01/08/2021

Can Cells Rewind The Wrinkles Of Time?

8:52 minutes

a red eyed white mouse in a gloved researcher's hand
Credit: Public Domain

As a cell ages, its DNA goes through a process called “methylation”—gaining extra methyl chemical groups. These groups can affect how the genes’ encoded information is expressed, without actually changing the sequence of genes. 

In work published in Nature, researchers explore whether reversing that methylation can reprogram the cells back to a more youthful state. They used modified adenoviruses to introduce three specific transcription factors into mouse retinal ganglion cells, a type of neuron found in the eye. These transcription factors helped revert the cell to a more immature state—and also seemed to let the cell behave in a more ‘youthful’ way.   

David Sinclair, a professor of genetics at Harvard Medical School and one of the authors of the study, joins Ira to discuss what the work means, and what it could tell scientists about the aging process. 

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Segment Guests

David Sinclair

David Sinclair is a professor in the Department of Genetics and co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School in Boston, Massachusetts.

Segment Transcript

IRA FLATOW: For the rest of the hour, looking at how cells age and whether there’s anything that can be done to slow, stop, or even reverse that process. As DNA ages, it gains dust bunnies, extra methyl groups tacked on. And those methyl groups can affect how the genes themselves are expressed without changing the actual sequence of genes.

In work published in the journal Nature, researchers are looking at whether reversing that methylation can sweep away some of the cruft and reprogram the cells back to a more youthful state. And it can, at least in mouse eye cells. Joining me now to talk about the work and what it means is one of the authors of that report– David Sinclair, professor in the Department of Genetics, co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Med School. Welcome to Science Friday.

DAVID SINCLAIR: Thanks, Ira. It’s great to be on.

IRA FLATOW: What do you mean when we say a cell is aging? What happens to the cell over time?

DAVID SINCLAIR: Well, this has been a debate for at least 40, 50 years. And there’s really a lot that goes on in aging cells. Many of your listeners would know about the shortening of the ends of chromosomes called telomeres. We get proteins that accumulate that exacerbate Alzheimer’s disease.

But there’s a new theory about aging that’s gaining a lot of traction, and that is the cells forget how to function correctly. Because they cannot read their DNA correctly. And that’s really what my lab has been focused on for the last few years. And we recently published about how to manipulate that process.

IRA FLATOW: In fact, your group looked at a way to wind back the clock in the cells. Tell us how you did that.

DAVID SINCLAIR: Well, what’s been discovered just in the last five or so years about aging is that there is this clock, these DNA methyl chemicals that accumulate like crust on DNA. And we can read those very easily. A student in my lab could tell you your rough biological age within about 5% error within about a day. It’s pretty easy. And what this predicts, actually, is that how old you are biologically, not chronologically.

Throw away the birthday candles. And some people are older than they would otherwise think. And some are younger. And this also predicts how sick and/or healthy they’re going to be in old age. And this DNA methylation clock, we think, is part of the system that goes wrong during aging. And what we tested was if we could reverse or scrape off those methyl groups and reset the cell, maybe aging would actually go backwards.

IRA FLATOW: And you did this in mice in eye cells, cells in the eye?

DAVID SINCLAIR: Well, yeah. We’re not an eye lab, but we thought the eye would be one place to start. Often, people ask me, did you choose the eye, because you thought it would work? In fact, my student at the time, Yuancheng Lu, picked the eye, because he likes the eye.

But what we did in the lab was we spent a few years, actually Yuancheng spent a few years failing to reverse the age of cells. And if he succeeded, typically those cells became tumorigenic. In other words, could form tumors in an animal or probably in a human, too. It’s very difficult, it turns out, to reverse aging partially without going all the way back to a stem cell which, of course, we don’t want to do. Because that’s essentially what a cancer is.

But he hit upon a really specific three-gene combination that was able to partially reverse the age of cells in the dish, but not go too far. And we applied that to the nerves at the back of the eye in mice. And it did reverse the age of those cells.

IRA FLATOW: So you restored the vision in mice who had lost their vision by turning the clock back?

DAVID SINCLAIR: Exactly right. But what was questioned at the time before our paper was, if you turn the clock back, is it just symbolic? Or does it actually have an effect on the cells? Similar to if you move the hands of a clock backward, you’re not going to change time. This was the belief.

But what we discovered is that this three-gene combination– these genes actually come from embryos, typically are turned on during embryogenesis, we call it. Those three genes actually didn’t just wind the clock back. But the cells came back to life and had a youthful pattern of genes on and off. And they actually started to function as though they were young again.

IRA FLATOW: You don’t wind the cells all the way back to where they were in the embryo. You just go a certain distance?

DAVID SINCLAIR: Yeah. So that’s the exciting part about this is that if you use this right, this combination, the cells have a barrier to losing their identity and going back too far, which is remarkable that it exists. We just lucked out. We didn’t know that that was even possible. But also, what’s fascinating is that the cells somehow have a backup copy of the youthful patterns. And we’re searching for where that information is stored right now.

IRA FLATOW: And you’re saying that there’s no reason why this could not be applied to other cells in the body to reverse aging?

DAVID SINCLAIR: Yeah. Actually, what’s exciting is that there are many labs now who are working on this. We call it partial epigenetic reprogramming. Or we’re starting to use the word rejuvenation. And they’re testing other tissues. We’ve now tested other cells in the eye, such as the ones that are involved in macular degeneration. It seems to be working there.

Colleagues of mine have rejuvenated muscle. And there are rumors of other tissues working. There was a recent paper from Spain– Manuel Serrano, a colleague of ours who rejuvenated the brain in mice and improved memory. So we think that this could be, dare I say it, a universal way to reverse aging in mammals and perhaps one day in people.

IRA FLATOW: I’m Ira Flatow. This is Science Friday from WNYC Studios. So let’s get to that part about people, because that’s what everybody is going to be asking. What do you need to have a proof of concept in people here?

DAVID SINCLAIR: Well, in the mice, what we saw were we had three different experiments. We saw nerves regrow when they were injured. We saw that glaucoma which is, I think, many people know is pressure-induced damage to the retina and just old age.

We took those three systems in mice. And our three gene-combination actually improved the function of the eye in all three cases. In the case of glaucoma and old age, we looked at vision. And it was improved. In the case of the old mice, it was actually restored to young mice.

I came home after getting that result with the lab and said we cured blindness, at least in mice. And I think my wife told me to go empty the dishwasher. But it was a really interesting find. But to your question, we think that we can– but we want to try to attempt to reverse blindness or vision loss in people. And we’re going to start with patients who have glaucoma.

IRA FLATOW: And when would that start?

DAVID SINCLAIR: Well, there’s a local company here in Boston– Life Biosciences that’s working towards that. It’s probably a couple of years, at least, before we start to put the gene therapy, as it is right now, into patients. But we’re working as hard as we can to safely make that possible.

IRA FLATOW: People are going to hear this interview. And they’re going to want to get in on this treatment or perhaps even the tests themselves. Is there any way to do that?

DAVID SINCLAIR: No, not yet. It’s not at the stage where I would say we know enough about it. It is a very powerful, potential medicine that’s doing things that we thought were impossible just a few years ago. But we’re not at the point where we can treat anybody. This is for most medicines, but particularly when it comes to gene therapy. This is truly rewinding the clock. And we don’t know some fundamental things such as, how long does the effect last? How many times can you repeat the process?

So we’ve engineered our gene therapy to be inducible. What that means is we can give a mouse and hopefully a patient an antibiotic that turns the genes on for, say, three weeks. And then you turn it off. And then perhaps you could turn it on a few years later if you needed to with your doctor’s permission. So that’s where we’re heading. But, no, please don’t contact me asking for any treatments just yet.

IRA FLATOW: Well, this sounds amazing, Dr. Sinclair. We wish you all the best of luck here.

DAVID SINCLAIR: Thanks, Ira. Really appreciate the chance to be on.

IRA FLATOW: David Sinclair is a professor in the Department of Genetics and co-director of the Paul F. Glenn Center for the biology of aging at Harvard Med School.

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