Senolytics: The Latest Breakthrough in Aging and Longevity Science - An Interview With The Neurohacker Science Team

What follows is a transcript for the podcast Senolytics - Neurohacker Science Team - Aging.

Topics within the interview include the following: 

• What is cellular senescence?
• What are the "Hallmarks of Aging" and why is cellular senescence an important hallmark?
• The difference between cellular senescence and autophagy.
• Classical places where senescent cells take hold in the body.
• The science to support senolytics from Mayo Clinic and Scripps Institute.
• How do senolytics work?
• The correct way to dose senolytics.
• What makes Qualia Senolytic a groundbreaking supplement in the longevity space?

Lauren Alexander: Hi, everybody. I'm really excited to announce today's podcast. First, I'll announce myself. I'm Lauren Alexander here at Neurohacker. You don't know me, but I have been working on nearly every episode of Collective Insights. I'm very excited to have a chance to be here directly with you. It's such an honor to serve this community.

Today we're covering one of the most exciting areas of longevity and anti-aging, which is senescent cells and senolytics. This is really at the cusp of all of the research right now, and the things that we're learning and discovering are, quite frankly, electrifying. To just speak a little bit about it, the belief has always been that the issues lie in the health of the tissues, but it looks like the health of the tissues lie in the health of the cell. Understanding how we can support the body to remove and eliminate damaged cells, and make room for more healthy and young cells seems to be a winning formula for unlocking health at scale.

I have with me two of the most brilliant minds on the subject matter, Dr. Nick Bitz and Dr. Gregory Kelly. Dr. Gregory Kelly has been on the podcast several times. He's senior director of product development and Neurohacker Collective, a naturopathic physician, and he's author of the book Shape Shift. We also have with us Dr. Nick Bitz. He also is a naturopathic physician, and specializes in Ayurvedic medicine. He's the leading voice in natural products industry, and is serving as senior VP of product development at Neurohacker Collective.

Without further ado, let's bring on our guests, Dr. Greg, Dr. Nick, and let's get right to it. Greg, tell us what is cellular senescence, and why should anybody care?

What is Cellular Senescence?

Dr. Greg Kelly: It's actually a huge question, but I'm going to keep this part super brief. The general idea of cellular senescence is that certain cells will become, at some point, unable to divide and create progeny, basically new cells that would be clones of themselves. Cells that are unable to make new cells are collectively called senescent cells.

Why that's important for aging as the science that's evolved, especially over the say last seven years, since 2015, and really starting to emerge around 2009. Is that as we get older, more and more of these senescent or aged, unable-to-replicate-themselves cells accumulate in our tissues. Not only do they accumulate, but that accumulation seems to track really strongly with the health both of our tissues, and ultimately of ourselves. When we talk about wanting to live healthier longer, a big reason, or a big impediment to that is the senescence cell load in our tissues. Nick, do you have anything you'd love to add to that?

Dr. Nick Bitz: Yeah, I think that's it at its core. When I think of cellular senescence, really when I get into the science, anything that's technical, I like to break it down in terms of Latin. Senescence, the root word comes from Latin, of course, and it's senex, which means to age. The concept as a whole is really critical to the process of aging. Cellular senescence is this idea that cells age. Just like the human ages, the cells age. What happens after the cell ages is really this whole area of science that is cellular senescence that...

For me is just super exciting. It's mind-blowing. It's a really ripe field right now, and there's a lot happening in this. What's intriguing from my standpoint really is that not only is this area just emerging, and there's a lot of new science in this area, but we're now finding that there's tools that can undercut the whole process of cellular senescence. Which, from my standpoint is really exciting, because we can do something to undercut aging.

Lauren Alexander: I know there's a lot of analogies to help understand cellular senescence, the zombie analogy, the plant analogy. Greg, can you maybe unpack a couple of, or both of those analogies?

Dr. Greg Kelly: Yeah. When you think of it, senescence cells, I mentioned they don't divide any longer. What the cellular senescence software or program that cells execute that stops them from dividing, that should lead to... This is where the plant analogy comes in. We tend to use the idea of leaves falling off a plant, because the process then that this senescence cells should go through is called apoptosis.

This is this time from a Greek word, not a Latin word. But the Greek word would imply something like leaves falling off a tree, root falling off a plant. That idea of falling off. Senescent cells should quite literally fall out of our tissues by going through this apoptosis process. What seems to happen with aging is that a fair number of... resist this falling off process, so they become non-removable.

You being a gardener, Lauren, you and I have talked about this. It's very akin to yellowing leaves on a plant. Ideally those leaves should just fall off, but as any gardener knows, some decide to just hang on and linger on the plant. They then use resources that would better be served going to a more vibrant new leaf. They impede new growth, and ultimately they impact both the health and the beauty of the plant. Senescent cells tend to do those same thing, which is why we use the plant analogy.

The zombie analogy we didn't create, but has existed in the field of senescent cells for quite a while. The idea behind that is because these cells are frozen, they haven't gone through apoptosis. Ideally they're queued up for that, but they haven't, so they're not gone through what's called programmed cell death. They're not able to reproduce. They're not quite living cells as you would think of that term. So they're stuck in this limbo in between, akin to like a zombie in a book or a movie.

The other reason that analogy of a zombie cell becomes important is, senescent cells can secrete chemicals into the environment surrounding them, and those chemicals can take healthy cells and turn them into new senescent cells. Very much akin to how a zombie can take a healthy human and make them into a zombie. That's why these two metaphors both work. I think I go back and forth, but I tend to be the gardener metaphor much more, because I think, as Nick mentioned, I've been driven for decades by the question of, "What does health like?" But I'm much more drawn to actionable things. In the different notions of what contributes to aging, right now removing senescent cells, doing something akin to pruning them off is, if not the most actionable thing, certainly one of the few that are actionable.

Lauren Alexander: Nick, anything to add here?

Dr. Nick Bitz: Yeah, very well put, Greg. I love listening to how you lay this all out. The concept of apoptosis, I think it's fascinating. We lose between 50 and 70 billion cells each day due to apoptosis. We have 37 trillion cells, and so we're constantly turning over these cells. Obviously, that has a huge impact in terms of health as well as dysfunction in the body. That is really, I think the core essence in my mind in terms of cell senescence.

I think this concept of transient versus lingering senescent cells is critically important here. For me, it was game-changing to really understand this whole concept. Cells will go through apoptosis, and if they don't, they will get plucked from the body and eliminated pretty effectively, usually within days or weeks. That's normal, and that's known as transient cell senescence.

But this idea of lingering, these cells are programmed to linger in the body for a number of different reasons. That is when you get this kind of zombie response in the bodies. These cells end up taking space in tissues, and basically the structure is changed, the function of that tissue has changed, and these cells are secreting these, what are known as SASP factors. SASP factors are in essence really just inflammatory compounds that are really influencing the microenvironment of that tissue. We now know that they're getting into the system as well, so they're not even local, they're systemic. Not only are they creating this kind of low-grade inflammation, both locally and systemically, but they're converting healthy cells into senescent cells.

In a lab setting, you can put just a couple senescent cells into healthy joints of mice, as it were. Just a couple cells, one cell among maybe 15,000 healthy cells, will create a senescence phenotype, and creates a lot of health issues. As an example, when you put it into a mouse joint, you see that the cartilage will erode, the mouse will have trouble walking, and their lifespan will shrink. Just one cell can really impact the entire body, and that is that kind of zombie effect in essence.

What Are the “Hallmarks of Aging” and Why Is Cellular Senescence an Important Hallmark?

Lauren Alexander: Wow. Well, I jumped right in, but I want it now tie in cellular senescence, and the hallmarks of aging, which some of our audience is familiar with. But maybe you can lay that out, and speak about cellular senescence role in the hallmark of aging, because it's not just a chart. One thing actually affects other elements that are listed in there. Who wants to take this one? Greg?

Dr. Greg Kelly: Sure. The hallmarks of aging was a 2013 paper. It essentially proposed that there's nine characteristics that organisms of all type, flies all the way up to humans, have in common. These are things like our telomerase or telomeres, I've heard that said both ways, getting shorter. It's often called DNA or genomic instability, but think of it as that our DNA has started to get corrupted, and doesn't make such good copies of itself.

Another one is mitochondrial dysfunction. I know I've done a podcast on mitochondria in the past with Dr. Molly. There's these nine things, and one of the nine is cellular senescence, which we've talked about. Much more recently, and by that I mean this December of 2022, I think it was three additional ones were proposed to be added. One of those is the gut microbiome, which we'll talk a lot more about in the future I'm sure on Collective Insights podcast.

Cellular senescence then becomes one of these characteristics that all aging organisms have, and we've talked about what that then does. This is the idea of a greater percentage of our tissues are taken up with these cells that are using resources, but not producing a lot of great health outcomes for us. Within the aging community, you also then see what I would say are camps of what's the main cause of aging. There's lots of theories that can fall into either of these camps, but the camps typically are dumped into aging as a result of damage accumulation, so the damage-accumulation camp.

What they would say is that the reason we age and express issues with aging is because of accumulation of damage over time in our cells, mitochondria, ultimately tissues. The other camp would be, "We're programmed to age." This is Darwinian, like evolution, the idea being that really our genes solely care about passing themselves on. Once we've passed beyond reproductive age, we're programmed, probably our immune system, our hormones, our DNA to essentially enact the, "Oh, get old, remove this person from the pool," so there's less now people competing for resources. Because Darwinian evolution, that idea of competition for scarce resources. Those two camps.

The thing about senescence cells is they actually make sense in either paradigm. There's certainly an aspect of damage accumulation. As Nick mentioned, one of the most exciting things was what happens when some of these are removed from older animals in terms of rejuvenation. But they also make sense in that programmed aging idea that the genes that would essentially make more cells resistance to being pruned away or falling off, get expressed differently as we age. The immune system we also know ages relatively poorly. Either camp tends to claim senescence cells as essentially validating their theory.

Dr. Nick Bitz: Yeah, I'll add to that as well. Currently, the hallmarks of aging is really, I'm going to say, the best model of aging that we have. Again, there's no one model that accurately describes aging as a whole. Of course, there's different ways to talk about this. One way that I've read in the literature, which I love, is this idea of…

It's really the parable of the blind men and the elephant. We've all probably heard this story before, but four blind men come up to an elephant and they are asked to describe the elephant, what is their experience of it? One man grabs the leg, and he can describe the leg. The other one grabs a tusk, the other one grabs a tail. They're all having their own kind of unique isolated viewpoint of what an elephant is, but it's not the complete picture of what an elephant is as a whole.

I think the hallmarks tries to encapsulate the aging process in a lot of really good ways. Each of those nine hallmarks was chosen for a really good reason. Number one, we know that it manifests during normal aging. Number two, we know that experimentally when you can increase it, it will accelerate the aging process. And then the third thing is that, experimentally, if you can lower it, you can actually attenuate the aging process, and increase healthy lifespan.

It really is based in good science. I love that cellular senescence is one of them. It is, in my mind, the one that really is connected to all of them, to eight of the other ones. They don't act in isolation. They really work together, and they influence each other in unique ways. There are primary hallmarks that lead to damage. Then there are secondary hallmarks that respond to the damage. And then there's kind of tertiary or integrative hallmarks that we see in a clinical setting, as it were, that are the true manifestation of the phenotype of aging over time.

And so the hallmarks of aging for me is just a really beautiful story. But to Greg's point, it's not the end all and be all. It's still an evolving mo model. We are adding to it. In 2002, there was a aging conference in Copenhagen where they have put forth new hallmarks that they want to add to these nine. Greg talked about the microbiome disturbance as being one. Another one is inflammation. We hear a lot about inflammation. I think we can all agree that, that is driving aging in large part, but currently it's not part of the hallmark model. I look forward to expanding that. In a year, maybe we're going to be talking about the 14 hallmarks of aging, but right now it's the nine. And cellular senescence, I think is the most interesting right now.

Dr. Greg Kelly: One thing just to add on to that, Nick mentioned that think of some of these as being interacting things, not separate things. Telomere attrition as an example, the original work that led to the identification of senescence cells was this realization, and this goes back to 1961, and a research named Hayflick. But the idea was, if you had healthy cells in a dish, they would only divide so many times before they just hit the wall, and couldn't divide anymore. That's now called the Hayflick limit, described as replicative senescence. They basically become aged because they divided so many times.

The key thing that causes that is our telomere shortening, as an example. We know that one of the things that can cause cells to choose to become senescent is if telomeres become too short. Then the reason that, that causes, it's called the DNA damage response, DDR. But we don't want cells to copy errors into new cells, so senescence is one of the software programs executed to prevent genomic instability. Genomic instability was another of the hallmarks. They tend to fit together. As Nick mentioned, cellular senescence is somewhat of a hub for a whole bunch of the different hallmarks.

Classical Places Where Senescent Cells Take Hold in the Body.

Lauren Alexander: Awesome, awesome. We've talked about... The thing I want to get to is visualization of where these senescent cells are lurking. It sounds like they can be anywhere, but are there classical places where they accumulate? I've heard you mention joints, perhaps brain tissue. Could we speak on maybe some of the areas that are classic for them to accumulate, why they accumulate in different areas. Maybe touch on what that accumulation could translate into. I know that's a big question, but let's navigate that area together.

Dr. Greg Kelly: I think for our audience, there's some cells that their job is to renew, replicate, make clones of themselves. There's others that are fully differentiated, and they're basically good for a lifetime. They don't go through what's called mitosis. They don't create new cells. Classically, what you would think of senescent cells is accumulating much more in places in the body where cells are replicating themselves. The knee joints is an example, skin, muscle tissue. Neurons in the brain used to be thought of as something that didn't replicate. That now there's definitely some at least limited neurogenesis in parts of the brain.

To answer your question, senescence can happen anywhere, but it's certainly much more likely to impact health in areas where cells are renewing quickly. Joints being an example of one of those areas. But as I mentioned, muscle skin. Adipose cells don't necessarily renew per se, but they can divide. A lot of what we think of as metabolic health issues are at least contributed to [inaudible 00:20:45] senescent cells and fat tissue.

Dr. Nick Bitz: I'll add. The research is still early days, and we're learning a lot more about senescence as a whole, and where these cells are, and how they manifest. With all that said, the science so far shows us that about 10% of all tissues in the body in advanced age have markers of senescence. You really do see it in all cells. Again, we have 37 trillion cells. Almost all of them are going through apoptosis at some stage in life, aside from neurons in the brain, peripheral nerves, as well as the cells that are in the lens of the eyeball.

Beyond that, I would expect there to be problems throughout the entire body. As an example, we're learning more about the brain as it relates to senescence, which is fascinating. We know that neurons don't turn over. You have your set of neurons for your entire lifetime, but the surrounding cells around neurons do go through apoptosis, and can become senescent cells, as it were. Which can impact cognitive function and really shift the structure and the function of the brain as we age.

Dr. Greg Kelly: I think for our audience, maybe the big picture is there's almost no common area thought of as an issue with aging that senescent cells aren't so far shown to impact in different animal experiments or human. If you can think of just physical function and appearance of aging, senescent cells directly contribute to that in almost every tissue.

Lauren Alexander: Yeah, no. As I was visualizing what you were describing, which is stiffness in joints, just the describing the symptoms of aging. Stiffness in joints, reduction in muscle mass and strength, maybe some cognitive aspects, skin aging manifestation. And then now you're tying it all to an accumulation perhaps of senescent cells in those areas, in those tissues of the body, does paint a picture that maps really cleanly with our idea of what it is to age.

Now getting into the exciting part of, "Okay, what can we do about it?" That's where senolytics come in. Mayo Clinic and Scripps Institute really kicked off this area of research, and founded the term senolytics. Maybe, Greg, you can speak to that research, and what the implications were for senolytics, and maybe a little bit on your study.

The Science to Support Senolytics From Mayo Clinic and Scripps Institute.

Dr. Greg Kelly: Sure. A quick history lesson. I mentioned the idea of replica senescence goes back to 1961, but I don't think it was termed senescence until the early 70s. Apoptosis is an example, telomeres, those things all came later. Senescence in a sense has been known about for 60 years, but it really wasn't until I would say around 2008, 2009, 2010, that the contribution to aging of what we would think of as what Nick said, lingering senescent cells, started to come on the radar.

Before that, there was the general idea that, "Oh, okay, cells can only divide so many times before they hit the wall, become senescent. That probably has something to do with aging, but what exactly that is, we don't really know." Emerging since that 2008, 2009 is that term that Nick mentioned, SASP, senescence-associated secretory phenotype, what senescence cells can secrete into the environment around them, and zombify other cells, or cause the equivalent of more yellow leaves on a plant.

That kind of caused a big uptick in interest in cellular senescence. And then in 2015, Mayo Clinic and Scripps Institute of Aging, as you mentioned, coined the term senolytic for compounds that would allow these senescent cells to complete this journey to falling off. What they did is, they looked at these apoptotic mechanisms. One of the commonalities in senescent cells, at least the lingering ones, is they tend to resist this falling off process, so they're apoptosis-resistant. They secrete these SASP factors into the environment around them, and then they express distinct proteins that essentially the ratio of those proteins determines whether the cell says, "No, I'm hanging out," or, "I'm going to fall off."

What the Mayo Clinic researchers and Scripp researchers did, they looked at some of these proteins in cells that give this apoptotic resistance. Identified compounds that they hypothesized may shift that ratio back in favor of, "Oh, I guess I'll go through this falling off process instead." And found two compounds that strongly did that. One of them is quercetin which we'll talk a bit more about. It's in our Qualia Senolytic. That birthed this idea of, "Oh, well, compounds that can shift its ratio and cause these apoptosis-resistance senescence cells to change their mind, and go through falling off, let's call those senolytics." Again, Nick loves Latin terms, so I'll let him tell you what the senolytics term means.

Dr. Nick Bitz: You teed that up perfectly, and that's exactly where I was going to start my little monologue here. Yeah, senolytic, it's a funny word, but again, if you break it down, it's really the conjugation of two words, senex and lidic or lytic. Senex, of course, means aging and lytic means to destroy. It's really to destroy senescence in essence. That's really the promise and the potential of senolytics.

I think if you even just push aside the technical jargon, it's really mind-blowing to think about this whole area of healthcare right now. I think you can get bogged down getting into the technical terms, and I think it turns off a lot of people. But the more that I'm talking about senescence and senolytics, I'm seeing people get inspired by just the idea of what these can do in the body.

I think if someone told you, number one, that there were these accumulating dead or dysfunctional cells that are building up in your body, number one. And that these cells are secreting these inflammatory chemicals all throughout your body. And the third thing is that you actually have the ability to go in there, and get rid of these senescent cells, I think anybody can be called to action because of that. I think it's really incredibly empowering for people to understand that you can stay in control of your health through some really interesting game-changing science that's occurring in the area of cellular senescence right now.

How these things work is really interesting as well. In essence, they induce apoptosis. They're selective, so they're not going through the body and they're inducing apoptosis for healthy cells. Because they are working specifically through these SCAP networks, which are these anti-apoptotic networks that these senescent cells express, we can go in there, undercut that, disturb that SCAP network. And in turn we basically move these lingering senescent cells into a transient phenotype. We make the cells susceptible to apoptosis so that the cell then is pulled from the body, makes space for new cells, and tissues that stem cells can come in there and do what they need to do to revitalize the tissues. I'll leave it at that.

Lauren Alexander: Wow.

Dr. Greg Kelly: One of the things we haven't talked about, but I know I've been asked it in a few other podcasts is, "Well, what causes cells to become senescent?" I think that's worth just a minute or two. We mentioned one of those would be that they've just hit the wall in terms of number of times they can reproduce. My intuition is that's probably not the driving cause of the type of lingering senescence we talk about with aging.

In a test tube, you can also cause cells to hit senescence way before that 50 divisions by doing things that would stress the cell culture. That's typically called premature stress-induced senescence. Anything you think of as what might be cellular stress. Radiation, not enough nutrition. Anything in that stress category can cause this premature stress-induced senescence. My intuition is, a lot of what's causing us to accumulate senescent cells, and especially these ones that linger, is collectively all the different stresses that as an organism that we're exposed to, but then that our cells are exposed to.

One of the things I think that's important to talk about is how cells respond to stress. Because the goal, one, we want to prune these away, we'll talk more about the compounds and Qualia Senolytic. I think we also want to do things to make ourselves more resilient so that they don't become prone to this stress-induced senescence. When I think of what happens when a cell is stressed, I think of it as a continuum.

The Difference Between Cellular Senescence and Autophagy.

First, they're going to try to protect themselves, so antioxidant defenses would be one of those things. They'll try to make themselves more resilient by creating more compounds that help them deal with oxidative stress, because a commonality of almost any type of stress is that it causes oxidative damage. If that ends up not being enough, then typically the next thing that happens is, some of the things within cells get mucked up a little bit. Proteins get misfolded, organelles get slightly damaged, mitochondria distressed. That's where this idea of autophagy, that I know the biohacker community loves and we love, comes in.

Autophagy is about recycling things inside cells. A classic signal that would cause cells to say, "Oh, let's prioritize," autophagy would be a short-term fast. Something like the fasting-mimicking diet that we've had Dr. Longo on our podcast in the past, and we've written about it. But short-term fast tend to send this signal like, "Oh, there's not enough protein and other things coming in, I better scan and find disposable versions of that inside cell. So, let me selectively find things that are already a little mucked up and recycle them to use those proteins." That's autophagy.

The next step after trying to defend themselves and become resilient, is selectively cleaning up or recycling things that are slightly damaged. When a cells move past the point that that would even work, then that's when you would have senescence. It's like, "Okay, there's enough damage in here. Let's not even muck around with anymore. Let's just freeze it where you are. Turn you into a zombie. We'll let the immune system worry about finding you down in the future." What I've seen those few times on podcasts is, people confused autophagy with senescence. I think the key idea I want to communicate is, think of autophagy as something that helps cells... or helps prevent cells from becoming senescent. But once they are senescent, autophagy is no longer the goal. We need to prune those cells off.

Lauren Alexander: In terms of practices, you need an autophagy practice, and you need a cellular senescence practice in order to keep these things tight and clean in the body, yet separate?

Dr. Greg Kelly: Yeah, and a resilience... At the core, my goal would be doing things through the month to give my cells more resources, make my mitochondria fitter so they can deal with some stress. I take Qualia as an example Monday through Friday personally, because that's what that would be designed for. Autophagy, yeah, people do the time-restricted type of intermittent fasting or short fasts. Those are very strongly autophagy-supportive strategies, in part because one of the signals that would cue a cell like, "Hey, execute autophagy" is when nutrients become relatively unavailable, but we don't want to do long fast. That's a completely different thing. We want to fast, and re-feed. We want to periodically... Whether we do those things or not, we want to prune away the yellowing leaves, and that's where senolytics come in.

Dr. Nick Bitz: Yeah, I think you're shedding light on a very interesting point here. I'm listening to you, and I'm having this realization that cellular senescence is a root contributor to aging, but it may not be the root. Meaning there are things that actually lead to cellular senescence. We can focus on cellular senescence, which is critically important, but we can actually go deeper, and get at these root causes that are leading to senescence. Autophagy, really optimizing that as a process, critically important.

The other thought that I had was just telomeres. If a telomere attrition or the shortening of telomeres is the primary cause or causative factor leading to senescence, how do we take care of our telomeres? Of course, there's a number of ways that we can do this. We can preserve length through the various antioxidants. I know there's good research on selenium and CoQ10, as it were. There's certain compounds, astragalus, a specific extract that is known to produce more telomerase, which adds nucleotides to the end of telomeres, and it can help, quote, unquote, "Restore telomere length."

Of course, the basics, the foundational things we know can improve telomere health too. Sleeping, quitting smoking, eating a very nutrient-dense diet, such as the Mediterranean diet, or the blue-zone diet, physical activity. I think that there's even a more root cause thing that we can talk about as well. But focusing on cellular senescence is great because, again, it's very actionable.

Dr. Greg Kelly: One of the... I don't remember if she was on our Collective Insights podcast, but one of the core... If you were to take two groups of otherwise the same age, adult humans, one of the things that predicts shorter telomeres is stress, very strongly predicts it. Again, I think, one, my intuition is that the telomere shortening that variant of cellular senescence is relatively not that important for aging. It's the stress induced, but stress is going to cause issues with telomeres as well.

Again, I think we talk a lot about it personally, you and I, Lauren over the years, is stress is like kryptonite for almost everything. The stress that we can mitigate in our lives for sure, I think, getting rid of some of those straws helps to make us more... or less likely to collapse under the weight of stress.

The Correct Way to Dose Senolytics.

Lauren Alexander: But some of this is healthy stress, and that hormesis, ingesting a senolytic is inviting a level of a stress in a way. I think it's really finding out that balance. I think as a biohacker, and part of biohacking community, we like to go all the way to the other end of the extreme. And so, finding that measured and balanced from medic response to stress I think is really the thing that you're emphasizing here. Something that I think is... We need to just pause and say, "Hey guys, not too much stress," because that does have a cascade of negative aspects associated with it.

Dr. Greg Kelly: By hormetic, just so our audience knows, we're generally talking about something that can do a Goldilocks principle. Like one bowl of soups too cold, one's too hot, and there's one that a just right amount. We're talking about a just right amount of something which gets to... We haven't talked about this yet, but the idea of how senolytic compounds are dosed. I'll let Nick... I'll cue this up for him. Why don't we take senolytic compounds every day, Nick, in high doses?

Dr. Nick Bitz: Yeah. More is not better. It's interesting when you dig into the studies on senolytics, they have showed that doing big doses for a short amount of time is the most effective way. It's more effective than doing continuous dosing of senolytics over time. In part, that's why we built the product that we built in the way that we did, and we recommend using it in the way that we do, which is two days out of every month. You hit these cells hard, and then you step back. You let the body rest and recover. That's critically important.

For us, it's really about safety first. I think that that is an area right now that the scientists are looking at. We are figuring out what compounds are senolytic. But if you're using these compounds in big doses every day, trying to get a really strong physiologic effect, that really shifts the safety profile in a direction that's not favorable. And so, I think you really want to encourage normal physiology. You don't want to override the body's natural intelligence. And you want to do the minimum effective dose.

That, to me, is really a critical component here to this conversation. It does take several weeks for these senescent cells, perhaps even months, for them to re-accumulate in the body. Once you hit them, they do go away for a good amount of time. Especially in the meantime, if you can get these foundational protocols in place to maintain core level, core foundational health, the hope is that you're not going to re-accumulate those senescent cells over time.

Dr. Greg Kelly: The other thing I think it's important for our listeners to understand is the idea of a threshold effect. It's thought that probably below a certain threshold amount of senescent cells in the tissue, what that may be for one person could be different than another. But below that, there's probably low enough amounts that they're not affecting our experience of healthy function. When they get a above that threshold, that's when they are. The goal of just this intermittent dosing is to gradually lower the amount so that you're going to dip back below that threshold progressively probably over time further and further below it. That's one thing.

The other thing, and this would be more a principle that I think is super important for health that's widely underappreciated. Is that I firmly believe that the way that we respond things isn't based on the quantity of something, it's based on the change in quantity of something. The analogy I use, and this goes back to the 1850s or 60s with the early experiments on our vision as an example.

If you went into a completely dark closet and lit one candle, crazy difference. It would just appear way brighter. But if you went into that same closet and there was 99 candles already lit, and you'll light one more, that one candle didn't really make that much difference. What matters for our senses to respond to things is not only change, but proportional change. The one candle change on itself was meaningless. One compared to zero, huge contrast one compared to already 99, tiny, tiny contrast.

One of the things we try to do physiologically, if we want receptors on cells, which are basically the ears and eyes of cells to have a big change, is create contrast. When you're taking, say, this large dose of fisetin and quercetin, and some of these other compounds just a couple days a month, you're creating a huge change. Now, if you took that same amount and said, "Oh, I'll just do a much lower amount, but every day," you're now in the closet with 99 candles. In terms of a working model, that's how I would also have people think about it. We want to create big contrasts.

What Makes Qualia Senolytic a Groundbreaking Supplement in the Longevity Space?

Lauren Alexander: Right. Wow. Well, well put. I'd love to transition the conversation about Qualia Senolytic. I know that this was a passion product for the research and development team based on the excitement behind the research on senolytics. And also there being an absence of companies formulating in the way that we believe that senolytics should be formulated. Greg, I know that you're a very vocal advocate, so maybe you could just share with us your perspective of what makes Qualia Senolytic so unique and innovative.

Dr. Greg Kelly: I think there's a few different things. One is, I think it's easy to think of senescent cells as all being the same, but they not. You'll see the term heterogeneous used quite frequently in scientific articles and studies. That idea, meaning that the senescent cells have things in common, they resist apoptosis, they secrete these factors. But what their surface might look like, what exact strategies they're using to resist apoptosis may differ and differ profoundly, especially tissue to tissue.

An initial finding that came out of the Scripps and Mayo work that led to the coining of the term senolytics was that quercetin was senolytic in bone marrow, endothelial cells. Those two types that they tested, but not at all in adipose tissue. Something could be senolytic, but that doesn't mean it's broad-spectrum senolytic. It may have tissue affinities. And so, one of the things I think that makes Qualia Senolytics unique is that we really factored for that. We said, okay, "Well, quercetin is good here and here, but not here, here, and here, and here. Well, what else can we put in that now would have activity in fat tissue?" Fisetin is something that has in research to date.

What might have some activity in the discs in your back, versus the joints in your knees, versed more cognitively for, as Nick mentioned, the cells that are supporting all of our neurons. When we created Qualia Senolytic, that's part of the reason there's nine different senolytic ingredients in it because we wanted to make sure we covered all the bases, so to speak. That would be one.

And then two, I think we're actually dosing it the way it's supposed to be dosed based on the research. High doses of these things two days a week. I've seen quite a few... Not quite a few, but a handful of things that call themselves senolytic products that dose crazy low doses in every day. That's something, but I wouldn't view it as senolytic.

The third reason goes back again to the original Mayo and Scripps work. They were trying to find things that worked on, and Nick mentioned the term, SCAP networks. They're called senescent cell anti-apoptotic pathways. But these are signaling pathways that cells use to do things like sense nutrients around them. There were also these anti-apoptotic or apoptotic proteins. What the original researchers tried to do before they identified senolytics was they wanted to identify things they thought might be senolytic based on how it was known in other stress cells these things affected these different proteins and pathways.

We did something similar when we were developing Qualia Senolytic. That's why things like milk thistle, and the soy, being isoflavones, are in it, because they do some of these same things that help rebalance or correct these cell signaling and balances of pro and anti-apoptotic pathways. I just think that the level of science-detail dosing, it's just nothing comparable. That's why you and I, again, had many talks over the years. We just got to do this because no one else is. At a minimum, even if no one else buys it, I want to take it.

Lauren Alexander: That seems to be how we green light our products these days, is just complete selfish reasoning. Nick, anything to add there?

Dr. Nick Bitz: Oh, boy. Where to even start? I'm super proud of this product. It's been fun to watch its development, and to watch the launch, and to see the enthusiasm about it. And to see that people are having felt experiences using it, which is amazing. I'll just say that I really like that we're using I would say seven of the most proven senolytic compounds, and then we're adding some novel science as well.

The team has introduced a couple new compounds that were chosen specifically based upon their mechanism. I think that what we're doing is that we're aligned with the science in a lot of ways. Our dosing of fisetin, as an example, is 20 milligrams per kilogram of body weight. That's what used right now in all of the clinical studies, and it's been working really well. And so we're dosing in that same way.

I love that. We were coming at it from a very natural approach. We're using natural food-like compounds to create this massive change in the body. When you look at our pills, they are just this yellow glowing, vibrant color, which is indicative of the kind of compounds that are in there. We're using a lot of flavonoid-rich compounds that seem to be very senolytic-active in the body. I like that. We've taken a more natural approach, more food-like approach rather than the pharmaceutical approach. And so I think that it speaks to the safety as well as the efficacy of what we're doing.

I love that we've done studies on our product, and we're continuing to do more science there to prove that the outcome that we expect is actually there. We do that for all of our products, but I think this area is ripe for research right now. We don't have biomarkers in the field of senescent showing the amount of senescent cells that accumulate over time, or the amount that is reduced after senolytic therapy. But we can look at the outcomes, we can look at the impacts on joint health, or skin health, or inflammation, as it were, to show that these things are having really strong physiologic effect in the body.

Lauren Alexander: Talk to me about what are the felt experiences. Maybe speak a little bit about our first study that we did about mobility and joints, and what the outcome was there. I think that that's pretty interesting to speak on.

Dr. Greg Kelly: What we did... There's no direct way to measure senolytic or senescence happening in tissue short of a biopsy. Instead, we tend to use surrogates. That's what you'd see in science, that they're using aspects of function to infer that. One of the classic things that happens as we age is, our joints become a little bit more stiff. We struggle a bit more with what I think of as activities of daily living. Walking comfortably up and down stairs, getting in and out of the car, bringing our groceries into our home, things like that.

What we did is, we recruited a subset of people that had at least a moderate amount of challenge with flexibility, and with some activities of daily living. And then we had them do three cycles of Qualia Senolytic. A cycle is the two days of dosing. And then we had them not take it for, in this case, we had them 12 days between doses. Part of the reason we did that instead of the full four weeks between doses, in a study, the longer the study goes, the hard it is to get everyone to complete it. Just to get more adherence to the study, we sped up the dosing a little bit. Over the course of what ended up being five weeks, each person would've done the equivalent of three dosing cycles.

And then we had them complete questionnaires before and after to measure these different things. What we saw was roughly a 50% improvement in being able to comfortably do these many different activities of daily living. And also about a 50% improvement in the flexibility, like being able to bend over comfortably, things like that. So we were... Yeah. And then some of the comments, we also put weight on the comments people leave when they're in our studies. That combination of things was really exciting, to see such a dramatic impact on people so quickly.

Dr. Nick Bitz: I'll just quickly add to that, that I think everybody's experience for the most part is going to be unique using this product. It really is based upon your level of senescent cell burden. Which of course we know the older you are, the more senescent cells you will have, and theoretically the greater impact Qualia Senolytic can have for you. But it's also largely contingent on where these senescent cells are in the body. Again, if they're all in your skin, if that's where you're accumulating them, you're going to see benefit over time theoretically. I think that's why there's not any one experience that you should expect. It really is personalized, and we're finding that across the board. People are experiencing it in pretty dramatic, but very individual ways, which is really neat.

Dr. Greg Kelly: That gets to that idea of, again, that threshold effect. If me, maybe most of my tissues... I'm below that threshold, still good to put them away, but I'm not going to be experiencing something from them. But maybe in this one other area, I'm above that tipping point, that threshold, so that's likely where I would feel it. But someone else that could be completely different. I know Lauren, you and I were at a conference in Las Vegas in December. A4M is the name of it. It's the big medical anti-aging conference. I generally stay at lifelong friends' home when I'm in Vegas. We grew up near Cape Cod in a little fishing town together, and I've been friends since third grade, so going way, way back.

Because friend category, he was a relatively early Qualia Senolytic customer. What he told me... Him and his significant other, their passion is taking in stray dogs and fostering them, so they have a shelter for dogs... that he'd struggled for years just being able to do that throwing motion. And that he's told me, "Oh, this is the weirdest thing. After my third month of taking Qualia Senolytic, all of a sudden I could throw things to the dogs without experiencing discomfort anymore. Completely what I would never have thought about, but that was where he was above the tipping point, and it somehow seemed like it dipped him back below.

Again, there's many different ways that these can hinder our performance. One of the areas I know I paid attention to early on, and this gets to something called anabolic resistance. But the general idea is, as we get older, the anabolic signals that would cause our muscles to grow bigger and stronger, we don't respond on as well. Think of it like there's already 99 candles in the closet. We just don't get that big change in signals.

Because of that muscle weakness, muscles getting smaller are a big issue with people as they age. In animals they found that senescent cells contribute to that, and doing a senolytic actually helps to reverse it. That was an area I personally paid attention to, because I didn't have the flexibility or other areas, but I had felt plateaued in my muscle workout. Early on I was paying attention like, "Oh, is it now easier to do more weights?" And it very much was for me, I got basically unstuck from a plateau.

Lauren Alexander: That's awesome. This is what's really interesting about this product, is that in many ways if you study the research, taking it is an insurance policy. Like, "This is a phenomenon going on in the body, and I'm going to have a pruning strategy once a month, two days a month, I'm going to take Qualia Senolytic." The fact that we have people that have felt experiences from taking the product is pretty exciting. For me, in my role, I get to see so much of that feedback. I hear everything from, "Less brain fog," to being able to throw balls better, or gain muscle better, less stiffness in joints. The diversity of experience is quite broad.

But even there's a lot of younger people taking the product and subscribing to the product. The thought process is like, "I want to deal with this before it's a problem. I want to prune before my plant is covered in yellow leaves." As a gardener, I'll tell you that it's really stressful on a plant, pruning three fourths of the plant in a day. It's actually a lot better to go and snip one yellow leaf at a time, and let it rejuvenate. When you let a plant go too long, that really causes a lot of damage even when you're going to repair it.

Okay, I'm going to stop myself because I could talk about gardening a lot longer than not anyone wants to listen to. But I think the point is that this product in many perspectives, it isn't just for an old population, isn't just for middle age. It really covers the whole spectrum of people depending on what your health goals are, and what you're trying to achieve. I think that that has a lot to do with the diversity in experiences, and felt experiences from taking our senolytic.

Also, because we have so many different ingredients in it from quercetin, curcumin. Some target the brain tissue, some target synactive, which targets the muscle tissue. We have all of these different experiences instead of it being very narrow. I know that we have to go soon, but I thought maybe we could rapid fire, you guys sharing a couple of your favorite ingredients, and why you chose them for the formula. Maybe, Nick, we dive in with you first just sharing an ingredient that you think is really impressive in the Qualia Senolytic formula.

Dr. Nick Bitz: Yeah. Herbs tend to be organ-specific. When you get into botanical medicine or herbalism, all herbs, generally speaking, have an affinity for certain organs. Milk thistles specific for the liver, ginkgo is specific for the brain. Hawthorne berry for the heart, ashwaganda for the testes, black pepper for the stomach, on and on and on. I love piperlongumine in this ingredient. It comes from the long pepper plant, which is native to Ayurveda.

This is a very old traditional rejuvenative substance. It's known as pippali. It's a close relative to black pepper. It's been used for rejuvenation traditionally. Of course, traditionally they didn't talk about it as a senolytic per se, but it was used as a rejuvenative mostly for the digestive system as well as the respiratory system. In terms of affinities, it definitely has an affinity for those two areas. I would guess and theorize that in terms of senolytic effect, those are the same areas that this nutrient, this compound is having its effects in the body. I love that we're using it. You don't see that widely used right now, especially in the dietary supplement space. But I love that it's historical, yet it's incredibly cutting-edge in this area of senolytics.

Dr. Greg Kelly: I was going to choose that one, too just because it's really unique that we have that. Nick didn't mention it, but quercetin was the first natural compound that was identified as a senolytic, and piperlongumine from Piper Longum was the second. I'm going to cheat and I'm going to grab the three yellow dye plants, and group them all together. Those are fisetin, quercetin, and luteolin.

As Lauren mentioned, and Nick mentioned, the color of the capsules is this really cool, almost like a light lemony yellow color. A big part of the reason is those three plant pigments, that they're all things that would be... Their names. Two of them, luteolin and fisetin actually come from their yellow color, one from German, one from Latin. And so, they tend to have some unique aspects, some overlap. I mentioned fisetin as an example, more globally active in tissues, sometimes the quercetin is at play out of host tissue as an example.

I think that Neurohacker Collective, we love the idea of redundancy, that the science team... Complex systems, they'll often use the word degeneracy, but think of degeneracy as meaning biological redundant. So we... I remember early on when Daniel Schmachtenberger first hired me, he said, "Greg, I love when we put a stack of things together, that having one ingredient that can multiple things, and having multiple ingredients that do the same thing. I love redundancy." So, that's why.

We could have just said, "Oh, we'll just give fisetin, because there's certainly biohackers that just take that." We think as a science team at Neurohacker Collective that when things like SCAP networks, and networks the term, that's part of complexity science. When things are using networks to survive, you need almost a network of things to go in and overcome that. So we love the redundancy, and that's why to me, that combination of the three yellow pigments, that redundancy of fisetin, quercetin, and luteolin, each with some overlap, each doing some unique things, is very distinctive in Neurohacker Collective and Qualia Senolytic.

Lauren Alexander: Great. Well, we have on our blog an entire writeup of every ingredient in Qualia Senolytic, and it's called The Formulator's View of Qualia Senolytic. It's written by Dr. Greg. I invite everyone who's listened this far to read it because you will really cement your understanding of cellular senescence, as well as get really educated on these natural compounds that are quite novel.

Before we wrap, of course, I'm head of marketing, so I put together a special offer for everyone that's listening. If you go to neurohacker.com/podcastoffer, you're going to get the best price available for Qualia Senolytic. It is special just for the listeners. So please, check it out. Know that we have a hundred-day money-back guarantee. Really just give it a try, and see for yourself what you can do with adding a senolytic practice to your health program. Again, that's neurohacker.com/podcast. Well, thank you so much, Greg and Nick. This has been super fun. I want to give you both the last word if you have anything to say. So go ahead.

Dr. Greg Kelly: No, I'm just really excited that we're able to share this product with our community. I was excited to finally have it available for myself, for my friends, for my family. I invite all of you listening to enjoy it. It's a great product.

Dr. Nick Bitz: I second that. I love creating products that I want to take, and this certainly has been one of them. I've taken several rounds. I've enjoyed the experience thus far. I love that this is actually getting at the root cause. I think we talk about that a lot, both the healthcare industry, the dietary supplement industry, biohackers. But are we always doing it? I'm going to say, "No." I like that this is really undercutting the root cause of aging, and it's really getting in there and doing some good work. I'm proud of this product. I hope that more people can continue to take it. It's been a lot of fun for me to dive into the science. I can't wait to keep learning more in this area.

Dr. Greg Kelly: One other thing I just want to mention too, and again, I think goes to our dosing. It's really... I mean, I know some people are overwhelmed with the number of pills they maybe take daily. This for me is super easy. I just one week in a month take this, and don't take anything else. That's it. I don't have to worry about it until the next month. I just love that dosing approach where we're getting basically days, days and days, if not longer, of benefits for just a simple two-day a month approach.

Lauren Alexander: Yeah. Can you make all our supplements like this? This is so nice. Only two days a month.

Dr. Greg Kelly: I wish.

Lauren Alexander: Please. Well, awesome. Thanks again. Community of Collective Insights. Thank you from the bottom of my heart. It is an honor to serve you guys. Have a great one.