Aging  

A new study using the nematode worm C. elegans indicates that vitamin D works with longevity genes to increase lifespan and prevent the accumulation of toxic proteins linked to age-related chronic diseases.

A new study indicates that vitamin D has much wider effects on the body than previously realized, and that the vitamin is deeply associated with many aging-related ailments.  The work was conducted with the nematode worm, C. elegans. Research at the Buck Institute for Research on Aging shows that vitamin D works through genes known to influence longevity and impacts processes associated with many human age-related diseases.

The study, which was published in recently in the journal Cell Reports, may help explain why vitamin D deficiency has been linked to breast, colon and prostate cancer, along with as obesity, heart disease and depression.

“Vitamin D engaged with known longevity genes – it extended median lifespan by 33 percent and slowed the aging-related misfolding of hundreds of proteins in the worm,” said Gordon Lithgow, the study's senior author. “Our findings provide a real connection between aging and disease and give clinicians and other researchers an opportunity to look at vitamin D in a much larger context.”

"Our findings provide a real connection between aging and disease and give clinicians and other researchers an opportunity to look at vitamin D in a much larger context."

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The study builds on the knowledge of the ability of proteins to maintain their shape and function over time, or protein homeostasis. This biological function is one of the main items to fail with normal aging – often resulting in the accumulation of toxic insoluble protein aggregates implicated in a number of conditions, including Alzheimer’s, Parkinson’s and Huntington’s diseases, as well as type 2 diabetes and some forms of heart disease.

“Vitamin D3, which is converted into the active form of vitamin D, suppressed protein insolubility in the worm and prevented the toxicity caused by human beta-amyloid which is associated with Alzheimer’s disease,” said Lithgow. “Given that aging processes are thought to be similar between the worm and mammals, including humans, it makes sense that the action of vitamin D would be conserved across species as well.”

If he receives funding, senior author Lithgow plans to test vitamin D in mice to measure and determine how it affects aging, disease and function – and he hopes that clinical trials in humans will go after the same measurements. “Maybe if you’re deficient in vitamin D, you’re aging faster. Maybe that’s why you’re more susceptible to cancer or Alzheimer’s,” he said. “Given that we had responses to vitamin D in an organism that has no bone suggests that there are other key roles, not related to bone, that it plays in living organisms.”

"One theme continues to emerge from our work – that aging and disease stem from common mechanisms. Delaying disease by delaying the aging process is a serious proposition,” states Lithgow.

SOURCE  The Buck Institute

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Aging  

Researchers have discovered that adult cells abruptly begin their downhill slide when an animal reaches reproductive maturity. They believe this genetic switch provides a target for future study.

Northwestern University researchers now have a molecular clue that pinpoints the start of aging in animals. In a study of the transparent roundworm C. elegans, they found that adult cells abruptly begin their downhill slide when an animal reaches reproductive maturity.

A genetic switch starts the aging process by turning off cell stress responses that protect the cell by keeping important proteins folded and functional. The switch is thrown by germline stem cells in early adulthood, after the animal starts to reproduce, ensuring its line will live on.

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While the studies were conducted in worms, the findings have implications for humans, the researchers report. The genetic switch and other components identified by the scientists as playing a role in aging are conserved in all animals, including humans, offering targets for future study.

Knowing more about how the quality control system works in cells could help researchers one day figure out how to provide humans with a better cellular quality of life and therefore delay degenerative diseases related to aging, such as neurodegenerative diseases.

"Wouldn't it be better for society if people could be healthy and productive for a longer period during their lifetime?" said Richard I. Morimoto, the senior author of the study. "I am very interested in keeping the quality control systems optimal as long as we can, and now we have a target. Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress."

The study, built on a decade of research, has been published in the journal Molecular Cell. Johnathan Labbadia, a postdoctoral fellow in Morimoto's lab, is the first author of the paper.

In C. elegans, the decline begins eight hours into adulthood -- all the switches get thrown to shut off an animal's cell stress protective mechanisms. Morimoto and Labbadia found it is the germline stem cells responsible for making eggs and sperm that control the switch.

In animals, including C. elegans and humans, the heat shock response is essential for proper protein folding and cellular health. Aging is associated with a decline in quality control, so Morimoto and Labbadia looked specifically at the heat shock response in the life of the roundworm.

"Our findings suggest there should be a way to turn this genetic switch back on and protect our aging cells by increasing their ability to resist stress."

"We saw a dramatic collapse of the protective heat shock response beginning in early adulthood," Morimoto said.

Morimoto and Labbadia found the genetic switch occurs between two major tissues in an organism that determine the future of the species: the germline and the soma (the body tissues of the animal, such as muscle cells and neurons). Once the germline has completed its job and produced eggs and sperm -- necessary for the next generation of animals -- it sends a signal to cell tissues to turn off protective mechanisms, starting the decline of the adult animal.

"C. elegans has told us that aging is not a continuum of various events, which a lot of people thought it was," Morimoto said.

"In a system where we can actually do the experiments, we discover a switch that is very precise for aging," he said. "All these stress pathways that insure robustness of tissue function are essential for life, so it was unexpected that a genetic switch is literally thrown eight hours into adulthood, leading to the simultaneous repression of the heat shock response and other cell stress responses."

Using a combination of genetic and biochemical approaches, Morimoto and Labbadia found the protective heat shock response declines steeply over a four-hour period in early adulthood, precisely at the onset of reproductive maturity. The animals still appear normal in behavior, but the scientists can see molecular changes and the decline of protein quality control.

"This was fascinating to see," Morimoto said. "We had, in a sense, a super stress-resistant animal that is robust against all kinds of cellular stress and protein damage. This genetic switch gives us a target for future research."

SOURCE  Nortwestern University

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 Cryonics  

Researchers have now proven that cryogenically-suspended worms maintain their memories after reanimation.

S ome animals can survive extended periods of actually being frozen.  Understanding and controlling this ability is a key area of researcher for the field of cryonics—in the hope that someday frozen humans who were about to die of disease or accident can be revived and restored.

Animals undergo the process by somehow regulating the way their bodies enter a frozen state, and at the other end of the cycle, controlling the thawing out process.

Until recently it hasn’t been understood whether important higher-level functions, like memory, are preserved in the natural cryonic process. Now, Natasha Vita-More and Daniel Barranco, have proven for the first time that cryogenically-suspended nematode worms keep their memories after reanimation.

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The researchers first trained the C. Ekegans worms to move to specific areas in an area when they smelled benzaldehyde (a component of almond oil). After learingn this task, the worms were bathed in a glycerol-based cryoprotectant solution and put into to a cryogenic state.

"This is the first evidence of preservation of memory after cryopreservation vitrification or slow freezing."

When the worms were reanimated, they were able to remember the lesson and moved to the correct position in their training area when benzaldehyde was provided.

Two different methods of freezing were tested on the worms: the first effort was based on the traditional way to freeze cells or organs in a low concentration of cryoprotectant and then slowly cool and reanimate the creatures. The second method  involved a more aggressive procedure known as vitrification.

Vitrification uses a higher concentration of cryoprotectant, but does the freezing and thawing rapidly so that ice crystals which can damage cell structures, do not form as readily. Only about a third of the worms that were frozen by the slow method actually survived reanimation, while almost all of those vitrified will survive.

Vita-More and Barranco did find though that worms frozen by either method retained the tested memory functions. They concluded:

Our results show that the mechanisms that regulate odorant imprinting (a form of long-term memory) in young C. elegans have not been modified by either the process of vitrification or by slow freezing in the adult stage. This is the first evidence of preservation of memory after cryopreservation vitrification or slow freezing).

The research is an important step for the study of cryonics, and is an indication that the process currently being undertaken at facilities like Alcor's may one day bear fruit for the people frozen within.

Demonstrating that worm brains can handle top-down freezing by artificial means is an important step towards doing the same for larger organisms, like humans. Additional research may make survivable cryonic suspension a real solution for the current problem of aging and disease.


SOURCE  Extreme Tech

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 Artificial Life  

The Open Worm project aims to build a lifelike copy of a nematode roundworm entirely out of computer code. Now the creature's creators have added code that gets the virtual worm wriggling like the real thing.

The open-source OpenWorm Project has had a major milestone,creatingt an artificial life form from the cellular level in silco.

"That's a simulated worm body with muscle segments that resemble an actual C.Elegans," project advocate John Hurliman told New World Notes.

"Each muscle segment can receive a contraction signal, and although the current setup just has a hardcoded algorithm driving the muscles, its movement closely resembles published literature on how C. Elegans swims."

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"The core algorithm for the physics simulation is called PCI-SPH, which is a somewhat advanced but well understood particle simulation method. The main source of complexity is the architecture: going from brain firing signals to muscle contractions to moving particles around."

The Open Worm project started in May 2013 and is slowly working towards creating a virtual copy of the C. elegans nematode. This worm is one of the most widely studied creatures on Earth and was the first multicelled organism to have its entire genome mapped.

The simulated worm slowly being built out of code aims to replicate C. elegans in exquisite detail with each of its 1,000 cells being modelled on computer.

The next steps for OpenWorm are to continue working on performance and hook up a synthetic brain, based on the worm's connectome.

Early work on the worm involved making a few muscle segments twitch but now the team has a complete worm to work with. The code governing how the creature's muscles move has been refined so its swaying motion and speed matches that of its real life counterpart. The tiny C. elegans manages to move around in water at a rate of about 1mm per second.


SOURCE  New World Notes

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 Life Extension  

Researchers, using a combination of genetic changes have multiplied the longevity of the nematode worm C.elegans by a factor that, in humans, would mean a 400 to 500-year old lifespan.

New research in simple animals suggests that combining mutants can lead to radical lifespan extension. Scientists at the Buck Institute combined mutations in two pathways well-known for lifespan extension and report a synergistic five-fold extension of longevity in the nematode C. elegans. The research, done at the Buck Institute and published online in Cell Reports, introduces the possibility of combination therapy for aging and the maladies associated with it.

The mutations inhibited key molecules involved in insulin signaling (IIS) and the nutrient signaling pathway Target of Rapamycin (TOR). Lead scientist and Buck faculty Pankaj Kapahi, PhD, said single mutations in TOR (in this case RSKS-1) usually result in a 30 percent lifespan extension, while mutations in IIS (Daf-2) often result in a doubling of lifespan in the worms – added together they would be expected to extend longevity by 130 percent. “Instead, what we have here is a synergistic five-fold increase in lifespan,” Kapahi said. “The two mutations set off a positive feedback loop in specific tissues that amplified lifespan. Basically these worms lived to the human equivalent of 400 to 500 years.”

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Kapahi said the research points to the possibility of using combination therapies for aging, similar to what is done for cancer and HIV. “In the early years, cancer researchers focused on mutations in single genes, but then it became apparent that different mutations in a class of genes were driving the disease process,” he said. “The same thing is likely happening in aging.” Kapahi said this research could help explain why scientists are having a difficult time identifying single genes responsible for the long lives experienced by human centenarians. “It’s quite probable that interactions between genes are critical in those fortunate enough to live very long, healthy lives.”

Former Buck postdoctoral fellow Di Chen, PhD, now an associate professor at the Model Animal Research Center, Nanjing University, China, lead author of the study, said that the positive feedback loop (DAF-16 via the AMPK complex) originated in the germline tissue of worms. The germline is a sequence of reproductive cells that may be passed onto successive generations. “The germline was the key tissue for the synergistic gain in longevity – we think it may be where the interactions between the two mutations are integrated,” Chen said. “The finding has implications for similar synergy between the two pathways in more complex organisms.”

Kapahi said ideally the research would move into mice as a way of determining if the lifespan-extending synergy extends into mammals. “The idea would be to use mice genetically engineered to have suppressed insulin signaling, and then treat them with the drug rapamycin, which is well-known to suppress the TOR pathway.”


SOURCE  Buck Institute for Research on Aging

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 Neuroscience  

Researchers in Vienna develop new imaging technique to study the function of entire nervous systems The scientists have found a way to overcome some of the limitations of light microscopy. Applying the new technique, they can record the activity of a worm’s brain with high temporal and spatial resolution, ultimately linking brain anatomy to brain function.

Researchers at the Campus Vienna Biocenter in Austria have found a way to overcome some of the limitations of light microscopy. Applying anew technique, they can record the activity of a worm’s brain with high temporal and spatial resolution, ultimately linking brain anatomy to brain function.

The research has been published in the journal Nature Methods.

A major aim of today’s neuroscience is to understand how an organism’s nervous system processes sensory input and generates behavior. To achieve this goal, scientists must obtain detailed maps of how the nerve cells are wired up in the brain, as well as information on how these networks interact in real time.

The organism many neuroscientists turn to in order to study brain function is a tiny, transparent worm found in rotting soil. The simple nematode C. elegans is equipped with just 302 neurons that are connected by roughly 8000 synapses. It is the only animal for which a complete nervous system, or connectome, has been anatomically mapped.

Researchers have so far focused on studying the activity of single neurons and small networks in the worm, but have not been able to establish a functional map of the entire nervous system. This is mainly due to limitations in the imaging-techniques they employ: the activity of single cells can be resolved with high precision, but simultaneously looking at the function of all neurons that comprise entire brains has been a major challenge. Thus, there was always a trade-off between spatial or temporal accuracy and the size of brain regions that could be studied.

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Now scientists at Vienna’s Research Institute of Molecular Pathology (IMP), the Max Perutz Laboratories (MFPL), and the Research Platform Quantum Phenomena & Nanoscale Biological Systems (QuNaBioS) of the University of Vienna have closed this gap and developed a high speed imaging technique with single neuron resolution that bypasses these limitations.

The teams of Alipasha Vaziri and Manuel Zimmer describe the technique which is based on their ability to “sculpt” the three-dimensional distribution of light in the sample. With this new kind of microscopy, they are able to record the activity of 70% of the nerve cells in a worm’s head with high spatial and temporal resolution.

“Previously, we would have to scan the focused light by the microscope in all three dimensions”, says quantum physicist Robert Prevedel. “That takes far too long to record the activity of all neurons at the same time. The trick we invented tinkers with the light waves in a way that allows us to generate “discs” of light in the sample. Therefore, we only have to scan in one dimension to get the information we need. We end up with three-dimensional videos that show the simultaneous activities of a large number of neurons and how they change over time.”

Prevedel is a Senior Postdoc in the lab of Alipasha Vaziri, who is an IMP-MFPL Group Leader and is heading the Research Platform Quantum Phenomena & Nanoscale Biological Systems (QuNaBioS) of the University of Vienna, where the new technique was developed.

The new microscopic method is only half the story. Visualization of the neurons requires tagging them with a fluorescent protein that lights up when it binds to calcium, signaling the nerve cells’ activity.

“The neurons in a worm’s head are so densely packed that we could not distinguish them on our first images”, explains neurobiologist Tina Schrödel, co-first author of the study. “Our solution was to insert the calcium sensor into the nuclei rather than the entire cells, thereby sharpening the image so we could identify single neurons.” Schrödel is a Doctoral Student in the lab of the IMP Group Leader Manuel Zimmer.

The new technique that came about by a close collaboration of physicists and neurobiologists has great potentials beyond studies in worms, according to the researchers. It will open up the way for experiments that were not possible before. One of the questions that will be addressed is how the brain processes sensory information to “plan” specific movements and then executes them.

This ambitious project will require further refinement of both the microscopy methods and computational methods in order to study freely moving animals. The team in Vienna is set to achieve this goal in the coming two years.



SOURCE  University of Vienna

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 Connectomics  

David Dalrymple's work on Project NEMALOAD, that intends to create a fully realized uploaded version of a nematode worm based on its connectome has yielded a new an app that displays video renderings of the worms' neural activity, where each frame can be rotated and manipulated in 3D.

David Dalrymple is an independent scientist, funded by the Thiel Foundation studying the neurology of the nematode worm C. Elegans, an important model organism in genetics and neuroscience.

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Dalrymple's work is part of Project NEMALOAD, which intends to create a fully realized uploaded version of a nematode worm based on its connectome.

According to the project's website:

C. elegans is a simple-minded animal: it has exactly 302 neurons (compare that to a human's roughly 100 billion). The pattern of connections between these neurons was painstakingly mapped out decades ago using electron microscopy, but it turns out that knowledge of the connections is not sufficient to understand (or even replicate) the information processor they represent. For example, some connections are inhibitory while others are excitatory, but this map doesn't say which is which. 

In order to learn how one neuron affects another, we need to see what happens when the first neuron is activated. NEMALOAD (“nematode upload”) is a project to integrate a number of recent technologies that should make this feasible, at least in C. elegans, and using this capability to replicate the information processing structure that governs the worm's behavior in a digital model.

In the video above, he demos Nemashow, an app built with Meteor and WebGL.

The app displays video renderings of the worms' neural activity, where each frame can be rotated and manipulated in 3D.



SOURCE  MeteorVideos, Image Project OpenWorm

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 Anti-Aging  

Researchers working on aging have found how death spreads in C. Elegans like a wave from cell to cell until the whole organism is deceased. The spread of death can easily be seen under a microscope as a wave of blue fluorescence travelling through the gut of the worm.

In the final hours of a nematode worm’s life, a wave of cell death propagates along the length of its body. But, as if to have one last hurrah, the dying cells put on a bright blue light show, according to a paper published online  in PLOS Biology.

The discovery of this peculiar death-related phenomenon came as a result of studies into aging, said University College London’s David Gems. One of the prevailing theories to explain aging in organisms, he said, is that throughout life there is a slow accumulation of damage to cellular components. In mammals, some of that damaged material accumulates in the lysosomes of aging cells as a substance called lipofuscin—“a sort of biological crap,” Gems said.

Gems studies aging in the nematode worm C. elegans, and like his fellow worm researchers, he assumed these tiny creatures also accumulated lipofuscin as they aged. Although lipofuscin had never been isolated from C elegans, the assumption was based on the fact that worms develop a fluorescent emission as they age, which fits with the fact that lipofuscin itself emits fluorescence. “Worm biologists said, ooh it looks like lipofuscin, and it became almost taken as a fact,” Gems said.

But Gems became suspicious. For one thing, although lipofuscin in a test tube has the same emission wavelength as the fluorescence produced by C. elegans, its wavelength in mammalian cells is different. And the fluorescence seen in the worms primarily builds up in slightly different organelles—lysosome-like gut granules.

Furthermore, Gems’s team discovered that while lipofuscin is composed of proteins and lipids damaged by oxidation, the blue fluorescence in the worms did not increase when they were exposed to oxidative stress. With suspicions now raised even further, Gems re-examined the data on age-related fluorescence in worms.

“What people had done is look at populations of worms,” he said, which glow brighter as the group ages. “But what we found when we looked at individual worms is that there is no increase in fluorescence until they die.”

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In the hour or two preceding death, Gems found, “you get this explosion of fluorescence—this extraordinary wave of fluorescence that goes through the worm. We thought, this doesn’t fit with it being lipofuscin.” Another anomalous finding was that it wasn’t just elderly worms that emitted blue fluorescence at death. Killing worms of any age, even larvae—which presumably wouldn’t have accumulated any lipofuscin—resulted in the same blue wave.

Analyzing the contents of isolated gut granules from the worms’ intestinal cells revealed the true source of blue fluorescence: a substance called anthranilate. The team found that while the fluorescence of anthranilate was quenched by the acidity within its gut granule home, when the organelles’ membranes deteriorated upon cell death, or necrosis, anthanilate was released into the more alkaline cytoplasm, activating its fluorescence. Inhibiting pathways involved in necrosis prevented the death-related burst of fluorescence.

The fluorescence essentially acts as a marker of necrosis, said Gems. Indeed the wave of head-to-tail fluorescence reflected a wave of necrosis through the dying worm. It is not clear why the wave of necrosis always initiates at the head, but it does so even if the insult that triggers death—for example, intense heat—is applied to the posterior end of the worm. “It’s a total mystery,” Gems said.

Such propagating waves of necrosis are also seen, albeit locally, within damaged tissues in humans, such as during a heart attack or stroke. Thus dying worms might provide more than a pretty light show. For studying how necrosis spreads from cell to cell in human disease, and how to limit that spread, “this is going to be a fantastic model,” said Curran.

Annalee Newitz at Io9 writes, "Humans may not glow blue as we die, but our cells do send out chemical signals like those we can see in worms. Perhaps one day we'll be able to untangle the chemical pathway to death, and prevent that chilling necrotic cascade from overtaking our bodies before we are ready to die."



SOURCE  The Scientist

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 Aging Research  

EPFL scientists reveal the mechanism responsible for aging hidden deep within mitochondria—and dramatically slow it down in worms by administering antibiotics to the young. A lifespan extension of 60 percent has been achieved in worms.

Resarchers at the Ecole Polytechnique Fédérale de Lausanne (EPFL) led by Johan Auwerx report in the journal Nature how a mechanism in mice plays a determining role in longevity. They have also gone a step further: by disrupting this mechanism using simple antibiotics in a population of nematodes, or roundworms, and have multiplied the animals lifespan by a factor of 1.6.

The process identified by EPFL scientists takes place within organelles called mitochondria, known as the cellular powerhouses because they transform nutrients into proteins including adenosine triphosphate (ATP), used by muscles as energy.

Several studies have shown that mitochondria are also involved in aging. The new EPFL research, done in collaboration with partners in the Netherlands and the US, pinpoints the exact genes involved and measures the consequences to longevity when the amount of protein they encode for is varied: less protein, longer life.

Laboratory mice in the BXD reference population typically live from 365 to 900 days. This population, which reflects genetic variations that occur naturally within a species, is used by many researchers in an approach known as “real-world genetics”. The benefit of working with this population in particular is that their genome is almost completely decoded.

The team led by professor Auwerx, head of EPFL's Laboratory of Integrative and Systemic Physiology, analyzed mice genomes as a function of longevity and found a group of three genes situated on chromosome number two that, up to this point, had not been suspected of playing any role in aging. But the numbers didn't lie: a 50 percent reduction in the expression of these genes—and therefore a reduction in the proteins they code for—increased mouse life span by about 250 days.

Next, the team reproduced the protein variations in a species of nematode, Caenorhabidtis elegans. “By reducing the production of these proteins during the worms' growth phase, we significantly increased their longevity”, says Auwerx.

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The average life span of a worm manipulated in this way went from 19 to more than 30 days, an increase of 60 percent. The scientists then conducted tests to isolate the common property and determined that the presence of mitochondrial ribosomal proteins (MRPs) is inversely proportional to longevity.

The researchers concluded that a lack of MRP at certain key moments in development created a specific stress reaction known as an "unfolded protein response" within the mitochondria. "The strength of this response was found to be directly proportional to the life span," says Auwerx. "However, we noted that it was more pronounced if the protein imbalance—the reduction in MRP— occurred at a young age. A similar stimulation in an adult did not affect the worms' longevity."

What's more, the effect can be induced without genetically manipulating the worms. "Exposure to certain readily available drugs inhibits ribosomal function and thus causes the desired reaction," says Auwerx. In other words, mitochondria are sensitive to certain antibiotics, and the drugs can be used to prolong life.

Worms given antibiotics don't just live to ripe old age. At maturity, which is 13 days, they also moved twice as much as the others, according to Laurent Mouchiroud, co-author of the study. "Around 20 days of age, the difference was even more pronounced because the 'control' individuals were often already in bad shape," he adds.

All indications are that the observed and proven mechanisms in worms should be similar to those in mice, and therefore possibly in other mammals. Further studies are necessary, of course, to confirm that aging and its deleterious effects could be slowed down in mammals using antibiotics at precise moments in development.

"This research gives us hope not only for increasing longevity, but also for lengthening the period of adult vitality, and doing this with simple drugs such as antibiotics," concludes Auwerx.



SOURCE  EPFL

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 Simulated Biology  

The OpenWorm project aims to build the first comprehensive computational model of the roundworm C. elegans. With only a thousand cells, it solves basic problems such as feeding, mate-finding and predator avoidance. Despite being extremely well studied in biology, this organism still eludes a deep, principled understanding of its biology.

The OpenWorm project aims to build the first comprehensive computational model of the Caenorhabditis elegans (C. elegans), a microscopic roundworm.

With only a thousand cells, it solves basic problems such as feeding, mate-finding and predator avoidance. Despite being extremely well studied in biology, this organism still eludes a deep, principled understanding of its biology.

If it succeeds, OpenWorm will have created a first in executable biology: a simulated animal using the principles of life to exist on a computer.

The international group collaborating on the project using a bottom-up approach, aimed at observing the worm behaviour emerge from a simulation of data derived from scientific experiments carried out over the past decade. To do so they are incorporating the data available in the scientific community into software models.

According to the organization, rigorous predictive models are the cornerstone of science and engineering. Unfortunately, today, there are no comprehensive predictive models of living cells and tissues. Consequently, the entire field of biology and medicine is in a kind of “pre-mathematical” era.

A revolution in the biosciences driven by simulation-based research, using predictive models running on high performance computing architectures with flexible user interfaces, is now possible. Simulating a living organism will have impacts on understanding mechanisms of disease, drug discovery and development, synthetic biology, bioengineering, neuroscience and artificial intelligence.

OpenWorm is engineering Geppetto, an open-source simulation platform, to be able to run these different models together. They are also forging new collaborations with universities and research institutes to collect data that fill in the gaps.

"If you're going to understand a nervous system or, more humbly, how a neural circuit works, you can look at it and stick electrodes in it and find out what kind of receptor or transmitter it has," said John White, who built the first map of C. elegans's neural anatomy, and recently started contributing to the project. "But until you can quantify and put the whole thing into a computer and simulate it and show your computer model can behave in the same way as the real one, I don't think you can say you understand it."

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David Dalrymple, an MIT graduate student who has contributed to OpenWorm and is working on a worm brain modeling project of his own, pointed out what he sees as a limitation to the effort. OpenWorm has incorporated a lot of anatomical data -- the structures of the worm's nervous system and musculature. The issue is, these studies were carried out with dead worms. They can't tell scientists about the relative importance of connections between neurons within the worm's neural system, only that a connection exists. Very little data from living animals' cells exist in the published literature, and it may be required to develop a good simulation.

"I believe that an accurate model requires a great deal of functional data that has not yet been collected, because it requires a kind of experiment that has only become feasible in the last year or two," Dalrymple told Alexis Madrigal. Dalrymple's own research is to build an automated experimental apparatus that can gather up that functional data, which can then be fed into these models. "We're coming at the problem from different directions," he said. "Hopefully, at some point in the future, we'll meet in the middle and save each other a couple years of extra work to complete the story."



SOURCE  The Atlantic

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 Mind Uploading  

David Dalrymple has proposed that studying neuroscience in conjunction with computer science will lead to a new form of mathematics. He is now working on an effort to combine neuroscience, connectomics, and artificial intelligence to develop a working framework for mind uploading starting with the nematode worm, C. elegans. The project is called NEMALOAD.

Transhumanists are familiar with the concept of uploading: transferring a mind from a biological implementation to a digital one. To most people however, uploading still sounds like science fiction, but technical capabilities are rapidly catching up.

Given recent advances in optogenetics, optoelectronics, and computational modeling, it has become feasible to upload the simplest nervous system known to science, that of the nematode worm C. elegans.

That is the aim of David Dalrymple's NEMAOAD project.

In order to learn how one neuron affects another, we need to see what happens when the first neuron is activated. NEMALOAD is a project to integrate a number of recent technologies that should make this feasible, at least in C. elegans, and using this capability to replicate the information processing structure that governs the worm's behavior in a digital model.

The project also has an explicit publicity mission, with three high-level goals. First: to encourage mainstream thinkers to take uploading seriously, and begin discussions regarding the ethical and societal implications of human uploading in advance of its arrival. Second: to challenge dominant paradigms in neuroscience and inspire other projects to build upon this foundation. Finally: to educate science enthusiasts about the mathematical, physical, and biological ideas that underlie real-world uploading.

Dalrymple took his first class at UMBC in the fall of 2000 and graduated with B.S. degrees in Computer Science and Mathematics in the spring of 2005. During this time he also spoke at TED 11, took a summer at sea, and worked with Kurzweil Technologies to create the earliest prototypes of the KNFB Reader.

After working for a year as an independent consultant out of his parents' basement, they let him move to Cambridge, Massachusetts in June 2006 to begin graduate studies at the MITMedia Lab. (As far as any of the administrators knew, nobody as young as 14 had ever entered an MIT graduate program in the past.) 

In June 2008, David received his S.M. in Media Technology, with a thesis titled "Asynchronous Logic Automata," and began the Ph.D. program in Media Arts and Sciences as a member of the Mind Machine Project under Marvin Minsky. In the summer of 2010, David attended Singularity University at the NASA Ames Research Center in Mountain View, California, which inspired him to refocus from the world of computer architecture, programming language design, and artificial intelligence to the world of biophysics and neuroscience. On the advice of the faculty, in 2011, David left the Media Lab Ph.D. program at MIT for the Biophysics Ph.D. program at Harvard. In 2012, David went on leave from Harvard and signed a research grant agreement with the Thiel Foundation to pursue his research goals in an independent context.

In this talk from Humanity+ 2012 in San Fransisco, Dalrymple gives a brief overview of the project.




SOURCE  Adam Ford

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 Medicine

By using a model, researchers at the University of Montreal have identified and "switched off" a chemical chain that causes neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis and dementia. The findings could one day be of particular therapeutic benefit to Huntington's disease patients.

By using a model, researchers at the University of Montreal have identified and "switched off" a chemical chain that causes neurodegenerative diseases such as Huntington's disease, amyotrophic lateral sclerosis and dementia.

The findings could one day be of particular therapeutic benefit to Huntington's disease patients. "We've identified a new way to protect neurons that express mutant huntingtin proteins," explained Dr. Alex Parker of the University of Montreal's Department of Pathology and Cell Biology and its affiliated CRCHUM Research Centre.

A main feature of Huntington's disease – a fatal genetic disease that typically affects patients in midlife and causes progressive death of specific areas of the brain – is the aggregation of mutant huntingtin protein in cells. "Our model revealed that increasing another cell chemical called progranulin reduced the death of neurons by combating the accumulation of the mutant proteins. Furthermore, this approach may protect against neurodegenerative diseases other than Huntington's disease."

There is no cure for Huntingdon's disease and current strategies show only modest benefits, and a component of the protein aggregates involved are also present in other degenerative diseases. "My team and I wondered if the proteins in question, TDP-43 and FUS, were just innocent bystanders or if they affected the toxicity caused by mutant huntingtin," Dr. Parker said. To answer this question, Dr. Parker and University of Montreal doctoral student Arnaud Tauffenberger turned to a simple genetic model based on the expression of mutant huntingtin in the nervous system of the transparent roundworm C. elegans.

A large number of human disease genes are conserved in worms, and C. elegans in particular enables researchers to rapidly conduct genetic analyses that would not be possible in mammals.

Dr. Parker's team found that deleting the TDP-43 and FUS genes, which produce the proteins of the same name, reduced neurodegeneration caused by mutant huntingtin. They then confirmed their findings in the cell of a mammal cell, again by using models. The next step was then to determining how neuroprotection works.

TDP-43 targets a chemical called progranulin, a protein linked to dementia. "We demonstrated that removing progranulin from either worms or cells enhanced huntingtin toxicity, but increasing progranulin reduced cell death in mammalian neurons. This points towards progranulin as a potent neuroprotective agent against mutant huntingtin neurodegeneration," Dr. Parker said. The researchers will need to do further testing this in more complex biological models to determine if the same chemical switches work in all mammals. If they do, then progranulin treatment may slow disease onset or progression in Huntington's disease patients.—



SOURCE  EurekAlert

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