the Waddington map, an embryonic stem cell is represented by a marble at the top of a mountain peak. During embryonic development, the marble rolls down the hill and comes to rest in one of hundreds of different valleys, each representing a different possible cell type in the body. This is called “differentiation.” The epigenome guides the marbles, but it also acts as gravity after the cells come to rest, ensuring that they don’t move back up the slope or hop over into another valley.
The final resting place is known as the cell’s “fate.” We used to think this was a one-way street, an irreversible path. But in biology there is no such thing as fate. In the last decade, we’ve learned that the marbles in the Waddington landscape aren’t fixed; they have a terrible tendency to move around over time.
At the molecular level, what’s really going on as the marble rolls down the slope is that different genes are being switched on and off, guided by transcription factors, sirtuins and other enzymes such as DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs), which mark the DNA and its packing proteins with chemical tags that instruct the cell and its descendants to behave in a certain way.
What’s not generally appreciated, even in scientific circles, is how important the stability of this information is for our long-term health. You see, epigenetics was long the purview of scientists who study the very beginnings of life, not folks like me who are studying the other end of things.
Once a marble has settled in Waddington’s landscape, it tends to stay there. If all goes well with fertilization, the embryo develops into a fetus, then a baby, then a toddler, then a teenager, then an adult. Things tend to go well in our youth. But the clock is ticking.
Every time there’s a radical adjustment to the epigenome, say, after DNA damage from the sun or an X-ray, the marbles are jostled—envision a small earthquake that ever so slightly changes the map. Over time, with repeated earthquakes and erosion of the mountains, the marbles are moved up the sides of the slope, toward a new valley. A cell’s identity changes. A skin cell starts behaving differently, turning on genes that were shut off in the womb and were meant to stay off. Now it is 90 percent a skin cell and 10 percent other cell types, all mixed up, with properties of neurons and kidney cells. The cell becomes inept at the things skin cells must do, such as making hair, keeping the skin supple, and healing when injured.
In my lab we say the cell has ex-differentiated.
Each cell is succumbing to epigenetic noise. The tissue made up of thousands of cells is becoming a melange, a medley, a miscellaneous set of cells.
As you’ll recall, the epigenome is inherently unstable because it is analog information—based on an infinite number of possible values—and thus it’s difficult to prevent the accumulation of noise and nearly impossible to duplicate without some information loss. The earthquakes are a fact of life. The landscape is always changing.
If the epigenome had evolved to be digital rather than analog, the valley walls would be the equivalent of 100 miles high and vertical, and gravity would be superstrong, so the marbles could never jump over into a new valley. Cells would never lose their identity. If we were built this way, we could be healthy for thousands of years, perhaps longer.
But we are not built this way. Evolution shapes both genomes and epigenomes only enough to ensure sufficient survival to ensure replacement—and perhaps, if we are lucky, just a little bit more—but not immortality. So our valley walls are only slightly sloped, and gravity isn’t that strong. A whale that lives two hundred years has probably evolved steeper valley walls and its cells maintain their identity for twice as long as ours do. Yet even whales don’t live forever.
I believe the blame lies with M. superstes and the survival circuit. The repeated shuffling of sirtuins and other epigenetic factors away from genes to sites of broken DNA, then back again, while helpful in the short term, is ultimately what causes us to age. Over time, the wrong genes come on at the wrong time and in the wrong place.
As we saw in the ICE mice, when you disrupt the epigenome by forcing it to deal with DNA breaks, you introduce noise, leading to an erosion of the epigenetic landscape. The mice’s bodies turned into chimeras of misguided, malfunctioning cells.
THE CHANGING LANDSCAPE OF OUR LIVES. The Waddington landscape is a metaphor for how cells find their identity. Embryonic cells, often depicted as marbles, roll downhill and land in the right valley that dictates their identity. As we age, threats to survival, such as broken DNA, activate the survival circuit and rejigger the epigenome in small ways. Over time, cells progressively move towards adjacent valleys and lose their original identity, eventually transforming into zombielike senescent cells in old tissues.
That’s aging. This loss of information is what leads each of us into a world of heart disease, cancer, pain, frailty, and death.
If the loss of analog information is the singular reason why we age, is there anything we can do about it? Can we stabilize the marbles, keeping the valley walls high and the gravity strong?
Yes. I can say with confidence that there is.
REVERSAL COMES OF AGE
Regular exercise “is a commitment,” says Benjamin Levine, a professor at the University of Texas. “But I tell people to think of exercise as part of personal hygiene, like brushing their teeth. It should be something we do as a matter of course to keep ourselves healthy.”41
I’m sure he’s right. Most people would exercise a lot more if going to the gym were as easy as brushing their teeth.
Perhaps one day it will be. Experiments in my lab indicate it is possible.
“David, we’ve got a problem,” a postdoctoral researcher named Michael Bonkowski told me one morning in the fall of 2017 when I arrived at the lab.
That’s seldom a good way to start the day.
“Okay,” I said, taking a deep breath and preparing for the worst. “What is it?”
“The mice,” Bonkowski said. “They won’t stop running.”
The mice he was talking about were 20 months old. That’s roughly the equivalent of a 65-year-old human. We had been feeding them a molecule intended to boost the levels of NAD, which we believed would increase the activity of sirtuins. If the mice were developing a running addiction, that would be a very good sign.
“But how can that be a problem?” I said. “That’s great news!”
“Well,” he said, “it would be if not for the fact that they’ve broken our treadmill.”
As it turned out, the treadmill tracking program had been set up to record a mouse running for only up to three kilometers. Once the old mice got to that point, the treadmill shut down. “We’re going to have to start the experiment again,” Bonkowski said.
It took a few moments for that to sink in.
A thousand meters is a good, long run for a mouse. Two thousand meters—five times around a standard running track—would be a substantial run for a young mouse.
But there’s a reason why the program was set to three kilometers. Mice simply don’t run that far. Yet these
