What does it mean to 'age'? And will science ever keep us from aging?

Tiny Matters

What is aging, exactly? Is it days on a calendar? The number of wrinkle lines on your forehead? And what causes aging? In this episode of Tiny Matters, Sam and Deboki tackle those questions plus if any of those ‘fountain of youth’ products on your newsfeed will actually keep you from aging, and if there will ever be a day where aging is a thing of the past.

Transcript of this Episode

Sam Jones: Maybe it’s because I’m now in my thirties, but I feel like I am being absolutely bombarded with things telling me that I can look younger, feel younger, preserve ‘whatever youth is left.’ I think it’s fair to say that we, as humans, are obsessed with aging and finding ways to not age. Deboki, am I out of line here?

Deboki Chakravarti: No, I totally agree. And I watch enough Real Housewives to know that there are a lot of very extreme things that people have come up with that they claim will help people fight aging.

Sam: So what is aging, exactly? And what causes it? Are any of those products in your newsfeed actually going to keep you from aging? And… will there ever be a day where scientists can stop us from aging?  

Welcome to Tiny Matters, I’m Sam Jones and I’m joined by my co-host Deboki Chakravarti.

Deboki: Sam and I are going to start off today’s episode with a surprisingly tricky question: What is aging?

Is it days on a calendar? The number of wrinkle lines on your forehead? We called up Laura Niedernhofer at the University of Minnesota to find out. Laura’s a professor in the department of Biochemistry, Molecular biology and Biophysics and the director of the Institute on the Biology of Aging and Metabolism.

Laura Niedernhofer: The joke we make about aging is we all know what it looks like, but we aren't able to precisely define it. It's a tricky business. So what we do have in the field of aging are what we call the hallmarks of aging. So there seems to be biologic changes that are near universal. And one of those changes is the accumulation of damage to a number of different parts of the cell. We believe that the damage to the DNA or the genome is one of the key drivers of aging.

Sam: Your genome is another word for all of your genes, and your genes are made up of deoxyribonucleic acid or DNA. DNA is made up of molecules called nucleotides, specifically the nucleotide bases adenine, thymine, cytosine, and guanine. These are often just referred to as ATCG. Maybe that rings a bell. So your genes are just sequences of A’s T’s C’s and G’s and they code for RNA which then codes for different proteins. So yeah, your DNA is essential. You do not want it to get messed up.

Laura: The sole job of DNA is to maintain your genetic code, which defines who you are and how all your cells work in unison to make you a complete person. And so DNA damage would be the chemical or radiation addition of extra atoms onto your DNA, and that messes with the code so that things can change.

Deboki: When it comes to things that can damage our DNA the list is, unfortunately, quite long. But Laura split them into two categories for us: damage that’s endogenous, meaning it’s caused by things already in our bodies, and damage that’s caused by our environment. A good example of an environmental one is the sun.

Laura: A classic one is the UV component or ultraviolet component of sunlight. And so this can directly reach the DNA in the cells of your skin, and this will damage it through just radiation and to illustrate how significant this is. If you are not able to remove that damage through DNA repair, it increases your skin cancer risk by 10,000 fold. So it's really a significant source of DNA damage. Another classic one is products through smoking.
Deboki: Cigarette smoke is disgusting. Sam is nodding her head in agreement.

Sam: It’s true. I am.

Deboki: Cigarette smoke is estimated to have over 7,000 different chemical compounds in it, many of which are toxic. And some of those compounds can damage the DNA in your lung cells.  

Now let’s talk about the ‘endogenous’ things—things that are already in our bodies that can damage our DNA. I’d bet it’s stuff you wouldn’t normally think of as ‘damaging.’

Sam: Definitely not. I have a bit of a background in this and sometimes I even forget.

Laura: So it turns out that the DNA in our cells is actually not stable in our oxygen rich and water rich environment. So it turns out that DNA damage can be attacked by oxygen, and it can also just fall apart in the presence of water. So it's pretty scary because we can't live without those things, right?
Sam: Our bodies are made up of about a trillion cells and every day in each cell there’s around 40,000 endogenous DNA damage events. And our bodies clean up almost all of it. How unbelievable is that?

And how do we do it?

Laura: We have five major DNA repair pathways, and each one of them is focused on a different type of DNA damage. The mechanisms are a little bit different between these different pathways, but there's some common steps that we could talk about. So in the example of UV-induced DNA damage caused by the sunlight, there's a pathway called ‘nucleotide excision repair.’ And so what it does is it scans your genome, looking at the entire content of DNA, and it's gonna look for any patch of distortion of this beautifully elegant helical structure that we have for our DNA.

Laura: Imagine a step ladder and you twist it. That would be your beautiful DNA helix. But what happens if you broke a step? All of a sudden it doesn't have the same sort of beautiful structure anymore. It starts puckering and breaking and bulging out, and this is what your body can recognize and repair. So this is a really good signal that there's something wrong in your genome. And it's time to call in the DNA repair army.

Sam: That ‘DNA repair army’ is made up of dozens of different proteins in your cell that will first check that there is in fact a chemical alteration to your DNA and, if there is, cut it out. From there the opposite strand of DNA will be used as a template—remember your DNA is a double helix, it has two strands that are paired up. So using the opposite strand, your DNA repair army will replace the nucleotides that were cut out.

Deboki: Fortunately, most of the time, the DNA repair army flawlessly does its job. But what about when DNA damage repair goes wrong or doesn’t happen? If your cell misses the damage, it’ll likely go on continuing to be its cell-self, doing things that cells normally do, like replicate. In that replication process it might just swap in random, inaccurate nucleotides to replace whatever bit of DNA is damaged. As cells divide those inaccuracies or what Laura calls ‘misinformation events’ start to build up and eventually, if you get enough of them, you end up with genetic mutations.

Laura: And mutations are the cause of cancer. Period. The link between DNA damage and cancer was the tying DNA damage to a health impact. Aging is a much newer consequence, but to me it's pretty profound because we all age and there is really strong evidence that DNA damage, when not repaired, will contribute to the aging of virtually every organ system in your body, not just the skin.

Sam: Laura and her colleagues are interested in studying the impact of DNA damage on aging. And to do that, they take away a cell’s ability to repair DNA damage and see what happens.

Laura: And then you have an exaggerated situation where you're getting more damage than a healthy normal cell or mouse or other model system. So I worked with a number of great colleagues across the globe where we took away DNA repair pathways and just observed what happens in a cell, what happens in a mouse. And there's unfortunately even people who have inherited defects in DNA repair, and so they also give us a very visual image of what happens if you have too much DNA damage. So we think of these patients who have what we call ‘genome instability disorders,’ they have an inherited defect in DNA repair. And this leads to lots of health implications. It really, to me, is accelerated aging. It's what's going to happen to all of us. It just happens much, much faster. And they do have higher risk of cancer, much earlier onset of cancer, and virtually every sign of premature aging affecting every organ system.

Sam: Laura has primarily used mouse models for her work. She and her colleagues made genetic changes to mice that got rid of their ‘‘DNA repair army’ and it had a massive impact.

Laura: We created mice that age six times faster than normal. And they spontaneously develop virtually every age-related disease that you can think about. They get osteoporosis, they have disc degeneration, they get a curved spine and lower back pain. They get cognitive impairment, they go deaf, they go blind, they have heart disease. So now what we're trying to do is to be really specific about this. We're knocking out DNA repair in one organ or cell type at a time to determine the impact. And we were shocked to learn that, for instance, if you knock out DNA repair in beta cells, which produce insulin in our pancreas, we actually can cause type 2 diabetes—so, adult onset diabetes—just by removing DNA repair pathways.

Laura: One of the things that became apparent recently is that a response to DNA damage as well as a number of different types of stress in a cell is for that cell to activate a pathway that will drive it into senescence.

Sam: Senescent cells are cells that have stopped growing and doing normal cell things like converting nutrients into energy or signaling to other cells. I like to think of senescent cells as cells on hold, indefinitely.

Laura: Senescence is a great thing because basically it's a very potent tumor suppressor. It will tell a cell that's damaged, ‘You are not to copy yourself again because that would risk mutations and potentially cancer.’

Deboki: But although senescence is a great mechanism for preventing mutations that could lead to cancerous tumors, senescence can also be problematic. Senescent cells secrete proteins that are inflammatory, meaning they essentially send an SOS to your body’s immune system, which then comes to clear them out. It’s kinda similar to how your immune system clears out viruses or dangerous bacteria. But here’s the problem: As you age, your immune system stops working as well as it did when you were younger. And that means senescent cells aren’t getting cleared as often or as easily.

Laura: And these senescent cells start to accumulate and then they drive chronic inflammation. So there is hard and fast proof that senescent cells contribute to virtually every age related disease as well as aging itself. And this is the way that I think we could attenuate the bad response to DNA damage by trying to help the body get rid of these senescent cells.
Sam: I’m pretty pumped about these senescent cells. Laura is too.
Laura: I am really excited about senescent cells. They are now considered a hallmark of aging, and probably one of the most druggable hallmarks of aging. So there are lots of new approaches to remove senescent cells from the body—these are called senolytic drugs—or to modify their inflammatory behavior, which are called senomorphic drugs. There are clinical trials ongoing already with these drugs. And so what I'm excited about is to see how they work because there's trials even on Alzheimer's disease… there's certainly evidence now in animal models that there is increased senescence in the brains of models of Alzheimer's disease. And furthermore, clearing those cells attenuates the disease. So I've got my fingers crossed for the clinical trials…. My guess would be we'll know the answer in about five years, which is super exciting.

Sam: So cool, right?

Deboki: Yeah, that’s definitely something to look forward to, it’s a really exciting part of aging research. But we also wanted to understand the fundamentals this field is built on. So we talked to researchers about the work they’re doing to define—from a scientific standpoint—what age is.

Sam: Some researchers are interested in connecting age to epigenetic changes, which are reversible modifications to your DNA. Epigenetic changes don’t tamper with your genes. Instead, they change the likelihood that a gene will be transcribed from DNA into RNA. In other words, they impact a gene’s activity, which can of course have a bunch of effects downstream.

DNA methylation is an example of an epigenetic change. It’s when a methyl group, which is 3 hydrogens bonded to a carbon, is added to your DNA.

To learn a bit more about how DNA methylation is related to determining age, I reached out to a friend from graduate school—Tina Wang, who’s currently a scientist at Johnson & Johnson, studying neurodegeneration, which is of course an age-related disease. Tina’s interest in aging research started over a decade ago.

Tina Wang: I had been fascinated by the idea that you can measure aging besides more than just the calendar days that pass by.

Deboki: When she was in graduate school, Tina became interested not just in the possibility that we could use DNA methylation changes to measure our “true”—I put that in air quotes—“true” age but that, across species, those changes might be consistent. I mean, if you go back far enough, we all come from a common ancestor. So she set out to answer this evolutionary question starting with… dogs.

Sam: Dogs are the best… I say as someone with two dogs. We should also mention that no dogs were harmed in the collection of any of this data. Tina loves dogs just as much as me, and actually also has two of them. Her dog Belli was an inspiration for this study because, when Tina adopted Belli, the shelter told her Belli was maybe 8 months old. Tina says there’s absolutely no way. Belli was at least 2, maybe 3 years old. And Tina thought, wouldn’t it be awesome to use DNA methylation data to more accurately figure out Belli’s age?

Deboki: Tina was also interested in looking at changes in DNA methylation in dogs, versus other model systems, because dogs get a lot of the same care as humans unlike mice or cells in a petri dish.

Tina: Dogs represent a really interesting organism relative to humans. They're the only other species that have as much medical care as we do, and they also have very short lives. So if you were to able to maybe develop something that measures age in dogs and, given the fact that like dogs have a huge variety of lifespan that's related to their size, related to their breed, and you could study them in terms of aging, they would represent a really valuable model organism to learn what we can actually do to maybe enhance our longevity or learn about the factors that actually affect aging.

Deboki: Tina found that, when comparing patterns of DNA methylation between dogs, humans, and mice, there was even more overlap than she expected and that, based on methylation changes, she could accurately predict calendar dog years and convert them to human and mouse years and vice versa. And when she looked into what genes were being impacted by those changes in methylation, she found they were mostly involved in animal development—genes that help us grow and become fully functioning mammals.

Tina Wang: My study maybe can show that there are indeed regions that are commonly affected by aging, that are shared between mammals, and then give more weight to the idea that you could use DNA methylation to measure aging for real.

Sam: I find this work so interesting. But it sure isn’t easy because humans live a very, very long time, and getting controlled data from someone across their lifetime is impossible.

Tina: The best way that you can measure aging is to see if you live longer. When you start applying these methylation age predictors, they are always in these cohorts that have been collected decades ago, and then they're trying to see if this age prediction influences your survival probability at the end…. With a mouse, you're three years old and you would be really old for a mouse.
So you can definitely start seeing that kind of effect a lot easier in mice. And I think that's why it's really hard to map these same things over to humans, because at the end of the day, you can't enroll people in this double blind placebo versus not placebo trial and then actually see if they live longer.
Sam: Tina told us she hopes this study and others like it will ultimately reveal a connection between changes in DNA methylation as we age and the health and physiology of the cells in our bodies.

Making that connection could open up a whole new world of aging-related research. Could you alter methylation patterns and slow aging? Maybe reverse it?! No, that’s a little too scifi, but this is a very cool field and I’m excited to see where it goes.

Deboki: So to bring things full-circle, let’s talk about the gimmicky things that people try out in the name of anti-aging. I’m thinking about stuff like diamond face creams that real housewives swear by or other very strange, and often very expensive, treatments. Like Sam and I mentioned at the top of the episode, we are inundated by ads for things that ‘reverse aging by 10 years’, like lotions that claim they’re the ‘fountain of youth!!!’

Sam: Ugh it’s so annoying.

Deboki: Well Laura says don’t be fooled by that ‘fountain of youth’ talk.

Laura: There are some good products out there, but you have to stop and think, is it really penetrating my skin or is it just plumping it up right now? I think a lot of it is very temporary effects and you can see that in dermatology, there are very few FDA approved products, and those are the ones that we know there's really good science behind.

Deboki: So in not-so-shocking-news, a cream that you smear on your face will not stop you from aging. It could possibly make your skin look better but it will not rewind time. A cream on the surface of your skin isn’t a panacea, it’s a temporary fix.

Sam: And Laura says completely stopping humans from aging isn’t actually the goal—at least it certainly isn’t right now. Scientists, to the best of her knowledge, are not thinking they’re going to get people to live for hundreds of years looking like they did when they were 25. They want us to live a long time, yes, but most of all they want us to spend the years we have as healthy as possible.

Laura: I believe very firmly that there are ways that we can keep people healthier in their old age. So basically this goes back to developing therapeutics that target those hallmarks of aging. It's going to be really tricky to get rid of endogenous DNA damage, right? We can't get rid of oxygen and we can't get rid of water, but what we can do is impact how a cell is gonna respond to it. So if you think of your genome, it's made up of 3 billion base pairs. So a little damage here or there is not going to be the end of the world. It's how your cells respond to it. And so if we can dampen that response I think we'll have avenues for stemming age-related diseases. Are we going to stop aging? No, never entirely. I don't believe it for a second. And I don't think we're gonna extend human health span ridiculous amounts, but I think we can keep people healthier in old age. And that's what our big priority is.

Sam: All right. Hopping right into it. So my Tiny Show and Tell this week has to do with regeneration. The focus is the axolotl, which is a very cute salamander. In every photo I feel like it looks like it's smiling. Definitely look it up. It will make you smile. I guarantee it will make you smile.

So beside being very cute, they're really good at regenerating bits of their brains after any sort of injury to their brains. Up until now, scientists were really only looking at structures in their brains after or during regeneration and not what was happening within their brain cells. So now scientists from a few different labs have come together to analyze gene expression in regenerating axolotl brains at the single cell level.

So this is called single cell transcriptomics. So it's essentially looking at within one cell all of the genetic changes that are happening during regeneration in this case. They did this single cell level analysis and then compared what they found to regenerating mammal brains to try and understand why the axolotl brain is just so much more capable of regeneration than mammalian brains.
They found a lot of stuff. I mean, you are looking at individual cells. That's a lot of data, but particularly they found that the axolotl brains were able to reactivate the production of new neurons using similar pathways to what they would've used in their super young brain.

So it's essentially if we somehow had a brain injury and then we were able to tap into pathways be used when we were babies or fetuses and we were generating all of these neurons. That's kind of what the axolotl is able to do as an adult, which is very cool.

So why did I think this is interesting? Well, in our episode on regeneration a couple months ago, we talked a lot about how scientists are trying to study excellent regenerators. So that includes planaria, the axolotl, hydra to essentially learn how humans might be able to harness that same ability. Yeah, this is another study that's adding to that growing knowledge base. So I thought it'd be kind of fun to share.

Deboki: Yeah, that's so wild. Well, I have a far less adorable animal to talk about, which are cockroaches. Specifically this is a story about cockroaches being very good at the thing that unfortunately they're very good at, which is surviving.

So in the 1930s in Lord Howe Island in Australia, it was thought to have lost one of its important residents, the wood-feeding cockroach thanks to rats that had been brought to the island in 1918. I feel like this is one of those classic we brought in these one creatures probably because they thought it was going to do something or maybe they just accidentally were on board and then they wiped out all of these cockroaches. On the one hand that feels like great news, but on the other hand, cockroaches are actually very important for the ecosystem. They're really great for recycling nutrients. So they are kind of important in that way.

So scientists have been looking to see if any of these species have survived in nearby islands and they had found kind of closely related species, but they were genetically different. So it seemed like just another tragic story of extinction, except recently a biology student named Maxim Adams from the University of Sydney was visiting Lord Howe Island I think for research. They just happened to turn over this rock that was under this one tree and there happened to be a Lord Howe Island wood-feeding cockroach under it. There's a whole family actually of them and at first apparently they were so surprised, they were like it can't be it. But then they were like yeah, I think this is it.
So it's good that they were able to find them because it turns out, like I said, cockroaches are so important for the ecosystem and scientists have been thinking about trying to reintroduce other species to the island because they're so important. But now they don't have to because it turns out this cockroach is doing just fine. It's alive.

Sam: That's awesome. So it's on the island, it's doing its thing. Are they going to try to propagate it or make it... Are they trying to build it up or they feel like it exists, it's obviously doing fine. We're not worried now.

Deboki: That's a great question. I don't actually know. Yeah, I actually don't have any idea about that and I don't see anything in the article that I'm reading. But that would be super interesting because if they're super important and you want to know that they're alive, but how many is enough? How many cockroaches is enough? Is it enough to have them just under this one rock? Should we try to make more of them? Should we just let them be? Yeah, it's all good stuff to think about.

Sam: Of course, you don't want to swing the pendulum in the exact opposite direction where now you have tons of cockroaches and now the question again is how do we get rid of them? But it's tricky. All the ecosystem conservation, what is the perfect balance? It's tough and we're making it harder as humans with climate change. So whoops.

Thanks for tuning in to this week’s episode of Tiny Matters, a production of the American Chemical Society.

Deboki: This week’s script was written by Sam who is also our exec producer and was edited by me and by Matt Radcliff who’s the Executive Producer of ACS Productions. It was fact-checked by Michelle Boucher. The Tiny Matters theme and episode sound design are by Michael Simonelli and the Charts & Leisure team. Our artwork was created by Derek Bressler.

Sam: Thanks so much to Laura Niedernhofer and Tina Wang for joining us.

Deboki: If you have thoughts, questions, ideas about future Tiny Matters episodes, send us an email at tinymatters@acs.org.  

You can find me on Twitter at okidoki_boki

Sam: And you can find me on Twitter at samjscience. See you next time.