There are some 200 different types of cells in the body, but they can all be traced back to stem cells. Before they differentiated into heart, liver, blood, immune cells, and more, they were called pluripotent, meaning they could become anything.
Back in 2006, Shinya Yamanaka discovered four genes that, when forced to express themselves, knocked cells back to their pre-differentiated state. For many, including the Nobel Prize Committee—which awarded Yamanaka the 2012 Nobel in medicine—this was an indication that we really might be able to, one day, reverse the natural process of aging. But there were significant problems. By turning these genes on, researchers caused cells to lose their identity. Since the cells can then grow into anything, they do, and that often results in cancer, but can also cause the cells to fail to do their jobs—problematic when you’ve got a heart or liver cell.
Researchers at the Salk Institute in La Jolla, California, may have a solution. They showed, in a recent article in Cell, that they were able to induce cells, including human cells in vitro and mouse cells in vivo, to behave like younger cells, increasing the life span of the mice and the resilience of the human cells. The research represents an important step in the way we understand aging at the cellular level and could, with time, point to therapies based on how, and whether, a set of genes that control the aging process are expressed.
“Mainly the concept here is the plasticity of the aging process,” says Juan Carlos Izpisua Belmonte, a professor at Salk and author of the study. “Imagine writing a manuscript. At the end of your life, if you pass the manuscript to many people, there will be many marks, a lot of addition. What we’re doing here … is eliminating some of these marks.”
Belmonte and his lab came up with a clever workaround to some of the problems caused by the Yamanaka factors. They knew that when these genes were turned on, the reprogramming of the cells proceeded in a stepwise manner—certain effects happened at different times. They reasoned that if you could turn the Yamanaka factors on and off, you could arrest the process before the cells regressed all the way back to pluripotency.
To get this to work, they introduced some genetic changes to lab mice. In these mice, those four genes can be easily turned on or off by a compound in the mice’s water. Then they ran the experiment in cycles, with the factors turned on for two days, then off for five.
They tried it out with two types of mice: some that had progeria, a rapid-aging genetic condition that reduces their lifespan to 16 weeks or so; and some that aged naturally to one year. Under the treatment, the mice with progeria tended to live to 22 or 23 weeks (about 30 percent longer than normal), and the natural aged mice showed greater resistance to muscle injury, metabolic disease and other hallmarks of aging.
“We really think that the epigenetic regulation is one of the main drivers of aging,” says Alejandro Ocampo, a research associate in Belmonte’s lab and the study’s lead author. “Because of the fact that it is dynamic, you have room and the possibility to not only slow it down, but also reverse it back to a younger state.”
But he adds that the work they’ve done so far is more about mitigating the effects of age than reversing it. To do so would require taking aged mice back to an earlier state, he says. “That experiment is much more complicated than what we showed.”
If that could be done, the outcome could be very important.
“Aging is the major risk factor for most diseases we suffer. If you are able to slow down or reverse the aging process, you can have a great impact on those diseases,” says Ocampo. “Our focus is more in expanding health span, so we want to extend the number of years that people are healthy.”
But when the researchers stopped delivering the treatment, the effects wore off quickly, points out Tom Rando, a neurology professor at Stanford, who proposed in 2012 that epigenetic reprogramming could be achieved by decoupling rejuvenation from the de-differentiation that leads to cancer and other problems. The research from the Salk Institute is important, he says, because it tackles that very idea.
“First of all, I’m impressed with the study, make no mistake,” says Rando. “It really is taking that next step, from the kind of phenomenology that we were observing and the mechanisms we were proposing, to a real intervention that aims at reprogramming to see if you could do that.”
Rather than just transitioning the same work into humans, Belmonte’s lab is trying to understand the mechanisms by which the rejuvenation works. You can’t create transgenic humans just to administer the treatment, the way they did in mice, so they’re looking at ways to use chemicals to do some of the same things those Yamanaka factors do when they’re induced, but applying the cyclic administration they developed in this study.
“This is just the beginning,” says Ocampo. “We are just starting to see that we can do this, but of course it can be done in a much better way when we know more about the process.”