Fifteen years ago, scientists made a stirring discovery when they demonstrated that they could reverse the process of aging in cells. By activating a set of four factors in the DNA, they reset the cell’s clock to zero, reverting adult cells to their embryonic state. The factors were named Yamanaka factors after their discoverer, Shinya Yamanaka, and a few years later, they earned him a Nobel Prize. For the first time, scientists saw a glimmer of hope that aging could be reversed.
“It’s quite amazing if you think about it,” Wolf Reik, a molecular biologist at the Babraham Institute in the United Kingdom, tells Popular Mechanics. “You can potentially reset the age of human cells back to zero.”
Scientists hoped that these cells, stripped of the tell-tale signs of aging, could be used to repair and rejuvenate damaged organs. Younger, healthier nerve cells, for example, could take over for brain cells killed by a stroke, or collagen-boosting 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 can’t send an electrical nervous signal or produce collagen, nor carry on any other function. Like a stem cell, it is nothing more than a blob of potential.
To overcome this, scientists have been tinkering with the timing and looking for ways to halt the reverse-aging process at the precise moment before the cell reverts to its embryonic form. Previous efforts in mice have shown some promise, but the gains have been modest, reversing the clock only three years or so.
But now, a group of scientists led by Reik showed that they could turn back the clock by up to 30 years. It is the farthest back anyone has gone without going too far. In April, they published the results in eLife.
“What’s new and interesting in this study is that they push the cells into reprogramming in a time-controlled way,” Manuel Serrano—a molecular biologist at Barcelona, Italy’s Institute for Research in Biomedicine, who was not involved in the study—tells Popular Mechanics. Serrano says that up until now, scientists were not really able to control the Yamanaka factors with much certainty.
To start, researchers collected skin cells from middle-aged adults between 38 and 53 years old. They specifically collected skin fibroblast cells, which are essential for wound healing and whose effectiveness declines 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 to zero, and that between Day 10 and Day 17, the cells were roughly 20 to 40 years old, respectively. The researchers decided to halt the action of the Yamanaka factors during this period, looking at the effects on the cells between Day 10 and Day 17.
At each pause, researchers evaluated the biological age of the cells using molecular “aging clocks.” Changes to the DNA that cause cancer, called epigenetic changes, were measured. They also measured collagen production because this protein imbues young skin with its characteristic firm and plump texture, but it declines with age. They even measured the cell’s mobility. When the skin is damaged, fibroblasts physically migrate into the wound to kick-start collagen production and initiate the repair process. As they age, fibroblasts become noticeably slower, which explains why older skin takes longer to heal.
The scientists found the sweet spot after just 13 days. The cells were youthful, but still retained their ability to produce collagen and move quickly into damaged areas. “Understanding that we could rejuvenate cells was amazing,” Inês Milagre—a researcher at the Gulbenkian Institute of Science in Portugal, and an author on the new study—tells Popular Mechanics. “But the most exciting thing was to see 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 that we should not expect the technique to be available in the clinic anytime soon. The activation of the Yamanaka factors can cause cancer, and it is still unclear whether this process will work in other cell types. “There are still so many unknowns,” she says.
Reik echoes these concerns and has plans to develop safer strategies. He thinks by better pinpointing how Yamanaka factors work, he will be able to find downstream molecules that are turned on by the genetic factors. By identifying those factors, which may be RNA or protein, he could develop therapeutics that don’t require messing with the genes in the cell, therefore lowering the risk of cancer and other side effects.
“We could call them ‘rejuvenation factors,’ and they would provide a safer way of rejuvenating cells,” Reik says.
Popular Mechanics, 6 May 2022