Episode 11: Senolytics - A Cellular Look at Aging

Welcome to Inside the Cure with Dr. Charles Moak from Allure Medical. Learn what it takes to cure diseases, not just manage their symptoms. Healthcare isn't going to save itself, so let's jump right in.

This is Dr. Charles Moak and I want to talk about some of the research that is happening in the anti aging or expanding health span. So space what's already been studied, what's been studied in animals and in humans and where we're going and just going to break it down in a few pieces today we're going to talk about senescence, which is a hallmark of aging. So senescence refers to cells that are no longer doing their job of dividing and dying, but they actually stop dividing and replace themselves. And they are resistant to cell death, which is a problem because our cells over time age and they have DNA damage when they replicate. And they're supposed to be cleared up through a process called autophagy. But some cells become senescent where they're damaged and they actually morph into fatter cells that have what's called vacuoles in them, basically a damaged cell. They don't die, but then they don't replace themselves with healthy cells. And this is a hallmark of aging which could lead to things like, you know, heart failure or joint disease, osteoporosis, kidney disease, brain disease, neurocognitive decline. All the things we think about of deterioration appears related to senescent cells or what some people call zombie cells. They're not functioning properly. They, they won't reproduce and they just won't die. And there's two pathways that seem to be controlling this senescent cell damage to our body. And the drugs are designed to interrupt those pathways. So one of the pathways is called the SASP or senescence associated secretory phenotype. And this pathway is where these senescent cells or these zombie cells are giving off signals, it's called cytokines and other little juices to other cells in the area to become damaged and senolytic, I'm sorry, become damaged and senescent as well. So these senescent cells, again, zombie cells or non functioning cells that won't reproduce and won't die, start signaling other cells to join the club. And this would lead to breakdown of tissues and the hallmarks of aging. The other component is what's called the SCAP pathway. And this is the senescent cell anti apoptotic pathway. So there's something called apoptosis, which is the death of cells. So this is something that's supposed to happen, our cells should die. We used to think, you know, decades ago that we were born certain number cells and we died with a certain number of cells and they just sort of age and our telomeres shortened. But what we know now is cells are constantly turning over and replacing themselves. And when DNA, your body has a process called autophagy that clears it up, eats those dead cells, that way the new healthy ones can live unobstructed. But senescence breaks that pathway. And we don't exactly know why it occurs. There's certainly some research suggestion, suggestion, explanations, we're not quite there yet. But these senescent cells are dangerous to our health span. So it decreases the amount of health that we have and it does lead to frailty, does lead to aging. So we have the SASP pathway, which is a senescent associated secretory phenotype that stimulates other cells to join the club and become aged as well. And scaps, which is senescent cell anti apoptosis pathway. And this is something that blocks senescent cells from dying in the first place. And through a drug discovery process, researchers have come up with some drugs that can be repurposed to either stop the cells from excreting these secret secretory phenotypes, or to interfere with the scaps, which is the senescent cell anti apoptotic pathway. So if we can block one of those pathways, then the senescent cell should go ahead and die. In our body's autophagy, which is our body's ability to clean up itself, will enact and other healthy cells will reproduce themselves and make healthy tissue. This has already been studied in animals. We actually can reverse age in animals, particularly mice. It hasn't been done on large scale on other larger mammals than mice, but it's certainly been done on mice. There's been some studies on dogs and other primates, but the first studies on humans have been done. They've been already published, but not actually proving that they can make somebody healthier, but what's called pilot studies to see if people who have significant frailty can have markers of improvement after taking drugs that are what we call senolytics or destruction of senescent cells. To the ones being hotly studied right now, they might not ultimately be the ones that make it to market. And again, I'm not giving health care advice, I'm just telling you about the research that's going on. But two drugs that are being tested pretty aggressively right now are called dasatinib, which is a tyrosine kinase inhibitor, which is used for treating leukemia. So it's a drug for leukemia. I think it's been around about 20 years. And Quercetin, which is a flavonoid that seems to directly inhibit this pathway that regulates cell death. So dasatinib and quercetin have been used in combination in animal studies to remove senescent cells and make the organism healthier and actually reverse aging. Aging has been reversed. We might not know what the definition of aging is specifically, but we know it's related to having frailty and things degrading and breaking down and eventually death. So the first question is, can we improve somebody's health span? Potentially? That's the period of time where they're feeling pretty good. And then the second question is, can you extend the. The period at which you're alive? We would not want to extend the lifespan without extending health span first. So most of the research is going on trying to extend healthspan. So there's a condition called idiopathic pulmonary fibrosis. And this is a condition of the lungs. Idiopathic means we don't know the cause, pulmonary lungs, fibrosis or breakdown. And idiopathic pulmonary fibrosis is fatal with a pretty rapidly fatal when somebody gets it. And we see that their lungs have a lot of senescent cells. The alveoli are senescent, they're not reproducing and they won't die and are not functioning well. So they're basically geriatric lung cells. And then they break down, the patient can no longer breathe, and then they die. So this would obviously be a good place to look for something that reverses senescence with a senolytic drug. So they had 14 patients that were in their about 70s on average, and they were pretty sick. And they put them on 100 milligrams of Dasatinib and 1,200 milligrams of Quercetin daily for three days. And they did it every week for three weeks. They had a total of nine doses. And they checked things such as how far they could walk in six minutes, their pulmonary function tests, their clinical lab frailty tests, and things such as quality of life and fatigue. And this is a study published in the United States in 2019. The results, they found that their sixth, and this is only after nine tablets or nine treatment days and over less than a month. And they tested them about a week after, and they found their 6 minute walking distance improved by about 21 meters or 60ft. So they were able to walk 60ft further they were able to walk faster in their 4 minute gait speed test, and they were able to get in and out of a chair faster. So these were all improvements in their functionality. They did not see improvements of their quality of life or grip strength or actual change in their pulmonary function, but they did get a little bit better. So that's pretty promising. Again, the first trial in humans published in the United States of dasatinib and quercetin, which are studied a lot in laboratory animals. Another study done in 2019 as well, from Mayo Clinic, they looked at diabetic kidney disease. Now, diabetic kidney disease is a big problem that when people have diabetes that they damages their kidneys over time. And this is the most common cause for somebody having kidney failure requiring dialysis. So this is obviously a big problem. And we look at their kidneys and biopsies. The cells are senescent, they're not functioning properly, therefore they have kidney disease. They're not dying, and they're no longer reproducing and making healthy cells. So they're giving off signals to kill off other cells. So it's a bad chain. And in their study, they picked the same drugs, dasatinib and quercetin. They use about the same dose of 100 milligrams of dasatinib and 1,000 milligrams of quercetin. And they did it in a little bit different fashion. So they gave it to them for three days total, and then they checked senescence cells about a week later. So in this case, what they did is they decided to not test whether or not their kidneys got better because it would probably take several rounds of the drug and maybe several years. They just want to see, can we use some method to see if these patients that would potentially benefit from a senolytic drug? Lytic means, you know, just damaging, so something would damage or kill senescent cells. So they did biopsies of the patient's fat and skin right around their navel. So they took biopsies or tissue samples from their skin around their belly button. And they wanted to see were there less senescent cells after treatment than before. So they took a biopsy before the three day intervention and then about two weeks after the three day intervention. And they used the rat model or mouse model as a example. And they knew that if you reduce the senescent cell burden by 30%, so 30% less senescent cells. It was a clinical, meaning it was clinically meaningful improvement. What they found was that there was a decrease in markers of senescence by between 17 and 62%. Now, there's a big range because they're using different lenses to look through to see what changes occur. These chemical markers, again, this is a relatively new science, so there's not clarity on what's the best way to measure senescence. We use these chemical markers of senescence. But they did see a decrease in this combination therapy of dasatinib and quercetin for three days. Again, this is people with kidney failure that will die from kidney failure or they'll be on dialysis and die from something else. And they saw a reduction in senescent markers by 17 to 62%. Again, we only need a 30% reduction to see a clinically meaningful improvement. This is just a three day study. They did three days and then they checked them two weeks later. So that's pretty promising. Now, these studies, what they do, when they're doing clinical studies, they do pilot studies where they just do a little test and obviously they want to make sure it's safe and they want to see if there was some evidence did something clinically meaningful occur. And it did. So then stage two would be follow them further and longer with more cycles to figure out how to how often should we do this? If it's going to work, do you need to do it more than three days at a time or less? The idea behind doing it three days at a time was that there's evidence in animals that you can do this pulsatile approach to using these drugs. Again, the dasatinib is a chemotherapy agent. We know chemotherapy agents have effects on other cells. And they found that just intermittently treating animals with senolytic drugs over time improve the animal's health span. Okay, so this is why they did this. The one short burst in the diabetes kidney disease study, and they did three cycles in the pulmonary fibrosis, which is actually a more severe disease. Another study in the Republic of Georgia, these are a little harder to read because they don't follow the same format we use in American studies. So they know what to make of this. But they did a little different study where they took healthy people that were about 50 years old on average, and they gave him a combination of 50 milligrams of dasatinib and 500 milligrams of quercetin with or without placebo. So they had one group that had the dasatinib plus quercetin, one had dasatinib plus placebo, one had quercetin plus placebo, and the only had placebo and placebo. And they checked their response to exercise. So they gave them this intervention for three days and two weeks later, they checked their ability to do the stairs again. So they had the patients go up eight flights of stairs. It was four stories. And they measured their response to the exercise. So they measured their blood pressure, diastolic and systolic blood pressure immediately after the stair climbing, right before and immediately after, and see how they responded before and after the interventions. And what they found was that in the dasatinib and quercetin group, they, they were more fit. Two weeks after they took this three days of drug, they actually had a lower increase in their systolic and diastolic blood pressure after running up four flights of stairs than either the placebo group or the dysatinib with plus placebo or the quercetin plus placebo. And they also reported that the subject's joints felt lighter. I don't know what that meant. They didn't really go and describe it. And they said the next time they would probably do some joint studies, but they were just testing whether or not unhealthy subjects would. They get more fit. And the idea would be if you did, if you removed a certain percentage, say 30% of senescent cells on a periodic basis, the organism could become more fit. And this is again extrapolated from animal studies. We know animals become more fit when we use senolytics. There's another process called Gerald conversion I'm not going to talk about in this podcast, but gero conversion is, is blocking that pathway into senescence in the first place. So those are the two. These are the two things we're looking at in terms of expanding health span and then potentially expanding lifespan would be to get rid of cells that are senescent, that are zombie cells that aren't functioning, that are abnormal, that won't reproduce and won't die. To eliminate those would be step one and step two. We would be to block senescence in the first place. And there's drugs being tested for that. Additionally, I talked about dasatinib and quercetin, but there appears to be other flavonoids that are probably more potent than quercetin that we'll talk about some other time. And they've. Since we kind of, they broke through this. Most researchers already use this D Q dasatin plus quercetin because it's been proven in animals and it's been studied in humans. And that keeps. That's relevant to use the same thing. But there may be even easier drugs or supplements available that could potentially accomplish the same. Thing, there's been a lot of interest in things like metformin, rapamycin. I'm not gonna talk about those right now. But there's a lot of drugs that are used for different conditions that may be repurposed in the certain combinations and certain frequencies to expand healthspan. Again, we don't really know yet. Just the original studies are going on. But I think it's really important to understand that this is coming in our lifetime if we don't screw it up and die prematurely. So previously, I talked about the importance of staying healthy and avoiding cardiovascular disease, which is a leading cause of mortality, neurocognitive decline, dementia, Alzheimer's and cancer. And we talked about how we can reduce our chance of dying from those things by early detection and intervention. And then I think step two would be how do we then reverse some damage that's already occurred on a cellular level. We know that fasting certainly does cause senescence, but that's not practical for a lot of people. It's very hard for people to fast. And these drugs are called fasting mimetics, these senolytic drugs that eliminate senescent cells. So we will probably see therapies emerge in the future. And the early stages will be testing it on animals, which has been done and that's ongoing, then testing it on humans, and then even finding other novel drugs, which is being researched right now into seniledixers. That there are companies that have substantial investments, that are startup firms looking for new drugs that could be patented and FDA approved for reversal of disease and potentially extending our health span. And this is coming. So I think we. We have to realize that frailty is not necessarily a sure thing at a certain age, something that might be put off longer and longer. Healthspan as we know it now would be. We live to a certain amount of time, and then we succumb from something such as heart disease or cancer or stroke or dementia, and then we die shortly thereafter. Once the big things occur, your mortality goes up. What can we do to extend that period before it happens and then keep ourselves in reasonably good shape where we have interactions with other people and we have our health. My coach, Dan Sullivan, does this verbal exercise called a lifetime extender. And he says, okay, so imagine the age at which you die, and you pick an age. Let's say it's 95. And he says, what were things like, you know, six months before that in your mind, were you healthy? And you think to yourself, yeah, I was pretty healthy before I. Before I died. Did you have friends. Did you have relationships? And you say, yeah, yeah, I had, you know, grandkids and great, caring kids and friends and young and old friends. And then did you. How was your financial situation? And it's like, well, you know, because I was that age, I was able to invest and accumulate some property, so everything was pretty good. Well, then Dan says, then why do you want to die six months later if you're healthy and you have friendships and you have financial security? And it's a good thing for us to think about is that we don't have to accept. We. Well, we do have to accept now, but we don't necessarily have to accept the history that our parents and grandparents went through of getting frail and then dying. Can we extend our lifespan or health span and is probably coming. I'm a firm believer that this is on its way. It's not here yet. I've been personally experimenting with different things to see if I could reverse some markers of aging. And it has been working. And then eventually we'll see drug therapies available to allow us to reverse some damage that's already occurred, prevent future damage from coming on, and then making our DNA a little bit younger than it is the day you first test it. So thank you very much.

Thanks for listening to Inside the Cure with Dr. Charles Mok. See you next time.