Old skins cells reprogrammed to regain youthful function

Close-up of human skin

What is regenerative medicine?

As we age, our cells' ability to function declines and the genome accumulates marks of ageing. Regenerative biology aims to repair or replace cells including old ones. One of the most important tools in regenerative biology is our ability to create 'induced' stem cells. The process is a result of several steps, each erasing some of the marks that make cells specialised. In theory, these stem cells have the potential to become any cell type, but scientists aren't yet able to reliably recreate the conditions to re-differentiate stem cells into all cell types.

Turning back time

The new method, based on the Nobel Prize winning technique scientists use to make stem cells, overcomes the problem of entirely erasing cell identity by halting reprogramming part of the way through the process. This allowed researchers to find the precise balance between reprogramming cells, making them biologically younger, while still being able to regain their specialised cell function.

In 2007, Shinya Yamanaka was the first scientist to turn normal cells, which have a specific function, into stem cells which have the special ability to develop into any cell type. The full process of stem cell reprogramming takes around 50 days using four key molecules called the Yamanaka factors. The new method, called 'maturation phase transient reprogramming', exposes cells to Yamanaka factors for just 13 days. At this point, age-related changes are removed and the cells have temporarily lost their identity. The partly reprogrammed cells were given time to grow under normal conditions, to observe whether their specific skin cell function returned. Genome analysis showed that cells had regained markers characteristic of skin cells (fibroblasts), and this was confirmed by observing collagen production in the reprogrammed cells.

Age isn't just a number

To show that the cells had been rejuvenated, the researchers looked for changes in the hallmarks of ageing. As explained by Dr Diljeet Gill, a postdoc in Wolf Reik's lab at the Institute who conducted the work as a PhD student: "Our understanding of ageing on a molecular level has progressed over the last decade, giving rise to techniques that allow researchers to measure age-related biological changes in human cells. We were able to apply this to our experiment to determine the extent of reprogramming our new method achieved."

Researchers looked at multiple measures of cellular age. The first is the epigenetic clock, where chemical tags present throughout the genome indicate age. The second is the transcriptome, all the gene readouts produced by the cell. By these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger compared to reference data sets.

The potential applications of this technique are dependent on the cells not only appearing younger, but functioning like young cells too. Fibroblasts produce collagen, a molecule found in bones, skin tendons and ligaments, helping provide structure to tissues and heal wounds. The rejuvenated fibroblasts produced more collagen proteins compared to control cells that did not undergo the reprogramming process. Fibroblasts also move into areas that need repairing. Researchers tested the partially rejuvenated cells by creating an artificial cut in a layer of cells in a dish. They found that their treated fibroblasts moved into the gap faster than older cells. This is a promising sign that one day this research could eventually be used to create cells that are better at healing wounds.

In the future, this research may also open up other therapeutic possibilities; the researchers observed that their method also had an effect on other genes linked to age-related diseases and symptoms. The APBA2 gene, associated with Alzheimer's disease, and the MAF gene with a role in the development of cataracts, both showed changes towards youthful levels of transcription.

The mechanism behind the successful transient reprogramming is not yet fully understood, and is the next piece of the puzzle to explore. The researchers speculate that key areas of the genome involved in shaping cell identity might escape the reprogramming process.

 

Warming oceans are getting louder

 Climate change will significantly alter how sound travels underwater, potentially affecting natural soundscapes as well as accentuating human-generated noise, according to a new global study that identified future ocean "acoustic hotspots." These changes to ocean soundscapes could impact essential activities of marine life.

In warmer water, sound waves propagate faster and last longer before dying away.

"We calculated the effects of temperature, depth and salinity based on public data to model the soundscape of the future," said Alice Affatati, an bioacoustics researcher at the Memorial University of Newfoundland and Labrador in St. John's, Canada, and lead author of the new study, published today in Earth's Future, AGU's journal for interdisciplinary research on the past, present and future of our planet and its inhabitants. It is the first global-scale estimate of ocean sound speed linked to future climate.

Two hotspots, in the Greenland Sea and a patch of the northwestern Atlantic Ocean east of Newfoundland, can expect the most change at 50 and 500 meter depths, the new study projected. The average speed of sound is likely to increase by more than 1.5%, or approximately 25 meters per second (55 miles per hour) in these waters from the surface to depths of 500 meters (1,640 feet), by the end of the century, given continued high greenhouse gas emissions (RCP8.5).

"The major impact is expected in the Arctic, where we know already there is amplification of the effects of climate change now. Not all the Arctic, but one specific part where all factors play together to give a signal that, according to the model predictions, overcomes the uncertainty of the model itself," said author Stefano Salon, a researcher at the National Institute of Oceanography and Applied Geophysics in Trieste, Italy.

The ocean soundscape is a cacophony of vibrations produced by living organisms, natural phenomena like waves and cracking ice, and ship traffic and resource extraction. Sound speed at 50 meters depth ranges from 1,450 meters per second in the polar regions to 1,520 meters per second in equatorial waters (3,243 to 3,400 miles per hour, respectively).

Many marine animals use sound to communicate with each other and navigate their underwater world. Changing the sound speed can impact their ability to feed, fight, find mates, avoid predators and migrate, the authors said.

Changing soundscapes

In addition to the notable hotpots around Greenland and in the northwestern Atlantic Ocean, the new study found a 1% sound speed increase, more than 15 meters per second, at 50 m in the Barents Sea, northwestern Pacific, and in the Southern Ocean (between 0 and 70E), and at 500 m in the Arctic Ocean, Gulf of Mexico, and southern Caribbean Sea.

Temperature, pressure with increasing depth and salinity all affect how fast and how far sound travels in water. In the new study, the researchers focused on hotspots where the climate signal stood out clearly from the model uncertainty and was larger than seasonal variability.

The new study also modeled common vocalizations, under the projected future conditions, of the North Atlantic right whale, a critically endangered species inhabiting both north Atlantic acoustic hotspots. The whales' typical "upcall" at 50 Hertz is likely to propagate farther in a warmer future ocean, the researchers found.

"We chose to talk about one megafauna species, but many trophic levels in the ocean are affected by the soundscape or use sound," Affatati said. "All these hotspots are locations of great biodiversity."

Future work will combine the global soundscape with other maps of anthropogenic impacts in the oceans to pinpoint areas of combined stressors, or direct needed observational research

Scientists reveal how Venus fly trap plants snap shut

 

Venus fly trap

Scientists at Scripps Research have revealed the three-dimensional structure of Flycatcher1, an aptly named protein channel that may enable Venus fly trap plants to snap shut in response to prey. The structure of Flycatcher1, published February 14 in Nature Communications, helps shed light on longstanding questions about the remarkably sensitive touch response of Venus fly traps. The structure also gives the researchers a better understanding of how similar proteins in organisms including plants and bacteria, as well as proteins in the human body with similar functions (called mechanosensitive ion channels), might operate.

"Despite how different Venus fly traps are from humans, studying the structure and function of these mechanosensitive channels gives us a broader framework for understanding the ways that cells and organisms respond to touch and pressure," says co-senior author and Scripps Research professor Andrew Ward, PhD.

"Every new mechanosensitive channel that we study helps us make progress in understanding how these proteins can sense force and translate that to action and ultimately reveal more about human biology and health," adds co-senior author Ardem Patapoutian, PhD, a Scripps Research professor who won the Nobel Prize in Physiology or Medicine for research on the mechanosensitive channels that allow the body to sense touch and temperature.

Mechanosensitive ion channels are like tunnels that span the membranes of cells. When jostled by movement, the channels open, letting charged molecules rush across. In response, cells then alter their behavior -- a neuron might signal its neighbor, for instance. The ability for cells to sense pressure and movement is important for people's senses of touch and hearing, but also for many internal body processes -- from the ability of the bladder to sense that it's full to the ability of lungs to sense how much air is being breathed.

Previously, scientists had homed in on three ion channels in Venus fly traps thought to be related to the ability of the carnivorous plant to snap its leaves shut when its sensitive trigger hairs get touched. One, Flycatcher1, caught researchers' attention because its genetic sequence looked similar to a family of mechanosensitive channels, MscS, found in bacteria.

"The fact that variants of this channel are found throughout evolution tells us that it must have some fundamental, important functions that have been maintained in different types of organisms," says co-first author Sebastian Jojoa-Cruz, a graduate student at Scripps Research.

In the new study, the researchers used cryo-electron microscopy -- a cutting-edge technique that reveals the locations of atoms within a frozen protein sample -- to analyze the precise arrangement of molecules that form the Flycatcher1 protein channel in Venus fly trap plants. They found that Flycatcher1 is, in many ways, similar to bacterial MscS proteins -- seven groups of identical helices surrounding a central channel. But, unlike other MscS channels, Flycatcher1 has an unusual linker region extending outward from each group of helices. Like a switch, each linker can be flipped up or down. When the team determined the structure of Flycatcher1, they found six linkers in the down position, and just one flipped up.

"The architecture of Flycatcher1's channel core was similar to other channels that have been studied for years, but these linker regions were surprising," says Kei Saotome, PhD, a former postdoctoral research associate at Scripps Research and co-first author of the new paper.

To help elucidate the function of these switches, the researchers altered the linker to disrupt the up position. Flycatcher1, they found, no longer functioned as usual in response to pressure; the channel remained open for a longer duration when it would normally close upon removal of pressure.

"The profound effect of this mutation tells us that the conformations of these seven linkers is likely relevant for how the channel works," says co-senior author Swetha Murthy, PhD, of Vollum Institute at Oregon Health and Science University, a former postdoctoral research associate at Scripps Research.

Now that they solved the molecular structure, the research team is planning future studies on the function of Flycatcher1 to understand how different conformations affect its function. More work is also needed to determine whether Flycatcher1 is solely responsible for the snapping shut of Venus fly trap leaves, or whether other suspected channels play complementary roles.

Exercise alters brain chemistry to protect aging synapses

 

Couple jogging in the park

When elderly people stay active, their brains have more of a class of proteins that enhances the connections between neurons to maintain healthy cognition, a UC San Francisco study has found.

This protective impact was found even in people whose brains at autopsy were riddled with toxic proteins associated with Alzheimer's and other neurodegenerative diseases.

"Our work is the first that uses human data to show that synaptic protein regulation is related to physical activity and may drive the beneficial cognitive outcomes we see," said Kaitlin Casaletto, PhD, an assistant professor of neurology and lead author on the study, which appears in the January 7 issue of Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

The beneficial effects of physical activity on cognition have been shown in mice but have been much harder to demonstrate in people.

Casaletto, a neuropsychologist and member of the Weill Institute for Neurosciences, worked with William Honer, MD, a professor of psychiatry at the University of British Columbia and senior author of the study, to leverage data from the Memory and Aging Project at Rush University in Chicago. That project tracked the late-life physical activity of elderly participants, who also agreed to donate their brains when they died.

"Maintaining the integrity of these connections between neurons may be vital to fending off dementia, since the synapse is really the site where cognition happens," Casaletto said. "Physical activity -- a readily available tool -- may help boost this synaptic functioning."

More Proteins Mean Better Nerve Signals

Honer and Casaletto found that elderly people who remained active had higher levels of proteins that facilitate the exchange of information between neurons. This result dovetailed with Honer's earlier finding that people who had more of these proteins in their brains when they died were better able to maintain their cognition late in life.

To their surprise, Honer said, the researchers found that the effects ranged beyond the hippocampus, the brain's seat of memory, to encompass other brain regions associated with cognitive function.

"It may be that physical activity exerts a global sustaining effect, supporting and stimulating healthy function of proteins that facilitate synaptic transmission throughout the brain," Honer said.

Synapses Safeguard Brains Showing Signs of Dementia

The brains of most older adults accumulate amyloid and tau, toxic proteins that are the hallmarks of Alzheimer's disease pathology. Many scientists believe amyloid accumulates first, then tau, causing synapses and neurons to fall apart.

Casaletto previously found that synaptic integrity, whether measured in the spinal fluid of living adults or the brain tissue of autopsied adults, appeared to dampen the relationship between amyloid and tau, and between tau and neurodegeneration.

"In older adults with higher levels of the proteins associated with synaptic integrity, this cascade of neurotoxicity that leads to Alzheimer's disease appears to be attenuated," she said. "Taken together, these two studies show the potential importance of maintaining synaptic health to support the brain against Alzheimer's disease."

The ‘surprisingly simple’ arithmetic of smell

 

Locust

Smell a cup of coffee.

Smell it inside or outside; summer or winter; in a coffee shop with a scone; in a pizza parlor with pepperoni -- even at a pizza parlor with a scone! -- coffee smells like coffee.

Why don't other smells or different environmental factors "get in the way," so to speak, of the experience of smelling individual odors? Researchers at the McKelvey School of Engineering at Washington University in St. Louis turned to their trusted research subject, the locust, to find out.

What they found was "surprisingly simple," according to Barani Raman, professor of biomedical engineering. Their results were published in the journal Proceedings of the National Academy of Sciences.

Raman and colleagues have been working with locusts for years, watching their brains and their behaviors related to smell in an attempt to engineer bomb-sniffing locusts. Along the way, they've made substantial gains when it comes to understanding the mechanisms at play when it comes to locusts' sense of smell.

To understand how it is that a locust can consistently recognize smells regardless of context, they took a cue from Ivan Pavlov. Like Pavlov's dogs, locusts were trained to associate an odor with food, their preference being a blade of grass. After going a day without food, a locust was exposed to a puff of odor (a puff of hexanol or isoamyl acetate), then given a blade of grass. In as few as six such presentations, the locust learned to open its palps (sensory appendages close to the mouth) in expectation of a snack after simply smelling the "training odorant." Just like us recognizing coffee, the trained locust could recognize the odor and did not let other factors get in the way.

At this point, researchers began looking at which neurons were firing when the locust was exposed to the odor under different conditions, including in conjunction with other smells, in humid or dry conditions, when they were starved or fully fed, trained or untrained, and for different amounts of time.

Under different circumstances, it turned out, researchers saw highly inconsistent patterns of neurons were activated even though the locust palps opened every time. "The neural responses were highly variable," Raman said. "That seemed to be at odds with what the locusts were doing, behaviorally."

How could variable neural responses produce consistent or stable behavior? To probe this, researchers turned to a machine-learning algorithm. "We wanted to see if given these variable neural response patterns, can we predict the locust behavior?" Raman said. "The answer was yes, we can."

The algorithm turned out to be very simple to interpret. It exploited two functional types of neurons: there are ON neurons, which are activated when an odorant is present, and there are OFF neurons, which are silenced when an odorant is present but become activated after the odor presentation ends.

"You can think of the ON neurons as conveying 'evidence for' an odor being present, and OFF neurons as 'evidence against' that odor being present," Raman said. To recognize an odorant's presence, researchers simply needed to add evidence for the odorant being present (i.e. add the spikes across all ON neurons) and subtract evidence against that odor being present (i.e. add the spikes across all OFF neurons). If the result was above a certain threshold, machine learning would predict the locust smelled the odor.

"We were surprised to find that this simple approach is all that was needed to robustly recognize an odorant," Raman said.

Raman likened the process to shopping for a shirt. Say you have a list of qualities you're looking for -- cotton, long sleeves, button-down, solid color, maybe a front pocket to hold your glasses -- and a few dealbreakers, such as dry-clean only or polka dots.

You may get lucky and find a shirt that is precisely what you are looking for. But, more pragmatically, you would make a purchase as long as many of the features you are looking for are present and the majority of features that are deal breakers are not presen