In this episode, I am speaking with Dr. Greg Kelly, a naturopathic physician and neurohacking expert about longevity, cellular energy, melatonin, brain enhancement, stress, and disease.
Table of Contents
In this podcast, Dr. Kelly and I discuss:
- How curing chronic diseases (such as cancer and heart disease) has little impact on the average lifespan
- The complex relationship between bodily stress and aging
- Melatonin – are the benefits of larger doses overblown?
- The role of mitochondrial health, gut health, and autophagy in promoting longevity
- Recommended probiotic supplements for supporting a healthy microbiome
- Effective strategies for reducing overall stress burden on the body
- Practical tips for managing your mental state and optimizing brain performance
- Why catching up on sleep debt often makes us feel more tired
- The best nootropics for enhancing cognitive function
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Ari Whitten: Hey, this is Ari. Welcome back to The Energy Blueprint podcast. With me today is Dr. Gregory Kelly, who is the Director of Product Development and Neurohacker Collective, a naturopathic physician, and the author of the book Shape Shift. With extensive experience in both natural medicine and nutrition, he’s been an influential figure in the field. He served as the editor of the Journal of Alternative Medicine Review and taught at advanced clinical nutrition, counseling skills, and doctor-patient relationships at the University of Bridgeport College of Naturopathic Medicine.
He’s also published hundreds of articles on natural medicine and nutrition, contributed three chapters to the Textbook of Natural medicine, and has over 30 journal articles indexed on PubMed. His areas of expertise include neurotropics, antiaging, and regenerative medicine, as well as weight management, sleep, and the chronobiology of performance and health. With no further ado, enjoy this conversation with Dr. Greg Kelly. Welcome to the show, Greg. Such a pleasure to have you.
Dr. Kelly: Thanks for having me today. It’s my pleasure.
Can we extend the average lifespan?
Ari: There’s a lot of things that we can talk about today, and I hope to get into a number of different topics with you. What I want to start with is cellular aging, and there’s a number of studies that are actually older, and some articles in mainstream news like the LA Times and some research out of USC and some other things that I found actually only recently that are 10, 20 years old.
They discussed something kind of mind blowing that I’m curious if you know about, I’m curious if you have any thoughts on. The gist of it was the notion that, if we cure a particular disease, like they give the example if all cancers were cured tomorrow, cancer is this thing for 100 years, we’ve been searching for the cure for cancer, for all these different types of cancers. If only we could cure all these types of cancers, we’d live so much longer.
They make the point that, if we cured all cancers tomorrow or all heart disease, the number one killer, and many other diseases like this, it actually would only move the needle of the average lifespan that a person is living a very, very small amount. The reason why, I’ll explain in a minute, but the general idea of this is that– Let me just explain why.
What they explain as the reason why is essentially that these are age-related diseases that occur as a result of accumulated cellular damage and cellular aging and that, even if these individual diseases cancer or heart disease or diabetes or neurological disease were cured, that most people would still die in roughly their mid-80s as a result of what we call dying of old age. Dying of old age is multi-organ failure. Basically, so much cell damage and cellular aging has accumulated that the body is essentially just shutting down.
I think we are broadly– my hypothesis is that conventional medicine and I think, more broadly, the functional medicine world is under the delusion that, by curing this or that disease, we are going to be healthy and live a much longer time. I think what is really underneath it is still a body that has accumulated a lot of cellular aging, a lot of cellular damage that, even if you cured that particular disease, probably wouldn’t live that much longer in most cases.
I think that this is a big deal, and I think it’s not well understood by most people. I think it shifts the conversation towards cellular aging, the rate of cellular aging as the really key thing that we need to be focused on if we actually want to live a longer lifespan and have a longer health span. What are your thoughts on this landscape?
Dr. Kelly: I would say that makes a lot of sense to me. I guess to, put it in a frame, when I was a naturopathic student, mid ’90s, we had a class on addiction. One of the things I remember from that class is they drew the upside down U curve, like the adaptational curve, and they said, okay, your first drink, you get pretty intoxicated. You keep drinking, you adapt to that, reach a plateau at some point. Then people that struggle with alcoholism, they’re on the downward curve.
One of the things that sunk in in that presentation was they said, now, imagine someone that’s had a problem with alcohol. They’re somewhere past the plateau, they’re sliding down, and they go to AA. For some reason, they stop drinking for a couple of years, and then they start drinking again. Where would they get back on that curve? Do they slide back towards a better direction? Do they get back on the same point on the curve that they stepped off, or do they keep progressing? Any thoughts on what the answer we were given was?
Ari: I don’t know.
Dr. Kelly: What they said is that, when they drink again, it was as if they continued drinking. They get back on the curve as if they continued drinking during, say, that two-year interval. Akin to what you just said with heart disease, cancer, the disease was progressing whether or not they drank. The drinking was just a symptom. I think that analogy makes sense. Aging is going on no matter what on a cellular level, whether we get on or off, like a disease curve, that cellular aging is still going on, if that makes sense.
Ari: Yes, exactly. Assuming you agree with me, and do you agree with me that it would be a much wiser use of most people’s focus, particularly if they don’t already have a disease that they’re actively trying to treat, it would be much wiser to focus on the rate of cellular aging from the broader meta level that we can speak about as far as speaking to the broader population, speaking to the audience that we’re now speaking to?
The message I think, should be, hey, if you really want to live a longer time and have a longer, health span, don’t rely on waiting till you get a particular disease and then trying to find a cure for it or reverse it. Focus all of your energy and efforts on trying to slow down cellular aging. Assuming that you agree with me, how do you conceptualize cellular aging and aging more broadly? If you don’t feel cellular aging is the proper term for it, what do you see as the physiological mechanisms or processes that are driving that?
Dr. Kelly: I think stepping back, I would agree. There tends to be two broad camps within the longevity community. One would be the general idea that aging is mostly because of damage accumulation in our cells and mitochondria. That the goal then would be either repairing the damage or cleaning it up. The other would be it’s usually called programmed aging, but the general idea of programmed aging is that, for some reason, as we age, an epigenetic program is essentially executed that causes more damage and acceleration.
In either case, damage isn’t the hub, it’s just what’s maybe the driving force. Fundamentally, I think understanding more about cells and mitochondria, what causes them to either become accelerated aging or what resources that they need or support they need to execute more than repair programs becomes foundational to healthy aging. I think we would both think that’s the same, right?
Dr. Kelly: Understand that piece. Let’s work on that. If we can slow that down, cells are fundamentally the building block for tissues and tissues for our health. This would be an old naturopathic principle, but basically, the health of a tissue is dependent on the health of the cells in that. An analogy I use, I used it to help some of our marketing people to understand something called [unintelligible 00:09:05] we’ll maybe get to.
Think about like a gardener and a plant. There’s this one plant, vital, all the leaves are green, robust, and now a couple of the leaves start to yellow. What a gardener will do is prune those away. That gives an opportunity now for new growth. It frees up the resources that were going to that damaged leave to go now to the healthier thing, and it keeps the whole organism healthier.
If we don’t prune that yellow leaf away, it’ll attract pests. It tends to now cause yellowing of nearby leaves, like the whole plant suffers. In that damage accumulation, we have something very similar to yellowing leaves going on in our cells all the time. The question is how effective our immune system and other natural processes are at treating them away.
One thing that’s fairly clear from research is that the older we get, the less effective pruners we become, right? Things we can do that help to prune away those cells, I think would be a big part of keeping the organism healthy, if that makes sense.
Interventions Testing Program
Ari: It is. Now, I want to ask you something, I’m going to be very direct here. This is something that I want to challenge you a bit here. Let me just find the specific guy that I’m referring to so that I can say specifics here. Hold on one second.
Dr. Kelly: Sure.
Ari: Okay. What I wanted to refer to is the ITP, Interventions Testing Program, and a guy named Richard Miller, who is one of the researchers. Are you familiar at all with this?
Dr. Kelly: Yes. ITP is great. They do excellent research.
Ari: Okay. You might be more familiar than I am because I know you’ve gone deep in this space. Maybe you’ll explain it better than me. Basically, the idea is, as I understand it, they essentially run rodent studies where they test different supplements and drugs to see if there is a signal in terms of improving longevity.
Dr. Kelly: Yes, so–
Ari: Yes. Sorry, go ahead.
Dr. Kelly: One of the things that they do– what you see in a lot of rodent studies is they’ll use the Johnson Lab strain of mice, the specific designation, but it’s basically a mouse model of metabolic syndrome. As an example, nicotinamide riboside, NMN, almost all of those studies have been on the Johnson Lab mouse. Those don’t tend to reproduce in humans, I guess to put it simply.
They have a genetic defense that makes them a great candidate for metabolic syndrome that we just don’t share. One of the things that ITP does is they use wild mice, so genetically diverse strains of mice, to more accurately try to capture what would happen in a genetically diverse population, like the humans.
They also then have three different labs, so they’ll try to replicate. What you see sometimes in science, it will be a great result at one lab, but it won’t be replicated at others. They’re really doing their best to use animals to try to get the best insights possible on what may be worth exploring in humans.
Ari: Right. Yes, thank you for explaining that. A few years ago, I went deep down the rabbit hole of the genetics of mice that are being used in most scientific experiments, and you find a lot of very unpleasant stuff there that, how much inbreeding is going on and using these genetically inbred mice over so many generations and how that, as you imply there, may obscure a lot of the findings in some of that research and how much it translates into humans.
Cellular senescence and fisetin
Okay. On the topic of cellular senescence, one of the most popular ingredients is fisetin, and this is something that I looked at, I know you guys have looked at, and I looked at when I was formulating my longevity formula. The research looks super positive. There’s tons of very, very positive research. Then I listened to an interview with Richard Miller where he was talking about testing fisetin in their mice for longevity.
He tells the story. I can’t recount all the details of the story, but he talks about some of these manufacturers of fisetin coming to him to get the fisetin studied. Basically, the gist of it is they studied it in multiple labs, and they even studied it over long periods of time at high dosages, and they found zero effect.
He talks about this with a smirk on his face saying like, “Hey, a lot of these companies, they run their own. They fund their own research, like pharmaceutical companies. They fund their own research, and then they get these very positive findings, but when we do the research in our tests, in our labs, we can’t replicate that finding.”
To be honest, as a supplement formulator myself, I know you guys are involved in that as well, it’s depressing just to realize that so much of the studies that maybe we want to believe in are not that legitimate. There’s fisetin. I know there’s some other compounds that are also thought to combat cellular senescence, but what’s your take on all of that?
Dr. Kelly: The only thing I’ve seen was him on a podcast talking about that research. It’s not been published anyway. Usually, they’ll eventually publish their research, that hasn’t been. One of the groups I follow is called Fight Aging, with an exclamation mark. [unintelligible 00:15:28] is the person that has that. My understanding of at least what’s been communicated is that the thought is that they actually use a much lower dose than what Mayo and Scripps have used in their research.
Mayo and Scripps collectively were the ones that did the original study that identified fisetin as senolytic compound, both first in vitro because that’s how it would work. Then as a candidate, the last time I looked, there was 10 human studies registered on clinical trials.gov, all using generally a 20-milligram per kilogram dose of fisetin, which is a lot higher than what you would normally see in supplements usually. I think yours has 125 milligrams per dose, but usually, it’s somewhere in that 100 is what you see, but that would be 1,400-plus in an average size human.
I think, one, it’s always important to wait till you can read the research and see what they’ve done because the truth is there’s been dozens and dozens of different labs that have used fisetin and measured– something to do with senescence in different animal models. I think ITP is great, but I don’t know that their findings would outweigh all the other findings because Mayo and Scripps are legitimate research endeavors as well.
Ari: Yes, excellent response. Are there any other compounds that you’re excited about with regards to combating cellular senescence?
Dr. Kelly: By far, the two most used is the combination of dasatinib and quercetin by far.
Ari: That was a pharmaceutical you mentioned, right?
Dr. Kelly: Yes. Dasatanib is a drug used typically for blood cancers. I guess we can maybe back up for a second, but cellular senescence isn’t a new concept. It goes back to Hayflick’s work in 1961, where cells in a culture will only divide so many times before they’ll just stop, so that was eventually termed cellular senescence. That’s been known about six years.
What happened around 2010 was the recognition that these senescence cells seem to be a big part of the aging is damage control. Then in 2015, Scripps and Mayo found that selectively removing them could rejuvenate tissues, again, mouse studies. The thing that they did originally was they looked at the mechanisms, like what’s going on to keep senescence cells alive.
That brings us back to that pruning yellow leaves. I think then, as a general sense, when cells get stressed, they execute a range of different programs depending on the amount of stress. In a simple sense, the first thing they try to do is defend themselves. Antioxidant defenses would get upregulated as an example. If the stress is more than that can account for and causes a little bit of damage, then you have things like autophagy which is a repair program, recycling things inside cells and mitochondria or repairing DNA.
We have things in our cells that can do those. If stress is beyond that, then that’s when you would either have one of three things happen. Cells will become senescent, they’ll go through apoptosis, which literally translates as falling off, so very much think of like that yellow leaf falling off, or they’ll go through necrosis which is– just think of trauma from an accident. It wasn’t a planned dying off, trauma caused it.
Depending on the degree of stress, one of those things will happen. Sometimes, the same stress like a higher dose will cause senescence instead of autophagy. The key thing with cellular senescence is it’s part of the healthy response that our cells make so that these damaged cells won’t reproduce themselves. What would happen in say, a 20-year-old? Senescence isn’t in and of itself a bad thing. It’s contextual.
20-year-old decides to do an intense workout, they’re going to make some senescent cells. Super important that they do because those help to bring the immune system into that tissue. They help with repair and rejuvenation. A week, 10 days later, those senescent cells would’ve been cleared out. Thinking back to that analogy of a plant, some leaves would’ve yellowed, but they would’ve fallen off the plant.
What happens is we get aged older that same intense exercise, an older– they’ve done this work in animals. The older animal will create senescent cells as well. A week, two weeks later, they haven’t fallen off. They’re still there. Then they can make essentially new senescent cells as well. That’s the zombie metaphor we often have.
The key thing for me, when I think of senescent cells, is that I use the distinction transient versus lingering. It’s completely natural and healthy to make these transient ones that fulfill a role, and then they fall off the plant or the immune system prunes them off. As we get older, for a lot of reasons, that just doesn’t happen, so they build up in our tissues.
Ari: Okay. There’s one nuance here that I think might be important. You gave the example of exercise creating senescent cells in this situation. The idea here is, you’re not really trying to say exercise specifically is a concern for here, but I think what you’re trying to say is any source of high levels of oxidative stress that exceed the cellular capacity to handle that stressor, that then results in a high level of damage to the cells. That’s what causes senescence. Correct?
Dr. Kelly: Yes. There’s that Hayflick limit, like telomere shortening. It was once thought that was the main reason for cellular senescence. In addition to that, is what would be called stress-induced premature senescence. Long before a cell would have short telomeres, you can cause it to become senescence by UV light, nutrient deprivation, all these different things that would stress itself. My bias is, in aging, that’s the more likely cause of cellular senescence, is these– like too much stress.
Dr. Kelly: Yes, go ahead.
The connection between stress and senescent cells
Ari: Let’s create a distinction here that I personally think is important, the distinction between the presence of a stress versus the presence of a stress that exceeds that individual’s capacity to handle stress. Let me be more direct about stating this. You gave the example of exercise creating damage that induces senescent cells, yet, we can also find research showing that people who exercise reduce their accumulation of senescent cells. Just explain that seemingly paradox to people.
Dr. Kelly: Yes. Again, go back to that idea of transient and lingering. It’s completely normal when cells or tissues are trying to repair, even like modest exercise, part of that, we remodel, say muscle, say weight lift weights. The goal is to make– this is the way I would think of it. Muscles get bigger and stronger, not so much because we lifted weight, but because we’re a complex adaptive system, they’re like, “Oh, the goal is to be better prepared for the future, so, oh, I better be bigger and stronger for the next time this stress happens.”
Stress is, like you mentioned, not good or bad. It is in an amount that can cause a positive adaptation. Then things that we would make in that remodeling process are completely fine, we need them. It’s when they last past that and interfere with other things. The key thing with exercise is that in– again, in a young animal, they’ll make these transient senescent cells. They’ll do their job for a couple days, and then they’re flushed out of the tissues.
In older animals, when they study, they don’t– they’re made, but they’re not removed. Exercise, we could say– it’s just an example, so like tense stress. As you suggested, things that keep an organism healthy will tend to slow the accumulation of senescent cells. Exercise is one of the only things so far that’s been repeatedly studied and seems to slow down the accumulation of senescent cells, but it’s very tissue specific.
In general, senescent cell can accumulate– well, they tend to accumulate in three tissues disproportionately, so three cell types, fibroblasts, think connective tissue, joint tissues, skin, fibroblast, they’re widespread connective tissue. The immune system and then endothelial cells, so endothelial are what lines or arteries and veins, but any tissue even. It used to be thought that senescent cells only were in dividing cells or only dividing cells could become senescent.
The idea was why would we execute this program if the cell wasn’t going to divide. Neurons is an example or a non-dividing cell. The neurons we have now, we don’t really– there’s very limited neurogenesis, the ability to make new ones, but now they know that neurons can become senescent. Because of that, they think senescence is much more like, again, that damage protection when stress has been too high or too sustained.
Again, the idea would be, once a cell becomes senescent, it should then on its own either go through this natural falling-off process, apoptosis, or the immune system should find it and remove it. The senescent cells shouldn’t linger. They should do their job and then go through this natural– again like yellow leaf falling off a plant or someone prunng it off. The key distinction with age is that more and more yellow leaves just accumulate in our tissues.
Mitochondrial dysfunction and accelerated cellular aging
Ari: Got it. What are some of the other main drivers of accelerated cellular aging?
Dr. Kelly: I think mitochondrial dysfunction would be a huge one. In my mind, mitochondria are maybe the single most important driver because I think, at the most fundamental level, things are about energy. If anything impairs the ability of that mitochondrial network to perform its job, energy goes down. That’s a commonality with almost anything with health is that there’s just not enough energy to do the job that tissue needs to do.
Ari: What do you see as– mitochondria are so interesting because now we are finding more and more roles for them. When you and I were going through undergraduate, graduate school physiology, biology courses, it was very much just– they’re an organelle in the cell, they’re the powerhouse of the cell. They take in carbs and fats, they pump out ATP. That’s all you need to know.
Now, we’re discovering more and more they have all kinds of roles, as involved in immune regulation, as environmental sensors, energy regulation, and that they are really the central hub of the wheel of metabolism, meaning the totality of all the chemical reactions occurring in our body. They do a lot, it turns out, and they’re really important.
What’s interesting is I encountered many different people with different paradigms around mitochondria and what they do and how to fix them. I would say, now, they’re in vogue in the functional medicine realm. I think most people’s model of them is still very simplistic. We run an organic acids panel and maybe a few other tests that have some indirect relationship to mitochondria.
If we establish that you have mitochondrial dysfunction, then we give you some acetylcarnitine and some ribose and some alpha-lipoic acid and B vitamins, and CoQ10 and PQQ, and voila, your mitochondria are healthy again. My personal view is it’s not nearly that simple. What do you see is– how do you understand? What’s your paradigm around the mitochondria and some of the key things that cause mitochondrial dysfunction?
Dr. Kelly: First, I think of them as a network. In a cell, we don’t have a mitochondria. We have a network of mitochondria that are interacting, communicating. Network complexity science, I think, is a much better model. The goal really is to create a healthy network. The network’s going to try to reshape itself to best match its circumstances, so exercise is an example.
In general, exercise will cause reshaping of the network. You’ll have mitochondrial biogenesis birth to new fitter versions of mitochondria, and mitophagy, you’ll prune away some of the less effective ones. Like any living ecosystem or living adaptive system, it’s going to try to do the best it can. One of my metaphor is that the key thing is making sure something’s supplied with the resources to be able to do what it’s endeavoring to do and remove any obstacles that might be in the way.
That drastically oversimplifies it, but to me, that’s the most useful construct. The things you mentioned, I think of as in the resources bucket, the mitochondrial nutrients, for lack of a better [unintelligible 00:31:02]. Those are needed for the network to be able to do its job, so nothing wrong with those. If there’s an obstacle in the way, then you also need to do that, and you need to give a reason for it to reshape itself. Resources without exercise would be less efficient to reshape the network than giving it a reason to reshape itself with exercise, if that makes sense.
Ari: Yes, it does. It makes a lot of sense. I agree completely. Are there any other factors that you see as having a big impact on causing mitochondrial dysfunction?
Dr. Kelly: I tend to follow Dr. Jack Kruse a lot, and his [unintelligible 00:31:45] very into light, circadian rhythms, grounding. I would maybe not be as full bore as them on those, but I think those are under-recognized. The fundamentals are to me the foundational pieces. At one point, about 20 years ago, I was teaching naturopathic students, their clinical nutrition class, and my first lecture was on body clock and circadian rhythms. My second one was on sleep.
The idea was those are the low-hanging fruit. It’s much easier to try to get those things aligned with our lifestyle and environment than it is to work on like say obesity as an example. Multiple things are impacting it. I would say, for mitochondrial health, fundamentally, they’re what turns the energy– the electrons, the energy that starts in the sun into ATP in our cells. I think the environment is maybe the single most important factor dictating the health of the mitochondrial networks.
Ari: Are there any other big drivers of aging other than mitochondrial damage, dysfunction, and cellular senescence? Are there any other key players that you want to put into this mix?
Dr. Kelly: Well, like immunosenescence, the immune system, it just performs vastly differently as we get older than in a younger. I know you’re familiar with it and your audience probably is as well, like the hallmarks of aging paradigm. There used to be the 9 hallmarks of aging which were expanded to the 12 in January 2023. The three they added were basically immune system, so immunosenescence, dysbiosis, the gut connection to aging, and then autophagy became its own.
Those three are also super valid. Autophagy, as I mentioned, I think of as similar to senescence. It’s part of the suite of stress response programs that cells and mitochondria have. Ideally, that one’s executed well before we have to enact the senescence program. The gut microbiome, I bet 10 years from now, there’ll be way more talk about the connection to the gut microbiome and aging, just because it’s, again, like crazy complicated.
There’s somewhere on the order of a thousand different species of gut bacteria in each of ours. Yours is different than mine. If you had a twin, you might have the same DNA, but you’d have different gut microbiomes. They make about a hundred thousand metabolites. It’s our second biggest connection of neurons outside the brain with the entire nervous system.
Think of just the magnitude of those interactions, a thousand species and hundreds of thousands of metabolites with almost as many neurons as our brain, and most of our immune system is in our gut. It’s a tough system to sort out but my guess is it’s a pivotal one for aging.
The best nutrients to support the microbiome
Ari: I know you guys are going to release a product related to that soon. Do you have any insights into what you feel are maybe strategies or nutrients or supplements that are uniquely beneficial for supporting one’s microbiome?
Dr. Kelly: Yes. The analogy I use is an ecosystem, and I think it’s the best one that they got. In an ecosystem, so Yellowstone, I remember the video when they reintroduced the wolves into Yellowstone, and how over the next couple years it completely reshaped that ecosystem. Wolves would be thought of in an ecosystem model as a keystone species, species that just has a disproportionate impact on that ecosystem.
Elephants in Africa would be another example, they just have a huge impact. On our gut, I think that idea of keystone species is really important. Some of the keystone species are sometimes now called next-generation probiotics or next-generation organisms. They’re your Akkermansia, Faecalibacterium prausnitzii, some things in that category where the things that–
I think of it as probiotics 1.0, the Lactobacillus bifidus are not keystone species. Not to say anything wrong with those, they’re important in inhabitants in the ecosystem. I know our goal, we were reading the research, was to figure out what had the biggest impact on the keystone species. That tends to be certain things in the prebiotic world. Like resistance starch as an example, bifidobacteria is one of the species that feeds on it. Another, I think it’s ruminococcus, is the genus. That’s a keystone species that’s also a primary degrader.
What often happens is then it’s called crop feeding. The metabolites those make then feed something else. A small amount of resistance starch tends to cause Akkermansia to also bloom as an example, even though Akkermansia doesn’t direct feed on it.
Ari: Absolutely. It’s either a positive virtuous cycle or a vicious cycle in the other direction when you have those cross-species interactions where they’re benefiting from the presence of the other species. Then if you take too many courses of antibiotics and some of those keystone species dwindle in numbers, then other beneficial species also dwindle and pathogenic species can flourish. Yes, agreed. Very complex system.
Dr. Kelly: Oh, I was just going to say–
Ari: Yes, go ahead.
Dr. Kelly: -another just insight is what I’ve seen in quite a bit of research still just feed high amounts of one prebiotic, so like in [unintelligible 00:38:25] or GOS, that doesn’t create a diverse ecosystem. You’re almost disproportionately feeding something but starving other things. Just one message for the audience is you’re probably better off lower amounts, but a variety of prebiotic-type things to create a more rich gut ecosystem.
Ari: Let’s talk about– Well, you know what? We talked a lot about mechanisms as far as aging. I’m curious on a practical level, as far as one’s lifestyle habits, what would you say are some of the biggest drivers of aging, and what would you say are maybe two or three of the things that you think are the most powerful anti-aging strategies one can engage in?
Dr. Kelly: I think the biggest drivers are things that– so an analogy that I used in my book was, when I was a kid, it was called The Last Straw, or the Camel’s Game. This goes back to the late ’60s. The gist of it was there was a plastic camel, there was buckets on either side. You would spin a wheel, and whatever color it landed on, you would put a straw of that color in. Some of the straws were denser than others.
At some point, one team would spin the wheel, get say a blue straw, put it in. That was the last straw. The back would collapse. I tend to use that as an allostatic stress model, so all of us can carry a certain amount of stressors like we’ve got some innate ability to weather the storm, so to speak. We all have some straws in our basket, and I think most of us, and it’s probably unknowable how close we are to that last straw. What you commonly see in health is the results of that last straw. There’ll be this one tipping point event that caused the back to metaphorically collapse, right? That’s often then thought of, oh, that was the cause of the problem.
In my model, no, it was all the other straws there in advance. The last straw would have been meaningless if the basket was empty. Fundamentally, my model is what are the removable straws and the biggest ones? Again, whether it’s health or aging, I think it’s going to be the same. It’s the things that have that disproportionate amount of weight in our basket are the ones that cause the largest problems, and the removable ones, the actionable ones, are the only ones we’re focusing on.
I believe Selye when he said that he – and Selye was the preeminent stress researcher, he coined the idea of biological stress – he believed, after all his work, that mental and emotional stress was the biggest, in my analogy, straw. I think when there’s mental emotional stress, resolving that, whatever that means. I often use the idea of congruence or incongruence.
As an example, I have a much younger brother. When he was 20, he thought eating at McDonald’s was grand. I was a vegetarian at the time. If I had eaten, then not only would I have had any effects physiologically from that, but I would have been incongruent because I was doing something I believe was bad if that’s right, so closing incongruences is big. The bigger the gap is that something’s incongruent for us, the bigger the straw.
Another thing I would focus on is just something consuming our mental bandwidth, are we ruminating about something? If we are, that’s a really strong clue that’s consuming a lot of our mental bandwidth, obviously, but that’s likely a big straw. Is there something we can do to close that loop so that that rumination would be behind us? That would be one big area.
Sleep is huge and just so mismanaged in general in our population, statistically. I worked for a corporate wellness company between– for about seven years as one of the jobs I had, and we would have a standardized health risk assessment questionnaire if we had all the employees. It was somewhere about 60% of the people would just in their answers would be telling us that they don’t get enough sleep, and that was people that were aware of it. I think sleep is huge and maybe not in our world, we talk a lot about sleep, we do a lot of things, make sure we get it. I think in society as a whole, sleep is just really poorly managed.
Then I think screen time has got ridiculous for many people. I know my screen time went through the roof during lockdown. I think often we don’t have to overcomplicate it. What are the most fundamental things to our health? It’s our thoughts, doing the things that we evolutionarily would have encountered and thrived on.
Melatonin supplementation – is it necessary?
Ari: Since you brought up sleep a minute ago, I’m curious to get your thoughts on melatonin. It seems to be quite the controversial topic in our space, or not even necessarily that controversial, but the diversity of views, I would say, is pretty dramatic. I believe that you guys in your sleep formula did not use melatonin if I remember correctly.
Dr. Kelly: That’s correct.
Ari: I’ve gone back and forth on this for a long time and talked to a lot of experts and dug into the research, and talked to a lot of people to assess their interactions with melatonin. I’m uniquely sensitive to melatonin, so I actually paradoxically respond with poorer sleep if I take a typical melatonin supplement. I often have disturbed sleep and I wake up groggy, with some exceptions. With Herbatonin, small doses of Herbatonin which is a plant-based compound, which is what I’m putting in my new sleep formula that’s coming out, I actually have a very good response to that.
I don’t know exactly why, to be honest with you, because I’ve also tried micro-dosing the synthetic melatonins and I don’t get the same response. I seem to get a very nice response with the Herbatonin, plant-based melatonin, but not consistently with other types. As far as the diversity of opinions that’s out there, it’s everything from supplementing with melatonin is bad for you and will disrupt different mechanisms in your body, to some people, prominent people in some cases, claiming that you should be using massive doses of melatonin on a nightly basis. I’m curious what your take is and why you guys decided to not use melatonin in your sleep formula.
Dr. Kelly: Sure. I can speak to that for sure since I designed the sleep formula. One of the analogies that I use, like signal-to-noise ratio, would be it. Have you ever heard of the Hook Weaver Law in any of your–
Ari: I have some vague familiarity with it but I can’t place it.
Dr. Kelly: The interesting thing is I came across it in a psychology book, never in physiology. The gist of the Hook Weaver Law has to do with vision and auditory responses. The general idea is those systems are based on proportional change instead of a quantity of change. The analogy I’ll often use is, imagine you go into a dark closet, you light one candle, wow. You notice a big difference in brightness. Now, you go into that same closet, there’s 99 candles lit, you light one more kind of a nothing burger. The one candle was meaningless, it’s the proportion of change and that the ears and the eyes are akin to the receptors on our cells.
My guess is the same principle drives physiological response no matter what the receptor happens to be so that proportional change. I think at the end of the day, there’s lots of unknowable things, melatonin being an example. Then we’re left to what are the principles that we might be able to apply, and so that’s my default, proportional change. Let’s now take the mega camp.
We give a mega dose, way beyond what physiology would be. We’ve now created a big proportional change. Again, in that signal-to-noise idea, we now have a closet full of light, right? Now we have to keep giving that big change to create the same proportion where physiology is more nuanced. What we would see is in a robustly healthy, say, 15-year-old getting enough sleep, good circadian rhythms, they would make a big proportional surge of melatonin around an hour of when they go to bed, say 11:00 at night, but then the amount is going to go crazy low by when they wake.
It’s a darkness hormone, so at light, it’s going to not be zero, but it’s going to be close, right? There’s going to be this, at a physiological dose, a huge proportion of change. What tends to happen, so say screens as an example, someone’s on their phone right in front of their eyes and at night lying in bed, because of the blue light blunt melatonin secretion so they’re not going to have a big surge or as big a surge, so they’re not going to get the same proportional change. They also may never get quite as low in the morning as that robustly healthy, so they’ll never have the right proportional change across the 24 hours.
To me, that’s what would be important, so what that then means to me is intuitively, I think of what you said, agreed with you, a much more physiological dose to create just a little bit of proportional change without flooding the system and ratcheting up the background noise level. We want to keep the closet as dark as possible fundamentally.
Now, does that mean that that’s going to work for everyone? Probably not. I tend to use the idea of useful. For some person, it may be a lot more useful to do a high dose and work for them. I wouldn’t discount that, but for the globally, if where I was making a product, I wouldn’t chase that, I think like a low amount. Then part of the reason we didn’t put any in ours, we consider Qualia Night, which would be our sleep-ish product. We actually designed it as a nitrile nootropic.
The idea was take this around dinnertime to help create a more relaxing window of time between then and sleep. If you do, then you’ll just more gradually fall into a deeper sleep and then naturally, you’ll make the melatonin. The other thing is that your system is just better able to do that than us figure out what’s right for everyone.
Now, the other thing, I think with melatonin that people don’t always appreciate, it’s considered a chronobiotic. Where it excels is at locking the circadian rhythm in time, not as per se like a great thing for sleep quality. I think it’s often misused because people are using it for the wrong purpose. It excels at that jet lag type of use case or if someone has delayed sleep onset issues to try to lock in their rhythms.
Ari: Especially, as you said, that big difference from the baseline to give a strong input for change in that sort of context. It’s worth mentioning, to put numbers on it, the physiological dose released into the serum is thought to be 300 micrograms, 0.3 milligrams. It’s common for supplements to be 10 times that much, like 3 milligrams as a starting point. Many of them are 5, 6, 10, 20, and there’s many people who are recommending 50 or 80 or 100-milligram dosages, which we’re now talking in the realm of 300 or maybe 350-fold greater than the physiological dose.
It’s worth saying that there’s definitely positive research on doing that in the context of certain disease models, but whether it’s– I think you and I agree that maybe that doesn’t necessarily mean it’s a good idea for healthy people not in those disease models to be using those amounts.
Dr. Kelly: Yes, you’d be creating a huge proportional change with that, say, that first dose. What happens is hormones are made, but then they have to be cleared out. They don’t just magically go away. What you end up doing is spreading that surge curve out for a longer period of time. That’s why some people with high doses of melatonin will feel a little bit– I don’t know what the right word, not hungover, but still drowsy instead of what should ideally happen is that before sleep, melatonin would have reached or before waking, melatonin would have reached its basically background noise level, a low amount, and then cortisol would surge to help with wake.
What ends up happening if melatonin went too high, it starts to bleed into these jobs of other things and then we will need more to get that same proportional change, but now we’re having a ripple effect on other things it may be interfering with. My bias when we created Qualia Night was just give tryptophan and cofactors in modest amounts to make melatonin, and for the vast majority of people, they’ll make it if they have the resources. The other thing with– I think this is also underappreciated, there’s been a few studies where morning light, with enough tryptophan in the diet, creates healthier melatonin at night. You often don’t need to go to the final thing, you just need the resources in the system and then the cues for it to do its job.
Then, I guess, the last point back in the late ’90s, Thorne, which is another supplement company I worked for back then, they called it microtonin. I think it was either 100 micrograms or 300 micrograms, but it was that low physiological dose, and that’s what I used with patients when I really needed something was that the dose it sounds like you’re taking with your supplement.
How sleep regulates our energy levels
Ari: Let me talk to you about energy levels. How do you conceptualize the body’s regulation of energy? What controls whether someone is fatigued or highly energized?
Dr. Kelly: I think that’s super complicated, but I have a little bit of a mind-body bias in terms of what’s weighing us down. One of the things I’ve seen multiple times is that someone in their normal life, pretty hectic, they’re holding it together, they go on vacation, and all of a sudden, they’ll get a cold, or they’ll all of a sudden need a whole bunch of sleep, or they get sick, they now sleep a lot, and then the aftermath of that is they feel like they need more sleep.
My general saying and belief is, if you can sleep, you need sleep. Let’s take depression and those things out of the thing but what seems to me to be the case is our system is really smart. Fundamentally, a lot of what we take for granted is designed to keep us safe and alive more than anything else. Sleep, as an example, I was an officer in the Navy before I became a naturopathic doctor and crazy sleep deprived just because of circumstances, rotating shift work, you name it.
My body held it together, but at one point after the Navy, I decided one winter- I was living in New Haven, Connecticut, at the time, and this was the late ’90s when no one was really talking much about sleep, -to basically say, okay, maybe I built up a pretty big sleep debt that I’m not even aware of. My body just figured out a way to get by without it. Let me just go to bed when it gets dark and sleep as long as I can and see what happens.
I started, this was winter, going to sleep around 7:00. I slept for 12 hours, no problem, for about two weeks, and then 11 hours. Then by the end of three, three and a half weeks, I was back to eight. For the first time in a long period of time, my hands all of a sudden warmed up. My hands were always– I had done massage as part of a side gig as a naturopathic student. I always felt bad. I was one of those massage therapists that did everything to try to warm their hands up, and all of a sudden, my hands were toasty for the first time.
I think when I convinced my body like, oh, we’re going to now make this a priority, it just pulled a bunch of that sleep debt out of the closet and repaid it. What I think often happens when someone starts to sleep a bit more, the super common piece of feedback I used to get is, “Dr. Greg, this doesn’t make any sense. Now I’m tired than I was before,” and that’s why. It’s like, oh, the system now, you act like I can now pull this thing out and finally get to it and work on it.
Ari: It’s interesting. First of all, what you’re saying is super interesting to me, and it’s something I don’t think I’ve ever heard somebody talk about before. I think my interpretation of it might be a bit different than yours, though. Or maybe it is the same, we’re just talking about it in different words. To me, it’s almost like your body was in some kind of compensatory adaptive mode that was dealing with this chronic stressor of low-level sleep deprivation. Then when you finally allowed it to rest, it was like a reset for the system.
The body got to go, “Oh, I’m finally safe. I actually can sleep the amount I need to sleep. I don’t need to be in this chronic mode of trying to go, go, go, and where I got to function in the face of not as much sleep as I’d like to,” where it’s making this kind of adaptive changes, which interestingly, you mentioned were reflected in the temperature of your hands, but probably would be also reflected in many other aspects of the way your body was functioning.
It was like you used this conscious, dedicated sleep protocol of a few weeks to allow your body to enter a feeling of, “You can relax, you’re safe. You take as much time as you need to recover.” In the context of the way that I see energy regulation through the work of Robert Naviaux’s cell danger response model kind of mitochondria in defense mode or energy mode, I would see what you did there almost as a very intentional way to get your body out of it being stuck in cell danger response in defense mode, and you created an input with that protocol that allowed it to get unstuck and shift back into safety mode, energy mode. Do you know what I mean?
Dr. Kelly: Yes.
Ari: That’s kind of the lens through which I would interpret something like that.
Dr. Kelly: I think not all cases, but just sleep neglect is probably the main reason in society, people just aren’t making it as much of a priority. I think when you talk about energy, a lot of it is [unintelligible 00:59:23]. As an example, one of my favorite studies, I call it the Multiple Stressor Study, but it was an Army Rangers study. They had noticed that Army Rangers often, after the fact, gained a lot of body fat at the point of this study. This study is 15 or so years old.
The context of Army Ranger experience in this study was sleep deprivation while they were out in the field, not enough food, crazy amounts of exercise, and cold, so stacking multiple stressors. They looked at things like everything just text. Cortisol goes up, thyroid goes down, all these things that if you were to get a blood work and look at it, you’d say, oh, you’re hypothyroid or you’re hypo adrenal. What they were was in need of recuperation. What then happens is as soon as they get access to food again, they obviously eat a lot of food that renormalizes some of those hormones, but at a higher set point, body fat, at least temporarily.
I think what often happens in medicine is we, well, people do these well-intentioned lab panels, but then you’re chasing effects. Many of us have the multiple stress problem, maybe different stressors than the Army Rangers, that are causing our appetite to be increased, our metabolism to seem like it’s slower, our energy levels to be reduced. The goal isn’t now to necessarily take Armour Thyroid or whatever the intervention, it’s can we now get out of this damage or damage response mode and let the system just rejuvenate and recuperate, in which case it’s likely able to make all the energy we need. It’s just saying at this point, I’m not going to make enough or all that energy because I want you to rest and recover.
The primary causes of mental fatigue
Ari: Yes, fascinating. What do you think about mental fatigue, specifically? Like brain-related energy levels or mental energy. How do you see that, what’s your paradigm to understand what’s happening there?
Dr. Kelly: I think the brain’s primary fuel is going to be glucose, whether we’re ketogenic diet or not, we’ll sustain blood sugar in part to make sure we can feed the brain. I think what invariably happens is we reach only to feed that energy in the brain because we overwork one part, super common. Maybe you’re a software programmer, you’ve been just staring at your screen hammering out code, and now you take a break and what do you do? You look at your phone, which is the same, similar. What you’re using, the visual system, and some of the other thing. The goal of a break would be maybe do something, like Selye, he would have called it deviation. Do something drastically different.
I think what ends up happening, one, people don’t practice deviation. When they take a break, they do something that’s taxing the brain in a very similar way, where, watching clouds drift by or fish in a fish tank or waves on the beach or running water, all those would use a different part of the brain, like that. It will give time now for the brain to shift resources into where it had run low from where maybe some excess that weren’t being used are. I think energy is at the heart of things, but going back to that original idea, is there enough resources, and then is there an obstacle?
Your cognitive formula, that would be supplying some of these resources. Things to make neurotransmitters and adapt to you, herbs, and things like that. Then, the obstacle, in this case, is that you’ve overworked this one part of the brain. Then, we can talk about multitasking and other things. People, our brain doesn’t really multitask in the way that we think it does. It does one thing and it can shift so fast back and forth that we have the illusion it’s multitasking. I think paying much more attention consciously to what we’re focusing on and doing one thing, and then making sure we take breaks and do something drastically different makes a huge part in giving us a much more sustained ability to be productive across our entire day.
Then the thing I always look at, and I would guess it’s the same for you, if someone takes a nootropic, I would expect, oh, yes, you’re going to feel something ideally in the next hour or two, but what’s happening at the end of your day? Are you a better version of yourself when you get home at the end of the day? Or did that nootropic just cause you to spend through resources faster at work and you get home and you’re cooked and a mean person to the significant others in your life? I always think–
Ari: That’s a function of to what extent were you pumping the accelerator pedal without putting any fuel back in the system or allowing the system to rest. Just pumping
fuel into it or just pushing the accelerator and revving that engine crazy to the max but without giving the system a break. Is that analogous to what you’re getting at there?
Dr. Kelly: Yes. I think caffeine to me, it’s not an exact thing but that would be more akin to turbo. It’s causing the thing to use more fuel and resources but you still got to supply the fuel and resources. I think what ends up happening, people mistake the turbo for the fuel. That’s why something like Bulletproof Coffee, as an example, I think agrees with a lot of people because now they’re getting fuel with the turbo as an example.
Ari: What do you think about caffeine more broadly? Because I have a lot of thoughts on it. I’m hesitant to go into all the details, but my very short version of that is I think that caffeine is widely misused and is, for most people, counterproductive, most people are using it in a way that is actually lowering their baseline energy levels. It’s an insidious process because they simultaneously think that caffeine is giving them energy and they’re unaware that it’s also the thing that actually lowered their baseline levels of energy.
As supplement formulators, you and I both, we know that one of the easy things that we could do to make people feel in effect from taking a supplement is throw a bunch of caffeine or stimulants in it. If you do that, you will get a whole bunch– It’s so easy, it’s so easy even a monkey could do it, and you know that, as supplement formulators, wanting people to, in a way, there’s a financial incentive to get people addicted to the supplement, to get people to– certainly to get them to feel an observable effect within minutes of taking it, but also for it to be addictive.
Caffeine is addictive, so there’s a lot of incentive as supplement formulators to do that, to throw a bunch of caffeine or other stimulants in it for those reasons, to give people that experience. The problem is that consumers are not educated enough in the science around that to know that if they use a substance like that every day in large amounts, that their brain will undergo adaptations that actually hinder their cognitive performance and their energy levels. For that reason, I exclude stimulants in caffeine from my brain formula. I’m curious what your thoughts are around this.
Dr. Kelly: I tend to be a Goldilocks Principle person. Most things, I don’t view as good or bad, it’s is there just the right amount to get whatever job you’re hoping to get done.
Ari: Used in the Goldilocks zone as far as frequency to– Like caffeine intermittently I think is no problem and is actually very useful.
Dr. Kelly: Yes, so that upside down you we talked about with alcoholism earlier, sometimes that’s Yerkes-Dodson is what you have. My bias is that most things are going to track with that, Yerkes-Dodson. We’ve never had it, we start it, we’ll adapt to it, we’ll perform better for a while, maybe get to a plateau, and if we misuse it, we’ll start to slide down the other side. The things that dictate the amount of time before we track through that would be, like caffeine was the original thing they studied in Yerkes-Dodson Study, is the intensity of something, so the dose.
The analogy I’ll often use, most of us, if we decided we’re going to run a marathon every week for the next year, we’d track through that curve. Maybe some people wouldn’t. I know my body would. I adapt for a bit but then I don’t, so that intensity of exercise. If, conversely, I said I’m going to walk two miles every day for the next year, I’d still probably be ascending, the better performance part because of the intensity. Now, if instead I also said okay, I’m going to walk every day except Sundays and take that as a rejuvenation, right, now I’ve spread that time out even further before [unintelligible 01:09:37] is my bias.
With something like caffeine, I think of it the same way as that exercise. What’s the dose? Is there a dose more like walking and a dose more like marathons? Is there a way to, like you would with a smart exercise program, put a de-loading phase in where you can re-equilibrate the system, recover? When I think of caffeine, I can just speak to my own personal views. I use a moderate dose of it on workdays, weekends, almost none. By a moderate, that’s way less than–
I remember a good friend in Mexico once I was visiting, this was when I was in naturopathic school, and he said, “Greg, what do you think of coffee?” I’m like, “Marco, what do you mean?” “Is it good or bad?” “I’m like, “Well, what are we talking about here?” He’s like, “I have about five, sometimes six cups a day,” and you’ve probably learned this too, well, how big is your cup? He comes and it’s like this massive 32-ounce thing. I’m like, “That’s my pot.” We’re now well past that part where now he was running a marathon. That’s how I think about it.
Personally, I’m almost there’s certain things that I don’t do, so artificial sweeteners, things like that I just don’t have, but most things I just think in terms of, is there a Goldilocks thing? How can help people get the best response out of this.? Not just for today, but long-term. Often that’s a lower amount of something, and then prudent breaks, like you mentioned.
The best nootropics
Ari: My last question to you is, as a nootropic formulator, what are your favorite nootropics?
Dr. Kelly: Well, one that has been getting lots of buzz lately, and I know you use it, is the polygala. I think that is crazily underappreciated.
Ari: Has it been getting lots of buzz? That’s actually unbeknownst to me because when I put it in my formula, there was actually very little research on it. I was mostly going off the fact that I was– One of the things that I do is not only monitor the research that exists but if a new supplement comes out, what do the reviews of users, what does the user experience look like?
It takes a lot of time to read through lots and lots of many hundreds, thousands of reviews but I kind of see the nature of that. I try to assess, oh, is this just a placebo? There isn’t really any noticeable effect here, or is this something that users are consistently reporting a very predictable type of effect with? I included it for that reason, that it was something that seemed to get really positive user feedback.
Then we’re big fans of Celastrus. At our company, we’ve just we’ve done a couple of A/B tests where we’ve had a formula with and without Celastrus. In terms of subjective experience of it, it’s just always been consistent. People like the version with Celastrus and not high amounts, but that’s panned out every time I run that A/B scenario. Those are three that I think are less appreciated.
Ari: Awesome. Greg, thank you so much for coming on the show. I really enjoyed this conversation. It’s nice to have a conversation with someone who is technically a business competitor of mine and just to have a really fun, very transparent conversation, and even get into some of the behind-the-scenes supplement formulation stuff that goes into that. Both from the perspective of how we assess different ingredients that are coming to market and also the business side of evaluating these kinds of things and if something makes sense.
The fisetin thing with ITP, there are so many complexities to it and it’s hard to be on the leading edge of it. Because if we sat around and waited for every ingredient that we used in one of our formulas to have 12 or 50 different human studies on it showing definitively, here’s the randomized controlled trials done by third-party independent labs, well, we might be waiting for 30 or 40 years for a lot of those studies to exist on many of these ingredients. I really appreciate you coming on the show, and it was an honor, it was a privilege to have this conversation with you. I really enjoyed it.
Dr. Kelly: Me too, Ari. It’s always fun getting to spend time hanging out with someone as bright as you are, so thank you.
Ari: Yes, thank you so much. I want to make sure you give a shout-out to the fact we’ve alluded to this number of times, but let’s just be very direct about it. You are with Neurohacker and you guys do nootropic formulations. You have Qualia Night, you have longevity formulas, immune formulas. Just give a little spiel for where people can find your products.
Dr. Kelly: Yes, yes. We’re neurohacker.com. We’re biggest on Instagram. That’s where we put a lot of time in to try to build a community and to provide a lot of content and information for people that may or may not want to buy products. I write blogs for neurohacker.com. Probably by the time this airs, our new product Qualia Synbiotic will be out. I wrote about an 18-page crazy-long blog on the gut ecosystem. I think that would be worth people’s time just taking a look at to learn more about the principles of how that ecosystem works.
Ari: Yes, absolutely. Greg, thank you so much. I look forward very much to our next conversation.
Dr. Kelly: Thanks, Ari.
00:00 – Intro
00:11 – Guest Intro Dr. Greg Kelly
01:18 – Can we extend the average lifespan?
10:33 – Interventions Testing Program
13:33 – Cellular senescence and fisetin
22:52 – The connection between stress and senescent cells
27:05 – Mitochondrial dysfunction and accelerated cellular aging
35:40 – The best nutrients to support the microbiome
39:29 – The biggest drivers of aging
44:00 – Melatonin supplementation – is it necessary?
54:00 – How sleep regulates our energy levels
1:01:46 – The primary causes of mental fatigue
1:11:40 – The best nootropics
Learn more about Dr. Kelly’s supplements here. Get 15% off your first purchase with the code ENERGY