The Hallmarks of Aging, with Dr. Robert Rountree

Robert Rountree:

This is The Thorne Podcast, the show that navigates the complex world of wellness and explores the latest science behind diet, supplements, and lifestyle approaches to good health. I'm Dr. Robert Roundtree, Chief Medical Advisor at Thorne and functional medicine doctor. As a reminder, the recommendations made in this podcast are the recommendations of the individuals who express them and not the recommendations of Thorne. Statements in this podcast have not been evaluated by the Food and Drug Administration. Any products mentioned are not intended to diagnose, treat, cure, or prevent any disease.

Hi, everyone, and welcome to The Thorne Podcast. We've got a very special episode for you this week. Instead of a guest, we're going to share with you a lecture I gave at the Peptide World conference in Las Vegas. And in this talk, what I did is I reviewed the nine hallmarks of aging, and I talked about different kinds of interventions that we can use to slow down the aging process. I hope you get some good insights from the lecture, as we cut now to Las Vegas.

Speaker 2:

I have our last speaker before lunch. His name is Robert Roundtree, MD. He received his MD from the University of North Carolina School of Medicine. He then completed a three year residency in Family and Community Medicine at the Milton S. Hershey Medical Center in Hershey, Pennsylvania, after which he was certified by the American Board of Family Practice. He's a diplomat of the American Board of Holistic Medicine. Dr. Roundtree has provided a unique combination of traditional family medicine, nutrition, herbology, mind-body therapy for his patients in Boulder, Colorado. There is a lot of peptides in Boulder, Colorado, probably because of the good work Dr. [Elizabeth] Yurth is doing, too. He has recently opened Boulder Wellcare, a private practice specializing in an individual health-care consulting. He is co-author of three books on integrative medicine. We are thrilled to have him here today, folks. Give it up for Dr. Robert Roundtree.

Robert Rountree:

Good morning, class. I'm here to talk about aging, which is problematic because I'm getting older just as I'm standing here. But my objective is to connect some of the dots about different pathways of aging that you might have heard about. How do these all fit together? Because if you go to a conference of geroscientists, they will all have their own little area that they focus on. There's the telomere group, right? There's the methylation group. There's the oxidative stress group. So how does all that fit together? That is really my task today. 

Here is my disclosure slide. I do consult for a nutraceutical company, Thorne HealthTech. 

I want to start this lecture by going back to Hippocrates who basically told us, use it or lose it. It's still pretty good advice, right? If you sit around watching TV all day, you can't expect to get younger. You have to use your body parts if you want them to stay active.

And this guy is proof. This is my hero. My hero, Robert Marchand. He died last year at the ripe old age of 109. Amazing. Isn't he a handsome looking dude? I mean, really. He's all dressed up in this biking outfit, and there's a reason for that. This guy did a lot of things in the course of his life. He was a truck driver in Venezuela. He was a wine dealer. He was a Canadian lumberjack, but at 101, he started bike racing, a hundred. You heard me right. At 101, he started bike racing and he trained for four years. By the end of that four years, he was fitter than most 50-year-olds. Wow. Use it or lose it. 

So this is living proof of what can happen. It's never too late to make changes. This is what I tell my patients, including a guy I saw the other day, 93 years old. Is it too late? No, there's things you can do. Maybe you got another 20 years ahead of you.

So the central question in biology is: Do we get old because we get worn down by all the things that happen to us – the oxidative stress, the repetitive motion, etc. – or is there a program or programs? Is there something that drives the aging process? And if we knew what that was, is there something we could do about it? Are there things that we can alter? And why even ask this question? Because you might say, "Well, everybody knows it's wear and tear.” 

But there are counter examples. And this beautiful creature who's saying to you right now, I'm not just another pretty face, right? This beautiful creature. The naked mole rat doesn't age. It doesn't age. Or at least it doesn't wear down as it gets older. So there's something going on with this animal's genes. Here's what we know about naked mole rats who live in Buroughs in east Africa. Is as they get older, they don't have an increased risk of dying. How do they die? We don't really know. Something eats them, right? They get hit by a car. I don't know. Birds pick them out of the sky. They can live 18 minutes without oxygen. They can live off fructose for 18 minutes, which means you can give them a soda, give them a Coca-Cola, and they can live for 18 minutes without oxygen. That's weird. They don't get cancer. They don't hardly feel pain. The females don't go through menopause. You don't see naked mole rats with estrogen patches on, right? They don't go through that. They experience neurogenesis for decades. They make new brain cells. What do they do with them? I don't know, math problems? What are they doing with those new brain cells? 

Here's the clue though. Why do they live so long? And why do they not seem to get older with time? They have active DNA repair. There's mechanisms in their system that repair the DNA actively. And they also have these proteins in their cells call chaperones, and those chaperones help their proteins fold correctly so they don't get misfolded proteins that jam up the system. So those are two different pathways, two different mechanisms involved in aging.

And this raises the question of biological age versus chronological age. And you all know that if you have a room full of people who are the same chronological age, that you will see quite a bit of difference from one person to another. Clearly, one person ages faster than another, and one person's organs will age at different rates, their brains age at a different rate than our heart, than our liver, than our kidneys. So when you're talking about biological age, you have to talk about organ specificity. And what determines biological age? A lot of things. The exposome, all the things we're exposed to in the course of our life. And obviously genetics and lifestyle, all that goes together.

Now, the typical way we measure biological age is with the standard metrics like blood pressure, body weight, resting heart rate, et cetera. But there's new developments in the field of AI, artificial intelligence that lets us look at really simple things like a CBC or a metabolic panel and analyze that and be able to predict biological age based on the simple blood parameters. This is really a huge development in gerosciences. 

We also can measure telomere length, right? I'm sure you've all heard of labs that offer that, and that's an interesting thing. It's not the whole story, but it's interesting.

We can measure DNA methylation patterns, the epigenetic clock based on research done by Steven Horvath and others. That's really gotten better and better and better. I think it's interesting. I do recommend it to my patients. I've had that testing done. 

And then finally, the gut microbiome signature. That's an evolving area as well. 

So this is just an example of a biological age test that uses a metabolic panel, DHEA, and a couple other simple markers to come up with biological age. And I was thrilled to see that apparently I’m about 10 years younger biologically than my physical, my birthdate age, which was very much a relief, because I ain't getting younger. 

So what are the pathways that keep coming up over and over again? 

Well, one of the key papers that was written in this area was by Dr. Carlos Lopez back in 2013 of the journal Cell. And the general scientists keep going back to this paper over and over again because it summarizes all the key factors that appear to be involved in aging. There's genomic instability, there's loss of telomeres, there's epigenetic alterations, there's loss of proteostasis, which is the proteins getting misfolded, jamming up, causing inflammation, what we call sterile inflammation, “inflamm-aging.” There's dysregulated sensing of nutrients, especially glucose, mitochondrial dysfunction. You've heard a lot about that. Cellular senescence. Those are old cells that stop dividing. I think of them as like the old guys that sit on the park bench all day and yell at you when you walk by, right? We have cells like that in our body. Senescent cells. Our stem cells get exhausted and our hormones go to pot, right? 

So Dr. Lopez basically puts all these together and says, "It's an interaction between these different hallmarks that create the problem," and we can deal with each one of them individually.

So what I did is I read his paper, and I thought, "I got to put this into a schema, a format that makes sense to me." 

So number one, there's genetic and epigenetic damage that occurs for a lot of reasons. There's accumulation of proteins in our cells, partly because we have impaired autophagy, the inability to get rid of those proteins. Our proteins then cause inflamm-aging that leads to oxidative stress and that leads to senescent cells accumulating. And then finally, you have this overlap with dysregulated nutrient sensing. 

So let's start with inflamm-aging. How do we find out about that? Well, we go to the blue zones and we ask, "What allows people to live regularly to be over 100 or 110? What are the indicators or the markers that there's something different about these people?" And they did studies on this in Japan of centenarians and supercentenarians, and what was the number one thing that came up? C-reactive protein. This simple blood test. C-reactive protein appeared to be the No. 1 best predictor of overall mortality.

Well, we know about C-reactive protein and inflammation. We can do something about that. 

So now for a word from our sponsor, our sponsor who tells us, "OK, you want to raise NF-KappaB, I've got a sure far way to do that, and I will sell you a lot of NSAIDs as a result of that." Have you ever noticed when you go to medical conferences that this is what they serve at the break? Hopefully not at this conference. This is part of my new book, the Pro Aging Nuclear Factor KappaB Retox Diet. So I'm putting people on the retox diet to guarantee accelerated aging. And we know all these things will raise NF-KappaB, and that will accelerate aging. 

So how do we down-regulate NF-KappaB without turning it off? Well, we can't get people prednisone. Prednisone would be great, glucocorticoids. But there's a problem with that, you don't want to take that for 20 years, do you? Instead, how about we tell people to eat less? Oh my God, what a concept. Eat less, restrict your calories. Enough to get hungry, or overnight fasting, intermittent fasting, time-restricted feeding. They all seem to accomplish the same thing. 

In addition, we know that omega-3 fatty acid, DPA DHA can down-regulate NF-KappaB. So can curcumin, green tea, resveratrol, NAC, alpha lipoic acid. Oh gee, I look at that list and I think, "I've taking pretty much everything on there." So yeah, it all fits together. Curcumin. I can't really give a talk on inflammation or aging or basically any other topic in medicine without mentioning curcumin because it is really a wonderful substance for a wide variety of indications.

We know lots of different things can raise NF-KappaB, oxidative stress, inflammatory cytokines, infections, DNA damage, and curcumin down regulates all of them. So by hitting this final common pathway NF-KappaB, you decrease inflammatory cytokines. So curcumin is one good way to go. 

But what about eating less? How does eating less, calorie restriction, how does that contribute to longevity? It influences multiple energy sensing pathways. And this is where it starts to get a little bit technical. For those of you who like to do a deep dive into the weeds, mitochondrial energy pathways, especially AMPK, sorry, that says AMKP. That's a typo. It should be adenosine mono phosphate kinase. A really critical pathway for energy regulation in the body. When you use up ATP, you start with three phosphates, you get rid of them, and now you have adenosine mono phosphate. Only one phosphate left. The body senses that, and it turns on all kinds of responsive pathways. The NAD pathway, I'm sure you've all heard of NAD, but when I go back over that again, NAD sirtuin pathway, all of those together activates something called PGC1-alpha. 

Not long ago, I was lecturing to a room full of trainers and I mentioned PGC1-alpha. All the trainers knew about PGC one alpha, but the doctors didn't. And I thought, well, that's really interesting. The trainers are working with this with their athletes, so they really know the importance of activating that PGC1-alpha. 

Then there's insulin signaling pathways. The mTOR pathway, which people know about because of this drug called rapamycin, right, which has got a lot of potential interesting compound is telling us a lot about the aging process. So mTOR, something to look at.

And then finally, the NRF2 pathway, the cytoprotective pathway. I'll call this the broccoli pathway. Because we know that eating broccoli is anti-inflammatory, improves detoxification, and slows down the aging pathway. So on the left, we have a picture of Lance Armstrong's mitochondria back in his heyday, right when he was doing the Tour de France and was really one of the most aerobically fit people in the world. That's what a healthy mitochondria looks like. 

Well, what happens to a person who overeats for years on end? They get to the point where they don't get energy from their food, they eat, but they don't get energy. What's going on? It's because their mitochondria look like this. The cristae they get damaged, and so they don't do their job. And here's a schema of what's going on. On the left, a healthy mitochondria that makes a lot of ATP from food and relatively few free radicals. And I want to point out, a few free radicals are critical. They’re cell-signaling molecules, and we need some free radicals. We need them. 

But what happens when the mitochondria get damaged from years of overeating, not exercising, environmental toxins, etc. Then the ATP supply shrinks and the free radical damage goes up. How does this contribute to aging? Well, as I said, mitochondria typically making free radicals – reactive oxygen species – that over time damages mitochondrial DNA, mtDNA, lets the mitochondria kind of lose their skilled ability to function properly, so you make more free radicals, and it's a vicious cycle that leads to accelerated aging. 

So how do we get more mitochondria? How do we rebuild the cristae? Exercise. Yeah, it's really that simple, but it's got to be good quality exercise, enough to acutely deplete you of ATP.

- ad break -

Did you know that unhealthy lifestyle factors, such as lack of sleep, overexposure to the sun, and an unbalanced diet can affect your body at the cellular level, leading to a lower level of NAD+, a crucial component in your cells? When your NAD+ level drops, it can result in many of the adverse symptoms of aging. Thankfully, nicotinamide riboside, or NR, can lend a helping hand. NR helps your body prevent the effects of early aging by boosting the body's production of NAD+. And because no two individuals are the same, Thorne offers a wide variety of NR-based formulas, such as our Advanced Nutrients multi, or Thorne's very own exclusive NiaCel NR formulas. See Thorne's whole lineup of NR-based formulas for boosting NAD+ when you visit Thorne.com, that's T-H-O-R-N-E.com.

-- ad break --

When you get depleted of ATP, you increase AMP, adenosine mono phosphate, and that turns on the kinases that then set off this whole cascading effect that tells the cell, the nucleus of the cell, to make more mitochondria. I want more mitochondria, you want more mitochondria, we all want more mitochondria. 

Now, this process, exercise, exercise training, not just sitting in front of a TV working the clicker. That's not enough. You've really got to do good exercise. It does two things, it increases mitophagy. And interestingly enough, there's another lecture going on in the other hall right now on mitophagy, and it's totally in line with what I'm talking about. Mitophagy is mitochondrial quality control, QC – getting rid of the bad mitochondria that are damaged and making new ones through biogenesis. So this is how we do it in Colorado. We go hiking up to 11,000 feet, and then wonder how we're going to get home. And I'm like, "Yeah, this lake is really beautiful." Have a little protein bar or something like that, and then I think, "Where's my Uber drone? It's supposed to be picking me up." And right about that time I put the oximeter on and I go, "84 percent. Is that bad? Hey, I think I should sit down for a minute." But you know what? That hypoxia that's created by this hiking up the high altitude, that's exactly the stimulus you need to make more mitochondria. So it's a good thing in the long run, even though I might have to go home and basically stare at the ceiling for four hours to think, "Why did I do that?"

So here are all the pathways that are coming together here. All together, we call this hormetic stress. Just enough stress to not kill you, but to stimulate the body to turn on these pathways. You've heard of Wim Hof, dropping into cold water, doing the cold plunges? It's the real deal. It's the real deal. So, cold temperatures, transiently, calorie restrictions, exercise, transient hypoxia, turn on the same pathways, the AMP kinase pathway, the cert one pathway, and that turns on PGC1-alpha. And that's what you want because that leads to more mitochondria and more mitochondria make you live longer and healthier.

Here nutrients that will support your mitochondria in doing that. Really important point, you can't sit in front of the TV and pop supplements and think that's going to make you live longer. The supplements only work if you're exercising and not overeating. I take pretty much... I'm a bit of a nutcase. I lecture on this stuff, I hear about it, and I think I'm going to take that. I'm going to take that, too. So I take almost everything on this page. CoQ10, quercetin, green tea, nicotinamide riboside, acetylcarnosine – carnitine and carnosine – resveratrol, creatine, omega-3 fatty acids, NAC, alpha lipoic acid. I'm like, why not? Why not? I mean, I only get one shot at this. I only get one shot. So if it sounds good, I'll do it.

And here's a big question. You've probably heard about using metformin to improve health span. Dr. Nir Barzilai, I’ve had the chance to hear him speak a number of times. He really, one of the premier researchers on metformin, and he is saying that metformin is not just for diabetics, that metformin may prolong health span. And I have a number of patients that talk to me about this. I'm not hesitant to give metformin to people who pre-diabetic. 

But what about people who are otherwise healthy? I'd be more inclined to give them something called berberine, which I've taken myself for 15 years now, and I'm still standing here. What is berberine? Berberine is an alkaloid that's found in a number of herbal medicines like Golden Seal, Coptis chinensis. It's really widespread amongst indigenous healing systems, and it's mostly been thought of as an antimicrobial, but it turns out it's a metabolic regulator. It lowers hemoglobin A1C. So it alters these nutrient sensing pathways. And this is what we're seeing in the literature. Berberine is a promising anti-aging natural compound, and it's doing this by modulating AMP kinase, and that impacts age related diseases. So as I say, Bob is big on berberine. Alliterative there. 

Then there's also this newly discovered herbal preparation made from fermented purple grapes. And I understand that it's quite tasty. And thanks to David Sinclair, we know all about sirtuins. And for a while there we thought sirtuins were the answer. They're deacetylases that are involved in regulating metabolism, insulin sensitivity, protection against diet induced obesity. So for a while there, resveratrol was the rage, but then we did all these studies on resveratrol, and it didn't seem to work.

It worked great for fat rats. It really seemed to help the fat rats, but then humans took it and it didn't seem to do a lot. And part of the answer might be that you need NAD for sirtuins to work. NAD fits in a pocket in the enzyme and the two work together synergistically. And as a result of that synergism, you get neuroprotection, you get cardioprotection, you improve fatty liver, you decrease white adipose tissue, you get better insulin sensitivity. So it's the two of them together that's important.

Now, what is NAD? Well, NAD is a chemical that you study in medical school so that you can pass the exams and hope that you never hear about it ever again, except suddenly it's come back into the literature. Nicotinamide adenine dinucleotide, it's a co-factor for metabolic activation. It's a cell signaler, and it's involved in DNA repair.

So that balance between ATP and free radical production, NAD sits right at the center. It's at the fulcrum of that. And having an adequate amount of NAD is critical. The problem is that there are a lot of things that consume NAD as we get older, especially DNA repair. They're enzymes called PARPs – poly ADP ribose polymerases. PARPs that repair DNA, and they require NAD. So it's our DNA gets zapped by UV radiation and oxidative stress and all kinds of other things in the exposome, it's sucking up the NAD. So our NAD steadily declines as we age. Also, the sirtuins that I'm talking about, if you need metabolic regulation, you're sucking up your NAD. So NAD levels are a hallmark of senescence. If they're lower, we're older. And so we want to know how do we bring it back. Calorie restriction, imagine that. Eating less seems to raise NAD. There are also things that you can take. Tryptophan, well, it doesn't work so well. Niacin used to be the rage, we don't use that much anymore because people flush and get liver toxicity. Niacinamide, seeing a lot of use in dermatology because it prevents skin cancers, probably by raising NAD in the skin. Then there's nicotinamide riboside, which I think is a very, very interesting compound. It ends up being made into NAD into the cells. There's also nicotinamide mono nucleotide, which is a phosphorylated form. It's a larger molecule. It has to be converted into NR before you can absorb it and use it. There's synergistic phytochemicals, resveratrol, quercetin, and apigenin. Apigenin is kind of up and coming. Right now we're seeing more research on that. 

What is NR? It's another form of niacin. It’s produced in our bodies. It’s also found in beer and cow’s milk, but you’d have to drink a lot of beer to get an adequate amount of NR. It was researched at Dartmouth, at Cornell, and the University of Iowa. Charles Brenner is the guy that did most of this research on it. He's the one that found that NR is converted efficiently into NAD. And when you have the NAD levels going up along with the sirtuins, that's what leads to the mitochondrial biogenesis and improved energy metabolism. So this is a slide that kind of summarizes it all. And you see NAD really sitting at the center at the top. What do you see to the right of NAD is consumption. That's what happens with aging. We also know that mitochondrial diseases damage DNA, use it up.

So we want to raise it, and how do we do that? With sirtuin activating compounds, stacks, resveratrol, fasting, exercise. Are you seeing how all these things fit together? They're diverse disparate pathways, but they all seem to converge around this one particular pathway. So when you activate NAD in conjunction with activation of sirtuins, you see at the bottom, mitochondrial biogenesis. Yes, that's what we're all going for. 

So how do we extend health span? Do something about your stress. Try to avoid getting up on stage in front of hundreds of people and remembering what your name is, OK? Do some kind of meditation or prayer every day. Have friends, friends appear to be a good thing from what I can tell. Good exercise. High intensity interval training, eating less. I have a lot of patients that I'm moving into the time-restricted feeding, either 12 hours overnight without eating or 14 or ideally 16.

Appropriate use of nutritional supplements and appropriate hormones. I've been prescribing them for years, and I guess I should have... shouldn't I have peptides on here too? Yes, if I said that, people aren't going to go, "What?" I actually was prescribing thymosin alpha-1 30 years ago, I didn't know it was going to become a thing, and it all became a thing.

So what are the categories we can look at for more research? Telomerase activators, anti-inflammatories, mTOR inhibitors like rapamycin, the AMPK activators like berberine, the cert-1, PGC1 activators like NR. And NRF2 activators like sulforaphane. So a lot of potential areas that we can dive into once we understand something about these pathways. And so this is kind of a summary, it's not complete. But rapamycin. I think we need to do more research on. Metformin, worthy of research. Berberine, I really want to see more research. NR, nicotinamide riboside with resveratrol is my favorite combination. DIM and sulforaphane, curcumin, ellagic acid, and then it's derivative, which is urolithin A, Got a lot of potential. Quercetin, green tea, omega 3 fatty acids, NAC, alpha lipoic acid.

So if this list sounds like it's just kind of randomly thrown together, what I'm trying to tell you today is it all fits in a pattern, right? If you understand these pathways and you understand how they interact with each other, it makes a lot of sense how using these particular nutrients would be helpful. So I’m going to end with a little thing from Dilbert, he's getting his HR advice, we can save money if we downsize the unhealthiest workers. Well, how do we identify the unhealthy workers? Let's close the parking lot near the building. So here you have all these people that can't make it to the building. They're keeling over and he says, "It's too late for broccoli."

So you don't want to wait until it's all over, although it is never too late, really, to make the changes that are needed. 

Thank you very much.

Thanks for listening to The Thorne Podcast. Make sure to never miss an episode by subscribing to the show on your podcast app of choice. If you've got a health or wellness question you'd like answered, simply follow our Instagram and shoot a message to @thornehealth. You can also learn more about the topics we discussed by visiting Thorne.com and checking out the latest news, videos, and stories on Thorne's Take 5 Daily blog. Once again, thanks for tuning in and don't forget to join us next time for another episode of The Thorne Podcast.