Shinya Yamanaka received the 2012 Nobel Prize for discovering his eponymous “Yamanaka Factors,” which can return cells to their embryonic state.
The factors seemed promising for reversing signs of aging, but they set the age of cells back too far in the past.
New research can stop the reverse aging process just before the cell returns to its embryonic form and turns its clock back 30 years.
15 years ago, scientists made a startling discovery when they showed they could reverse the aging process in cells. By activating a set of four factors in DNA, they reset the cell’s clock and return adult cells to their embryonic state. The factors were named Yamanaka Factors after their discoverer, Shinya Yamanaka, and earned him the Nobel Prize a few years later. For the first time, scientists saw a glimmer of hope that aging could be reversed.
“It’s pretty amazing when you think about it,” says Wolf Reik, a molecular biologist at the Babraham Institute in the UK Popular mechanics. “They can potentially reset the age of human cells to zero.”
Scientists hoped that without the telltale signs of aging, these cells could be used to repair and rejuvenate damaged organs. For example, younger, healthier nerve cells could replace brain cells killed by a stroke, or collagen-producing skin cells could be injected directly into stubborn wounds. The only problem is that the Yamanaka factors reset the cells too far. A cell that is zero days old cannot send an electrical nerve signal or produce collagen or perform any other function. Like a stem cell, it is nothing more than a blob of potential.
To overcome this, scientists have tinkered with the timing, looking for ways to stop the reverse aging process just before the cell returns to its embryonic form. Previous trials in mice have shown promise, but the gains have been modest, only turning the clock back three years or so.
But now a group of scientists led by Reik have shown that they can turn back the clock by up to 30 years. It is the furthest way back anyone has walked without going too far. In April, they published the results in eLife.
“What’s new and interesting about this study is that it pushes the cells to reprogram in a timed manner,” says Manuel Serrano — a molecular biologist at the Institute for Biomedical Research in Barcelona, Italy, who was not involved in the study Popular mechanics. Serrano says scientists have not really been able to control the Yamanaka factors with any degree of certainty.
First, the researchers collected skin cells from middle-aged adults, between 38 and 53 years old. They specifically collected skin fibroblasts, which are essential for wound healing and whose effectiveness decreases with age. Using viral vectors, they injected the Yamanaka factors (a set of four genes) into the cells and turned them on. Previous research showed that it takes a total of 50 days for the Yamanaka factors to reset the clock and that between day 10 and day 17 the cells were around 20 to 40 years old. The researchers decided to stop the action of the Yamanaka factors during this period and examined the effects on the cells between day 10 and day 17.
At each break, the researchers assessed the biological age of the cells using molecular ‘aging clocks’. Changes in the DNA that cause cancer, known as epigenetic changes, were measured. They also measured collagen production, because this protein gives young skin its characteristic firm and plump texture but declines with age. They even measured the mobility of the cell. When the skin is damaged, fibroblasts physically migrate to the wound to boost collagen production and start the repair process. As we age, fibroblasts slow down noticeably, which explains why older skin takes longer to heal.
The scientists found the sweet spot after just 13 days. The cells were young but retained their ability to produce collagen and move quickly to damaged areas. “To understand that we can rejuvenate cells was amazing,” says Inês Milagre – a researcher at the Gulbenkian Institute of Science in Portugal and author of the new study Popular mechanics. “But the most exciting thing was seeing that the cells were functionally younger,” she says.
According to Milagre, the work is an important milestone and proof that the Yamanaka factors can be fine-tuned. However, she says we shouldn’t expect the technique to be available in the clinic any time soon. Activation of the Yamanaka factors can cause cancer, and it’s unclear whether this process works in other cell types. “There are still so many unknowns,” she says.
Reik shares these concerns and plans to develop safer strategies. He believes that by better understanding how the Yamanaka factors work, he will be able to find downstream molecules that are activated by the genetic factors. By identifying these factors, which can be RNA or protein, he could develop therapeutics that don’t require interfering with the genes inside the cell, reducing the risk of cancer and other side effects.
“We could call them ‘rejuvenation factors,’ and they would provide a safer way to rejuvenate cells,” says Reik.
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