The Cellular Mechanisms of Stress

In this episode of the Health Optimization Medicine Podcast, Dr. Scott Sherr, Dr. Allen Bookatz, and Jodi Duval explore:

• Why can fatigue, brain fog, and exercise intolerance persist even when standard laboratory results appear normal?
• How does the Cell Danger Response change mitochondrial energy production and cellular signaling when a cell perceives a threat, and what are the three phases of this response?
• Why can ongoing environmental, infectious, gut, or psychological stressors keep sending danger signals and prevent the cell from progressing from inflammatory defense into repair and recovery?
• What role can gut barrier integrity, LPS, mitochondrial nutrients, circadian rhythm, sleep, and parasympathetic regulation play in helping the cell move through the Cell Danger Response?
• How can hormetic stressors such as exercise, temperature exposure, and hyperbaric oxygen therapy potentially support adaptation, and why does the dose matter when a system is already under stress?
• Why does the HOMeHOPe approach emphasize clinical metabolomics, organic acids, HRV, and mitochondrial function markers to help determine how much stress an individual can safely tolerate?
• What does the HOMe Cell Danger Response completion protocol actually involve, and how can threat-load reduction, titrated hormesis, mitochondrial support, parasympathetic signaling, gut barrier support, and circadian alignment work together to help the cell complete its response?

What We Discuss:

00:00 – What Stress Looks Like Inside the Cell
00:51 – The Cell Danger Response Explained
01:42 – What Does a Cell Need to Complete the Danger Cycle?
02:05 – Why Fatigue Can Exist with Normal Labs
03:14 – The Three Phases of the Cell Danger Response
04:41 – When the Danger Response Does Not Complete
05:20 – LPS, Gut Barrier Integrity and Ongoing Danger Signals
06:18 – Anti-Aging vs. Peak Healthspan 
07:26 – The HOMe Cell Danger Response Completion Protocol
07:38 – Step 1: Threat Load Reduction
08:06 – Step 2: Titrated Hormetic Stress
08:29 – Step 3: Mitochondrial Nutrient Support
08:49 – Step 4: Parasympathetic Safety Signaling
09:06 – Step 5: Gut Barrier and Circadian Support
09:41 – Do This on Monday: Extended-Exhale Breathing
10:34 – The Strongest Critique of the CDR Framework
11:21 – Why the Dose of Stress Matters
11:47 – Three Takeaways for Cellular Stress
12:16 – Why the Cell May Stay in an Inflammatory State
12:48 – Completing the Cell Danger Response
13:43 – From Stress Response to Health Optimization

Full Transcript:

[00:00:00] Dr. Allen Bookatz: Your mitochondria cannot tell the difference between a virus, a toxin, and, and a relentless email inbox. All three get read as the same thing, danger. When that danger signal never turns off, your cells do exactly what they're built to do. They hunker down. They stop producing energy at full capacity at least, and they wait for the all clear.

[00:00:25] Dr. Allen Bookatz: So if you're exhausted for, like, no obvious reason, your cells aren't malfunctioning. They're just waiting for you to tell them that it's safe

[00:00:37] Dr. Scott Sherr: Welcome back to the Health Optimization Medicine Podcast. My name is Dr. Scott Sherr, board-certified internist and health optimization medicine doctor. Joining me today on our clinical panel are Jodi Duval, naturopathic doctor and HOMe practitioner, and Dr. Allen Bookatz, chief of emergency medicine and HOMe doctor.

[00:00:51] Jodi Duval: So today we are opening this month's theme on stress with a cellular deep dive, as we always do. [00:01:00] Is your fatigue actually your mitochondria trying to save you? Hmm. So we're unpacking Dr. Robert Naviaux's cell danger response, the ancient hardwired program every cell runs when it perceives a threat, and why so many of our patients are stuck mid-program.

[00:01:18] Dr. Allen Bookatz: I'm so glad you said that, Jodi. Mid-program reminds me of like the, like a stalled computer. And- Hmm ... you know, and that, that framing overall takes us right into our first mandatory comparative reframe, functional medicine versus HOMe/HOPe salutogenesis. So we, in functional medicine, they approach chronic fatigue and inflammation by hunting for the trigger, the toxin, the pathogen, the deficiency.

[00:01:42] Dr. Allen Bookatz: By suppressing or removing it, that's how the care is rendered, and it's legitimate. And in some senses in HOMe/HOPe, we actually ask similar questions, but we actually ask a fundamentally different question here We ask, what are the conditions that the cell needs to [00:02:00] safely complete this, its danger cycle and return it to a full bioenergetic output?

[00:02:05] Jodi Duval: Alan, that brings us to our $64,000 clinical question of the day. Why do patients with completely normal labs still present with profound fatigue, brain fog, and exercise intolerance? 

[00:02:18] Dr. Scott Sherr: And we see this all the time in clinical practice, Jodi, coming to us with normal labs in quotes, right? It's because normal labs measure structure, not signaling state.

[00:02:26] Dr. Scott Sherr: And a cell can be structurally intact and still be metabolically paused in the cell danger response. Standard labs weren't built to catch a mitochondrion that's deliberately downshifted ATP output because it still perceives the environment as unsafe. 

[00:02:40] Dr. Allen Bookatz: Yeah, Dr. Scott's exactly right here. So the patient sitting in front of you, right?

[00:02:45] Dr. Allen Bookatz: They're-- we see it all the time. Mm-hmm. The blood work is clean, their imaging is clean. We check some of just the, the basics of their endocrine system, and nothing is in crisis, and yet they still can't get through a workday. You know, we use terms like adrenal [00:03:00] fatigue or my adrenals are burnt out. But in fact, the mitochondria themselves are actually running this legit defensive program here, and nothing on a standard panel is designed to see things like purinergic signaling or a stalled metabolic phase.

[00:03:14] Jodi Duval: So on that note, let's go deep on the mechanism, Alan. So walk us through the three phases of the cell danger response. 

[00:03:24] Dr. Allen Bookatz: All right. So I like to think of it like a construction site after an accident, right? So we have phase one, CDR1. That's the, we'll call it inflammatory lockdown state. That's-- it's glycolytic, so ATP gets released extracellularly as that purinergic alarm and immune cells get called in and the site overall gets fenced off.

[00:03:45] Dr. Allen Bookatz: So think of it like when you fall down, you scrape your knee. What happens, right? Immediately you get pain, it gets red, it gets tender, and it gets swollen. So you're spl- splinted and you're instructed biologically not really to move it. CDR2 [00:04:00] is proliferative. So we have cells that are now dividing, new tissue gets laid down, and the crew starts rebuilding.

[00:04:06] Dr. Allen Bookatz: We carry on our analogy. That's now our scab is forming, right? And we're having a little bit of pain, but we know that it's-- it seems to be filling in, we'll just say. But there still needs to be care taken because the skin is not necessarily intact. And then we have phase three, CDR3, and that's differentiation and recovery.

[00:04:25] Dr. Allen Bookatz: So mitochondrial biogenesis comes back online, oxidative phosphorylation resumes, and the fence finally comes down, and there is safety. And that's obviously now where everything is healed. We have intact skin, and we're ready for the next fall. 

[00:04:39] Dr. Scott Sherr: Yeah. If it all happens. 

[00:04:41] Dr. Allen Bookatz: Then it all begins all over again.

[00:04:43] Dr. Scott Sherr: Yeah, if it all happens in the first place, which we'll talk about here in a minute. And, and but this brings us to our second mandatory comparative reframe, conventional preventative medicine versus health optimization medicine. Conventional preventative medicine screens for disease markers that might show up in maybe 20 years, cardiovascular risk scores, cancer screening [00:05:00] intervals.

[00:05:00] Dr. Scott Sherr: What HOMeHOPe does is ask what the cell's real-time metabolic and purinergic signaling state is telling us right now, today, about its capacity to generate energy, Jodi. 

[00:05:09] Jodi Duval: Absolutely. So from a naturopathic lens, I guess this is also why chronic environmental and gut burden matters so much, as we all love talking about little pieces of shit.

[00:05:20] Jodi Duval: And so here we are again. LPS. We're back 

[00:05:23] Dr. Scott Sherr: at little 

[00:05:24] Dr. Allen Bookatz: pieces of shit. LPS. 

[00:05:24] Dr. Scott Sherr: LPS. Yes. 

[00:05:26] Jodi Duval: Tell me about- 

[00:05:26] Dr. Scott Sherr: I feel like we should have, like, sign that we- ... little pieces of shit ... we, we, we should, like, have signs that we put up every time we say LPS. Yeah. Okay. 

[00:05:31] Dr. Allen Bookatz: I, uh... That's my endearing childhood nickname right there. 

[00:05:34] Dr. Scott Sherr: Yeah.

[00:05:35] Dr. Scott Sherr: Yeah, yeah. Oh, Alan. That's for a different podcast maybe. Oh, 

[00:05:39] Jodi Duval: no, Alan. 

[00:05:42] Dr. Scott Sherr: Although that's how the, the cell danger response gets stuck too with that, those kinds of things. 

[00:05:46] Jodi Duval: That's trauma. Yeah. Yeah. Absolutely. 

[00:05:49] Dr. Scott Sherr: Yeah. 

[00:05:49] Jodi Duval: So when we, when we obviously have-- We, we talk about lipopolysaccharides or the little pieces of shit, we have to talk about the leaky gut barrier.

[00:05:55] Jodi Duval: And so that lets those through into circulation, and that's [00:06:00] how the endotoxin, you know, they keep signaling danger to the mitochondria continuously. So the cell never gets this clean window to move from CDR1 into CDR2 and 3, and that is that spiral of doom on the screen when your program gets stuck.

[00:06:18] Dr. Allen Bookatz: Yeah. It's like a festering open wound that just won't heal. So anywho, that, that lands us to our third comp-- mandatory comparative reframe here. Anti-aging medicine versus HOMeHOPe peak health span. So in anti-aging, it sounds like, you know, against aging, 

[00:06:36] Dr. Scott Sherr: which is sort of inevitable, I suppose. However, age-related diseases are not.

[00:06:40] Dr. Allen Bookatz: Anti-aging medicine chases lifespan extension and biomarkers of chronological aging. And it's not necessarily wrong, it's just not fully complete. HOMeHOPe cares about whether your mitochondria are actually completing their danger cycle every single day, moving through CDR 1, 2, 3. Because that daily completion is what [00:07:00] peak health span is actually all about.

[00:07:02] Dr. Scott Sherr: The Health Optimization Medicine Conference is happening. Two days of events, October 2nd and 3rd, Chicago, Illinois, at the Drake Hotel. CMEs available to practitioners who need them. Just 150 people with amazing speakers on the cutting edge of health and wellness. This is a community. It's not your average conference.

[00:07:19] Dr. Scott Sherr: If you're interested, go to homehope.org and save 25% on your ticket by using conference25 at checkout. I hope to see you there. 

[00:07:26] Jodi Duval: All right. So let's deliver the actionable one cent solution. Scott What's the step-by-step protocol for helping a stuck cell complete its danger cycle? 

[00:07:37] Dr. Scott Sherr: All right, so let's break it down here.

[00:07:38] Dr. Scott Sherr: So here is the home cell danger response completion protocol. The first one, they're all super important. Like, I don't think I can choose which one's more important here. There, there's four or actually five steps here, if you can follow along. So number one is threat load reduction. Identify and reduce active danger inputs, environmental toxins, unresolved infection, [00:08:00] food sensitivities, and chronic psychological stressors, so mitochondria stop receiving continuous unsafe signaling.

[00:08:06] Dr. Scott Sherr: This is not an easy step, everyone, but it's so, so important to address. Number two is titrated hormetic completion, meaning use properly dosed acute stressors, zone two exercise, contrast temperature exposure, or hyperbaric oxygen therapy, which I know and love, as a controlled threat resolve signal that teaches the system it's safe to complete the cycle, followed by real recovery windows.

[00:08:29] Dr. Scott Sherr: Number three is mitochondrial nutrient support, things like CoQ10, PQQ, magnesium, and NAD+ precursors to support the metabolic machinery as the cell transitions from CDR1 through CDR3. Number four, parasympathetic safety signaling. So nightly vagal tone work. Alan loves to sing. I can sing, too. You can hum.

[00:08:49] Dr. Scott Sherr: You can, you can do things with your earlobes as well, which you can also use, right? Ooh, I love my earlobes. Strange things with your earlobes. Yeah. Okay, but all right. But extended ex- exhale 

[00:08:59] Dr. Allen Bookatz: Scott, can you, [00:09:00] can you rub my earlobes? In, in the name of parasympathetic safety, 

[00:09:05] Dr. Scott Sherr: of course. Only, only because you asked nicely.

[00:09:06] Dr. Scott Sherr: But- This is a little bit of a K-hole ... in addition, in ad- Okay, there's other things too, guys, right? So extended exhale breathwork or HRV biofeedback to interrupt chronic sympathetic input that keeps retriggering that purinergic alarm. And number five, gut barrier and circadian support. Address gut mucosal integrity to reduce those LPS, those little pieces of shit-driven CDR1 signaling, and anchor circadian rhythm and sleep architecture, which does double duty with glymphatic clearance as well.

[00:09:34] Dr. Allen Bookatz: Did you just say double duty under gut barrier? 

[00:09:37] Dr. Scott Sherr: I, I did, Alan. Nice, nice work. Nice work. 

[00:09:41] Dr. Allen Bookatz: All right, yeah. Taking us back to childhood here. Yeah. So, um, the, the original CDR1. All right, so Scott gave you folks the whole protocol here. So here's your do this on Monday action, the part that costs nothing. Well, maybe some time and some oxygen, I suppose.

[00:09:55] Dr. Allen Bookatz: But let's-- We're just gonna, we're actually just gonna do this together. So for the next five [00:10:00] minutes, all of us here, we're gonna do some extended exhale breathing. I'm gonna go ahead and count us. Ready? So everyone, four seconds in. And eight seconds out

[00:10:16] Dr. Allen Bookatz: And for-- No, I'm not gonna keep going here. So, but you can go ahead and just- You get the idea. Yeah ... take that loop and put that on repeat, and then you'll be, you'll be good. So but anyway, it-- by doing that, by extending your out breaths, it's a direct parasympathetic safety signal telling your mitochondria that the threat has now passed, and it's safe to move into repair.

[00:10:34] Jodi Duval: Yeah. That's exactly right. If we're breathing, we, we're not running away from the tiger, are we, Alan? Mm. All right, so let's steel man this counterargument. So what's the strongest critique of this framework, Alan? 

[00:10:49] Dr. Allen Bookatz: All right, so let's go ahead and step into those, um, nice, uh, shiny shoes of the metabolic skeptic here.

[00:10:58] Dr. Allen Bookatz: So if a patient's mitochondria [00:11:00] are already in a defensive posture and it's stuck there, then isn't deliberately adding a stressor on top like, you know, intensive exercise or heat just adding more danger signal on top of an overly already overloaded system? I, I don't know. That's a fair concern if the dose isn't respected, right?

[00:11:21] Dr. Scott Sherr: Yeah, Alan, that is actually a legitimate critique for an untitrated dose, and it leads us to our fourth mandatory comparative reframe, lifestyle medicine versus HOMeHOPe metabolomic guidance. So standard lifestyle medicine gives broad unmeasured advice like reduce your stress or exercise more. HOMeHOPe uses precision clinical metabolomics, organic acids, HRV, and mitochondrial function markers to titrate exactly how much hormetic stress a given patient's system can safely metabolize right now.

[00:11:47] Dr. Scott Sherr: So the dose builds capacity instead of adding to the danger signal. With this part, I, I want to go over three clippable takeaways from this episode. So takeaway one is fatigue and brain fog with normal labs can be smart, protective for [00:12:00] the mitochondria, not a sign the cell is broken. 

[00:12:02] Jodi Duval: Absolutely. And I think takeaway two should be the cell danger response has three phases, inflammatory, the cut, proliferative, the forming of the scab, and restorative when the scab comes off.

[00:12:16] Jodi Duval: And so chronic illness often means the cell is stuck in the first one. We keep ripping off the skin before the scab starts to form, and it continues to be inflamed. 

[00:12:27] Dr. Allen Bookatz: Takeaway three, so reducing the ongoing threat load and sending titrated safety signals through hormesis, vagal tone, and gut and circadian rhythm support.

[00:12:39] Dr. Allen Bookatz: So let that cell finish the cycle that it knows how to run. 

[00:12:45] Dr. Scott Sherr: Alan, take us away. All right, so here's where we land. 

[00:12:48] Dr. Allen Bookatz: The cell danger response is salutogenesis in real time, a deep program that every cell already runs to protect you, and our job isn't to override it with suppression. It's [00:13:00] to give the cell the exact chemical, metabolic, and psychological safety signals that it needs to complete the program on its own.

[00:13:07] Dr. Allen Bookatz: There's wisdom here, folks. If you've got a patient whose labs look fine but who still can't g- get through their day, then their cells aren't healing. They're just waiting for that all-clear signal, and that's a signal we can send 

[00:13:22] Dr. Scott Sherr: Absolutely, Alan. I mean, it's not easy. We went through the process, the five steps above.

[00:13:27] Dr. Scott Sherr: It, it-- This is not an easy process for our patients or any of us to create this all clear. But when we can, it's truly how we shift physiology and really help people have a more health-optimized life. And so I just wanna thank everybody for listening to another episode of the "Health Optimization Medicine" podcast.

[00:13:43] Dr. Scott Sherr: To learn more about our framework at HomHope, check out our practitioner certification at homehope.org. You have multiple modules to check out, including our bioenergetics module, which is specific about the mitochondria. We have our exposomics module ab-about toxins, our metabolomics module around real-time cellular processes.

[00:13:59] Dr. Scott Sherr: And [00:14:00] join us next week as we continue to this month's stress theme with another deep dive into clinical health optimization. We'll see you next time. 

Bye.

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