Senescent Cells, Senolytics & Healthy Aging: What Do We Know?

In this episode

In this episode, we’ll talk about a major hallmark of aging and one of the most exciting and cutting-edge areas in today’s longevity and anti-aging science called cellular senescence. Senescent cells are damaged aging cells that stop multiplying but don’t die when they should.

Almost like zombies, they stick around, causing a lot of trouble to nearby healthy cells and accumulate in aging tissues all over the body. Removing senescent cells has been shown to be a promising and powerful anti-aging strategy that can help with many age-related issues.

But do we know enough yet to benefit from these exciting discoveries? Is there something that we can do today to help our body get rid of senescent cells? And if so, what is the best way? Are there any risks?

Our guest today is Dr. Anil Bajnath, MD, an anti-aging precision medicine physician and an expert in cellular senescence and senescent cells. We’ll dive into the science of senescent cells and how they affect the aging process. We’ll then look into practical things we can all do to help our body naturally reduce senescent cells with supplements and lifestyle tips.

Also in this episode:

• Dr. Patti Shelton, MD, LongevIQ medical communications officer
• Amir Ginsberg, LongevIQ founder.

Related articles by Dr. Bajnath & links

• Dr. Bajnath website
• The Longevity Blueprint: a Personalized Anti-aging Approach
• Berberine vs Metformin: Which is Better for Anti-aging & Longevity?

Episode summary

Main topics

• (0:00:00) Podcast and episode intro, medical disclaimer
• (0:02:07) What are senescent cells?
• (0:03:26) What causes cellular senescence?
• (0:04:54) How the body removes damaged cells
• (0:08:19) The nine hallmarks of aging and cellular senescence
• (0:09:35) Where in the body do senescent cells accumulate?
• (0:10:37) Testing and markers of cellular senescence
• (0:13:24) At which age should we consider taking senolytics?
• (0:14:30) How to remove senescent cells
• (0:16:34) Do fasting and autophagy remove senescent cells?
• (0:18:12) Main senolytics in research: dasatinib and quercetin
• (0:19:15) Main senolytics in research: fisetin
• (0:20:30) Senomorphics: rapamycin
• (0:22:48) Are senolytic foods effective?
• (0:24:10) Senolytics side effects, risks & cautions
• (0:26:27) The importance of cleaning the terrain before starting senolytic protocols
• (0:28:52) Senolytic protocols: continuous use vs. intermittent (hit and run)
• (0:30:58) Combining senolytics, senomorphics and other agents
• (0:35:50) Can senolytics also affect healthy tissues?
• (0:36:28) Is combining senolytics necessary?
• (0:40:39) How do you feel while taking senolytics?
• (0:41:37) Natural senolytic supplements dosing
• (0:42:51) Test- don’t guess.

Transcript

This podcast episode was edited to improve readability.

Podcast and episode intro, medical disclaimer

[00:00:00] Dr. Patti: This is Dr. Patti Shelton, and you are listening to the LongevIQ Podcast. We discuss anti-aging and longevity science and how to benefit from it so we can all live long, healthy, happy lives.

Just before we get started, a quick medical disclaimer. This podcast is for informational purposes only. It is not intended to diagnose, treat, cure, or prevent any disease or to provide or replace medical advice.
Please use this information to educate yourself as much as possible and share this information with a qualified health practitioner that you trust.

In this episode, we’ll talk about a major hallmark of aging and one of the most exciting and cutting-edge areas in today’s longevity and anti-aging science called cellular senescence. Senescent cells are damaged aging cells that stop multiplying but don’t die when they should.

Almost like zombies, they stick around, causing a lot of trouble to nearby healthy cells and accumulate in aging tissues all over the body. Removing senescent cells has been shown to be a promising and powerful anti-aging strategy that can help with many age-related issues.

But do we know enough yet to benefit from these exciting discoveries? Is there something that we can do today to help our body get rid of senescent cells? And if so, what is the best way? Are there any risks?

Our guest today is Dr. Anil Bajnath, MD, an anti-aging precision medicine physician and an expert in cellular senescence and senescent cells. We’ll dive into the science of senescent cells and how they affect the aging process.

We’ll then look into practical things we can all do to help our body naturally reduce senescent cells with supplements and lifestyle tips.

Also joining us today, as always, is Amir Ginsberg, the founder of LongevIQ. Welcome, Dr. Bajnath. Thank you so much for being here with us today.

[00:01:56] Dr. Bajnath: Thank you so much for having me. It’s a true pleasure. Thank you.

What are senescent cells?

[00:02:00] Dr. Patti: We know you are a true anti-aging expert. You live and breathe this topic every day. So we would love to talk to you a little bit about senolytics, and maybe you could start with just for anyone who isn’t really aware of what senescent cells are, what senolytics are, just a very kind of high-level overview of what we’re talking about.

[00:02:20] Dr. Bajnath: Oh, perfect. Yeah. I think cellular senescence is a really fun topic when it comes down to aging health and disease formation. It’s really interesting because the conversation kind of stems and originates back in, I think, 1961 in Dr. Hayflick’s lab. Where he was studying fibroblast cells in culture and had identified these fibroblast cells reaching their end mitotic potential, meaning each cell had its ability to undergo X amount of cellular divisions before it reached its endpoint of its ability to divide.

That later became known as the Hayflick Limit. And what also was discovered around that time is that these cells that reach the Hayflick Limit don’t necessarily die or removed from circulation.
And they’re not necessarily alive either. And it’s interesting how these cells reach this phase of cellular senescence, or also known in the literature as zombie cells.

What causes cellular senescence?

[00:03:26] Dr. Bajnath: There are multiple different mechanisms that contribute to the development of cellular senescence, and a lot of that could be due to injury. So various mechanisms of cellular injury.

We also know that there are several different forms of genotoxicity and cellular toxicity, cytotoxicity that could potentially occur due to different environmental signals and inputs leading to a whole host of accumulation of damage within a single cell. That damage could be on a membrane level and it could be associated with membrane lipid peroxidation due to trans fatty acids and different fried foods and things of that nature that could literally release smoke into the cell membrane and lead to the cell membrane damage, which ultimately can lead to a loss of cellular regulation and a loss of integrity of its internal compositional structure.

Additional damage could lead to protein misfolding and DNA damage and different forms of reactive oxygen species could actually be toxic to your DNA. This is known as genotoxicity.

And then there’s also mitochondrial damage with uncoupling, which could lead to a loss of regulation and increased permeability that can mediate a whole host of different dysfunctional processes downstream. Now it’s this accumulated damage that could lead to the potential of the development of cellular senescence.

How the body removes damaged cells

[00:04:54] Dr. Bajnath: When these cells reach this kind of burden, so to speak, where a cell loses its ability to autoregulate and repair, it has the potential of transitioning into this unique state. Now before it gets there. Typically some cells have a few different mechanisms to correct that damage and remove themselves from circulation to prevent their persistence in existence, so to speak. And those mechanisms that are built in inherently include what’s known as programmed cell death, also known as apoptosis.

So apoptosis is one of these inherent programming features. If a cell reaches a point where it needs to be disassembled, there’s an auto-destroy button that allows a controlled removal from affecting any other cells. Apoptosis is one of those mechanisms where cells are removed from circulation.

Another very important mechanism for which cells are removed from circulation is autophagy.
Autophagy, as you may know, is the body’s internal process of cellular recycling and self-eating. And this is usually triggered by various mechanisms, including intermittent fasting and different factors such as AMP kinase signaling and mTOR inhibition.

And then another main mechanism for which these zombie cells are removed from circulation is through cellular necrosis. Now, it’s important to differentiate between apoptosis and necrosis because both are very important features. However, necrosis actually kind of elicits this highly uncontrolled inflammatory response. So that’s something that should be taken into consideration.

But what happens if a cell cannot be removed from circulation? It ends up getting locked into the state of cellular senescence, where it’s no longer actively dividing, all right? And it’s not necessarily destroyed, either. And it’s important to differentiate that because there are different cells that get locked into cellular arrest, okay?

And cellular arrest could occur in different phases of the cell cycle. There’s, you know, this G1 phase (* cell growth), S phase (* DNA synthesis), G2 phase (* cell growth), and M phase (* nuclear and cell division) of normal cell cycle regulation.

What differentiates senescent cells from quiescent cells, for example, is that they’re arrested in what’s known as a G1 phase or Interphase, for which cells are still actively undergoing internal synthesis, which is considered metabolically active.

Again, there, there are other forms of these cells, like I said, the quiescent cells versus senescent cells, which is very important to take into consideration. Ultimately, when these cells are arrested in this development, they have the ability to continue to spew out these really noxious substances known as Proteins or senescence-associated secretory phenotype (* SASP), these different proteins that influence and poison the well around them.

It’s been said that just one senescent cell out of 7,000 to 15,000 or so could initiate the entire degenerative process. We know that there’re multiple different factors that contribute to its development. And it is actually very intricately related to the hallmarks of aging.

And it’s been said that just one senescent cell out of 7,000 to 15,000 or so could initiate the entire degenerative process. We know that there’re multiple different factors that contribute to its development. And it is actually very intricately related to the hallmarks of aging.

The nine hallmarks of aging and cellular senescence

[00:08:19] Dr. Bajnath: Cellular senescence is actually one of the nine hallmarks of aging. I think we’ve discussed this before, but just for your audience, if they’re not familiar with the hallmarks of aging, this is a paper that was published back in Cell Biology in 2013 with Dr. Lopez and his group that have characterized the main fundamental hallmarks that influence and mediate the biological aging process.

It starts with your primary hallmarks of aging, which include genomic instability, telomere attrition, epigenetic alteration, and loss of proteostasis.

It then moves into what are known as antagonistic hallmarks, which are further characterized by deregulated nutrient signaling, mitochondrial dysfunction, and ultimately cellular senescence and cell dysfunction.

Now, cellular senescence is the seventh hallmark of nine. The last two terminal hallmarks are also known as integrative hallmarks that are responsible for this inflammaging pathophenotype, which includes stem cell exhaustion and altered intercellular communication.

So cellular senescence is downstream, but still just a little upstream regarding the whole dynamics of the hallmarks of aging.

Where in the body do senescent cells accumulate?

[00:09:35] Dr. Patti: And is this something that’s happening in all tissues throughout the body more or less equally?

[00:09:40] Dr. Bajnath: That’s a great question. So, some tissues are considered post-mitotic, right? Like neurons and certain Leydig cells in the testicles and things of that nature are considered kind of post-mitotic tissues for which they’re not actively undergoing replication.

So they have a different mechanism or similar, but a different mechanism of their ability to develop senescent cells or zombie cells. So, the potential for this accumulation of damage could be anywhere. Actually, these senescent cells have been shown to accumulate systemically in the bone. Cellular senescence has been associated with osteopenia and osteoporosis. In the lungs, clinical studies suggest it influences idiopathic pulmonary fibrosis in the kidney. It’s been shown to also affect fibrosis as well as heart failure. It’s been implicated in various different neurodegenerative diseases. There are a couple of clinical trials going on with that as well.

Testing and markers of cellular senescence

[00:10:37] Dr. Patti: How would somebody know if they have a high burden of senescent cells? Is there a way to test? Do we just go by symptoms or their age? How would somebody know?

[00:10:48] Dr. Bajnath: That’s a great question. Right now, I don’t think there is a set consensus that this is the magic biomarker that determines our body’s potential senescent cells’ burden, unfortunately.

I think the closest thing that we have to that right now is measuring SA beta-galactosidase. SA stands for senescent associated beta-galactosidase. A couple of other clinical markers are emerging. The Buck Institute out in California has done the greatest amount of research regarding characterizing and developing what’s called a SASP Atlas. But the thing is, not all senescent cells are the same.

There’s a life cycle to this cell as well. There’s something called early senescence and late senescence, and it’s characterized by different phenotypic characteristics that deal with its ability to express various SASP proteins. These SASP proteins are involved with everything from the cell’s ability to evade apoptosis, modulate inflammation, to alter cellular signaling and nutrient signaling. These SASP proteins vary amongst every single senescent cell. So, I think the consensus right now is that there are a couple of surrogate markers that could be potentially obtained. And I think SA beta-galactosidase is seemingly one of the more promising surrogate markers. And then also p21 and p16, which are different molecules that are unique to senescent cells.

Sometimes, there’s an upregulation of senescent cells, like in wound healing. So, not all senescence is necessarily bad, right? We need a balance of senescent cells in our system to a certain extent to help with natural cell turnover and things of that nature.

However, sometimes, there’s an upregulation of senescent cells, like in wound healing. So, not all senescence is necessarily bad, right? We need a balance of senescent cells in our system to a certain extent to help with natural cell turnover and things of that nature.

And we do see this transient elevation in certain, like p21 for example, when there’s some sort of wound healing taking place. Another biomarker on the horizon is oxylipin, but that has not been validated in humans as yet.

And then there are about two papers that I’ve seen on Ferritin, which is also known as an acute phase reactant during an inflammatory process, being associated with a senescent cell burden. I’ve seen this a lot of times with individuals that just have this burden of chronic inflammation, and their Ferritin levels are high. Some papers associate that as being a good surrogate marker for cellular senescence.

At which age should we consider taking senolytics?

[00:13:24] Dr. Patti: Around what age do senescent cells begin accumulating and show up in tissues? Is that highly variable between humans?

[00:13:33] Dr. Bajnath: Actually, we have senescent cells in utero. Senescent cells are really important for embryogenesis and embryonic development, involved with childbirth. As we grow, these senescent cells play a very important role in development and regeneration.

When senescence cell accumulation outpaces the immunological system’s ability to remove it from circulation – that’s when it hits the tipping point and accelerates the aging process.

I don’t think there is a set number per se because it’s so dynamic, but from an aging standpoint, it is argued that individuals in their mid-twenties potentially begin the process of accumulation of these senescent cells, leading to its burden. And it’s argued that some of these senolytics protocols out there could actually begin in the age of thirties or so. You know, to be taking this into consideration for like a graceful aging kind of program.

How to remove senescent cells

[00:14:30] Dr. Patti: It’s a perfect transition into how do we help the body remove senescent cells, and maybe we can talk a little bit about lifestyle types of things, and then we can get into the supplements, the senolytics, senomorphics, or whatever type of chemicals we might be using to do that?

[00:14:46] Dr. Bajnath: Well, that’s a great question, and I think it’s always going to be important to stay kind of lifestyle-heavy first. Because these are within our locus of control of trying our best to implement and execute different lifestyle and dietary factors, that ultimately will have an enhanced impact on our epigenetic expression, which is another hallmark of aging.

I really think that’s our greatest opportunity for outcomes, you know, where we make conscious dietary and lifestyle changes to enhance favorable gene expression. And we have that with the ability to be cognizant of the foods we’re eating, right? Minimizing glyphosate and GMOs and all those other things that lead to upstream damage, right? And the genotoxicity (* DNA damage) and everything else.

There’s this theory called the unitary theory of aging, which deals with if you target potentially one hallmark of aging, it’ll have effects on other hallmarks upstream and potentially downstream. But this is where I kind of argue that sometimes, going in just to remove the cellular senescence doesn’t mean you’re gonna have the regenerative potential. And I think that’s where some of these human studies failed.

There was a recent study by the organization Unity. Very specific proprietary formula, looking at intraarticular injections and osteoarthritic knees. And the study did not do well – just because you remove senescent cells doesn’t mean you’re going to have the regenerative potential afterward to help with just the regeneration of that degenerated articular hyaline cartilage.

Do fasting and autophagy remove senescent cells?

[00:16:29] Dr. Bajnath: I think targeting senescent cells needs to have a very specific strategy. One of the more evidence-based strategies for removing senescent cells outside of these protocols per se is just looking at intermittent fasting and modulating autophagy.

New England Journal of Medicine has published a wonderful publication looking at upregulating autophagy through intermittent fasting. Intermittent fasting has been shown to really help with all sorts of longevity-promoting mechanisms and cancer prevention.

Those are strong words from the New England Journal of Medicine. Okay? So I think that’s important to look at. So we know that whenever we’re doing this intermittent fasting time-restricted feeding, we have the ability to upregulate some of those recycling mechanisms through autophagy, which helps with decreasing that burden, that senescent cell burden.

So that’s one thing to look at, but again, going back to that unitary theory of aging, (* I think there is a big opportunity) if we work upstream with our dietary and lifestyle factors, organic eating, movement, and activity. I like to explore the different biohacks. I have a hyperbaric oxygen chamber in my practice that I like to use that has been shown to help with telomere attrition.

But to answer your question, I think what you’re asking and what your audience would probably want to hear about is, what are the different senotherapeutics options that are available commercially, right? Where’s the research going and everything else.

Main senolytics in research

[00:17:53] Dr. Bajnath: There are two different main ways to address this issue (* of senescent cells). It’s either through senolytic agents, which are basically agents that create senolysis, which lyses the cell, breaks it down, and removes it, so it’s going to destroy it.
And then there’re senomorphics, which work on modulating some of these SASP proteins that we had discussed.

Main senolytics in research: dasatinib and quercetin

[00:18:12] Dr. Bajnath: Regarding some of the senolytic therapies, the one that has so far, the leading amount of evidence in human studies is the dasatinib and quercetin. So far, three published studies; one is coming from Wake Forest, and another is coming from Mayo Clinic. It has been shown that dasatinib, quercetin, or DQ, in short, as we discussed, is a viable and safe option for removing some of these senescent cells from circulation.

And there are actually so many different clinical studies that are active and underway right now in phase two trials that are assessing the role of DQ and so many different types of outcomes from hematopoietic stem cell transplant patients, Alzheimer’s disease, COVID patients, cardiovascular disease. And so the list is growing, right? So the dasatinib and quercetin trials are growing right now, and that’s one of the more promising interventions as a senolytic therapy.

Main senolytics in research: fisetin

[00:19:15] Dr. Bajnath: Another really exciting kind of intervention is something called fisetin. Fisetin is a flavonoid derived from strawberries, and it actually outperformed nine other different flavonoid compounds.

There’s this one study, and it’s a mouse study, where they compared 10 different flavonoids, and fisetin outperformed everyone. It was demonstrated to be associated with an increase in lifespan in these mice. And fisetin, again, is found in various forms of citrus, fruits, strawberries, and things of that nature. I don’t even think there’s an LD50 (* Median lethal dose), meaning they have not found a lethal dose of this molecule as yet.
It’s really exciting. There are a bunch of human clinical trials that are coming downstream with this. And it’s something to look out for to be used and incorporated in a senolytic program and protocol. Again, this is still the Wild Wild West. Research is growing and emerging. I’m confident that in the next, I want to say, 6-18 months, we’re going to have a better understanding as some of these clinical trials are wrapped up on how we could start leveraging these powerful reagents to remove senescent cells from our system and tissue. That’s as far as the senolytic trials.

Senomorphics: rapamycin

[00:20:30] Dr. Bajnath: Then we have these Senomorphic agents, and this is kind of where it’s like, all right, how do we modulate autophagy? Right? And this could get into the whole rapamycin and sirolimus kind of research.

Rapamycin is an immunosuppressive drug that’s used in transplant medicine. It was originally discovered in the soil of the Easter Island. It was originally adapted for and was going to be used as an antibiotic until it was found to have really powerful immunosuppressive effects to prevent host vs. graft rejection. It’s used regularly in medicine to prevent that process from taking place. But what is now being used for its ability to induce autophagy through its inhibition of mTOR. And as you may know, mTOR is the mammalian target of rapamycin, or the mechanistic target of rapamycin, and mTOR is like that master regulatory switch, so to speak.
And when that switch is turned off, our body’s ability to turn on the conservative mechanisms for self-preservation, where it starts breaking down all the kinds of worn-out tissues and junkie cells, so to speak, through the process of autophagy so that our body could go in there and recycle things.

So rapamycin is being used now in similar effects to like a senolytic protocol to just go in there and turn on that cellular housekeeping, so to speak.

Rapamycin is a really interesting molecule. Again, some of the studies needed for this purpose, intention, and outcome are still lacking. However, there is a clinical study undergoing right now. It’s phase two and should be finished within 12 months, called the PEARL Trial. This will assess the safety and efficacy of rapamycin in aging. That’s going to be really exciting because that could be something we could potentially start infusing. And again, in a strategy towards graceful aging.

And then, we’ve had conversations before about all sorts of different agents that have been shown to also work a little similarly but differently with an ability to inhibit mTOR. There are various different supplements and agents out there. So, the list goes on.

Are senolytic foods effective?

[00:22:48] Dr. Patti: You mentioned the fisetin in food, and so that kind of leads to the question, can people get enough of these things through their diet to have a clinically significant impact, or do we need doses that are just much higher, than we could ever eat the strawberries to acquire?

[00:23:03] Dr. Bajnath: I really think we are going to need it in supplement form, unfortunately, because you would have to eat pounds and pounds of fruit, you’ll probably, you know, have diarrhea first before you can consume and tolerate all those foods, you know, to get the appropriate amount of fisetin from the diet.

But it’s not to say don’t eat those foods, by all means. Again, eat a colorful rainbow diet. Try to get those different polyphenols and flavonoids in there.

Food is not just medicine but also information communicating with our DNA, influencing our gene expression, turning up and down that volume switch, and epigenetic expression. And we need to make sure that we’re feeding our DNA the appropriate information.

In the class that I teach at the university, I’m a professor at George Washington University and the course director for two classes. The first class is Omics of Medicine, where I teach other docs that are in the fellowship in integrative medicine how to connect these molecular dots, so to speak, from genome to pathophenome.

One of our greatest opportunities from a Nutrigenomic perspective is harnessing these different foods and flavonoids because we know that food is not just medicine, but food is information communicating with our DNA, influencing our gene expression, turning up and down that volume switch and epigenetic expression. And we need to make sure that we’re feeding our DNA the appropriate information.

Senolytics side effects, risks & cautions

[00:24:10] Dr. Patti: You’re mentioning several prescription drugs, dasatinib, and things like this. Are these things currently available to people for anti-aging purposes or not yet? And are there any cautions you would urge as we think about using these for that purpose?

[00:24:26] Dr. Bajnath: In my practice, it’s something that I do offer to patients on a very case-by-case basis. It’s not something we just jump right into. It should be used as a part of this kind of longitudinal age management program. And before you jump into anything of this nature, You should definitely be cleaning out the terrain.

And when I say the terrain or the milieu, it’s just making sure that the environment is ready to receive that message. It should be done with grace and caution because it’s not easy to do. There are side effects. You need to be monitoring things. There are different expert opinions on what to look out for in this process. Now, regarding dasatinib, this one’s a little bit trickier to prescribe because it is a chemotherapeutic agent used for leukemia. It’s a tyrosine kinase inhibitor.

It’s very expensive. I have sourced it for my patients and made it available through compounding. But that’s a different discussion. Essentially, even on GoodRx and some of these discounted resources, it’s about $15,000 a month for dasatinib on average. Now it’s definitely not that way on a compounded level, and you’re not using those higher doses that cancer patients need.

But that is something that is out there. There’s only a handful of docs in the country that I think are really exploring these interventions. I had the privilege to spend time and speak to a lot of these docs with my involvement with the American academy for anti-aging medicine.
So definitely at the forefront of exploring these strategies and these different interventions for anti-aging. So that’s dasatinib.

Now the sirolimus is a little bit more commercially available, and there are different strategies around that, so that’s very easy to come across. The cost per consumer is a little bit lower. But again, you need to make sure you’re working with a skilled provider that knows how to appropriately dose titrate this medication (* adjust the dose for maximum benefit without adverse effects) because common side effects besides aphthous ulcers (* canker sore) include the risk for potential secondary infections from immunosuppression.

The importance of cleaning the terrain before starting senolytic protocols

[00:26:27] Dr. Bajnath: This goes back to the terrain theory, that the terrain needs to be clear first and foremost because when it comes down to these secondary infections, you could really disrupt the balance with immunosuppression and allow for opportunistic growth of dysbiotic microorganisms in the gut, the urogenital system, and all throughout, even believe it or not, in the vasculature.

We have biofilms all throughout our body, right? Starting with our mouth and the plaque in our mouth. There are these biofilms in the vasculature.

For your audience that may not know what that is, biofilms are essentially these little colonies. I call ’em like these, like mega-resorts for microbial colonization within the body. We have it in our lungs, digestive tract, and urogenital system; we have these biofilms everywhere.

And biofilm basically houses these different microorganisms. They get together, and they share a drink. Usually, what you’re drinking, they have a meal. Usually, what you’re eating. And they protect themselves from the immune system. The immune system does not have the ability to go in and attack them.

Let’s say we’re cleaning the terrain for some reason like we identified infectious issues, dysbiosis, or whatever. Making sure you’re disrupting and breaking down those biofilms and dealing with these opportunistic potentials and secondary infections are gonna be very important before entering in a, I think, a senolytic protocol.

So again, immunosuppression and secondary infections are big potential side effects for this, and even for those that think otherwise, the healthy with no major issues, just make sure and probe that a little bit further. Do your due diligence because these secondary infections are real potential.

And then, not to mention again, it has the potential for blunting some of these meds. Being chemotherapeutic, immunosuppressive agents blunting the potential for hematopoiesis which is basically your body’s bone marrow’s response to producing red cells, white cells, and platelets into circulation. So monitoring platelet levels in activity, your red blood cell count, your H&H (* determines the ratio of red blood cells to total blood), and your white blood cell count is important.

Now, some docs will make the argument that when you actually start seeing that little dip, this is when you know that you’re targeting and ramping up, so to speak. So some docs embrace that dip, but you just have to be careful with that and monitor it through routine blood work.

Senolytic protocols: continuous use vs. intermittent (hit and run)

[00:28:52] Dr. Patti: As far as continuous use versus intermittent or the hit-and-run approach, how do you go about using these agents?

Dr. Bajnath: All the literature has been looking at it from a hit-and-run kind of hypothesis. And again, that just means short durations on and then taking some time off to recoup and clear the medicine outta your system. That gives your body some time to regenerate from that kind of insult because it is an insult. You know, you’re taking a chemotherapeutic immunosuppressive drug.

Right now, the hit-and-run has the most amount of research to demonstrate its efficacy. And most of the clinical trials are three days on, four days off, and anywhere from one to three weeks so far. But there are a few different clinical studies undergoing right now that have a little bit longer duration and a lower dose. Again, the next 6- 18 months are going to be really exciting as these studies begin to be published.

So, hit and run is the way that I would recommend it. Some people recommend the sirolimus kind of weekly dosing, but I have mixed opinions about that.

[00:29:59] Dr. Bajnath: Also, I think it should be used in the context of the individual. Everything is N of 1, and N of 1 means essentially that you are at the center of your own clinical trial.

And this, you know, kind of resonates with the biohackers and longevity enthusiasts because we know that what’s good for me is not maybe the best option here for you. So I think we need to take into account all those unique variables that influence healthy expression in determining the best course of everything, and there are so many different factors to take into consideration when dealing with this.

In my practice, I like to connect those molecular dots, so to speak, from genome to pathophenome. Then at a certain point, once we get into the age management side of things, we need to prepare the terrain through intermittent fasting. Maybe a fasting-mimicking diet and so forth to lead up to receiving the message of these different medications.

Combining senolytics, senomorphics and other agents

[00:30:58] Dr. Patti: There’re so many different senolytics and senomorphics. Do you normally recommend people just take one or two? Would they maybe want to take all of them to target different pathways within the cells? How would we go about choosing how to do that?

[00:31:12] Dr. Bajnath: I actually have different protocols here for different conditions. So I have a protocol for osteoporosis for neurodegeneration, Alzheimer’s, and cardiovascular issues. So there are different kinds of strategies, and it’s not just doing just a senolytic and then done, but it’s how to identify during this time period, one to three months, what are the additional supplements and other targets that we need to work on as well. So with these protocols, I use different supportive agents as well. It just depends.

But there is a therapeutic order. And again, one of the things that we did not touch on was the association with NAD, for example, and the development of these different senescent cells and circulation. So where does NAD come into play with all this, and when do we start repleting NAD, before or after? All these little things should be looked at first before executing this kind of program.

[00:32:09] Dr. Patti: You mentioned that we need to consider the potential to regenerate tissues as well as removing these senescent cells. So maybe talk a little bit about strategies people might use for that regeneration. Combining senolytics with stem cells or things like this.

Dr. Bajnath: That’s a great question because as we get older and we start accumulating all this damage, the wear and tear of life, of love and lost, everything that leads to who we are, you know, and where we’re at, Geez, there are so many different factors. They’re different arguments in this space as well that, you know, maintaining a certain level of senescent cells is important for preventing cancer.

That’s also out there in the literature. I don’t wanna sit here and say, Oh, you need to remove all these cells. Sometimes we take things, explore, and go too far, and the next thing you know, we’re doing harm. So the goal is not to do harm with this but to try to leverage this to help improve our aging process. So again, I want to make it clear that this is still the wild, wild west. There are no set regimens or anything else. It’s an emerging field of science and aging medicine.

You need to be prepared. If you’re gonna be removing these agents from circulation, remember how I said that it could have the potential of immunosuppression and then suppress your hematopoiesis, your body’s ability to synthesize these cells.

I believe every 10 seconds approximately, we’re putting out one million white blood cells, 30 million red blood cells, and about 50 million platelets into circulation, right? So that’s taking place every 10 seconds. We’re just spewing out those cells. So we need to make sure we have the appropriate regenerative potential after we remove senescent cells.
And I think that comes with nutritional status, right? And having the co-factors needed to undergo the appropriate cell signaling for regeneration and collagen synthesis for tissue repair.

I also think that one of the big factors here deals with the Yamanaka factors. And I don’t know if you’ve heard of this, but one of the Nobel Prizes in the early two thousand was given to a Japanese researcher that demonstrated the ability to regenerate stem cells with very specific targeted factors. And this later became known as the Yamanaka factors for its ability to regenerate stem cell integrity and cause cells to revert back to its kind of natural primordial programming, so to speak.

Essentially, there are a lot of things to take into consideration.
You know, we have these CHIP cells as well. (Clonal hematopoietic cells of indeterminate potential). So CHIP cells are a part of it. Yamanaka factors are a part of it. And knowing how to go in there. But to answer your question, yes, if we’re dealing with, you know, somebody with really bad ALS. Right? And we’re gonna explore a senolytic kind of protocol here, per se. It’s gonna be important to have something on the back end to help with the potential for regeneration. Myelin sheath formation, nerve regeneration, and so forth. So I think stem cells, exosomes, and peptides are all exciting different interventions on the horizon that have some therapeutic potential.

And, you know, we have these institutions. The University of Florida has a regenerative medicine institute that’s booming right now and exploring a lot of this and several other universities around the country. We’re starting to see these regenerative medicine research institutions.
That’s huge, with the academics. So I think it’s a very exciting time in medicine that we are exploring these different resources for trying to combat the aging process here.

Dr. Patti: Amir, do you have any questions you’d like to add?

Can senolytics also affect healthy tissues?

[00:35:50] Amir: Can senolytics also affect healthy tissues?

Dr. Bajnath: It depends on the senolytic. But yes, absolutely. I definitely think these drugs; one of the biggest arguments about chemotherapeutic agents is that they sometimes have non-discretion. It’s gonna go in there, especially with dasatinib; it’s a tyrosine kinase inhibitor. So, all these cells are expressing tyrosine kinase, right? So it’s gonna shut down this process within healthy tissues as well. And we could have the innocent bystander effect with that. And this is why these agents need to be managed and monitored very closely in these kinds of protocols.

Is combining senolytics necessary?

[00:36:28] Amir: It actually leads to the next question. There’s a common best practice of combining different senolytics. Is this because each one of them targets different types of senescent cells or different areas in the body where they accumulate, or do they work in synergy. What is the reason behind it?

[00:36:45] Dr. Bajnath: That’s a great question, and that boils down to, I think, the mechanism of action of these senolytics. So it’s important to keep in mind that a lot of these senolytics have been discovered through a library outta Mayo Clinic. Dr. Kirkland’s lab out of Mayo Clinic is leading the way in this research. What he’s found through this library of different agents, he’s pulled out some of these top agents. Dasatinib and quercetin just seem to be the ones that have the most efficacy, but they’re targeting different molecular pathways and endpoints.

This would be better graphically represented, but with the senolytics more specifically, it has the ability to affect on a nuclear level with P53 and MDM2 pathways. It could also affect PPAR alpha pathways, Bcl2 pathways, and the PI3K pathways. So, it depends on the agent you’re targeting and the main mechanism because there are four main ways to remove senescent cells from circulation.

One is through inducing apoptosis (* programmed cell death), right? So those are basically going to be targeting pathways more specifically that inhibit the pro-survival pathways, right? And when you map out the different pathways that influence pro-survival, there are FOXO4, P53, HDAC, ATMs, caspases, Bcl2, PI3CK, and PI3K.

All of those things are involved with the cell’s ability to evade apoptosis. So senolytics that target apoptosis are very unique. Again, fisetin, the dasatinib and quercetin. And there are multiple other agents, including statin drugs which are now being considered
to have some senomorphic potential. Cardiac glycosides like digoxin are considered senolytic because they inhibit sodium ATPase enzyme activity in a cell.

So, it really just depends, and I do agree that targeting different mechanisms will be beneficial. However, again, it’s still wild, wild west. I don’t want to be overly aggressive.

I do believe that there is a healthy balance of senescent cells that are needed to have a benefit. There are some arguments again that going in there and removing those senescent cells and trying to modulate the SASP is your body’s defense mechanism against developing cancer. So that is something that I just really want to caution the audience and everybody that let’s not get too excited yet; that this might be the next major intervention. It should be used with responsibility.

But I mentioned there are four different ways. We spoke about the apoptotic way of removing these cells. There’s another way; the SENS Institute in California, for example, these researchers use natural killer cells called CAR-NK cells to target specific proteins to remove senescent cells from circulation. This is adapted from the CAR-T model for cancer therapy, which is chimeric antigen receptor cells. And they’re using the NK vs. T cells to help remove these cells from circulation through an immune-mediated mechanism.

Another less favorable way is going through and actually genetically manipulating senescent cells. That’s actually less studied and less favorable because of the cancer risk.

And then the fourth way of removing these senescent cells is a modulation of SASP. This is where we get into mTOR, MAP kinases, JACK-STAT pathways, Nuclear factor kappa, beta, and so forth. So again, they’re different molecular targets for different things depending on the situation.
And I think it’s important to look at the big picture of what’s going on first before jumping into an aggressive protocol.

[00:40:38] Dr. Patti: Fantastic message.

How do you feel while taking senolytics?

[00:40:39] Dr. Patti: While people are on their hit-and-run, do they normally feel better during it? Do they often feel terrible during it and better after? What would people expect?

[00:40:47] Dr. Bajnath: Fatigue is oftentimes a very common side effect. Decreased exercise tolerance and endurance are some of the symptoms that I’ve seen. In most cases, those are some of the biggest kind of noticeable side effects of it.

It’s not a pleasant process of going in there and taking a chemotherapeutic agent. But what’s exciting is, you know, it’s the fisetin. I am really hopeful that the fisetin trials in humans shine through here because I personally would rather use natural agents versus these aggressive drugs and chemotherapeutic immunosuppressive agents.
Fisetin being an alkaloid derived from a natural source. Again, not everything derived from a natural source is always safe, but I would feel more comfortable with something of that nature. I usually stack fisetin with some of the senolytic protocols I have here.

Natural senolytic supplements dosing

[00:41:37] Amir: We hear from a lot of people that use natural supplements like fisetin and quercetin because they also have other benefits. I’m not sure if the dosage is similar to the dosage of hit-and-run senolytic protocols, but is this something that people should be concerned about? Do you feel natural options are usually safer compared to drugs like dasatinib?

Dr. Bajnath: Yeah. You know, right now, I think the bulk of the studies that are being done on fisetin is looking at 20 mg per kg in body weight for dosing. And then some of the other more commercial protocols are around 1200 to 1500 milligrams of fisetin, generally speaking, for dosing. Versus taking quercetin for covid prophylaxis due to its zinc ionophore benefit and activity of around 500 milligrams. Whereas some of the upper dosings of quercetin were anywhere from a thousand and above.

A lot of these flavonoids have multiple different targets and benefits clinically. Like I just mentioned with quercetin being a zinc ionophore, it is also something that’s very important in mast cell stabilization and preventing this kind of dysregulated histamine response in some individuals.

So there are a lot of different pleiotropic benefits and activities from these different alkaloids that are from these natural sources.

Final thoughts – Test – don’t guess

[00:42:51] Dr. Patti: As we’re wrapping up here, what would be your general advice for somebody concerned about senescent cells? Your top tips for how to optimize the lifestyle and how to think about what to do.

Dr. Bajnath: Test- don’t guess. Make sure that there is something on board. If you’re looking to get a snapshot of where you’re at with some of this, I really like dr. She with Jinfiniti labs outta the University of Georgia. He’s received so much NIH funding for his research in senescent cells and cervical cancer. His lab is really, really well-defined. There are mixed opinions on some of those forms of testing and everything else, but right now, in regards to commercial facing testing, I think Jinfiniti labs is maybe worth looking into to kind of get a better understanding and a baseline of like intracellular and NAD concentrations and SASP proteins on top of. I don’t know of another place where you can measure SA beta-galactosidase, right?

And then again, the P16 and P21. Still not there. Get a ferritin level. See, you know where you’re at. Test – don’t guess. Make sure that you’re doing this under the supervision of somebody that knows what they’re doing because there’s a lot of potential harm that could come from this, you know, and it’s still the wild, wild west.

And I love biohacking. Just make sure you know what you’re doing and not pretend you know what you’re doing. Consult with somebody that knows what they’re doing, right?

Dr. Patti: Seeking that expert advice.

Dr. Bajnath: Yeah.

Dr. Patti: Thank you so much for being here and sharing all of this. Lots to think about for a lot of people. Whether they were aware of senolytics before or not. Lots and lots of new information to think about. So thank you so much for sharing all of this amazing wisdom.

Dr. Bajnath: Oh yeah, absolutely. Thank you.