Targeting Senescent Cells? Dose and Timing Matters – with Dr. Greg Kelly

Dr. Greg Kelly, renowned expert in longevity medicine, and Senior Director of Product Development at Neurohacker Collective joins New Frontiers to discuss cellular senescence, its role in aging, and the senolytic agents that target it. Dr. Kelly updates us on the state of play when it comes to biomarkers of cellular senescence, the variability of senescence and senolytic activity across tissues, as well as the interconnectedness of all the Hallmarks of Aging and the interventions that target them. He also explains the unique aspects of Qualia Senolytic, including perhaps-surprising dosing strategies. All this with the goal of optimizing human performance and pushing healthspan such that we might minimize the number of years spent in decline.

In this episode of New Frontiers, learn about:

Dr. Kara Fitzgerald – Hi, everybody. Welcome to New Frontiers in Functional Medicine, where we are interviewing the best minds in functional medicine. And again, as always, today is no exception. I’m really excited to be here chatting with Dr. Greg Kelly. I’ve known him for years. He is a naturopathic physician. He’s the senior director of product development at Neurohacker Collective. He’s the author of the book Shape Shift. He was the editor at the journal Alternative Medicine Review, which is where I met him. He’s been an instructor at the University of Bridgeport and the College of Naturopathic Medicine. He taught classes in advanced clinical nutrition, counseling skills, doctor-patient relationships, and more. He’s published hundreds of articles on natural medicine and nutrition, contributed three chapters to the seminal Textbook of Natural Medicine, and has more than 30 journal articles indexed on PubMed. His area of expertise includes nootropics, anti-aging and regenerative medicine, weight management, sleep, and the chronobiology of performance and health. Welcome to New Frontiers, Dr. Kelly.

Dr. Greg Kelly  – Oh, I’m delighted to get to talk with you and your listeners today.

Dr. Kara Fitzgerald – Yeah, yeah, I’m thrilled to have you. I became a huge fan of your work, as you know, when you were the editor over at Alt Med Review, and I was a peer reviewer and got to actually peer review some of your brilliant content. In fact, you guys, a lot of these are… Are they still available? And I know they’re full text.

Dr. Greg Kelly – So it was a journal that was started by the original owners of Thorne, the dietary supplement company, and when they sold it, they kept it. And then a couple of years later, for a variety of reasons, they lost interest in keeping the journal alive. So it’s still indexed on PubMed, but the links that used to be there to the full text, I think, have all gone away. But if you just Google Alternative Medicine Review, there’s a website where they’re all archived.

Dr. Kara Fitzgerald  – Okay, okay. So then we’ll put that link on the shownotes, people. Cruise over to the shownotes. There is actually a couple of really juicy discount codes for Neurohacker Collective (Code KARA) and some of their products over there, but also, we’re going to have a link to some of his articles or the clearinghouse for articles and any of the other research that we touch on today. We’ll have links there and also the full transcripts, and we’ll have shownotes, we’ll have summaries, etc. But of course, you know that I was a reviewer and a huge fan of your inulin article. If anybody wants to be an expert in that prebiotic, whose time is still coming, maybe we’ll be able to actually just drop that actual PDF in on the shownotes page. Just read it, you guys. It’s such a great discussion on inulin and I feel like I’m an expert from Dr. Kelly’s education.

Dr. Greg Kelly – Thank you.

Dr. Kara Fitzgerald  – Yeah. Yeah. There’s a bunch of really good articles we can pop over there. But here you are, you’ve had an interesting kind of a storied career in the natural medicine space. A lot of us know who you are and have learned from you, but now you’ve got Neurohacker Collective, and I want you to describe what it is. You’re clearly an expert in longevity medicine. Now, you’ve got Neurohacker Collective, which is an extremely interesting concept to me. You guys are doing really interesting work over there. And part of it is this suite of supplements that you’ve been involved in designing. So first I want to know your own journey into longevity medicine. I want to hear all about that and how you got to where you are. And then I want to also learn about Neurohacker Collective, and you know, what it is and…

Dr. Greg Kelly – Sure. So, I’ll do the whirlwind tour of the Life of Greg. I was ROTC in university engineering school, so when I got out, do not pass go, go directly into the Navy.

Dr. Greg Kelly – So my formative years in my early through late 20s were as an officer in the US Navy, primarily in Hawaii and San Diego and on ships for most of that time period. And when I first got to Coronado, California to do a brief training before going to my ship, it occurred to me that I had no idea how to eat. I had just always eaten whatever someone put in front of me. My mom was a great chef. And then in college, it was just the cafeteria and things like that. And one of the guys that I knew was a gym rat and in great shape, and so I just said, please help me. I have to shop for myself now and I don’t know what to do. And at the time he gave me a book, Eat to Win by Robert Haas. It was the high complex carb, type of diet that was popular in `84ish, but in reading that, I realized, okay, wow, I’ve been, maybe not poisoned, but certainly not being fed impeccably.

Dr. Greg Kelly – And so that just got me really interested, at a fairly young age, in taking better care of myself. So I was the weird officer on the ship that ate things that no one else did and exercised. When I eventually got out of the Navy five and a half years later, and this was somewhat selfishly, I decided, okay, I want to even learn more about taking care of myself so that I’m not dependent on the medical system. And in that couple of year journey, I stumbled on some naturopaths in Hawaii, Oahu specifically, and thought, my god, what a cool life these people have. And so I went to naturopathic school and was in the first class at what was back then Southwest College of Naturopathic Medicine. So I graduated in `96, and in that time period when I was a student, Thorne, they were called Thorne Research back then, decided to, for the first time ever, have student reps at each of the universities, and I was the one picked to be their original student rep at Southwest and they liked what I did.

Dr. Greg Kelly – I started to do trade shows for them back in my last year in naturopathic school, and that was great for two reasons. One, I would go to these trade shows, like Environmental Medicine Conference, or other functional medicine ones, and realize, wow, this education at this brand-new school isn’t too shabby. I’ve learned some great things that these doctors in practice are only being taught at these seminars and conferences. But anyway, so I worked full time for them for my first year out. That’s when they birthed Alternative Medicine Reviews. In the early years, I contributed a lot of the articles because we were desperate for outside writers. And I was like, sure, part of my job is to write articles, I’d love to do it. And then, I left a year later because I really wanted to practice and ended up working with Peter D’Adamo of Blood Type fame in Connecticut for the next three years, and then transitioning later to my own practice part time and teaching at the University of Bridgeport.

Dr. Greg Kelly – So that kind of got me through the early 2000s, and since then I’ve been back and forth either in the supplement world or corporate wellness. My most recent starting with Neurohacker Collective about six years ago as the product developer for them, and really the science voice for that brand. And we’re best known as Qualia, and very likely in the not-too-distant future, we’ll be changing the branding away from Neurohacker Collective to entirely be Qualia.

Dr. Kara Fitzgerald – Oh. That’s interesting. I kind of like it. Neurohacker Collective. I mean, you know, just there’s a lot of experts involved. I mean, are you a collective or are you a traditional company? I mean, you just seem different, whatever’s going on over there.

Dr. Greg Kelly – The original idea was Neurohacker, so we were a brain-first company, both with our podcast and our original product, Qualia Mind. And the idea with collective, is what I think of as “we is smarter than me”. There are just brilliant people out there that if we can tap into more of them, like you, as an example, when you were a peer reviewer for Alt Med and the other great peer reviewers we had.

Dr. Greg Kelly – We had some of the biggest names, people in the functional medicine community would know were peer reviewers, which helped uplevel the journal, right? Because often some of the contributions needed significant work. So that’s still in place. We still rely heavily on thought leaders and expertise outside of Neurohacker Collective, both for creating new products, but for other things as well, because really, the goal of the company is to improve human performance and health. And one of our founders, the way he would describe it is like his example with blogs. There’s just a lot of noise out there. We don’t want to do something if we can’t make the world better. So, we don’t want to contribute to mediocrity. And the only way to not do that often is by tapping into people that really know a topic well.

Dr. Kara Fitzgerald – You’re one of the founders.

Dr. Greg Kelly  – No, the founders are two brothers, James and Daniel Schmachtenberger. Daniel is more the science person. And then, a third friend of theirs. And then I was hired really to be, at the time I thought, Daniel’s “mini-me”, in order to free him up to do other things. I really took over all his roles because he was the original formulator for what became Qualia Mind

Dr. Kara Fitzgerald – Okay cool.

Dr. Greg Kelly – And every product since, it would be me. My fingerprint would be the most dominant on the product.

Dr. Kara Fitzgerald – And we’ll talk about product design and where you’re sourcing your ingredients because it’s good. And then just the whole longevity focus. It sounds like it’s been sort of a thread through, but you’re really planting yourself in the longevity space now.

Dr. Greg Kelly – Yeah. So, I don’t know what your experience would have been at naturopathic school, but mine was that many of my classmates, actually, most of them, were there because they’d had some illness and a naturopathic doctor or something tangential, like a homeopath, had made a big contribution to them getting better.

Dr. Greg Kelly  – And so I was the weird one. I had never seen a naturopath. I just stumbled into them inadvertently, right, and thought they had cool lives. And it was the same when I was teaching at the University of Bridgeport. Most of my students would have had a health issue and kind of came in through that direction. But what drove me from even that young age was always, what does health look like, and then what do I do to get more of it? And not only get more of it now, but how do I invest in ways that make sure I’m still having it when I’m 70, 80, etc. Because, you know, my dad passed away from cancer at 68. His dad from cancer, in his early 70s. So, at a pretty young age, I looked at my dad, he was, you know, very heavy and had, you know, we would not recognize this then, sleep apnea and the high blood pressure, the whole kit and caboodle of things. Super hard-working executive and did a crazy commute I would never be willing to do.

Dr. Greg Kelly – But at a pretty early age, it’s like, well, I so appreciate what he’s done to make my life easy. I want a very different outcome in my life and so, being a curious person, it’s just always driven me. And there’s probably no better area to ask the question, what does health look like than in aging?

Dr. Kara Fitzgerald – Absolutely. Yeah, absolutely. You’re a rare bird in early naturopathic medicine. You’re right. You know, most of us were called to the field because of some kind of a crisis. For me, it was kind of a classic chronic fatigue picture and traditional medicine had really nothing to offer me.

Dr. Kara Fitzgerald – I can just say that it was naturopathic medicine that walked me to health early on in my journey, when I was thinking about medical schools, actually, and it really tipped it for me. But fabulous. That’s such an interesting story. And, yeah, of course, studying aging is, I think, the best way to study the chronic diseases that develop with aging.

Dr. Kara Fitzgerald – You’re going to define the hallmarks of aging, so maybe we should start with what aging is and a definition of it. And then you’re particularly interested in something called cellular senescence. So let’s define that and talk about that. First, what’s aging to you? And how do we measure and quantify it?

Dr. Greg Kelly – Yeah. So, I just think of aging as that progressive deterioration in function as time passes. Right? So, it eventually, at least given our current technology, it catches up with us all. But we want to do, at least in my opinion, as much as we can to make sure that we have atypical aging compared to normal. There would be different statistics on this, but in general, someone who’s 60 in North America would be expected to live until their early to mid-80s, but at least a third of that time will be in significant decline. Right? Maybe in assisted living. So, when I think of aging, it’s that. It’s a problem, right? And we all know it, because of our loved ones and other people that we’ve seen go through things. So, I don’t really get into, “Oh, I think we can move the needle and make people live to 180,” like Dave Asprey will say, or some of the other longevity aspirants, right? I just think, “Oh, can we make a difference?” And instead of that final third being really unenjoyable for people, could we move the needle substantially and make it so maybe it’s only a year that’s unenjoyable. My goal has always been to get as close to the end as possible, getting to live life my way. So, when I think of aging, it’s that thing that interferes with us getting to live life our way. And when I think of what the goal is, it’s to cut into that time period.

Dr. Greg Kelly – And when I think of then, why aging, and you would know this, there are generally two big camps. There’s the aging is damage accumulation camp, and there’s the programmed aging camp, and they’ll often then spin any research into their narrative about why we age. And I think there are aspects of both. I think, as the work you’ve done shows, there’s definitely an aspect of programming to cause what we think of aging with the epigenetic clocks. And with cellular senescence, that would fit almost more into the damage accumulation, that cells are accumulating damage that’s causing tissue and organ dysfunction, and that’s then manifesting many of the issues we have that we think of as aging. So, I don’t think either group is all right. I think they’re both partially right. And there’s probably lots more we don’t know.

Dr. Kara Fitzgerald – Yeah. Of course, there’s much, much, much, more. But I do agree with you. I think that has been my conclusion as well. We’re in lockstep with both. There is some sort of a program phenomenon. I mean, obviously, you know, we all develop similarly. If you’re a woman, you’re going to hit menopause in a fairly predictable range, etc. The longest we’re going to live, generally right now without a Yamanaka cocktail, is about 120, so that would be like sort of the program breakdown or the evidence for that program piece. But then, yeah, we’re inundated with environmental exposures that also wreak havoc. Yeah. So I think both are true. Yeah. Okay. So then just take us through the cellular senescence. Maybe move through the hallmarks in general, and what they are, and then cellular senescence specifically.

Dr. Greg Kelly – So I think it was published, I want to say it was 2014 or 2015, was the original Hallmarks of Aging and they identified nine characteristics that organisms of all types, including primates and humans, share in common as we age.

Dr. Greg Kelly – These were things like telomere attrition and DNA damage. But one of those nine was cellular senescence, the accumulation of what are called senescent cells. And then at the beginning of 2023, there was a new Hallmarks of Aging: An Expanding the Universe paper that added three more. They added, macroautophagy, dysbiosis, and chronic inflammation as the three new ones. So there’s this suite of things that all organisms tend to have as characteristics as we age. And some are thought of as more, like, leading to others. So, you know, certain things would then cause… As an example, telomere attrition could cause a DNA damage response in a cell, so now the cell enacts the cellular senescence program. And then because of that, that contributes to the chronic inflammation. So there’s somewhat of a directionality built into these hallmarks. And of the different ones that there is an ability to modify, I would think of cellular senescence, at least currently, as being among the more interesting. You know, telomeres, I think stem cells, that’s another one of the hallmarks. There are technologies to try to mitigate that.

Dr. Greg Kelly – So, cellular senescence, when I first saw the work, it was Mayo Clinic in 2015 that coined a term we’ll talk about called “Senolytics” with two compounds. And it was an animal study, so very preclinical, but giving that cocktail of ingredients to older mice made them perform much more like young mice. And it’s like, wow, that looks interesting. Right? And I don’t know about you, but periodically I get inundated, just like I’m sure you do, with, “Oh, this is the new thing.” Or in the supplement world, every vendor or supplier for a brand will be like, “Oh, my ingredient is fantastic. You need to read our new study and buy our ingredient and put it in your products.” And quite often I think in terms of statistically significant and clinically meaningful. I ideally want both and what I’ll often see is, “Oh, this was statistically significant for sleep.

Dr. Greg Kelly – And instead of taking 38 minutes for someone to fall asleep, it was 35. Clinically, pretty meaningless, right? And I often think of these new things, what might we care more about 5 or 10, 20 years down the road? And when I first saw these papers published on senolytics, it struck me like, oh, in 2030, I bet we’re going to be caring a lot more about this than we do now. Where other things I look at, it’s like, yeah, we might have already moved on from that. So it intrigued me at that time and on a couple of my vacations from Neurohacker Collective, I took many articles on cellular senescence and senolytic compounds to read as my over-coffee vacation reading.

Dr. Kara Fitzgerald  – That’s really interesting. Yeah. That was insightful of you to consider hanging your hat there. So define it. Why did cellular senescence grab you so much?

Dr. Greg Kelly  – Yeah. So just for the audience, what cellular senescence means and the way I would just describe this simply. This is a drastic oversimplification. Just as for our whole body, cells can also be stressed by things. And if stress is manageable and they have the resources, they’ll try to adapt and become more resilient. So these are things like increasing antioxidant defenses as an example, but all kinds of things, right, to essentially toughen themselves up. But if stress is more than that, they’ll probably take on some damage. And that’s where the repair mechanisms, autophagy being one that is, you know, a buzzword that’s thrown out a lot. And autophagy means there’s damage to proteins or organelles within cells, but not so much damage that it can’t be repaired. So cells are going to try to repair that damage. But if stress is even beyond that, then it will create an unrepairable cell. And unrepairable cells ideally should go through what’s called apoptosis, which is from a Greek word meaning falling off in the sense that a leaf or fruit fell off a tree or plant.

Dr. Greg Kelly – But cellular senescence is somewhere in between. It’s enough damage that the cell is beyond repairable, so autophagy wouldn’t help, or autophagy has missed the opportunity for that to be valuable for a senescent cell. But senescent cells in the context of aging are things that have figured out ways to not go through apoptosis so they linger in tissues and then accumulate over time. And the goal of what eventually has become senolytics is to finally convince them to recapitulate that journey and to go through apoptosis. And so, what makes something a senescent cell is that it’s permanent cell cycle arrest, is the way they would describe it. But just think in a more simplified sense, it doesn’t make offspring cells anymore. It’s intended not to make copies of itself. So that would be one thing.

Dr. Greg Kelly – Another would be what are called SASP factors, or senescence-associated secretory phenotype is what it stands for. But they just secrete compounds into the microenvironment around them. SASP factors is why they’re so detrimental to the health of tissues and organs because it fundamentally shifts the terrain within tissues in unwanted directions.

Dr. Greg Kelly – And then the third characteristic of senescent cells is that they can often, through those SASP factors, turn otherwise healthy cells into new senescent cells, so they can create a snowball effect over time. And because of that, as we would both know, and we’re probably taught by the old-timers, the health of our tissues is reliant on the health of the cells in those tissues. As senescent cells accumulate more and more through the aging process, we are filling tissues with cells that are taking up resources, still using nutrients and other things, but instead of contributing to healthy function, they are actually contributing to dysfunction.

Dr. Kara Fitzgerald – What are some of the biomarkers that suggest senolytic burden?

Dr. Greg Kelly – That’s a great question. And there’s no one great marker. If people at Bucks Institute or Mayo Clinic were trying to take a biopsy and look for senescent cells, they would stain it, first off. They would look at morphology, such as size, things like that. They would look for an enzyme, beta-galactosidase, as an example. They would look for thinks like p16 and p21, which are thought of as senescence markers. But they’re going to look at collectively a bunch of those things together before they could pinpoint something being a senescent cell. It makes it one, really hard to measure. There’s no simple blood test we could do at this point that would give an indication of tissue load of senescent cells. It also means that in research, the scientists really need to know what they’re doing to, you know, do a good job in identifying senescent cell load. And so, I guess, simply put, there’s no one marker that would always show this is a senescent cell versus a non-senescent cell. Things that would indicate senescence can sometimes be found on otherwise healthy cells. So, it’s more of a panel of things a scientist would look at.

Dr. Kara Fitzgerald – Yeah, right. Are any of the classic markers that we can run at a standard laboratory suggestive or perhaps surrogate? Like, would we see an increased inflammatory burden? Might we see an uptick in CRP, or is it too general to actually capture senescence?

Dr. Greg Kelly – So I think that’s still all being investigated. The field is relatively new. The term senolytic was coined by Mayo scientists in a paper published in 2015, and that really put the field on the map, so to speak. I mean, cellular senescence and senescent cell accumulation with aging had been known about for a while and maybe the most formative study was around 2010 when they genetically modified animals to not create senescent cells and found that they just aged in a much more healthy manner. But it wasn’t really until the Mayo scientists found compounds that you could take orally that may help manage senescent cells that a solution emerged as possible on the map that the field really exploded. And so, since then, there’s been a lot of smart people trying to figure out ways to almost have a surrogate to see, you know, is the burden going up or down with things like beta-gal in blood, the inflammatory markers, things like that.

Dr. Greg Kelly  – And we’ve done a few n-of-one type of tests with a lab called Jinfinityi that has a panel they’ve been trying to develop for that, and we just don’t see much of a signal there in the classic inflammatory markers to date. And I think timing is ultimately going to matter. It looks like maybe with beta-gal, as an example, that you’d expect that to go down over time, maybe if you were doing things to manage senescent cells. And originally the founder of that lab thought, oh, that’s what would happen. We’ll do a few cycles of senolytics and we should see beta-gal numbers go down. But when we’ve done it with him, it looks more like at least acutely, in the few days or more after senolytics, that amount goes up. Which actually makes sense because now you may be releasing more of that into circulation. So the timing factor and what to look for is all still being worked out.

Dr. Kara Fitzgerald – Just define beta-gal actually. And why you think it would increase, just for the for the audience.

Dr. Greg Kelly  – Oh, so beta-galactosidase is an enzyme that senescent cells, not 100% of them, but much more commonly than other cells, make a lot of that enzyme. And it would be part of those SASP factors that is secreted, and it’s an enzyme that would break down other things. So, you know, that SASP panel of things they secrete are, you know, the inflammatory markers that we would all test for, cytokines, things like that. So that’s why- because it’s not 100% specific, but much more prominent in senescent cells, that’s why it was one of the things that’s been looked at.

Dr. Kara Fitzgerald – Yeah, that makes sense I think p16 is available, maybe only in the research setting, but I think I did come across a lab making that available in some capacity. I think there may be a paper or two looking at senescent cells as actually tending to cancer. I mean, is there any benefit for this? I mean, and I know we have an excessive burden and it’s damaging the local environment and likely the systemic environment as they accumulate, but I have heard that argument put forth that we don’t want to turn it off completely. Speak to that.

Dr. Greg Kelly (00:28:13) – Yeah. So, this goes back, I think, to the early 2000s. There was a discussion among the experts in the cellular senescence domain whether they should just call all senescent cells the same senescent cells or have more specific terminology. Because the classic way that cellular senescence was thought to occur was telomere attrition going back to the Hayflick Limit, right? That was the origins of what became termed cellular senescence. But that’s just one way a cell can become senescent. A DNA damage response with plenty of telomere length can cause the senescence program to enact. If you do things to a culture, like nutrient deprivation or ionizing radiation or anything else, it would be called premature stress-induced senescence.

Dr. Greg Kelly – And so that’s my bias of what causes most cellular senescence is stress fundamentally, not the telomere attrition. And then classically, it was thought that senescence would only happen in cells that were making copies of themselves, things like neurons or muscle fiber cells, which either don’t create clones of themselves through our lifetime or would very slowly do that. Because, as an example, you’ll often hear that the average life of a cell is seven years, which is true, but that average is really distorting what is real. Some cells turn over within weeks to months, but cells in our heart, maybe it’s every four decades. Liver cells, it’s 1 to 3 years. Muscles, it’s about 15, right? So each tissue has its own life cycle of cells. And so, I’m kind of getting to your question in a roundabout way, but the general idea was, okay, the reason that cells must do this this cellular senescence thing and stop making copies is because they don’t want to make damaged copies of themselves, which then could lead to a worse type of stressed cell, which would potentially cancerous cells.

Dr. Greg Kelly – And for the listeners, think of whether it’s a senescent cell or a cancer cell or many other types of cells, all collectively, they’re stressed cells. They’re cells that should be targeted either to go through apoptosis like they should if they’ve taken enough damage, or the immune system, because of stress markers on their surface, should find them and eventually gobble them up. So it was thought for a long time, oh, this must be why we have senescent cells to prevent that. And the way I think of it now, and this is a more simplified story, as always, things are more complicated in reality, is think of things as transient senescent cells and lingering senescent cells. So, you know, maybe we’re 20 and a cell is really stressed and we don’t want it to copy itself so it becomes senescent, but it would transiently be found in our tissues. It would have become senescent on its way to either eventually going through apoptosis or the immune system identifying it and removing it.

Dr. Greg Kelly – So transient ones probably are useful for preventing a stressed cell from going into a replication phase that could lead to something we don’t want. That’s not the aging context. What we have is what I thought of as lingering senescent cells. Ones that have figured out a way to avoid going through apoptosis. So instead of having that beneficial role, they’ve now kind of turned the tables, and they can actually make the SASP factors. Ideally it would, in a transient case, quickly pull in immune cells to clean up the debris, repair the damage, and move on. So classic example, we lift weights. We’re 22 and maybe we overdid it. We’ll create some transient senescent cells to repair the muscle tissue. When someone’s my age, early 60s, you know, we overdo it and it will create almost an explosion of senescent cells in the muscles. And unlike that young 20-year-old or 25-year-old Greg, that a week later the senescent cells would be gone, they were transient, you’d still see those weeks and weeks later, they’d linger in the tissue.

Dr. Greg Kelly – And those lingering ones are thought now, and there’s a lot more research going into that area, as potentially contributing to a microenvironment that’s more conducive to other stress cells proliferating.

Dr. Kara Fitzgerald  – That’s really interesting. I mean, I can see why this is a topic that you really drilled into. It’s fascinating. And there’s a lot of room from a functional, you know, from your background training in thinking about it, and I know people want to know the solution. But can we see that? How do you know that you’ve got a burst if you overdo it at 60-something? That you’ve got this massive burst of senescent cell activity. That’s fascinating.

Dr. Greg Kelly – Yeah. So we only know that because of researchers at places like Buck Institute and Mayo Clinic that really know what they’re doing and have done those scientific experiments, where they’ll see that crazy burst and then they’ll just linger indefinitely.

Dr. Greg Kelly – And other studies that have been done in that particular context, usually I would think of it as anabolic resistance is the term you’d see in the studies with the general idea to think of insulin resistance. Anabolic resistance is the equivalent for anabolic signals to our muscles, so weight training or adequate protein. In young animals, they have a great anabolic response to those things. In older animals, older humans, we tend to be resistant to that. It’s why we often see struggles with maintaining muscle size, strength, and quality in older populations. And so far, these are only animal studies, so for the audience listening. But what they found is that a main driver of anabolic resistance is the accumulation of senescent cells and doing cocktails of senolytic compounds to old animals to remove some of that burden reverses that phenotype so that the quality of muscle tissue becomes more “youngified”, for lack of a better way to describe it.

Dr. Kara Fitzgerald – So I just want to admit that this just hasn’t been an area of intense focus for me. I’ve been kind of planted in epigenetics since we published our first paper and we’re continuing to research in that arena and there’s a lot going on in the space. So this is really interesting and new for me to hear. I mean it makes sense that the publications, the research that you’re doing, has focused on a physical response to your senolytic agents. I’ve got a ton of questions here, but I want to talk about the intervention. I think that just knowing my audience, there’s two lines of thinking. There’s one, what do we do about this accumulated senescent cell burden? What do we do? So we want to talk about senolytics. We want to talk about your specific senolytic product.

Dr. Kara Fitzgerald  – Maybe some of the drug/senolytic combinations, so we want to talk about interventions. But you know there’s this other line of question going on in my head, and probably some of the listeners around. What would an appropriate exercise prescription be? And what else are we seeing that prompts senescence, wildfires physically, you know. And so how do we think about this from, a lifestyle perspective. And then also we need to layer on the intervention. So maybe both of those buckets you can speak to.

Dr. Greg Kelly – Yeah. The way I would think about it is, with the passing of time, inevitably all of us will accumulate more senescent cells, both because of a programmed aging aspect. It just seems like our genes are modified in a way that makes it more likely they’ll proliferate. Two, the immune system as we get older tends to not be so great at detecting stress cells, right? Immunosenescence is what that’s often referred to.

Dr. Kara Fitzgerald – And what you said in the beginning is one senescent cell begets another, begets another. So that environment just becomes ripe for development.

Dr. Greg Kelly – Right. And that’s part of the reason they’re often thought of as zombie cells is because they won’t die and they make new versions of themselves from otherwise healthy cells. And so, it will vary person to person and even in the same person, tissue to tissue, but we can pretty much bank on, at my age, 62, that I have more than I would have at 50 if I’m not doing things to, the way I would describe it, prune them away. And I like the plant metaphor because of apoptosis. It comes from that, you know, leaves fruits falling off a tree. A good gardener will see yellow leaves and prune them away periodically, but if they don’t, yellowing leaves beget more yellowing leaves, and eventually that whole plant will suffer.

Dr. Greg Kelly  – So, I think of senescent cells like that, like the yellowing leaves that, if we’re not careful, accrue more and more over time, and senolytics act as the gardener that would periodically come in and prune off the unhealthy leaves. And then in terms of how it manifests, really almost any issue that our listeners can think of that’s more common in aging has been linked to accumulation of senescent cells. And by that, I don’t mean it’s the sole cause, but it’s certainly a contributing factor for most of these things, whether it’s a performance area or it goes into more of a medical issue. And then the types of cells that can become senescent, as I mentioned, it used to be thought, well, only cells that are dividing cells would, but now it’s at least fairly well established that even non-dividing cells may become senescent. Again, that would be completely independent of the reason that stops them from proliferating.

Dr. Greg Kelly  – And the areas that we’ve chosen to look most at is joint health. The original types of cells that were thought to be most prone to becoming senescent were fibroblasts or connective tissue cells, so think joints, skin, those types of things, endothelial cells, so think our vessels and then immune cells. So you can pretty comfortably think of any aging-related thing you’re thinking about that those types of cells are involved with, senescent cells are likely contributing fairly robustly to it.

Dr. Kara Fitzgerald (00:39:05) – Have you altered any of your lifestyle habits since you were 50, thinking about senescent cells?

Dr. Greg Kelly – Actually, that’s a good reminder of something you were getting at that I didn’t answer. So, something like exercise would be exercise done smartly. Not running a marathon every week would help to slow the accumulation of senescent cells. So it’s more preventive if that makes sense. There’s really no evidence that I’m aware of that it would help remove it, and its tissue specific. So, exercising muscle tissues it would accumulate more slowly, but it might mean stressed cells in other tissues, if there was another source of stress, it may be accumulating. For me, getting back to your question- And I think calorie restriction is likely a significant slower of it. Those are the things that have been studied. But the things that you and I would do with clients who we are working with, or the things you did in your studies to help people slow or reverse their biological age, my guess would be those things will eventually be found also to slow the rate of accumulation of senescent cells just because they’re good things. And stress, I believe, is the main culprit and is driving the initial insults that cause cells to become senescent.

Dr. Kara Fitzgerald  – Well, and it’s an elegant sort of example that you’re putting forward of the interconnectedness of all of the hallmarks. You know, we can think about inflammaging and cellular senescence and then it makes me think about our intervention. Definitely it was very heavy in altering the microbiome, and that’s of course dysbiosis, being now appropriately a recognized hallmark. And then all of this influencing the epigenome, the caloric restriction having similar beneficial effects in the epigenome as well. So yeah, there’s just a very interconnectedness.

Dr. Greg Kelly – Yeah. I didn’t mention mitochondrial dysfunction as one of the original nine hallmarks, but that was one of the original things known to cause cellular senescence. And we all know that there are lots of things that contribute to mitochondrial dysfunction in our patients and with aging. And then getting to what have I done differently? So, the big thing I noticed since 50, what was sufficient to keep Greg in good shape at 50, no longer necessarily was at 55.

Dr. Greg Kelly – Going back to the Navy, I was sleep deprived for, I would say, that entirety of time. In naturopathic school I was on a three-year timeline. I did my degree in three years because Southwest offered it at the time, and I was in Navy Reserves one weekend a month. But I also, at one point, just to make money because we weren’t eligible for student loans my first year, I worked three nights a week, eight at night till eight in the morning at a teen shelter, and two of those nights I would just go directly to school from that and then sleep for a couple-hour nap between classes at the end of the day. So I was pretty crazily sleep deprived in my 20s and 30s, and at some point, like a wake-up call, like, oh, sleep is probably my friend. And so, before my 50s, sleep has just been a non-negotiable. But what I’ve noticed, and you probably see this too, it’s just so rare that people sleep well even at younger ages.

Dr. Greg Kelly – So I feel really lucky, maybe that I paid attention to it starting early and still sleep well now at 62. And then I’ve always been a big advocate of, you know, body clock things. So, you know, morning light, evening sunsets are integrated into Greg’s life. But big picture, I haven’t really changed much. I’ve been largely doing most of the same healthy things for decades, and I think of the behaviors we’re coaching people to do as akin to the investments that we might make financially, right? There are some day traders that are trying to make a windfall in a day or a week. I’m playing the long game and have been for quite a while, and just try to make smart investments in my health most days.

Dr. Kara Fitzgerald – That makes so much sense. I love it. Yeah. I really appreciate it. All right. So let’s get to what everybody wants to know, and that is these senolytic agents, you know, the product that you’ve put together, maybe the journey on figuring out what the senolytic combinations. Some of them are, you know, at a glance, they’re not intuitive enough to the non-scientist. So let’s talk about, you know, when you move through some of your longevity thoughts, what do we need to be doing? And where do we start senolytic agents?  I’m thinking about myself. Obviously, it’s time for me to be considering one in my stack more intentionally. I probably have some components, but who are we prescribing these to?

Dr. Greg Kelly  – Great. So, the original Mayo work, and the way they started is they said, okay, there’s these SCAP networks, so Senescent Cell Anti-apoptotic Pathways for the people interested listening.

Dr. Greg Kelly – But long story short, these are protein networks within cells that senescent cells use to resist apoptosis. And so, Mayo started by looking at what compounds do we know mechanistically would correct these pathways and then tested those. And the two that they originally identified were quercetin, which has been a long-used dietary supplement, and a medication called dasatinib, which is an immunomodulator. And what they found is that in this original study, quercetin was senolytic as an example in endothelial cells, but not in adipose tissue. Dasatinib was senolytic in adipose tissue but not endothelial cells. And it was in a few other tissues. And stacking them together was additive in terms of the senolytic benefits that they had in terms of more broad tissue effect and having a more impactful effect on the animals. So that was 2015. The next senolytic, at least planned, compound that I saw identified was piperlongumine, which is found- Oh, go ahead.

Dr. Kara Fitzgerald – I just want to ask you, I’m sorry, it’s the geek in me. How the heck did they figure those out? I mean, did they use some…What is it called like? The only thing that’s coming to mind is a high-throughput technology. I mean, did they just blast structures of a ton of compounds to see those both like…

Dr. Greg Kelly – My sense was, for the way SCAP networks work, some of these are nutrient-sensing pathways. Some are inhibiting apoptotic proteins. So, they just looked at things that were known to impact either those proteins or those nutrient-sensing pathways. And then I believe what they did is they just took healthy cells and senescent cells in cell cultures and applied these compounds to see which ones disrupted, much more preferentially, the senescent cells. That wouldn’t be my expertise, but I think that’s how they approached it. Understanding what might work from mechanisms and there’d be big portfolios of that because those same pathways have been researched in cancer, as an example, and then applying those agents,

Dr. Greg Kelly – And then once they thought, okay, these look like they work in cell culture in vitro, let’s now give these to animals and see. So that was the progression. And then piperlongumine was the next one. That was, I think, 2017. And some listeners probably have heard of piperine, which is sometimes used as a bio-enhancer, often combined with turmeric. Piperlongumine is a similar alkaloid, but from a different plant instead of black pepper, it’s from something called long pepper. And so that one was senolytic, but for a different reason than quercetin. It works in completely different mechanisms. And then the same Mayo/Scripps Institute researchers, I think it was 2018, they published it, but they thought, oh well, quercetin is doing this. Let’s try a bunch of other flavonoids and see if others are similar. And quercetin was one, they retested, but what they found at the time was that fisetin was even more versatile and a stronger senolytic than quercetin had been, and that was probably when I got most excited because all of a sudden, it’s like, oh, now there’s two things that seem like they’re working.

Dr. Greg Kelly – And in that study, then they actually gave fisetin to the animals and again, measured performance in the older animals, and that improved. The other things they noticed in that panel was that something called luteolin and, our friend curcumin, which many of us use routinely with clients, were also senolytic, just not quite as robustly as fisetin was. So, what happened in terms of developing the product Qualia Senolytic, is we looked and said, okay, these look like great potential candidates. Are there plant compounds that may mimic some of what dasatinib does mechanistically that we could maybe sub in for that? And the things that eventually, and this was one of my vacation projects that I mentioned over coffee and a glass of wine periodically, was that it looked like milk thistle and soy isoflavones were the two most promising for stacking with these other, what I think of as the yellow-pigmented flavonoids, to be complementary.

Dr. Greg Kelly – And that eventually led to what’s today called Qualia Senolytic. And at the time, this was the end of 2019, early 2020, when I had finished all of my reading into the area and the big struggle was how to measure if it’s helping because there was no test. At the time, I got Ryan Smith from TruDiagnostic on the phone and asked, “What about your epigenetic age? Maybe that would work.” He’s like, “No, that’s not useful for this.” Horvath had actually looked at that in 2015 and long story short, cellular senescence and cellular aging, in terms of the DNA methylation patterns, are just distinct processes. So, for a while, we would just stall. How would we test this to see if it’s benefiting people? Eventually, I just saw on ClinicalTrials.gov that a couple companies were trying to advance a drug candidate as a senolytic and were measuring joint function using the WOMAC pain scale (Western Ontario and McMaster Universities Osteoarthritis), which is a pretty widely used thing. I’m like, “Oh, well, that’s something we can do.”

Dr. Greg Kelly – And so that was our first study on our product before we launched it. We recruited people with various issues with joint performance, did three cycles of Qualia Senolytic, and a cycle is two days on and somewhere between 12 days and a month not taking it and then two days on again. So we repeated that two-day on, 12 days off cycle three times and saw pretty dramatic improvements in WOMAC scores. And so at that point, I thought from the Qualia perspective, we like to have products people experience. We want to make sure that they’re safe, but that they do what they’re supposed to do. So we launched it mostly thinking, oh, there’ll be some longevity docs, maybe a few functional medicine docs, some weird biohackers that say, oh, like, I’d like to take this. And I wanted to take it, so selfishly, I had been pushing the snowball up the hill that we should make this product, even though we probably won’t sell very much of it.

Dr. Greg Kelly  – And the craziest thing is that it sold out in six weeks initially when we launched it. And since then, we’ve done a placebo-controlled study where we used WOMAC again. We also used the Rand SF-36, which is a widely used general health and quality of life questionnaire and that was complete. The placebo-controlled study was completed in the fall and what we saw was a statistically significant improvement in joint performance compared to placebo, and overall, about a 66% decrease in WOMAC scores, which I mentioned earlier, I care about statistically significant, but also will the patient or the client notice this difference. And that’s a big change in WOMAC scores in such a brief time.

Dr. Kara Fitzgerald  – And you did that cycling structure? I mean, how did you…

Dr. Greg Kelly – Yeah. So, our general recommendation for just healthy aging, and what I do myself, is I take it two days once a month, typically the first weekend of the month. For that study, just to make sure we got better adherence, we did three cycles over about five weeks, so we did two days on, 12 days off, two days on, 12 days off, and then a final two days on. So, try to condense three months of taking our general recommendation into five weeks. So that’s what we did. And that would be probably about the most frequently I would advise someone to do it.

Dr. Kara Fitzgerald  – Okay. Yeah. Go ahead, finish that thought.

Dr. Greg Kelly – And the idea is, the simplest idea for listeners is if you pruned a plant every day, that would not be such a great idea. You want to prune it periodically and then give it an opportunity for new growth. And so, from the get-go, the Mayo scientists had what they termed hit and run dosing, where they would intermittently give these compounds. And a lot of that was driven, I think, because Dasatinib is a pretty powerful medication, right? So they didn’t want to be inadvertently creating harm. But really, if you think about it, all we’re trying to do is disrupt these SCAP networks temporarily, transiently really, so that they’re normalized in the cells that are exploiting this pro-survival will finally toggle into apoptosis.

Dr. Greg Kelly  – … And so it’s not like we’re trying to occupy a receptor or give a hormone day in, day out. That’s not how it works. And the other thing I think, and this is just my idea, so it could be 100% wrong, is that a lot of the natural compounds, the quercetins and fisetins, are working not as aggressively on the pro- and anti-apoptotic proteins. They’re working more on the nutrient-sensing pathways. And I think, oh, when would Greg’s ancestors have had way more fisetin or quercetin in their diet? And quercetin, we all know is from onions. But it’s really most concentrated in the parts of onions we throw away: the skins, the little root filaments that come off the bottom. Fisetin, you hear strawberries, but you’d have to eat a boatload of strawberries to get a big dose of fisetin.

Dr. Greg Kelly – If humans were eating tree bark, as an example, which in famines our ancestors may have, then you’d get a much bigger dose. And so, I’m a big believer in not only what you do, but what’s the signal that you’re sending? And I think it’s called the Weber-Fechner law. Have you ever heard of that?

Dr. Kara Fitzgerald – No.

Dr. Greg Kelly  – So the funny thing, I never learned about it in naturopathic school, but when I was teaching a Mind-Body Medicine course at the University of Bridgeport, I had found a psychology textbook and had read through that, and that law was in it. And long story short, our senses aren’t designed on quantity. I should say, they don’t detect a quantity of change, they detect proportions of change. And so, the simple story would be, if you and I went into a dark closet and lit one candle, we would notice a big difference. But if we went into a closet that had 99 candles lit and one lit, one more, we might not notice any difference.

Dr. Greg Kelly – Right? So, one candle on its own is meaningless. It’s the proportion of change that matters, right? And cells have receptors that function as their ears and eyes. And so I think if we were to say, as an example, give the same amount of quercetin every day, every day, every day, that’s going to create a different cellular response potentially, than giving a big dose once or twice a month. Because it’s change that matters to drive response for anything that’s receptor oriented. But anyways, that would be my bias. And so, I think this hit and run approach, even though it was created because of a different reason, is what makes the most sense to me. We want to send a really strong signal to cells, which requires not only senolytic compounds, but a big dose of them in a brief time and then a vacation from them.

Dr. Kara Fitzgerald – What is the big dose?

Dr. Greg Kelly  – So the generally used dose of fisetin that’s currently being studied by Mayo and other researchers is 20 milligrams per kilogram. What we use in our product is 1400 milligrams, so that would get you in that range for an average-ish weight person, and then we stack that with quercetin. Usually that’s given like the study that emailed about before that TruDiagnostic had done, they used 500 milligrams and that, which isn’t a big dose of quercetin. So, it’s more like again, thinking of the change in quercetin. We use a more bioavailable quercetin, Quercefit, is what we use in our particular product, but somewhere 500 to 1000 milligrams would be the right range for quercetin, as an example.

Dr. Kara Fitzgerald – So you and I were dialoguing a little bit about that study that was released last year, you know, looking at the dasatinib with quercetin plus fisetin, actually, and looking at DNA methylation changes to this clock, specifically, and the outcome wasn’t fabulous, but I think you’ve just answered the question in that you don’t anticipate these interventions to really tweak the clocks.

Dr. Greg Kelly  – Yeah. So the original study that Horvath co-authored, I think it was 2016, it published, he basically concluded that – I have it written down here-

Dr. Greg Kelly – “Cellular aging is distinct from cellular senescence”, was sort of the conclusion. And then a 2021 study looked again at clocks, and their conclusion was, “cellular senescence, although undoubtedly a major contributor to the aging phenotype, is not associated with epigenetic aging”. So for listeners, I would just say think of these as two completely distinct things. What the current generations of clocks are measuring in cellular senescence aren’t necessarily moving in unison. So the study that was just published, but I saw the preprint last August, like you mentioned, the first did a group that did the dasatinib and fisetin, I think it was 50 milligrams of Dasatinib and 500 of quercetin once a month for six months, and did for a second and third generation clocks and did several of each, actually, and as your listeners would know, those different clocks measure very potentially different things, and they didn’t really see any significant effect.

Dr. Greg Kelly – And then they followed on by adding, I think it was 500 milligrams of fisetin, what I would think of is a suboptimal dose of fisetin as a senolytic, and then redid that. And the thing I personally found most interesting, and it wasn’t statistically significant, was that when fisetin was added in, it was better overall than just the D (dasatinib) and Q (quercetin), and that the third-generation clock, so the Dunedin Test for Aging, actually slowed a bit in the fisetin group-

Dr. Kara Fitzgerald – Did it hit significance?

Dr. Greg Kelly – No, it was not even strong enough to be a trend. I think the p-value was like 0.3 something, but to me, that’s interesting. Okay. Like that’s slowed a little bit. And this is just, they’re just not great tools. So Ryan Smith, when the study was completed but while it was in publication, I emailed him, because he’s been trying to work on a test that would create- And Ryan Smith is the founder of TruDiagnostic, for listeners, that would be better suited for measuring senescent cell burden.

Dr. Greg Kelly  – And, you know, his comments at the time were, this just isn’t a useful tool for it, unfortunately. But he knew that going really into this study and it was, you know, proved that to be the case.

Dr. Kara Fitzgerald – Yeah. And they are trying to expand what they’re looking at and assess, you know, methylation patterns associated with senescent cell burden. Okay. I have a couple questions on that. I have a handful of questions based on these last comments you’ve made. Did they pulse the dosing? Okay, they did pulse it.

Dr. Greg Kelly – Yeah. So, it’s once a month and they did it spread over three days instead of two, which is not abnormal. That’s, I think, part of the reason the fisetin dose was lower. I just think you create a better signal-to-noise ratio doing a higher dose in a briefer amount of time. Typically, what we’ve seen with Qualia Senolytic is people tolerate it much better than I would have anticipated originally.

Dr. Greg Kelly – We do see occasionally some mild GI types of things, but I thought we would see more just because polyphenols aren’t well absorbed. So, you are getting more. They get to the gut microbiome and have an effect there. And then maybe one of the more interesting things, and I’ve just heard this recently, as we’ve had both our head of customer service and then at least four people that have called her as customers have said that they’ve started menstruating again after several cycles of Qualia Senolytic, which seems really unusual. Like it seems like maybe for those particular women, there is something that is causing the reproductive system to act in a younger way. So we’ve seen a lot of interesting things with it. And, you know, for listeners, senescent cells impact different people in many different ways. And there’s a general thought of thinking in terms of a threshold effect, that it’s only when they become above a certain threshold in a tissue that you’d start to see noticeable dysfunction or subjective issues.

Dr. Greg Kelly  – And I know my personal goal is to prune right away to make sure I stay below that level. So, because I don’t expect to feel anything per se. But if someone’s already having an issue like we see in the people we recruited in our placebo-controlled study, then we generally see improvements in that area.

Dr. Kara Fitzgerald – Have you measured any of the biomarkers we talked about in yourself? Have you tracked them?

Dr. Greg Kelly – I haven’t in myself, but we have our head of research at the Neurohacker Collective has done with Jinfiniti. They’ve done some exploratory panels with the whole panel of inflammatory cytokines and beta-gal, and I think, again the timing has been the issue, that what we seen in the few days after that, those things tend to slightly go up in the blood, so it’s still- I guess the bottom line, I felt like we were helping him, the owner of Jinfiniti, figure out what his test meant, and it wasn’t ready yet for us to invest more in it.

Dr. Greg Kelly – And I know, like I said, TruDiagnostic has been trying to work on this area going back at least to 2020 if not before, so I’m optimistic that at some point all of us will have access to a test that’s better suited for measuring the senescent cell load and whether its senolytics or helping us manage it. And in the meantime, getting back to what I mentioned at the beginning, my journey has been much more about helping people perform better in their daily lives.

Dr. Kara Fitzgerald – Yeah. No, I appreciate that healthspan in lockstep with lifespan. Yeah, 100%. I mean, I think many of us are just walking along with you on that. I don’t necessarily know that I’m ready to live on Mars forever, you know? We hit escape velocity. I don’t know that I’m super excited about that, but, yeah, healthspan commensurate with lifespan.

Dr. Kara Fitzgerald – I’m all in. So, huge questions… Speaking about epigenetics, DNA methylation in particular, we know these are epi-nutrients. This is a cocktail of epi-nutrients. We know that fisetin, quercetin, both, curcumin incredibly, you know, the soy isoflavones, probably the other compounds and milk thistle, etc. I mean, these guys are epi-nutrients. There are data on them that they influence DNA methylation, the enzymes, and we can see that they do anti-aging things more broadly in the epigenome. So, tumor suppressor genes are turned off as we age. They’re hyper-methylated and inhibited classically, and these compounds turn them back on. And most of the cell studies, some animal studies, but we are getting more human data, including ours, showing that they favorably influence the methylome more broadly. So the clocks are surrogate markers of the aging journey right now.

Dr. Kara Fitzgerald  – I don’t know that we’ve got a clock actually capturing the aging phenomena itself. The arms of, you know, the programmed and the, you know, all of that. But certainly, as surrogate markers, I think they’re important. But it also does mean that they might not capture everything. There’s a scientist, Vittorio Sebastiano, out of Stanford who, who’s been doing cellular rejuvenation using Yamanaka interventions and he has developed a clock they’re using in the laboratory setting. It’s not available to us. It looks at the entire methylome. I mean, the methylome is 30 million CPGs strong. It’s massive, you know, and the tools that we have available to us are huge. What TruDiagnostic is doing is massive. But we’re still looking at hundreds of thousands versus millions of CPGs. His clock does appear to be capturing the rejuvenation process like the changes in the hallmarks of aging. He may be capturing more information there.

Dr. Kara Fitzgerald – So to your point, the current clocks were inadequate to capture it, but more broadly, like if you did an epigenome-wide association study, like if you looked more broadly at the methylome, you would be seeing some movement, is my guess. And we know this from human data. We know that in people who eat a Mediterranean diet or a Mediterranean diet that’s turned up with additional polyphenols, we see DNA methylation patterns changing favorably. We’re looking at that EWAS (Epigenome-wide association study) data ourselves. In our study, we clocked the polyphenol intake in a daily, hitting the targets daily in our eight-week intervention. And it’s about, you know, three grams of polyphenols, which is intense. You know, it kind of dwarfs a standard Mediterranean, for example, even some of the polyphenol-heavy ours is more. But you’re only doing it for eight weeks. You know, it’s a finite amount of time, and we do see methylation changes beyond the clocks themselves.

Dr. Kara Fitzgerald – So I think there’s a place for investigation with what you’re doing in epigenetics. The lens would just have to be a little bit different. It couldn’t be so trained on those clocks.

Dr. Greg Kelly – Yeah. And they actually did report on that in the clock paper that looked at D and Q. And in the D and Q over six months, I think there were only two methylation sites. Listeners don’t take my- But anyways, it was relatively trivial. But when the fisetin was added in, it was like 208 probes changed, with about 50% becoming more hyper-methylated and about 50% being less. So, adding the fisetin in made a huge difference in the CPGs.

Dr. Kara Fitzgerald – Interesting. That’s really fascinating. In Sebastiano’s clock they showed caloric restriction having a similar influence. They haven’t tested a lot of interventions, but they did show caloric restriction having a similar influence, a similar pattern of influence on the methylome as the Yamanaka cocktail, interestingly enough. I mean, I think we’re collectively headed in the right direction.

Dr. Kara Fitzgerald  – I mean, to me, it’s extremely exciting. Okay. So, question, or thought number two that I want to hear you speak to is that these botanicals are used all the time in practice. People are prescribing these. We prescribe turmeric all the time for everyday use. We use high-dose quercetin in allergy season for a loading dose. And then we taper off and do a maintenance dose. But we’re not pulsing these interventions. And so, is this a problem? You know, we’re not pulsing. Anyway, speak to that.

Dr. Greg Kelly – Yeah. This would be more, you know, my belief. I, for a couple of decades now, I got back into circadian rhythms in the late 90s. And then from there, complexity science. And one variant of that is complex adaptive systems, which we clearly are, right. And our cells are, right. So, they’re constantly adapting. And so again, let’s go back to our senses.

Dr. Greg Kelly – If we were to hold an image unmoving in front of our eyes, no matter how bright or colorful, it would only be a matter of time and a fast time before our brain adapted and stopped seeing it. The same with background noise, right? We’ll quickly filter that out. And so, you know, my bias is that we want to play the same game that senses are playing. And senses on cells are receptors, and they’re listening for changes to things in their environment and if something’s continuous, then they’ll eventually ignore it. Right? Like it’s not changing anymore. That’s just the rules of the game, so to speak. So what you’ll see on the Qualia brand of products like Qualia Mind, was our original nootropic flagship product, from day one, we’ve always had five days on, two days off, and what we find is that works. And what we’ll often then tell people is, oh, like every three months, maybe take a week or two weeks off just to reset all the receptors.

Dr. Greg Kelly – The other thing that’s, you know, I would say common in our industry would be like, oh, well, just take this 2 or 3 times a day. I think that’s almost always, maybe not 100% of the time, but more often than not, less good than taking one dose at the best time of the day that matches the optimal circadian timing for that particular intervention, as an example. So my bias has always been – not always, going back to when I was a young man starting out, with exercise, I was stupid. I went to the gym pretty much every day. So I had the lifting down, but not the recovery down. We want to do something and then recover. And even ProLon, which I’m sure our listeners are familiar with, ProLon, Valter Longo’s Fast Mimicking Diet, a lot of the magic from that has to do with the fasting and then the refeeding that follows it. Right? So I just think in terms of a mental model, I think a good mental model is that, you know, say as an example, using quercetin to manage some type of joint issue.

Dr. Greg Kelly – You know, if you don’t take it for a day or two, you’re not going to significantly impact the quality of that person’s life. But if you intermittently take a little bit of time off, it doesn’t have to be every week, I think you’re more likely to get a sustained benefit over more prolonged periods of time.

Dr. Kara Fitzgerald – And your dosing higher for that period. We should point that out. You’re just going in really, really aggressively and then stopping. This is really interesting. It’s just really interesting. I’m excited about what you’re doing and the lens that you’re looking through to design these products. It’s just careful. I know your source material is really high, and I’m sure there’s been as much attention there. I’m so glad that we had this chance to kind of do a drill down onto this focus and just really kind of bring who you are to our listeners.

Dr. Kara Fitzgerald – I think they’re going to be excited about it. Yeah. Anything else you want to throw out there?

Dr. Greg Kelly – Yeah. I would say two things. One is that, and this goes back to the original work of the Mayo scientists, that something can be a senolytic compound, but that doesn’t mean it’s senolytic in all tissues. Right. So that’s why you’ll see D and Q is the most common stack to date in studies. And certain things, like as an example, olive leaf seems like it has a proclivity towards chondrocytes that are senescent. We know quercetin is endothelial cells. So part of the reason you’ll see nine ingredients in Qualia Senolytic is because we’re trying to cover more tissues, because there’s like an additive nature to that. So that would be one thing. And the other is that something can be senolytic, but that doesn’t mean the amount you’re taking is going to be senolytic. I’ve seen a couple of senolytic dietary supplements that will be like, take this once a day, every day for 30 days, each serving is 100mg of fisetin. That amount of fisetin is unlikely to be senolytic. Even getting away from the hit and run dosing idea. My mental model would be like temperature. 70 degrees isn’t the same as a sauna, right? They’re going to do completely different things. So those would be the two things. Like we designed ours to have multiple ingredients to support more of a whole-body impact on managing senescent cells. And then we put in amounts that are meaningful enough to expect to have benefits. And then the last thing I always think of is did a product do what it was supposed to do? Which is one of the reasons that both you and I like to study things and see in the real world, did this thing that seemed like a good idea actually help people. So, when you think of Qualia Senolytic, I feel like we’re the only ones that have done even one of those things, never mind all three.

Dr. Kara Fitzgerald  – That’s awesome. And could you just go through the ingredients of it again?

Dr. Greg Kelly  – Yeah, sure. So, the number one in terms of the dose is the fisetin. It’s 1400 milligrams in a daily serving, so a big dose. Then quercetin as the Quercefit, which Indena is the supplier of that. It’s a very bioavailable quercetin. And then luteolin, which is actually very similar structurally to quercetin, but it has maybe more brain activity. So those three would all work somewhat similarly in their mechanisms within cellular nutrient sensing. Then we have piperlongumine, which again, long pepper is the source of that. But you need to get a lot of long pepper to get a reasonable dose of piperlongumine. Then we’ve got the olive leaf extract and the curcumin, which I think of those as more targeted towards joint and connective tissue as helping to manage senescent cells. And then the last part is what I think of as the stack of milk thistle and the soy isoflavones.

Dr. Greg Kelly  – So it’s those nine ingredients. Oh, and then I missed one. It’s Senactiv which is a clinically studied mix of notoginseng and sweet chestnut rose that’s been shown in a human study to help remove senescent cells after exercise from muscle tissues.

Dr. Kara Fitzgerald  – Well, it just sounds like such a great design, and we didn’t go through all the ingredients so I’m glad that we took the time to do this. And incidentally, just with my clinician hat on as we head into allergy season, this would probably knock your allergies out too. That’s so funny. You know, with the quercetin and fisetin and luteolin. Those three would have that sort of side benefit if anybody happens to have allergies as well. Well, listen, Dr. Kelly, it was awesome to spend this time with you, a really fun conversation. I think we covered a lot of really good, interesting ground.

Dr. Greg Kelly – I agree, it was wonderful to get to catch up and talk with someone who’s such a good listener and, you know, asks such great questions into this area that I think most of us, ten years from now, will be like, yeah, we saw this coming.

Dr. Kara Fitzgerald  – Good for you. Good for all your good work out there. Yeah. Thanks again for joining me on New Frontiers.

Gregory Kelly is Senior Director of Product Development at Neurohacker Collective, naturopathic physician (N.D.), and author of the book Shape Shift. He was the editor of the journal Alternative Medicine Review and has been an instructor at the University of Bridgeport in the College of Naturopathic Medicine, where he taught classes in Advanced Clinical Nutrition, Counseling Skills, and Doctor-Patient Relationships. Dr. Kelly has published hundreds of articles on natural medicine and nutrition, contributed three chapters to the Textbook of Natural Medicine, and has more than 30 journal articles indexed on Pubmed. His areas of expertise include nootropics, anti-aging and regenerative medicine, weight management, sleep and the chronobiology of performance and health.

Dr. Greg Kelly

Neurohacker Collective

Qualia Mind

Shape Shift by Dr. Greg Kelly

Alternative Medicine Review

Textbook of Natural Medicine

Qualia Studies

Inulin-Type Probiotics – A Review (Part 1 and 2)

Qualia Senolytic Placebo-Controlled Clinical Study Results

Qualia Senolytic Beta Study

James Schmachtenberger

Daniel Schmachtenberger

Jinfiniti

Quercefit

Study: The Hallmarks of Aging

Study: Hallmarks of aging: An expanding universe

Study: The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs

Study: The Clinical Potential of Senolytic Drugs

Study: Epigenetic clock analyses of cellular senescence and ageing

Study: The relationship between epigenetic age and the hallmarks of aging in human cells

DunedinPACE Test for Aging

Vittorio Sebastiano

Dr. Fitzgerald’s Study: Potential reversal of epigenetic age using a diet and lifestyle intervention: a pilot randomized clinical trial

FxMed Blog: The 12 biological hallmarks of aging viewed through a functional

FxMed Podcast: Decoding Aging: The Science Of Cellular Rejuvenation With Dr. Vittorio Sebastiano

DrKF Clinic: Patient consults with DrKF physicians including Younger You Concierge

Bio Age Lab Test

Bio Age Self Assessment Quiz

Younger You Group Program

Younger You book

Better Broths and Healing Tonics book