Hormesis, Fasting, 
and Stress

Edward: What is the Calabrese hormetic lifestyle? Radical. Okay, so I am an over-the-top lunatic. Let's just describe me as a hormetic person. Anybody who follows my lifestyle is probably certifiably nuts.

Brent: Welcome to the Life Lab by Death Clock. I'm your host, Brent Franson. The mission of Death Clock is to help 100 million people live ten years longer. Today, we speak with Doctor Edward Calabrese about hormetic stress. Hormetic stress is basically when we are introduced to some low-level stress, like when we exercise or when we sauna, and it actually creates a response in our body that is good for us, that makes us healthier.

Brent: He is one of the world's leading experts in hormesis. He is a professor at UMass Amherst. He's been there for 50 years. He's a wonderful guest, a really interesting guy. I hope you enjoy.

Brent: Doctor Edward Calabrese, welcome to the show.

Edward: Thank you very much. Happy to be here.

Brent: So today we're going to be talking about hormetic stress, which I think of as the sauna episode. I think we'll speak much more broadly than just sauna. But before we get into what stress is, can you give us a sense of your background, your potted bio?

Edward: Yeah, my background for the audience to hear is I'm a standard routine university professor in the world of toxicology, located at the University of Massachusetts School of Public Health, and I am an environmental toxicologist. So I'm in the Department of Environmental Health Sciences at Amherst, Massachusetts. It's a big campus, probably 35,000 people.

Edward: And I've been here on this campus as a professor for 50 years. So I know where all the dead bodies are, so to speak. My area, in a general sense, is toxicology. But over time, I came to understand that life wasn't just about the bad things done to ourselves by environmental agents, but I got very interested in how the body deals with low-level stresses.

Edward: And I pursued that considerably over the last—since probably the mid-1980s. So I would have to say that I have been on the hormesis bandwagon, trying to teach other people how to spell the term and what it means for the last 40 years. But actually, just to let your audience know, even though I got on the bandwagon in the mid-1980s, there's a reason for that actually, they should know about that.

Edward: The very first ever conference on the topic of hormesis was on radiation hormesis. And it was conducted in Oakland, California in August of 1985. I may be the only one alive today who was invited to participate in that conference, but that's when things started to click in a positive sense for the awareness of hormesis.

Brent: So let's just define hormesis. The way I think about hormesis is it's a low-level stress to the body that creates some positive benefit. I might put a vaccine into this category—you can tell me if that's technically correct or not. We would put sauna into this category.

Brent: We would put fasting into this category, exercising—we go lift weights and we're actually damaging the muscles, but the muscles repair themselves in a way where they're stronger than they were before. So how would you define hormesis?

Edward: Okay. How I define hormesis is a dose-response relationship characterized by a low-dose stimulation and a high-dose inhibition. Now, typically, if you are looking at this in a graphic form, if it's a low-dose stimulation, you're going to see a bit of a bump going up on a dose response.

Edward: And then when you get to a high dose, it just goes down. So it's like an inverted U.

Brent: Just to be clear, if I put that in simpler terms, low-dose stimulation would mean health-improving. And then high-dose inhibition means health declining. So if we were to use sauna as an example, if I do 20 minutes at 185 degrees, I'm going to get a little bit healthier.

Brent: But if I stay in there for two hours, I might die. So I get healthier in the U curve—I'm getting some benefit out of it. And then at a certain point, in terms of the size of the dose, amount of time in the sauna, or the temperature, it drops off and it becomes bad for me.

Brent: Is that fair?

Edward: I think that's how 99% of the people out there would describe it. I have to tell you that I'm in the 1% that doesn't define it that way, although...

Brent: Is it technically wrong, or are you just saying you'd prefer to describe it more specifically?

Edward: In general, it's correct. I'll tell you where it gets a little squishy, because people should know about that. Okay, you have this low-dose stimulation and high-dose inhibition. Generally speaking, it's an adaptive response, meaning it probably gives some ramped-up benefit to the cells of the organism that experience a low-level stress.

Edward: But what I want the audience to know is that sometimes that low-level stress can be viewed as potentially harmful. In either direction, the low-dose stimulation or the high-dose inhibition may be something that you don't find to be attractive or desirable. Let me give you an example. We're probably all aware of harmful bacteria that could kill people or organisms.

Edward: And we're aware of antibiotics that we take when we get sick to kill bacteria. And this has been shown experimentally: you could take a harmful bacteria and give a low exposure dose of an antibiotic, and inject these microbes into mice.

Edward: At low doses, the antibiotic that's supposed to kill the bacteria actually stimulates the bacteria to grow. And at low doses, it stimulates it enough that it resulted in the death of those mice. At higher doses, the antibiotic acted like you would think it would.

Edward: It actually slowed down, shut down, and killed the bacteria, and the mice lived. So in that particular case, at low doses, the antibiotic was actually beneficial for the bacteria, but then those bacteria were harmful to the mice. So it gets a little confusing, but in that case, it's still following what you're saying. It just so happens that in reference to the bacteria, the low doses were beneficial for the bacteria.

Edward: The harmful doses were harmful to it.

Brent: Is that why you have to take the full course of the antibiotic, to avoid this response?

Edward: Yeah, exactly. This is very interesting too in the work, and might be quite surprising to people. In 2005, I published an extensive paper on tumor cell lines. I looked at about 135 tumor cell lines causing just about every kind of tumor that you could ever imagine in animals and humans.

Edward: Well, I took various sorts of chemicals, and what we found was that these 135 different tumor cell lines were all stimulated to grow and reproduce at low doses, and at high doses it shut down the tumor growth. As a result of that study, I obtained a very large database from the US National Cancer Institute that was testing thousands of chemicals with many different concentrations.

Edward: And they were looking for agents that wipe out the cancer cells to take right into the clinic to help people survive. I was interested in the low dose of these cancer agents. I found that most of those cancer agents that were designed and were very effective in killing tumor cells and preventing them from growing at low doses invariably guess what they did?

Edward: They enhanced the proliferation of the tumor cells. It was a hormetic response. They were doing something that was making that tumor cell adaptive or growing even faster than it was normally growing. So hormesis is a very interesting thing in nature where low-level stress can be translated into benefit, but those benefits have to be seen within the context of your life, the environment, or however you're trying to see the big picture.

Brent: So that's an interesting example because there are two layers at work there. The cancer drug at a low dose is being applied and it's actually strengthening the cancer. If you are the cancer, you would say that low dose is good for me, it's made me stronger. But the cancer is existing within a human being and hurting that human being.

Brent: So the response in that case at a low dose is actually negative for the human. It really depends on the angle at which you're looking at it.

Edward: To make it a little bit more complicated, it could be that the dose enhancing the tumor cell to grow may also be a dose that is enhancing the immune surveillance of your body.

Edward: So they could be counteracting each other. Life is very complicated. We don't really study things in a holistic sense; we tend to isolate and focus as targeted experts. But when you're looking at a cancer output, you're not just looking at how the tumor cell is growing—you're also looking at how your immune system is identifying, targeting, and getting rid of it.

Edward: And it acts on the immune system as well at low doses under different circumstances. You can activate the immune system hormetically to go right after and suppress metastasizing growth of tumors. It's a medical weapon.

Brent: The lack of predictability around the response at low doses feels like a word of caution on microdosing related to GLP-1s. We know studies show that they do well at higher doses in treating obesity.

Brent: And a lot of people are saying, "I'm going to use this off-label; I'm not obese, but there are heart benefits or other benefits, so I'll take a microdose of that medication and get a fraction of the result." I don't know if hormesis is at play here.

Brent: You can tell me if it is, but hormesis serves as a good example that just because something works at a certain dose doesn't mean you'll get the same outcome, just less of it, at a smaller dose. In the case of hormesis or antibiotics, taking less might actually risk strengthening the bacteria as opposed to wiping it out.

Brent: Our physiology is very complicated and you can't draw those kinds of conclusions.

Edward: Anytime you modestly stress an organism, it senses the stress and adapts to it. It upregulates a whole complex series of pathways and prepares itself. Hormesis detects a change and tries to strengthen itself against potential risk.

Edward: In the course of life, it has to ask, "How long do I have to keep this strength up?" In general, if you begin to upregulate hormetic mechanisms in an experimental system, they usually remain upregulated for seven to 14 days—one to two weeks.

Edward: For example, if you go in a sauna—or take very cold showers, as cold as the water gets—you really don't have to go every day.

Edward: If you're looking at targeted actions, you're going to turn on adaptive mechanisms that will be up and running in 24 to 36 hours. It takes a while because you're producing new protein and doing a lot of work, and then they are maintained at a certain level for a number of days.

Edward: Then they begin to slow down and you have to go back in and pump them up again. It depends on the cell, the species, and so forth. For myself, with something like a cold shower, I take it twice a week.

Brent: I think that's different with sauna. As I understand it, the research around sauna says the effect is dose dependent—the more you do it, the more benefit you get. Studies looking at reductions in all-cause mortality show that people who do it three days a week have smaller reductions than people who do it five or seven days a week.

Brent: What's happening there if you're sustaining the benefit?

Edward: In the big picture, a lot of literature supports hormetic benefits across biology. The most benefit you will get out of the system—whether for lifespan or any endpoint you measure—the biggest boost you're going to get on the optimal hormetic scale is 30 to 60%. That's really it. Nonetheless, 30 to 60% can be a magnificent lifesaver in so many ways.

Edward: The more hair you can grow, you know, whatever endpoint that you're trying to measure, how much these cells can, can reproduce the biggest boost that you're going to get on the optimal harmonic scale is 30 to 60%. And that and that's really it. And so but but nonetheless, 30 to 60% can be a magnificent lifesaver in so many different ways.

Edward: It puts you over the top. If we try to induce a heart attack or stroke on you and give a preconditioned hormetic dose to try to prevent that, you can pretty much prevent death from the heart attack and probably 80 to 90% of the damage caused by a stroke or heart attack.

Edward: A modest increase can have a profound benefit. In terms of extending life, the best you can do with hormesis is really 30 to 60%.

Edward: If humans can live 100 years unhormetized, the hormetic life could probably add 30 to 60% on that in an idealized fashion.

Edward: That's what hormesis can actually give you.

Brent: Stressing the body at low doses through hormesis can help us live longer, on the order of 30 to 60%, which is great. We can stress the body through exercise, sauna, or fasting. But how do we know the difference between harming the body and stressing the body?

Brent: I assume a small amount of cigarette smoking is not better than zero, or a small amount of cyanide is not better than zero. There are going to be cases where we harm ourselves at any dose, and cases where low doses actually strengthen us in some way.

Brent: How do we know the difference?

Edward: For the most toxic stuff we could be exposed to, like methylmercury, ricin, or lead, I have copious amounts of data showing that even the most toxic chemicals have adaptive features in experimental systems at very low doses.

Edward: Not that I would recommend taking methylmercury or lead, but the statement that any amount is going to be harmful is actually not true. Biological systems can sense danger and respond by producing an adaptive response to it.

Edward: So there's a lot of information, you know, on that.

Brent: A lot of your work reminds me of your research on radiation. Small doses of radiation are not bad for us; they might actually be good for us. In cases of radiation exposure, like Fukushima, we don't need to clean up to absolute zero radiation because the cost difference between absolute zero and a tiny detectable amount is very high, even though the biological impact is negligible, if not positive,

Brent: between a little bit of radiation and zero. If that's an accurate summary, you're saying that's true across basically any poison, just as it is for radiation?

Edward: Yes, I and others have published on that. Let me give you a radiation story: we live in a world of radiation from the Earth and cosmos. Researchers in different countries have attempted to raise animals in zones shielded from any possible source of radiation, going deep underground or into mountains.

Edward: They tried to block out any source of radiation and grew invertebrates and vertebrates in those settings to observe the absence of radiation. What do you think happens to those animals when grown without radiation?

Edward: They actually do a hell of a lot worse than the control group. In the insect world, they become sluggish, don't move around well, and don't want to reproduce. When you reintroduce background radiation into their environment...

Edward: They come to life, get very active, respond normally, and become much healthier in their behavior.

Brent: Is it just that the system is more alert? What's actually happening? The analogy I use to understand this is two villages: one village is never attacked, so over time they become complacent. They don't have a defensive perimeter or watchguards to make sure marauders don't attack.

Brent: They become more vulnerable to attack over time. The second village experiences periodic small attacks, so villagers keep watch, build fences, and train to defend, making them less vulnerable than the village that never gets attacked.

Brent: Is that a good analogy? Is there an equivalent set of biological processes happening when we're exposed to something harmful that parallels keeping watch and having a trained defensive group?

Edward: Yes, your cells are designed so that at a certain level, they detect changes. Just like a dog is very aware of environmental changes and stays alert...

Your cells sense changes in temperature, oxygen levels, and cellular conditions. In hormesis, a major driver is sensing changes in reactive oxygen species within cells.
Well, your cells are very much like like your pet. They can sense a change in temperature. They can sense a change in oxygen levels. They can sense they have many different the cellular senses. And and when it comes to harmonies is one of these, these these big players is when it senses changes in reactive oxygen species within cells.

Edward: If you have hydrogen peroxide above a certain low concentration, it turns on adaptive systems. Once you turn on a system, it plays out for one to two weeks.

Edward: To protect itself, the cell turns on protein synthesis and reorganizes, which takes 24 to 36 hours.

Edward: If no stress arrives, all the new protein is positioned while you live a quiet life again.

Edward: After seven to 14 days without action, the body calms down again. You have this upregulation and downregulation. Giving yourself a type of hormetic stress can protect you from the danger of a stroke or heart attack.

Edward: This can be applied to protect people at high risk of stroke. If I were running a nursing home or assisted living facility, I would introduce optimized stresses to protect against compromising conditions. Hormesis needs to be understood for human benefit.

Edward: You can introduce optimized stresses that will protect against conditions that could ultimately be very compromising to people. Hormesis really needs to be understood for human benefit; there are many ways it can be applied.

Brent: How do you recommend incorporating this? We've listed examples like sauna, cold plunge, fasting, and exercise, which all create a hormetic response in some way.

Brent: What else? If we could wave a magic wand and everyone adopted a set of habits to bring more hormesis into their physiology, what would that set of habits be?

Edward: What is the Calabrese hormetic lifestyle? I am definitely a hormesis radical—an over-the-top lunatic. Anybody who follows my lifestyle is probably certifiably nuts, but be that as it may.

Edward: What do I do that many people do that could have great benefits? The best medicine in life is exercise. I was a college junior in '66, so you can figure out how old I am.

Edward: I've always exercised, starting in sixth grade trying to run a sub-minute mile. In 1969, I started keeping a diary of what I did for exercise every single day. When the Challenger went down, I knew what I was doing exercise-wise.

Edward: When the Red Sox won the World Series, I knew exactly what I was doing. So I have an exercise log from 1969 to the present time.

Edward: Before I even knew the word hormesis, I knew exercise was compatible with good health. For the last 25 years, I've done intermittent fasting, but I've become radicalized on it. I used to be a somewhat normal person, but no longer.

Edward: Normal for me was eating two meals a day paired with a rigorous 75- to 120-minute workout to shift from glucose to ketone metabolism for three to four hours every day.

Edward: Seven years ago, I decided to challenge myself to go to one meal a day.

Edward: After about two weeks, I didn't get hungry during the day anymore. I've gone seven years with one meal a day without a single day of weakness.

Edward: Picture Thanksgiving: everyone sits down at 1:30 p.m. for dinner, and I'm the only one at the table not eating.

Brent: Why isn't that your one meal? To be specific: you exercise one to two hours per day, and fast for how many hours?

Edward: 23.

Brent: Because you have one meal, you fast 23 hours a day. At what time are you eating that meal?

Edward: 7:00 p.m.

Brent: So you wake up and consume exclusively water?

Edward: And green tea. Anyone following my work knows I've published extensively on hormesis in peer-reviewed literature, including on dietary supplements like Ginkgo biloba or aloe vera.

Edward: I take many supplements, but only those I have published a paper on. I don't go by advertisements or word of mouth.

Edward: I thoroughly review the literature with skilled collaborators, co-publish in top journals, and only then decide if I should take a supplement.

Brent: Which supplements are you taking?

Edward: I take about 40 different supplements on top of everything else I do.

Brent: Okay. Are you taking a fiber supplement?

Edward: I don't take a fiber supplement—that's about the only thing I don't supplement, because I get enough based on what I eat.

Brent: You get enough fiber in your diet. Are you taking magnesium?

Edward: Yes.

Brent: Are you taking fish oil?

Edward: Yes, I am.

Brent: Creatine?

Edward: Yes I am.

Brent: How much creatine?

Edward: I take 40 things, so I don't want to mistake the exact dosage, but yes, it's a standard part of my routine.

Brent: Do you take all these supplements at 7:00 p.m., or do you take them on an empty stomach?

Edward: I used to divide them between morning and afternoon when eating two meals a day. With one meal a day, you get much better GI tract absorption taking them with your meal.

Brent: Are sauna and cold plunge in the mix? It sounds like cold showers are.

Edward: If I had access to a sauna, I would use it. Working out for an hour and a half to two hours is sauna-like in itself.

Brent: How are you splitting that workout among cardio, flexibility, balance, and strength?

Edward: As soon as I wake up, I do 30 minutes of bodyweight stretching and strengthening, like push-ups.

Edward: For outdoor exercise, I'm a year-round bicyclist in New England.

Edward: I ride down to 26 degrees Fahrenheit, as long as there isn't snow or ice. Short day length in winter is the main challenge.

Edward: In the summer, I might go for a 50-mile, three-hour ride in the afternoon over steep hills after fasting for 21 hours.

Edward: Yeah.

Brent: Are you vegetarian or vegan? What does your diet look like, and what is the size of that meal?

Edward: Transitioning to one meal a day required dietary adjustments. When I switched seven years ago, I lost 15 pounds within a few months.

Edward: I am not heavy and couldn't afford to lose that weight. I prefer eating a comfortable meal without feeling bloated.

Edward: To maintain my one-meal routine without losing weight, I needed to increase calorie density healthily.

Edward: I incorporated nutrient-dense, high-calorie foods like mixed nuts and trail mix.

Edward: That allowed me to put back on 10 to 12 pounds.

Brent: You eat those mixed nuts during that meal, not throughout the day?

Edward: That is my dessert.

Brent: Why is your mealtime at 7:00 p.m.? Recent longevity discussions focus on eating earlier—like Bryan Johnson eating at 11:00 a.m.—so digestive time doesn't impact sleep quality.

Edward: During my years at UMass, I walked downtown for lunch with students or had breakfast and dinner with my wife.

Edward: When I switched to one meal, skipping breakfast created home routine friction, and drinking only green tea at lunch annoyed colleagues.

Edward: I chose 7:00 p.m. so I can share dinner with my wife and maintain a social life alongside work.

Brent: His choice relates to sleep quality. You're saying you eat at 7:00 p.m. because you love your wife and want to share dinner with her.

Edward: Exactly. Even if eating at 11:00 a.m. added two years to my life, I'd choose the social experience and family routine.

Brent: The family meal is very important. I have four kids and my wife is a great cook; cutting out dinner would disrupt our whole family system.

Edward: My two sons and wife watch what I do, but none follow my routine—they treat me as an N-of-1 study. I have more influence in the broader world than at home.

Brent: That tends to be the case. How are your biomarkers—your cholesterol, blood glucose, and A1C levels?

Edward: They're excellent.

Brent: Do you take any medication?

Edward: No, I don't take any prescription medications. I'm turning 80 in August, and doctors are surprised when I tell them I have zero prescriptions.

Edward: I have too many supplements to fit standard medical charts, so those conversations end quickly.

Brent: Is part of it genetics for you? How were your parents at 80?

Edward: My father's family was from Italy and my mother's from Poland. They were uneducated in formal schooling, but knew how to work hard and survive in America.

Edward: My father was a janitor and lived to 95. He smoked Chesterfield Kings for 20 years before quitting cold turkey in his 40s.

Edward: My mother lived to 86. Many relatives lived close to 90 or beyond without special health routines.

Edward: So I inherited longevity genes from both sides of my family.

Brent: Is your extreme lifestyle a direct application of your research on hormesis and adaptive stress, or would you have been a health enthusiast regardless of your major?

Brent: Or do you think you would have been a health freak? Either way, no matter what you studied.

Edward: I started tracking my exercises in 1969, so I was interested early on and likely would have followed health trends regardless of my field.

Edward: My research and life reinforce each other; my work directly informs how I live, which is rare and rewarding.

Edward: It's frustrating that despite hormesis growing into a recognized discipline, many scientists remain hyper-focused on narrow subfields and miss the broader application.

Edward: Most scientists who observe hormesis don't recognize the full picture due to narrow specialization.

Edward: Hormesis is an untapped capability to optimize public health. I'd welcome discussing its potential with healthcare leadership at HHS.

Edward: Hormesis sits at the center of public health.

Edward: A major paper in Cell listed hormesis among the eight hallmarks of health, marking its transition into mainstream science.

Edward: I saw that as validation for decades of work in the field.

Brent: Why are you proud of taking zero medications? Isn't the difference between a medication and a supplement simply that medications undergo rigorous randomized controlled trials to prove efficacy—a much higher bar than for supplements?

Brent: There's nothing inherently wrong with medication; they are tested substances that cleared high standards. Why is taking zero medications inherently better if you take 40 supplements?

Edward: I view not needing prescriptions as a personal health report card, alongside good genetics from my parents.

Brent: Isn't that a false dichotomy? Saying taking medication implies something is wrong while supplements are purely for wellness? Both are substances put into the body, and the body doesn't distinguish FDA approval status in its physiological response.

Brent: You know, the body doesn't really care about that. You know, it doesn't draw that type of distinction.

Edward: That's a fair point worth reflecting on. In the 1980s, I researched environmental pollutants and high-risk groups, which led to a New York Times profile where the journalist challenged my assumptions.

Edward: The reporter pointed out logical contradictions in my views, which made for a memorable interview.

Edward: Your point about supplements versus medications is an insightful question I haven't fully considered before.

Edward: My perspective may have been too simple. People often criticize my disciplined lifestyle as extreme, but staying healthy feels like validation of my approach.

Edward: Appearing healthy feels like an answer to those who doubt my lifestyle choices.

Brent: I'm thinking more about the supplement industry and its lack of strict regulatory barriers compared to pharmaceutical trials.

Brent: We tend to distrust big pharma despite strict oversight, while giving supplements a pass. I've begun questioning whether taking zero medications is automatically superior.

Brent: I don't criticize your routine, but extreme discipline can be hard for most people to replicate without extreme willpower.

Brent: Many listeners might feel they can't fast 23 hours a day, exercise two hours daily, or take 40 supplements consistently.

Edward: Most people prefer a conventional routine, but staying active in research at 80 keeps me engaged and fulfilled.

Edward: Intellectual stimulation and social engagement contribute significantly to health and longevity.

Edward: You make your own luck, and engaging with academic debate has kept me energized.

Edward: And it's for me, it's always been let's let's fight it out with facts and let's fight it out in the journals and we'll see who wins.

Brent: You know you're making an impact when people challenge your ideas. You certainly don't seem 80. Thank you for sharing your work on hormesis with us.

Edward: It was a lot of fun and good luck.

Brent: The Life Lab by Death Clock is recorded in Boulder, Colorado and San Francisco, California, produced by Patrick Goodnow, music by Patrick Lee, and hosted by Brent Franson, founder and CEO of Death Clock.