathway of harvesting solar energy to produce either oil or food with efficiencies that exceed other biosolar production methodologies. More broadly it establishes a mechanism for incorporating the functionality found in living systems into systems that we engineer and build."

The next step for the team will be to try to make the technology feasible for large-scale applications like carbon capture at coal-burning power plants.

"This involves developing a strategy to extract both the lipid shell of the algae (used for biodiesel) and the cytoplasmic contents (the guts), and reusing these proteins in the foam," says Wendell. "We are also looking into other short carbon molecules we can make by altering the enzyme cocktail in the foam."

Montemagno adds, "It is a significant step in delivering the promise of nanotechnology."

Journal Reference:

1. Wendell et al. Artificial Photosynthesis in Ranaspumin-2 Based Foam. Nano Letters, 2010; 100305125936067 DOI: 10.1021/nl100550

Courtesy: ScienceDaily

Bacteria drive electric mud?

Underwater mud can conduct electricity, possibly with the help of bacteria in the sediment -- a result that helps explain the large amount of electrical activity researchers have detected in ocean sediments, a study published in this week's in Nature reports.

The finding could change how researchers think about microbes' contributions to geochemical processes.

"It's an interesting and important contribution," said Dirk de Beer from the Max Planck Institute for Marine Microbiology, who was not involved in the study. The findings show that processes crucial for life in underwater environments, such as oxidation and reduction reactions, "run faster than we think they can, and in places where we don't expect them," said de Beer.

Researchers made the discovery, because, like many great scientist, they got lazy about cleaning their petri dishes, said lead author Lars Peter Nielsen from Aarhus University in Denmark. "We had some stinky mud standing in the lab," said Nielsen, and they noticed that the sulfides -- "the stinky part" in the upper centimeter of the mud -- changed color over time, indicating that the sulfide had been oxidized. Sulfides are present in mud that lacks oxygen, which should have been true of all the mud in Nielsen's petri dish save that at the very surface, and yet as far as a centimeter down, the sulfur had been converted into elemental sulfur -- a process that requires an electron acceptor like oxygen.

When they depleted oxygen from the surface water, sulfide levels in the mud rose, and when oxygen was bubbled back into the water, the sulfide levels dropped. Oxygen can't diffuse into the mud as quickly as this fluctuation took place; instead, the researchers showed a link between this change and the movement of electrons.

Nielsen and his colleagues believe that conductance is driven by bacteria stratified in different layers of the sediment. The bacteria at the surface, with access to oxygen, respire, consuming the electrons. Those electrons are produced by the bacteria in the sulfur rich lower sediments as they convert food into energy. "One will eat, the other will breathe and together they will share the energy," said Nielsen.

Researchers recently discovered that some bacteria have so-called nanowires, hair-like extensions on the cells' surface that can conduct electricity. Nielsen and his colleagues speculate that these nanowires are responsible for conducting the electrons. But these wires are very short, said de Beer, and it's unclear how they would extend their reach to the centimeter conductance that the researchers observed.

One possibility suggested in the study is that semi-conductive granules of pyrite, a mineral present in the sediment, might act to bridge the gaps between the nanowires. As yet, though, there is no direct evidence for this idea. "It's possible that some of the bacteria in the sediment are conductive," said de Beer, but that remains to be shown. Another possibility, said de Beer, is simply that the minerals in the sediment, rather than the bacteria, are conductive.

He noted that oxygen can reach lower levels of sediment not just by the electrical process Nielsen's group proposes. It can also be carried via burrowing animal and sediment mixing caused by ocean currents. "How important this concept is in the real environment needs to be proven," said de Beer.

One potential issue, noted Fons Stams from Wageningen University in the Netherlands, who didn't participate in the research, is that the authors didn't directly measure electrical conductance, but instead measured pH -- which depends on the level of free electrons -- as a stand-in. De Beers agreed, noting that "pH is influenced by many things." For changes seen over such a distance -- about 1 centimeter -- and at such a speed, however, conductance "is the only possible explanation," said de Beer.

De Beer, who researches sediments on the ocean floor, envisions taking advantage of this phenomenon to produce energy in-situ during deep sea dives. The electrical current in sediment may not be enough to fuel something as large as a submersible, he said, but it could fuel a light bulb or more importantly, deep sea monitoring equipment.

Courtesy: The Scientist

Hot Road to New Drugs: Efficient Identification of Drug Candidates

The search for new therapeutic agents is time-consuming and expensive. Pharmaceutical companies may have to screen thousands of compounds for the ability to bind a target molecule before they hit upon a promising drug candidate.

A group of Biophysicists at LMU Munich led by Professor Dieter Braun, a member of the Cluster of Excellence "Nanosystems Initiative Munich" (NIM), and a partner in NanoTemper (an LMU spin-off), have now developed a unique technology called "microscale thermophoresis" that allows to measure intereactions under close-to-native conditions, thus improving the decision making process in drug development.

The technique takes advantage of the Soret effect -- the tendency of molecules to drift along temperature gradients, usually from warm to cold. If a compound encounters and binds to another molecule, its thermophoretic parameters change, and its trajectory may even be reversed. This phenomenon can be exploited to determine whether a molecule that is known to play a causative role in a given disease binds to a test substance. In the test, which can be carried out directly on blood samples, the thermodiffusion of a labelled biomolecule of interest is measured in the presence and absence of a candidate binding agent. If the two bind together to form a complex, the resulting change in their thermophoretic behaviour can be detected.

"Detection of binding activity is the first step on the road to a new drug," says Braun. "The new method also has potential applications in medical diagnostics, and in food and environmental monitoring."

The procedures conventionally used to identify candidate drugs are normally carried out in artificial buffer solutions, and the results often have little relationship to a compound's binding affinity for its target in the blood.

The new thermophoretic technique, on the other hand, allows one to perform the binding test directly in a blood sample and therefore gives more reliable results. The substance to be tested is mixed with a blood sample containing a target that is known to be associated with a disease state and has been labelled with a fluorescent tag. A tiny drop of the mixture is taken up into a thin glass capillary tube, and a focused beam of IR-laser light is used to heat a small volume of the solution in the middle of the tube. This gives rise to a temperature gradient that falls off towards the outside. The response of the labelled molecule to the variation in temperature can then be followed using fluorescence methods.

Upon heating of the sample, it immediately becomes apparent whether or not the fluorescent target-molecules in the sample behave differently in the presence of the drug test compound than they do in its absence. Any difference in thermophoresis between the two samples indicates that the test substance binds to the labelled target, and provides the first hint that it may have therapeutic potential.

"Our method will not only be a boon to drug discovery," says Braun. "It can also be used in medical diagnostics, food testing and environmental monitoring. One could, for instance, employ it to diagnose autoimmune diseases and infections, or as the basis for a rapid test for the presence of antibiotics in milk or toxic substances in water."

Journal Reference:

1. Philipp Baaske, Christoph J. Wienken, Philipp Reineck, Stefan Duhr und Dieter Braun. Optical Thermophoresis for Quantifying the Buffer Dependence of Aptamer Binding. Angewandte Chemie International Edition, 2010; NA DOI: 10.1002/anie.200903998

Courtesy: ScienceDaily

Fish Use UV Patterns to Tell Species Apart

If you’ve seen one damselfish, you’ve seen them all.

That may be true for people, who have a difficult time telling some damselfish species apart. But the fish themselves see it differently, according to a study in Current Biology. They can use ultraviolet facial patterns to tell one species from another.

Ulrike E. Siebeck of the University of Queensland in Australia and colleagues studied Pomacentrus amboinensis and P. moluccensis, two species of damselfish capable of seeing light at the ultraviolet end of the spectrum. They are also highly territorial: P. amboinensis males, for example, will chase off unfamiliar members of their species because they are seen as competitors, but go easier on P. moluccensis intruders.

To people, the two species of reef fish look practically identical. But under UV light they are revealed to have distinctly different patterns in the scales around the eyes. “These are really fine, intricate patterns that we can’t see at all,” Dr. Siebeck said.

The question for her and her colleagues was whether the patterns, and the ability to see them, had an effect on behavior. In a series of experiments in which, among other things, they placed fish inside a glass chamber equipped with UV filters, they showed that P. amboinensis used the patterns to discriminate between the two species.

The work provides support for the idea, suggested by others, that the ultraviolet part of the spectrum may be a way for some species to communicate secretly, in ways invisible to those that cannot see UV.

Courtesy: NewyorkTimes

Protein Shown to Be Natural Inhibitor of Aging in Fruit Fly Model

Scientists at the University of California, San Diego School of Medicine, have identified a protein called Sestrin that serves as a natural inhibitor of aging and age-related pathologies in fruit flies. They also showed that Sestrin, whose structure and biochemical function are conserved between flies and humans, is needed for regulation of a signaling pathway that is the central controller of aging and metabolism.

The work, led by Michael Karin, PhD, Distinguished Professor of Pharmacology in UCSD's Laboratory of Gene Regulation and Signal Transduction, is the cover story of the March 5 issue of the journal Science.

Sestrins are highly conserved small proteins that are produced in high amounts when cells experience stress. Sestrin function, however, remained puzzling until the Karin group found that these proteins function as activators of AMP-dependent protein kinase (AMPK), and inhibitors of the Target of Rapamycin (TOR). AMPK and TOR are two protein kinases that serve as key components of a signaling pathway shown to be the central regulator of aging and metabolism in a variety of model organisms, including the worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster and mammals.

AMPK is activated in response to caloric restriction, a condition that slows down aging, whereas TOR is activated in response to over-nutrition, a condition that accelerates aging. Activation of AMPK inhibits TOR, and drugs that activate AMPK or inhibit TOR can delay aging in several different model organisms including mammals. But how the body keeps the activity of these two protein kinases in balance to prevent premature aging was unknown. Additionally, the presence of three different genes encoding Sestrins in mammals made it difficult to identify their exact physiological function in live animals.

The new study took advantage of the finding that the fruit fly Drosophila, whose AMPK-TOR signaling pathway functions in the same manner as its mammalian equivalent, contains a single Sestrin gene. Using a variety of genetic techniques, first author Jun Hee Lee inactivated the Sestrin gene of Drosophila and found that although Sestrin-deficient flies do not exhibit any developmental abnormalities, they suffer from under-activation of AMPK and over-activation of TOR -- confirming that Sestrin is needed for keeping this pathway in check. Most importantly, the biochemical imbalance incurred by loss of Sestrin expression resulted in several age-related pathologies.

"Strikingly, the pathologies caused by the Sestrin deficiency included accumulation of triglycerides, cardiac arrhythmia and muscle degeneration that occurred in rather young flies," said Karin. "These pathologies are amazingly similar to the major disorders of overweight, heart failure and muscle loss that accompany aging in humans."

Lee and colleagues at UC San Diego and the Sanford-Burnham Institute in La Jolla, California, went on to demonstrate that feeding flies with drugs that either activate AMPK or inhibit TOR conferred protection against most of these early aging, degenerative symptoms. The researchers also found that over-activation of TOR is likely to accelerate aging of heart and skeletal muscles by disrupting an important "quality control" process called autophagy. Autophagy allows cells to rid themselves of and replace damaged mitochondria, the little power plants that provide all cells, especially muscles, with energy. However, when mitochondria get old, they produce high concentrations of reactive oxygen species (ROS), or free radicals, that can lead to tissue damage.

Karin explained that the process of autophagy -- which counteracts aging -- allows the replacement of "old" and defective mitochondria with "brand new" mitochondria. Sestrin-deficient flies, however, were found to exhibit accumulation of damaged mitochondria and ROS several days prior to the detection of muscle degeneration. Feeding these flies vitamin E, an antioxidant which neutralizes free radicals, prevented premature muscle degeneration and heart failure.

In future work, the Karin group plans to examine whether the mammalian Sestrins also control aging and metabolism, and whether defects in proper Sestrin expression will provide the explanation to some of the currently unexplainable degenerative diseases associated with old age.

"Maybe one day we will be able to use Sestrin analogs to prevent much of the tissue failure associated with aging, as well as treat a number of degenerative diseases, whose incidence goes up with old age, including sarcopenia and Alzheimer's disease," said Karin.

Additional contributors to the study -- a collaboration between three laboratories at UC San Diego School of Medicine, UCSD Division of Biology and the Sanford-Burnham Institute -- are Andrei V. Budanov, Eek Joong Park, Ryan Birse, Teddy E. Kim, Guy A. Perkins, Karen Ocorr, Mark H. Ellisman, Rolf Bodmer and Ethan Bier.

The research was funded by the National Institutes of Health, the Superfund Basic Research Program and American Cancer Society.

Journal Reference:

1. Jun Hee Lee, Andrei V. Budanov, Eek Joong Park, Ryan Birse, Teddy E. Kim, Guy A. Perkins, Karen Ocorr, Mark H. Ellisman, Rolf Bodmer, Ethan Bier, and Michael Karin. Sestrin as a Feedback Inhibitor of TOR That Prevents Age-Related Pathologies. 2010: 327 (5970): 1223-1228, DOI: 10.1126/science.1182228

Courtesy: ScienceDaily