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