Reducing Aging and Increasing Quality of Life with Senolytics - Dr. Michael Ruscio, DNM, DC

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Reducing Aging and Increasing Quality of Life with Senolytics

Healthy dietary, supplemental, and lifestyle interventions for longevity with Dr. Greg Kelly

There are many research-backed ways to increase quality of life and slow or prevent age-related diseases. In this episode, Dr. Greg Kelly–naturopathic physician and author of Shape Shift–expands on senolytics, a class of drugs that show positive effects on aging, brain and skin health, and anabolic resistance. Hear how senolytics, along with strength and resistance training, walking, perfecting your circadian rhythm, and consuming protein, can help you age and feel well.

In This Episode

Intro…00:08
Theories of Aging…04:10
Caveats of Calorie Restriction…09:53
Why Timing is Important…17:07
Undereating Can Be Problematic…20:05
Strength, Muscle Mass, and Mobility…25:32
Health Markers for Anti-Aging…33:53
Senolytics: Types, Dosing, and More…41:56
Outro…01:00:36

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Intro:

Welcome to Dr. Ruscio radio, providing practical and science-based solutions to feeling your best. To stay up to date on the latest topics, as well as all of our prior episodes, make sure to subscribe in your podcast player. For weekly updates, visit DrRuscio.com. That’s DRRUSCIO.com. The following discussion is for educational purposes only and is not intended to diagnose or treat any disease. Please do not apply any of this information without first speaking with your doctor. Now let’s head to the show.

Dr Ruscio:

Hey everyone. Today I spoke with Dr. Greg Kelly on Theories of Aging and also cellular senescence. We discuss some of the hallmarks of aging models: stem cell exhaustion, telomeres, mitochondrial damage, senescent cell accumulation, autophagy. We discuss this really important concept as it pertains to aging, which is life span versus life quality, [and] some fundamentals of assessing how you are aging. We also outline the connection between immunity and aging, and some exciting research initially stemming from Scripps and Mayo on senolytics. These are compounds that can help to prune dead or dying cells from your body. And these are mainly various polyphenols. And there’s a quite interesting dosing protocol for some of these senolytic supplements, which is essentially two days per month. So what I find appealing about this, if nothing else, is it’s a minimal amount of pills to pop and obviously would be fairly inexpensive since you would only take this herbal senolytic cocktail on two days out of the entire month.

Dr Ruscio:

And he gives some specific formula and dosing recommendations. Now, Dr. Greg Kelly is a naturopathic physician. He is currently the director of product development at Neurohacker Collective and has authored the book “Shape Shift”. Formerly, he was the editor of the Journal of Alternative Medicine Review and has been an instructor at the University of Bridgeport in their College of Naturopathic Medicine, where he taught classes in advanced clinical nutrition [and] counseling skills in doctor patient relationships. Dr. Kelly has published numerous articles on various aspects of natural medicine and nutrition, and has also contributed to the “Textbook of Natural Medicine. And, in aggregation, has more than 30 journal articles indexed in PubMed. His areas of interest are neurotrophics, -aging, regenerative medicine, weight management, and chronobiology of human performance and health. [This was] a great conversation on aging and I hope you will enjoy it as much as I did. And with that, we will go to the show. Hey everyone, welcome back to Dr. Ruscio Radio. This is Dr. Michael Ruscio, joined today by Dr. Greg Kelly and we will be unpacking some insights on the topic of aging. Hey Greg, welcome to the show.

Dr Greg Kelly:

Thanks for having me today. I’m thrilled to talk with you and your audience, Michael.

Dr Ruscio:

Yeah, same here. And, of course, to talk you need to have a healthy brain and healthy aging. And I know brain health and aging are two things that you’re pretty well steeped in. So where do you want to start? Because obviously aging is a multi-dimensional topic. How do you think about aging, and where do you start with this area of health?

Theories of Aging

Dr Greg Kelly:

So I would usually start with the two camps when it comes to the main reasons we age. And so you have camp one — it’s usually thought of as damage accumulation — but that we age because damage progressively accumulates in ourselves, which makes all kinds of other things go wrong. The other camp would be programmed aging, is the way it’s described, but think of it as if our cells have this software program that they’re executing that is causing us to experience aging. And then things like, failing to repair [and] damage accumulation are secondary to that. So both would agree that damage accumulation is a big part. They would just differ on which is the first thing and then the after effect. But I think, fundamentally, when it comes to aging at this point in terms of our knowledge about what can be done about it, for sure, we would want to do things to prevent damage and (to the extent possible) remove any damage that we can. So I think when the audience thinks of aging and actionable things we can do with aging, that’s the way I would tend to emphasize it. What things (lifestyle, diet, etc.) we can do that would slow aging or slow the likelihood that things will damage and then accumulate over time.

Dr Ruscio:

Now with this damage accumulation, is this mitochondrial damage? Is it DNA damage? Is it a combination of the two? Are there other factors, if we’re going to the ground floor of where the damage is occurring, that you frame these through?

Dr Greg Kelly:

Yeah, and it’s not my framing, but there’s a model that was proposed in 2014 called the “Hallmarks of Aging”. So what they did, is they looked at different model organisms. So everything from us, all the way down the food chain to mice, rats, and then even model organisms like flies and worms. And what they essentially said is there’s these characteristics that aging has in common, no matter what the organism is. And they identified nine of these characteristics as the hallmarks of aging. So some of these are stem cell exhaustion, so that would almost be more in the programmed aging category, I would say. Another would be the attrition of telomeres. So our telomeres — the tips of DNA on our cells — those slowly get worn away as cells reproduce. A third would be mitochondrial dysfunction (so clearly that’s one of them).

Dr Greg Kelly:

A fourth, and one we’ll talk a lot more about today, is the accumulation of senescent cells. So for each of these characteristics, there’s certain underlying physiology, but there it’s all interrelated. So stem cells can become exhausted dealing with senescent cells, and telomere attrition causes cells to become senescent. So I think, for sure, science is still sorting out almost like that “chicken-and-the-egg” question — what’s coming first. But I would say that, of those characteristics, the key thing from the damage accumulation would be this accumulation of senescent cells. I’m sure your audience would’ve heard of the term autophagy, but in the “Hallmarks of Aging”, that’s called proteostasis. So basically, a lot of the inner organelles of our cells are made up of proteins and the mitochondria, as an example, [in] mitochondria, there’s not much DNA. So mitochondria don’t make much of their own machinery.

Dr Greg Kelly:

They actually take machinery from the cell and incorporate it in. But to do that and move it through the membrane, they’re essentially folding. And then once the proteins are inside the mitochondria, unfolding them. So that’s protein quality control or proteostasis. And where autophagy would come in is that autophagy is what we do as a maintenance and repair program to repair misfolded proteins and damaged organelles inside, whether it’s the mitochondria (then that’s mitophagy) or inside the cell (autophagy). So I personally think of all of these things as interrelated. And if we were to take a cell and it’s being stressed by something, let’s just say something even good, like maybe too much exercise, the first thing it’s going to do is try to adapt to that. So maybe it adapts by making more mitochondria in that cell, creating a fitter network so it can make more energy.

Dr Greg Kelly:

And then too much exercise is going to be oxidative stress. So it’s going to upregulate antioxidant defenses. And if some of the proteins inside the mitochondria and cell become misfolded, then autophagy will come in as a repair process. And if the cell eventually is so stressed that none of those things are good enough, then that’s where you would have senescence creep in. And so these things are all interrelated, but a senescent cell is to the point, and the analogy I tend to use when speaking about it is, visualize a plant. Most leaves are vibrant green [and] super healthy, but now you have a couple yellow leaves. So the senescent cells in our tissues are akin to those yellowing leaves on the plant. They’re cells that, now they’re damaged, they’re stressed, [and] they’re sucking up resources. And if we don’t do a good job pruning them away, they’ll eventually cause the rest of the plant to underperform.

Caveats of Calorie Restriction

Dr Ruscio:

Sure. And this is where I think things like fasting come in and certain herbs that are antioxidant or anti-inflammatory. But something I’ve been thinking about ever since our conversation with Dr. Gabrielle Lyon and her many theories on the importance of protein optimization for muscle mass and muscle strength is this concept I’ll loosely term “lifespan versus life quality”. And it’s not to say that those are inversely related, but there does seem to be — and I’d love to hear if you agree with this, disagree with this, or agree with some and not with other points — but there does seem to be some antagonism for, if you’re optimizing for life quality, (let’s say you want to optimize your muscle mass, optimize your muscle strength) you’ll be undergoing things that are somewhat inflammatory like exercise. And that might be kind of a “Goldilocks” where too much may accelerate aging and not enough may also accelerate aging.

Dr Ruscio:

One could argue that consuming a chronic, low-calorie diet may prolong lifespan but may not necessarily improve life function or quality of life. There’s a balance, right? If we go to the extremes, we can make it look bad fairly easily. But I guess the thing I’ve been wondering, and curious how you think about this, is how do we find that balance point? Do we gain five years at the end of our life, but we’re somewhat frail and underfed? And so the 90 years before that final five were not as high of quality as they could have been. What do you make of that?

Dr Greg Kelly:

So for me it’s about the quality every day. So I would trade less time at the end for better quality most of the way there, personally. And I think, so one of the hallmarks of aging is cellular nutrient signaling. So that’s where it gets you into the growth hormone IGF-1 pathway, mTOR — I’m sure some of those things would’ve been heard by different members of your audience. But the idea is that if those growth-promoting things in some model organisms are slowed or inhibited, then that extends longevity. But the downside of that would be potentially (like you mentioned) frailty, loss of muscle tissue, etc. And I remember going back, so calorie restriction is by far probably the most studied intervention for aging in model organisms. And one of the ones that goes back the furthest, and I remember (and this probably goes back 20 years) reading some of this research and thinking, well I wonder if anyone’s actually noticing how lethargic these semi-starved animals are?

Dr Greg Kelly:

And so, like with primates, that was one of the things — these don’t appear to be particularly happy primates that are put on calorie-restriction diets. And I tend to use real world examples. So I was a huge fan of the TV show “Survivor” for years. I think I probably saw almost every episode of the first, I don’t know, 10-20 seasons. And I was particularly interested because I wrote a book on shape at one point. And you the emphasis of the book was that we have this…so I would take height and weight as the example. I was always one of the shorter people in my friend group, all of my friends were football players and basketball players. And I was one of the skinnier [people], I was like the long distance runner kind of build in high school and college. And while I was dissatisfied with my lean mass and my strength (and that seemed actionable), I was [also] not happy with my height. But I’ve never spent a day worrying about trying to do something to get taller.

Dr Greg Kelly:

So to the extent we think something is changeable is really the extent it makes sense to invest things into that. And where I’m going with this had to do with that idea of calorie restriction. Part of the reason that, from a weight loss perspective, calorie restriction seems to make sense is that energy balance equation. And if it was that easy, then that would be great. But what you would see in Survivor, is they’re calorie-restricted almost from day one (I don’t know the current seasons, but the ones I’ve watched). And so what invariably happens is they think more and more about food, they’re hungry all the time, [and] they get irritated easily —I mean, there’s no secret why the reward challenges are all food. So in any of the long-term underfeeding studies, and one of the better ones was what happened in Biosphere 2 — the dome built out in the desert near Tucson, Arizona in the early nineties. These, I want to say it was eight or nine scientists, lived there for two years.

Dr. Greg Kelly:

[They] thought they’d be able to grow enough food to essentially keep the energy balance equation even. They couldn’t, they could only grow enough to eat about 1800 calories a day. And so they all lost weight for about six months. It was a great study, because the head person, their MD on staff, is the most famous proponent of calorie restriction in longevity. I think it was Dr. — It was something like Waldorf, but don’t quote me.

Dr Ruscio:

It sounds familiar, yeah.

Dr Greg Kelly:

So anyways, as soon as they got out, they regained all of that lost weight really quickly. But a hundred percent of the weight they lost, that was regained, was regained as body fat. So, they became more frail. Scientists would call that dieting-induced adiposity or body fat overshoot. That’s the result of going that route. And I think it’s because this is a really intelligent system that we are walking around with every day — that’s smart, adapts, and it learns. And my story is, well what did it learn from not getting enough food in two years in the desert? It’s next time I’ll be more prepared, and more prepared is having more body fat

Dr Ruscio:

And this harkens to some of what we discussed with our friends over at Mind Pump and Sal DiStefano. Which is a lot of what you hear from, I don’t want to say body building per se, but those who are in the health and fitness camp will say, “eat more to improve your body composition.” And I do think there’s something to be said for that, and it sounds like this is mapping onto the Biosphere experiment. And I also believe that, and maybe it was a different Biosphere, but weren’t some of them caught sneaking food? Like they broke the perimeter they were caught sneaking food into the supposedly sealed biosphere?

Dr Greg Kelly:

I wouldn’t be surprised at all, but I’ve never heard that. But I do know for the Minnesota semi-starvation study in World War II, that definitely happened.

Dr Ruscio:

So presumably they weren’t feeling great if they were going to those lengths.

Why Timing is Important

Dr Greg Kelly:

Yeah, and then getting back, I think things like mTOR to me, I think are somewhat understood. So I’m big into timing of things — circadian rhythms, chronobiology —and believe that most things that are important, it matters doing it, but it also can make a difference when you do it. And the same with measuring things. And one of the [studies] — I’ve only ever seen one study on it — but they did calorie restriction (I want to say it was mice), but it was an animal model. But then they measured mTOR in the blood at different points over 24 hours. And really what calorie restriction did is shift the timing. But it did that, mTOR like many things has a physiological rhythm. So depending on when they measured it in that experiment, it could look lower, the same, or higher. Because fundamentally all it did was shift the rhythm a bit later, because mTOR is initiated when we have protein.

Dr Ruscio:

So it made it look like the fasting intervention was beneficial, but if you broadened out the sampling window over a 24-hour period, that potential benefit was attenuated?

Dr Greg Kelly:

Yes, and so I think there’s probably nuances like that, that are just being missed. So at this point, I think it’s much better to go into old age with better and more quality muscle tissue than doing things that would impact our ability to create and maintain it.

Dr Ruscio:

Right, and this is why it’s so important to look at outcome measures. And we’ve really harped on this on the podcast, but while mechanism and biomarker are interesting, they should be always cross-referenced, again, against outcome measures. Because like you’re saying — and what a beautiful example — during a certain time point in the intervention, mTOR looks good, but it actually didn’t have any long-term difference. And, therefore, you could have done a bunch of, I’m assuming it was mainly (like you were saying) protein restriction, but it didn’t really have a favorable net outcome. Am I correct there, in how I’m encapsulating that?

Dr Greg Kelly:

Yeah, I think this was more of an acute study, so they didn’t do anything long term. I just thought it was interesting, where there’s this idea that gets lost — that timing matters. And my guess is that — there’s mTOR 1, mTOR 2 — there’s a lot of things that the smart people on mTOR focus about. But when you talk about outcome measures, the things we know that really track with healthy aging are like grip strength. Better grip strength is good. More muscle mass tends to be better, all else being equal. So these would be, again, animal studies. So it’s hard to necessarily extrapolate. But periodic methionine restriction also induces longevity. So in these studies, often what they’ll do is they’ll have say a mouse eat a regular diet for a couple weeks and then put them for a week on a methionine-restricted diet and just cycle.

Undereating Can Be Problematic

Dr Greg Kelly:

So I’m just prone to believe that cycling things on and off is probably, ultimately, going to turn out to be a much wiser strategy than thinking, “oh, I can live the rest of my life calorie restricting, and being a bit hungry is not going be hard to do.” I don’t think that’s likely to pan out for most people. In the same sense that most people on “Survivor,” [where] the very last episode usually shows the few people that are still on the island, and then it jumps forward in time and shows everyone back in the studio audience. And you can see their faces look like they’ve ballooned in comparison. Because they, like the Minnesota experiment or the Biosphere people, rapidly regain that lost weight, but usually a poor quality of weight.

Dr Ruscio:

Yes, this makes complete sense. And it also makes sense that some of these interventions they need to have a correct timing and rhythm and intensity and duration like fasting. I found personally that if I do one meal per day, one day per week (Sundays I typically just have one meal) that’s enough for me. It helps to keep my hunger level where it seems to be balanced, where I don’t tend to drift into this progressive overeating. It’s not so intense that my sleep gets really derailed or I notice, otherwise, signs of fatigue (or what have you). And I do wonder how prevalent of an issue undereating can be with some people. And I would assume this audience would be the group most at risk for that, because they know so much about food. They know a lot of the bad things about food, and that can be enough to make one avoid half a dozen foods, plus also intermittent fast. And then, before you know it, you’ve been chronically undereating for a few years.

Dr Greg Kelly:

Yeah. So again, one of my favorite studies (I think it goes back to the early nineties) we definitely wouldn’t be able to — not we, but scientists — wouldn’t be able to do this. But they had known that calorie restriction, or I’m sorry, sleep deprivation in mice eventually leads to wasting and premature death. And so what they did, (and I might mess this up because it’s been a while since I read the study) but there was a couple different groups of mice in the experiment. And they decide, we’ll put this one group on a normal amount of calories, but higher protein to be more anabolic. And we’ll put this other group, as a comparison, just on a standard rat chow diet that’s not focused on being higher in protein. And then we have this third group, we’ll let them do whatever they want. We’ll just put this really high-fat food out and they can go to town.

Dr Greg Kelly:

And the intuition of the researchers was that the best result would’ve happened for the normal amount of calories, but higher protein. But what they found was that the mice allowed to eat whatever they want, gravitated to the high fat chow, ate about two-and-a-half times more, and outlived these other mice. So I think of that as the multiple stress problem. In an unstressed life, calorie restriction may be great. But when you start to lump in other stressors, like in this case sleep deprivation, then they didn’t need even the regular amount, they needed more. And there’s a huge amount of research now on sleep deprivation and what it does to appetite.

Dr Ruscio:

Sure, I think that that’s right on. And yeah, I mean something even I myself have been trying to be a little bit better about finding [is] that balance point of eating enough. Because it’s easy for me (if I’m being honest) — especially after my morning routine of, I’ll do a minute (maybe two) in 34 to 36 degree water, have a quad espresso, and now I’m having two scoops of whey protein — and I can ride that buzz, so to speak, for hours without eating. And, I’ve tried to be a little bit more mindful of getting a bit more nutrition in. And what’s interesting there, and this is something that Mike Nelson — he may have borrowed this from Ben House, I’m not sure who coined this initially — but they call it “gain-taining”, meaning eating enough to maintain gains. It’s kind of a “meathead” term — like, “oh, you want gains, you want stronger muscles, better performance.”

Dr Ruscio:

So they call it “gain-taining”. You eat up until the point where you won’t gain weight. Or I could say it this way — you eat as much as you can so that you don’t gain weight, but just underneath that threshold. And that seems to be best for performance. And that’s the other side of this equation. And I think one that’s important to clarify. Which is, if you’re striking this minimal, minimal calorie balance, that tends to be a shorter road in terms of how long you can ride that experiment before you start to notice problems with sleep, skin, hair, performance, sexual function, what have you. So the other end of the spectrum is this “gain-taining” perspective — eat as much as you can without gaining weight, essentially. And of course, food quality there matters, but within a healthy diet paradigm.

Strength, Muscle Mass, and Mobility

Dr Greg Kelly:

Agree a hundred percent. And we’ve talked about muscle a few different times, and I know we started on aging and senescent cells. So I wanted to introduce this idea — so scientists call it anabolic resistance — but the key idea is, as we get older, the same things that would provide a really strong anabolic signal when we’re say 20, 25 produce a much more muted one as we get older and older. So that’s lifting weights, it’s higher protein. So the reason I’m bringing it up, is we started talking about senescent cells and how they accumulate with aging. And one of the studies that really grabbed my eye and I thought was super cool, frankly, was they had these young mice and these old mice. And [they] had them do the equivalent of an intense exercise session, and both of them produced senescent cells after that.

Dr Greg Kelly:

So that would be a common thing. So I guess one key point is that there’s transient senescent cells, and then there’s lingering ones. So no matter what our age, when we exercise intensely, we’re going to create some senescent cell. Completely healthy, right? That’s part of what allows us to repair and rejuvenate the tissue post-exercise. But if they linger, then that’s like the yellow leaves on the plant — so we want to get rid of those. But what happened in this study is, the senescent cells that accumulated had essentially caused this anabolic resistance in the old mice. And when they did something that was senolytic to remove them, it reversed that anabolic resistance. So when we get back to that original idea of [how] it cleaned up the damage and now their muscles were responding a lot more, like the muscles in these younger mice were.

Dr Ruscio:

And this is great, we discussed this with Dr. Gabrielle Lyon and a few years ago with Jeff Moss. And I think this lends even more credence to making sure you optimize protein intake and also muscle mass. But how do you optimize muscle mass? You say it, but how do you actually do it? So optimizing protein intake would be one. And then intense exercise, I would argue to some extent weight-bearing, although you could probably get around it with explosive work, plyometrics body weight. Sure, to some extent. But things that make you strong and fast, I guess would be one way of aiming for this. And I paint this picture because there does seem to be this kind of other culture that is plant-based, low-calorie. And I wouldn’t say, I don’t want to paint with too broad of a brush or make this seem like there’s a disparagement, but I’m just trying to paint a different camp of thought and some of the growing concern I have in that camp of thought.

Dr Ruscio:

There seems to be less of an emphasis on weight training, body composition, protein intake and muscle mass in that camp. Again, this is a broad brush, there’s definitely exceptions to this, no offense is intended. But the more that I’m learning about this, I’m realizing that certainly trying to optimize for muscle mass is a great end point for function. Can you move quickly? Can you run fast? Can you lift heavy stuff? If a lot of effort was put toward that end point, at least from some of the human outcome data that we have. And as you said a moment ago, grip strength is a great predictor. And there’s also some, I believe there are hip strength assessments that have a fairly high correlation with longevity. Have you seen any of these? I don’t know exactly how the assessment is done, but I have seen various hip strength assessments that, like grip strength, map on to longevity.

Dr. Greg Kelly:

I’m not familiar with those, but I know they’ll commonly do a five-minute walk task — so how briskly [they can walk].

Dr Ruscio:

Gait speed.

Dr Greg Kelly:

And basically the ability to sit up from different positions. So all of these have in common some degree of neuromuscular strength. So that nerve-muscle communication is crazy important as we age — proprioception, so like that balance. So what I invest in (and I’m 60 for our audiences perspective) I us Jaqiush’s X3 bar as my heavy lifting experiments — so heavy duty straps, basically. But I do that at least three times a week. I go for brisk walks most days, sometimes all clustered together, sometimes spread out five minutes every hour through the working day. And then I work on my balance. I live by the beach, so I try to walk on the ocean, walk on rocks, walk on grass. So that’s the proprioception. And I think that diversity, to me, makes sense. But if you said, “if you could only do one of them,” it would be something like resistance training, for sure.

Dr Ruscio:

Sure, sure.


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Dr Ruscio:

Are there any other, I guess this is the key question that we’re unpacking here, but any other fundamental assessments people should be thinking about? One would maybe be, do you notice it’s harder for you to walk quickly? And let me make one comment here, a side remark. I recently discovered that my hip mobility was not where it needed to be. My strength I think has been okay, but I’ve drifted away from this concept that Aaron Alexander and I discussed on the podcast now, maybe two years ago, of the floor culture or floor sitting. And I kind of gradually just said, “I don’t need that.” I’m doing all this other stuff — I have a sit-to-stand desk, I exercise regularly, but really that’s come back to bite me in the butt (or I guess in the hips). Because my hip mobility has waned, and I’ve noticed it’s been harder for me to go from the floor to standing up.

Dr Ruscio:

Or sometimes I would get up and there’d be some low back tightness. And I’m saying to myself, this is not good. I should have no problem going from seated to standing up. And there should definitely not be this feeling of tightness — it has to be stretched out before I can move. Eventually, I pieced together that, even though I was moving, I was sitting > I was standing > I was sitting > I was standing > I was squatting > I was benching > I was deadlifting. I was all in the same plane. And very rarely was I (as I’m doing now) folding my laundry from the floor. It hit me just the other day — I’m standing up in the same position, my laundry is on my bed, and I’m folding in a pile on my bed. And then moving to another section on my bed where I put the folded clothes. I took all this stuff, threw it on the floor, and I’d be either in a full squat or in a 90/90 sit stretch in one position [or] a 90/90 sit stretch in the other position. And these little things go a long way. So mobility definitely does matter. Not to discount mobility, but my tangent aside: grip strength, circadian rhythm, gate speed — what are some other kind of pillars that people should be thinking about?

Health Markers for Anti-Aging

Dr Greg Kelly:

Well, when I was seeing patients, which is actually quite a bit the rear-view mirror now, but I used to have all my patients use just a digital thermometer — put it as far back in their mouths [as they can] and do their temperature a few times a day. First thing in the morning, probably when they get home from work, early evening, and before bed. And that was what I used to do as a quick and dirty circadian rhythm test. And what I saw in my healthiest patients, [is] they would have the biggest swing from the morning low to, usually the high point of temperature is about 14 hours after we wake, and you should dip going to bed. So that was a simple thing I used to have my patients do to engage them.

Dr Greg Kelly:

I’m a big fan of heart rate variability. I think that’s a great technology to measure our resilience and how we’re doing. And then, other than that, I tend to think more [of] the feedback my body gives me. So almost like what you described, I’m not a person that innately is attached to what I think of more as the process. I’m attached to outcomes. So if my body’s not responding well, something I’m doing is probably not working. It’s on me to figure out what that is and change things. So even diet-wise, I’d be much more of an intuitive eater than a rule-based eater. Or if, for whatever reason, tomorrow I woke up and said, “body, what do you want?” And it said, “Starbucks ice cream,” — I’d go find Starbucks ice cream for it. Now, it doesn’t usually do that.

Dr Ruscio:

Important clarification, yeah.

Dr Greg Kelly:

And if I was doing that every day, then there’s something else. But fundamentally, I trust my body, and I try to stay very attuned to what it’s communicating to me and address it as early as I can.

Dr Ruscio:

And your comment on temperature just really sparked an insight for me. So, sadly, sometimes this is proclaimed to be a way to know if you’re hypothyroid. And I could not disagree with that more fervently. Now, perhaps, some people who are frankly hypothyroid and not on medication will have a low temperature. But thankfully, we have very simple lab testing that can tell you if you’re hypothyroid or not. What I would submit to people, and I have an extremely strong suspicion that there’s a cohort of people who aren’t feeling well, partially because they have food reactivity. So they’re avoiding foods, they may also not have a lot of energy (so they’re lower in activity), and they’re probably not getting in enough protein nor have enough muscle mass. And all these things, to a greater or lesser extent, drive body temperature.

Dr Ruscio:

One of the things that Dr. Lyon discussed in the podcast was the thermic effect of food, especially of protein. And how that will help you generate — as the traditional Chinese medicine cohorts or doctors call it — Qi. So this is something to think about. Are you eating enough calories? Are you eating enough protein? Are you eating enough muscle mass (or do you have enough muscle mass, sorry)? And all of this can map on a temperature. And that’s a really important measure to look at. Because I will say that when I’m fasting, especially if it’s prolonged, my body temp goes down. So it’s one way of seeing are you too low-calorie, are you too low-carb.

Dr Greg Kelly:

Exactly. So I’m not a fan of using first-morning body temperature for thyroid either. So when I was a naturopathic student — so this was somewhere probably [around] 1995 —I would bike to and from school every day. If you had asked me, I would’ve said (if not the healthiest person in my class), I was certainly among the [top] three to five that were really healthy. And we did that, a Barnes Thyroid Test. My morning temperature was 96.5 or something that was low enough [to where] the naturopathic doctor having us do that wanted to put me on Armour Thyroid. And I’m like, well that’s crazy talk. I don’t have any [symptoms], I don’t feel like I’m hypothyroid.

Dr Ruscio:

This is where it comes from guys. This is a good example of where, again, probably only done with the best intentions, but this needs to be revised. Definitely.

Dr Greg Kelly:

And that’s what got me into measuring circadian temperature. Because in some medical textbook I had, it showed a chart of cortisol rhythm, body temperature rhythm. And I’m [wondering] how come naturopaths doing this don’t realize body temperature has a circadian rhythm. And sure enough, I measured mine and it was 98.8, say 14 hours later. So I had a big swing, more than a two-degree swing. And what I saw when I had a lot of old students and patients measure theirs when I was in practice is that the healthiest people always would be diagnosed as hypothyroid from that. But they had that big amplitude swing. And what you see in really unhealthy people, [is] sometimes that amplitude is gone. So it’s low, but it’s low uniformly at all time points. So it’ll be 97.5, 97.5, 97.6, [it] doesn’t have that swing, that amplitude. And then occasionally, you’ll see it inversed. Where instead of being low in the morning and much higher 14 hours later, it’ll be flip-flopped. And that’s usually someone that has fairly disrupted rhythms.

Dr Ruscio:

Interesting. One of the things that probably maps onto this, to some extent, is the immune system. I remember this old — to bring old school naturopathy back into the picture again here — this old slide. I believe Bill Timmins had made it, the late Bill Timmins. And it was something like the macrophages trying to race against pathogens, and they lose speed as they age. It was kind of like this life cycle of the macrophage. And they get slower as you get older. So how does immune function and aging tie in to one another?

Dr Greg Kelly:

So that usually would be termed immunosenescence. And senescence just fundamentally means aging. So earlier we talked about senescent cells. So senescent cells are a very specific type, but immune cells, stem cells, any kind of cell in our body can become senescent. But what happens in immunosenescence, that immune aging is fundamentally…just think of the immune system as the equivalent of what you visibly see with people as they age. They are frailer, they’re slower, they’re less fit, they’re less competent in doing all their jobs. So going back to this idea of senescent cells (these yellowing leaves equivalents inside of our tissues). Fundamentally, the health of tissues is dependent on the health of the cells in those tissues. And often we’ll hear this idea that we turn over cells every seven years. Which on average is true, but it’s true and misleading.

Dr Greg Kelly:

So red blood cells are the majority of what turns over every day. They live about four months, but cells in our muscle tissue live about 15 years on average. Fat tissue is about eight years, liver is about three, heart (I think) is 40. The neurons in our brain literally live our entire life. So [for] different tissues, the rate of aging of cells and their turnover is vastly different. The immune system is on the quicker side, because it’s blood cells. So, we’re talking now probably more in the months, rather than years or decades. But part of the reason that the cells turnover is the rejuvenation piece. And one of the reasons that, at this point, I’m really interested in senescent cells, what role they play in damage accumulation, [and] how that impacts things like the anabolic resistance, our skin health, our brain aging — all these these things — is because, at least in the animal studies to date, removing those by itself acts to rejuvenate these tissues. Just essentially pruning away the equivalent of the yellow leaves.

Dr Ruscio:

Now there are certain compounds, and I believe you term these, senolytics, that can help with this reversal of the yellowing of the leaves.

Senolytics: Types, Dosing, and More

Dr Greg Kelly:

Yeah. So in 2015, Scripps Institute of Aging and Mayo Clinic coined the term senolytic. And the idea is these are things that preferentially target senescent cells to remove them. So I would just use the idea of pruning them away. And the first two they identified, one was quercetin (the dietary supplement found in things like onions). The other was an immunomodulator medication called dasatinib. And one of the things I thought that was particularly interesting, is that that combination was more potent than either by themselves. And part of the reason was quercetin was much better as a senolytic in intervertebral disc cells (as an example), but didn’t work in adipose tissue. Where dasatinib, it was flip-flopped. It was more active in the adipose tissue. So that 2015 study, when they give these compounds and it found that it rejuvenated these lab animals, these mice, led to really what’s been a huge amount of research in the seven years since.

Dr Greg Kelly:

And since then, because quercetin was such a potent one, one of the areas that Mayo Clinic and Scripps continued to look at was, are there natural compounds from plants that are also senolytic? And what they found, I think it was 2018, was that fisetin, which fisetin would be another polyphenol, protective compound that plants make, was more potent even than quercetin. I think it was between those two, piperlongumine, which is from Piper longum (a relative to black pepper) [and] luteolin, which is another very similar structure to quercetin. So what’s happened is they’ve identified these different compounds that seem to target these yellowing leaves in our tissues and get them to remove themselves.

Dr Ruscio:

So the dasatinib, I believe is how you pronounce it. That’s, I believe (from a quick Google search here), originally used compound for chemotherapy?

Dr Greg Kelly:

Yeah, it’s a class of immunomodulators called tyrosine kinase inhibitors. But what was interesting is other similar medications in that drug category don’t seem to be senolytic, just something about what dasatinib does. And the way the original senolytic compounds were identified, is that senescent cells all have certain characteristics in common. So one key point is that every senescent cell in my body, as an example, isn’t going to be exactly like every other one. But they’ll share some characteristics. And they tend to exploit in common similar pro-survival strategies. So they’ve figured out ways to hang around. Instead of being the transient ones I mentioned, they’ve figured out ways to linger. And what those scientists did in 2015, is they looked at these networks of things they were exploiting and said, are there compounds that we know of from other science that might disrupt these? They’re called SCAP networks, and that’s how they found compounds to test. And when they tested them, quercetin and dasatinib just turned out to be convincing these senescent cells to continue the journey to basically self-destructing.

Dr Ruscio:

Now in this study, or in any follow-up studies with this combination or any of the other compounds, has there been an examination of outcome measures? Maybe skin elasticity, skin wrinkles, sexual function, cognitive function? Because this is one of the things that, and I haven’t looked very closely, but with one area — I have looked with NAD. The science has moved over the past maybe five years. So for our audience, I was a bit critical of NAD. There are some interventional trials looking at clinical endpoints. I’d say the evidence there is still somewhat in its nascency, but this is one of the quandaries I have with this realm of anti-aging compounds. Have we gotten to the point yet where we can tie these things to clinical endpoints?

Dr Greg Kelly:

Yeah. So one, senescent cells are hard to measure. In animals, they really would do biopsies to measure — take out those cells, put them in a dish, then stain them. Those certain characteristics the senescent cells have that would make them stand out from healthy cells. But since that’s harder to do, a lot of what they do would be much more outcome based. So as an example, the original fisetin study in mice measured a whole bunch of, or looked at a whole bunch of things for healthy aging in the mice. So muscle tissue, the vibrancy of hair. Since then, there’s been a lot of studies that have looked — again, these are almost all animal studies (the human studies are mostly still in progress on senescence or senolytics) — but have looked at brain function, joint function, skin function. So the elasticity, wrinkles — things like that in animals. And those models are useful for predicting what might happen. They’re not necessarily going to happen in humans. But so far, across the board in any tissue that’s been studied, removing senescent cells (so doing something that’s senolytic) rejuvenates that tissue.

Dr Ruscio:

And are there certain compounds at certain doses that you think people should, or specific formulas even, that you think people should consider adding into their supplement protocol? And if so, in keeping with their earlier theory about pulsing or using in cyclic nature, is this a one month every quarter sort of thing? I know there’s, and it’s escaping me (the name) at the moment, but it’s a peptide that is supposed to reverse DNA damage. It was discovered by a Soviet scientist and used to reduce radiation exposure [and] DNA damage accrual. And you’re supposed to do [it], I believe it’s one month, one to two times per year. So just as one example I’ll throw out there, but what compounds, what dosage, and what would you recommend using? I know a big question there. I could probably do a whole hour on just that, but maybe some starting points.

Dr Greg Kelly:

So it was the Mayo research, I think Kirkland is his name, coined the idea of hit-and-run to approach dosing. So the idea would be [that] you do something that’s senolytic for a couple days, and then you have weeks to a month (or potentially even longer) before you would do your next cycle. And so that hit-and-run dosing idea, I think is just woven all through the senolytic research. And I think that’s the way to go. In terms of compounds, the most common two that have, in terms of the most animal research and the few human studies that have been published to date, is D + Q, so the quercetin and dasatinib combination.

Dr Ruscio:

And it’s called DnQ for short?

Dr Greg Kelly:

That’s how I — I don’t know if other people call it that.

Dr Ruscio:

Gotcha, gotcha.

Dr Greg Kelly:

But that requires a prescription [and] dasatinib is a pretty intense immunomodulatory drug. So moving past that, the next most studied and the one that has the most ongoing studies registered in clinicaltrials.gov is using fisetin. And the dosing of that is usually about 20mg/kg in most of the registered studies. And that’s, at least in the anti-aging experts that I’ve been in touch with, that’s what they do personally and are having some of their clients do at this point. And fisetin is I think useful. It does some, like I said, it can get at the adipose tissue where in the animal studies quercetin wasn’t able to hit that tissue. And at Neurohacker Collective we actually launched a senolytic product in June that I’d been working on since 2018. And we have both of those. So what I would say is a senolytic dose of fisetin, similar for quercetin, but the idea would be that you would just take these two days, once a month. For someone younger, two days once a quarter would be more than sufficient.

Dr Ruscio:

Oh wow. So that’s not a big commitment, really. Two days, once per month.

Dr Greg Kelly:

Yeah, I think of it a lot like what we were talking about earlier, as some of the fasting behaviors. I wouldn’t want or recommend to a patient or friend to live calorie-restricted for the rest of their life. But doing a periodic fast once in a while to promote autophagy and other cleanup of cellular debris, I think is a fantastic strategy. And senolytics to me make sense in that same way. That doing a dose periodically, as something to prune off the equivalent of the yellow leaves in our cells, but just like you wouldn’t want to prune a plant every day. If you did that, you’d essentially destroy the plant. You’d over prune it. That’s the same idea with senolytics. So it would be something that you would do periodically, as a maintenance. And what we did, again, it’s hard to measure. There’s no great blood test right now to measure whether you’ve moved the needle of senescent cells.

Dr Greg Kelly:

But what we did is we recruited some people that had basically issues with mobility, flexibility, activities of daily living. And we had them do three cycles of this senolytic stack over about five weeks. So instead of a dose or two doses and then a month off, we accelerated it a little bit for the study. But what we saw was about just a little bit more than a 50% drop in the groups’ overall issues with flexibility and with anything related to those activities of daily living. So we saw a huge difference for fundamentally taking six doses over the course of about five weeks.

Dr Ruscio:

Okay, so like a dose per week, essentially, is what you were doing?

Dr Greg Kelly:

What we did is one weekend, two weeks off, one weekend, two weeks off, one weekend. [That] was, I think, what we tried to get everyone to do. There was a few people that ended up a bit more “in between”, but our general recommendation is just take it one weekend every month.

Dr Ruscio:

Gotcha. Okay. And another way we could rationalize what you did is this sort of loading period. And then from there you go to the lower dose, longer term. I mean, just as a theory, I don’t know. It sounds like this is kind of up in the air in terms of the best way to dose it still, but interesting nonetheless.

Dr Greg Kelly:

I think the key thing is that just don’t think of it as something you would do every day. It’s something you would do intermittently, you know, so that hit and run idea I think is the key, key concept. And then how long that window [is] between, I think is very discretionary.

Dr Ruscio:

And worth echoing, because there’s definitely this “more is better” [concept]. And I’ve felt this gravitational pull. So this is not a knock, it’s something I fight myself, but “well if one weekend per month is good, what about two or what about three or what about four? Heck, why not every day?” It’s easy to fall into that quicksand.

Dr Greg Kelly:

Yep, and I think that there seems to be a lot of people that want to “do”. We get a lot more credit for doing than recovering from the doing and we need both.

Dr Ruscio:

Yes, well said.

Dr Greg Kelly:

It’s even something like the fast-mimicking diet that Valter Longo has created and studied, which I think is a fantastic diet. I love all the research they’re doing on it. But when I’ve spoken to a few of the people from his team, what they’ve told me is that there’s benefits from fasting, but benefits from the refeeding (when you break it). So you need both. And in my younger days, when I was an officer in the Navy and a lot less wise about diet lifestyle, I was one of those people convinced that more is better. So if half an hour in the gym was sufficient, well two hours had to be even better, right?

Dr Ruscio:

Sure, yeah. Guilty also.

Dr Ruscio:

What’s the other compound, you said you were working on two?

Dr Greg Kelly:

So the senolytic compounds that I think have been the best studied fisetin, quercetin, [other compound]. Piperlongumine I think looks extremely promising and works very distinctly from those other two. Curcumin from turmeric, that was another one that Mayo identified as a senolytic. And that one was more in, and this makes sense for how turmeric is used, more in chondrocytes. So in our joint tissues. Olive leaf extract, specifically oleuropein, which is a polyphenol in olive leaves, that also has been identified as a senolytic. And again, looks like that one more works on joints. And so my bias is that we want more of a cocktail of these things so that we can make sure that we’ve got different tissues covered.

Dr Ruscio:

Multi-tissue effect. Sure, that makes sense.

Dr Greg Kelly:

And that’s how I approach it, and that’s why the senolytic that I created, and that I take personally, is built with nine different plant compounds. And the last one I’ll mention is a branded ingredient called Senactiv™, but it’s made up of Panax notoginseng and a red chestnut extract. And the company that made it has quite a few studies, but it’s one that they’ve emphasized looking at what happens in muscle tissue after [taking] it. And it’s one that, at least in the two studies to date that have looked at, seems specific for removing senescent cells from muscle tissue post-workout. So, again, that idea of anabolic resistance, I think it’s great to make sure we eat enough protein as we get older, [and] continue to do the resistance training to give that anabolic signal. But we still need to overcome this tendency to anabolic resistance that accumulates with age. And I do think that these animal studies are onto something. That senescent cells are a big part of the reason these anabolic behaviors don’t produce the same result in a 65-year-old that they do in a 25-year-old. So I think in addition to those, we want to be doing things to rejuvenate the tissue and get rid of those yellow leaves in our muscle tissues.

Dr Ruscio:

Now I’m assuming at Neurohacker Collective you have a page, or somewhere, where someone can obtain the supplement [and] the dosing recommendations. If so, where would you point people to check out more about that if they wanted to run this experiment?

Dr Greg Kelly:

If you go to neurohacker.com, and then I write blogs about every product. So there’s one that’s called Qualia Senolytic: The Formulator’s View of the Ingredients (something similar to that) on our blog that I go through what senescent cells are in much more detail, and then each of those ingredients and it’s role in that formula. So that would be the best place to learn more.

Dr Ruscio:

Gotcha. And so the brand is Qualia and the supplement name is Senolytic?

Dr Greg Kelly:

Correct, yes.

Dr Ruscio:

Okay. And I’m sure this is all there, but just put it out there one more time. This is — was it one weekend per month that you were recommending people to take this compound?

Dr Greg Kelly:

Yeah, so that’s our base recommendation is that you would take it two days a month. Personally, weekends are the day I choose to take it, in part because those are days that I don’t do a lot of other supplements. So it’s an easy day, once a month. A weekend is a lot easier for me to integrate in my existing supplement protocol. But there’s no hard and fast [that] it has to be a weekend.

Dr Ruscio:

Gotcha. Cool. Cool. Okay, anything else that you’d want to make people aware of?

Dr Greg Kelly:

No, I think we’ve covered a lot of bases and it’s been awesome getting to speak with someone that’s so diverse in their knowledge as you are.

Dr Ruscio:

Yeah, thank you. And I like what you’re doing in terms of following these compounds, because certainly quercetin and curcumin, I’ve been following research on that. We use both of those quite routinely at the clinic. And I really appreciate and I find it refreshing, this, you don’t have to do high doses long-term. This is something — I really loved the analogy of pruning where we periodically prune. I’m assuming this is going to be very low risk, also low cost. So it’s much easier to justify this experiment. And, again, that’s a real breath of fresh air amongst what seems to be a very different narrative that we see in a lot of the fields. So it’s been great, Greg. Really appreciate it.

Dr Greg Kelly:

Thanks. Well thanks for having me, and it’s been wonderful getting to hang out with you this afternoon.

Dr Ruscio:

Yeah, same here. Thank you, again.

Outro:

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➕ Dr. Ruscio’s Notes

The Main Reasons We Age

  • Damage progressively accumulates in cells 
  • Programmed aging (cells failing to repair) 

 

9 Hallmarks of Aging 

  • Genomic instability 
  • Telomere attrition
  • Epigenetic alterations
  • Loss of proteostasis
  • Deregulated nutrient-sensing
  • Mitochondrial dysfunction
  • Cellular senescence
  • Stem cell exhaustion
  • Altered intercellular communication

 

How to Improve Aging Outcomes and Quality of Life 

  • Consume enough protein and calories daily 
  • Maintain grip strength and muscle mass 
  • Measure heart rate variability (HRV)
  • Walk every day
  • Get into a healthy circadian rhythm 
  • Consider senolytics

 

Senolytics for Aging 

  • Senolytics are a class of drugs that target senescent cells to remove them.
  • The combination of Quercetin and Dasatinib has proven to be helpful, as well as Fisetin. 
  • Senolytics dosing is dependent on age.
    • For adults, take them two days once a month.
    • For someone younger, take them two days once a quarter.

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