Metformin is Poisoning Your Cells

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

• Why did the massive 21-year DPPOS study shock the anti-aging establishment by showing metformin completely failed to outperform a placebo for reducing long-term multimorbidity risk?
• How does taking metformin as an off-label longevity drug act as a "mild toxin" to healthy cells, and why is complex 1 inhibition detrimental to a non-diabetic individual's mitochondrial bioenergetics?
• Why do active individuals taking metformin experience blunted cardiovascular fitness gains, reduced muscle hypertrophy, and a higher rating of perceived exertion during their workouts?
• How does conventional "anti-aging" medicine's focus on preventing disease with off-label drugs fall short of true health optimization and the maintenance of a peak biological quality of life?
• How does Health Optimization Medicine use clinical metabolomics to identify bioenergetic bottlenecks, and why is it crucial to strictly pulse natural glucose-sensitizing adaptogens (like berberine) only on rest days?

What We Discuss:

00:00 - Metformin is a Mitochondrial Poison
01:35 - The Rise of Metformin in the Biohacking Community
02:53 - The Landmark DPPOS 21-Year Pre-Diabetes Study (JAMA, June 2026)
05:41 - The Bioenergetics of Exercise and Mitochondrial Hormesis
06:24 - How Metformin Blunts Cardiorespiratory Fitness (VO2 Max Cut in Half)
07:45 - The mTOR Blockade: Why Metformin Halts Muscle Hypertrophy
09:17 - Lifespan vs. Healthspan: The Biological Peak Quality of Life
11:03 - The Solution: The 3-Phase Health Optimization Protocol
12:05 - Monday Morning Protocol: Circadian Anchors, Co-factors, and Rest-Day Pulsing
13:11 - Targeted Electron Support: Methylene Blue as a Complex I Bypass
13:31 - Salutogenesis in Practice: Imbalances vs. Disease Prevention
15:35 - Refining the Clinical Position: Healthy Biohackers vs. Sedentary Populations
17:37 - Salutogenic Framework: Building Cellular Coherency and Metabolic Safety
18:06 - Defining True Health: Salutogenesis and the Future of Medicine

Full Transcript:

Dr. Ted Achacoso (00:00): Metformin is a mitochondrial poison. Why are healthy biohackers taking a Complex I inhibitor to live longer? The massive 21-year prediabetes follow-up study just dropped in the Journal of the American Medical Association, and the results are an absolute shock to the anti-aging establishment. Metformin completely failed to outperform a placebo for reducing long-term multimorbidity risk.

Meanwhile, intensive lifestyle intervention slashed multiple chronic disease risks by over 20%. We have been sold a metabolic illusion. You cannot chemically poison your way to cellular longevity while ignoring the fundamental laws of mitochondrial bioenergetics.

Dr. Allen Bookatz (00:45): Welcome to the Health Optimization Medicine Podcast. Here is your clinical team for today: Dr. Scott Sherr, board-certified internist and Health Optimization Medicine practitioner; Jodi Duval, our naturopathic doctor out of Australia; our clinical metabolomics specialist for today, Dr. Jup Kuipers, a general practitioner from Amsterdam; and leading the scientific review today, Dr. Ted Achacoso, founding pioneer of Health Optimization Medicine and Practice, joining us from Washington, D.C.

And yes, me, Dr. Allen Bookatz, chief of emergency medicine and HOMeHOPe practitioner. Today, we are going after one question: Is your longevity pill silently blunting your mitochondrial fitness? We’ll get the mechanism, the clinical protocol, and the one thing most practitioners get wrong in the next 25 minutes. Let’s get into it.

Dr. Scott Sherr (01:35): Welcome back, everyone. I’m Dr. Scott Sherr, your showrunner for today. We are diving straight into the deep end of the metabolic pool. For the last 10 years, metformin has been the darling of the anti-aging and biohacking communities. Influential longevity doctors have been handing it out off-label to healthy, non-diabetic adults like candy, simply to lower blood glucose and mimic caloric restriction.

But on June 15, 2026, the National Institutes of Health released the long-term results of the DPPOS study in JAMA. This brings us to our clinical question of the day: Should a metabolically optimized, active individual ever use a Complex I inhibitor to extend their lifespan? Dr. Bookatz?

Dr. Allen Bookatz (02:15): Thank you, Dr. Scott. Here’s the real $64,000 question. Conventional and anti-aging medicine are locked into preventing disease. That’s right, preventing disease. They look at a healthy person and think, “Let’s get them on some type of medicine or pill so they don’t become diabetic later.”

But therein lies the trap. Prevention of disease is still disease-centered thinking. Health optimization is health-centered. The real question isn’t whether this lowers a number that pops up on a glucometer or a simple lab. It’s: What is this off-label drug actually doing to a healthy cell?

Jodi Duval (02:53): That is definitely a massive disconnect, Allen. Just because you are not sick does not mean you are healthy. When you give a healthy cell a mild toxin like metformin, you are forcing it into a protective state.

Let’s refer this to Jup, our HOMe expert for today, and break down the clinical metabolomics of this prediabetes study. Jup, what did this 21-year follow-up actually show us?

Dr. Jup Kuipers (03:25): Thank you, Jodi. Let’s lay out the hard science published in JAMA on June 15, 2026. They conducted a 21-year follow-up analysis of the landmark Diabetes Prevention Program, or DPP, and its outcomes study, known as the DPPOS.

They followed over 1,100 participants for more than two decades. The study was titled “Lifestyle and Metformin Interventions and Risk of Multimorbidity in Adults With Prediabetes.” The researchers tracked multimorbidity, which means developing two or more chronic conditions over time, including hypertension, cardiovascular disease, chronic kidney disease, cancer, and cognitive decline.

The results were quite stark. The intensive lifestyle intervention group, which focused on diet and achieving at least 150 minutes of moderate-intensity exercise per week, had a 21% lower risk of developing two chronic conditions and a 25% lower risk of developing three. By contrast, the group assigned to metformin did not experience a statistically significant reduction in multimorbidity risk compared with the placebo group.

The hazard ratio was 0.91, meaning it failed to show a statistically significant difference.

Dr. Ted Achacoso (04:50): Let me jump in here because this gets to the absolute core of our framework. Pathogenesis is the study of the root causes of disease, and that area falls under illness medicine and functional medicine. Salutogenesis, on the other hand, is the study of the root causes of health, and that area falls under Health Optimization Medicine and Practice.

Metformin belongs to the disease pathway. It was designed to treat type 2 diabetes by inhibiting Complex I of the mitochondrial electron transport chain. When you inhibit Complex I, you decrease ATP production, which increases the AMP-to-ATP ratio. This activates AMP-activated protein kinase, or AMPK, which suppresses hepatic gluconeogenesis and lowers blood glucose.

We also have a natural cofactor that activates the AMPK pathway: alpha-lipoic acid.

Dr. Jup Kuipers (05:39): Exactly, Ted. While that is useful for a person with diabetes, profound insulin resistance, and a highly dysfunctional liver, it is a disaster for a healthy, active individual. Let’s look at the bioenergetic mechanisms of exercise.

When you exercise, your skeletal muscles contract and create a brief, acute spike in reactive oxygen species, or ROS, temporarily depleting ATP. This acute, controlled cellular stress is a salutogenic signal. It tells the cell to undergo mitochondrial biogenesis, meaning to remodel and build more efficient, more coherent mitochondria to adapt to a workload. This is called mitochondrial hormesis.

Dr. Scott Sherr (06:24): But when you introduce metformin, you block that entire signal. Metformin’s Complex I inhibition blunts the exercise-induced adaptive stress response. Double-blind, placebo-controlled trials have demonstrated that adding metformin to aerobic exercise blunts cardiorespiratory fitness gains, meaning your VO2 max improvement is cut in half compared with exercise alone.

Jodi Duval (06:45): Absolutely, Scott, and it is even worse for strength training and hypertrophy. A landmark 2019 study showed that metformin actively blunts muscle hypertrophy and strength gains in response to progressive resistance training. I see this with clients who have been on metformin, and they report feeling the effects as well.

It interferes with the mTOR pathway and mitochondrial remodeling in muscle fibers. If you are lifting weights while taking metformin off-label, your muscles cannot build the machinery to grow stronger. They comment that they do not feel like they are gaining anything while they are in the gym.

Dr. Allen Bookatz (07:27): I see this clinically all the time, Jodi. Patients on metformin tell me everything feels harder than it normally should. We have a term for this: a higher rating of perceived exertion, or RPE. I think of it as their mitochondria being chemically throttled.

They are working harder for the same output. Lactate builds up faster, and they are stuck with nagging, unexplained fatigue and generalized weakness. They cannot hit their gains or their repetitions when they are trying to work out. They are trading away actual cardiorespiratory fitness, the single strongest predictor of all-cause mortality, for marginally lower fasting glucose numbers. It is a pretty terrible trade-off.

Dr. Ted Achacoso (08:16): That’s why anti-aging medicine falls short here. Lifespan without healthspan is not a win. Anti-aging medicine tries to extend lifespan using off-label xenobiotic drugs, but it ignores biological peak quality of life.

The target is not just a longer quantity of life. The target is a longer biological peak quality of life. If you are reducing your VO2 max, blunting your muscle mass, and making exercise feel harder, you are actively accelerating biological decay in the name of anti-aging.

Dr. Scott Sherr (08:47): Pardon the interruption. This episode is brought to you by the fourth annual Health Optimization Medicine and Practice Conference, happening October 2 and 3 in Chicago, Illinois, at the Drake Hotel.

You are all cordially invited to something that is not a typical conference. This is truly a community, and you will feel that the moment you walk in. This is not wellness aesthetics or disease management dressed up in optimization language. This is actual, rigorous, measurable, deeply human health optimization.

It is a small group. Only 150 seats are available, and we have already sold a lot of them. It is going to be an intimate gathering. If you want your ticket, you need to get it soon. We have a great lineup of speakers, including Dominic D’Agostino, JJ Virgin, Kiran Krishnan, Dr. Ted Achacoso, the founding pioneer of Health Optimization Medicine and Practice, myself, Dr. Scott Sherr, Lucia Aronica, an epigenetics researcher, Elizabeth Yurth, and many more.

If you are a medical practitioner, we will have at least five CME credits for you. This is a room that is going to genuinely change how you practice and, I think, how we all live. We have a discount, but it is only for a short period of time.

Go to homehope.org and save 25% on your conference ticket by using code CONFERENCE25 at checkout. That’s homehope.org, code CONFERENCE25 at checkout. Get it soon because we are selling out fast. I hope to see you there. Take care.

How do we solve this? Let’s talk about the actual Health Optimization Medicine protocol. In our framework, lifestyle advice becomes precision medicine only when health markers guide the prescription. We do not guess. We measure. Jodi, let’s walk through how we use clinical metabolomics to guide this transition away from chronic Complex I inhibitors.

Jodi Duval (10:24): As always, Scott, our first step is to run a comprehensive organic acids panel, wherever you are in the world. There are different versions of this, including NutrEval, metabolomics panels, and even NutriSTAT here in Australia, to measure actual mitochondrial metabolites.

We assess the citric acid cycle, specifically the ratio of citrate, succinate, fumarate, and malate, to see where the biochemical bottlenecks are. We check urinary organic acids for lactate and pyruvate to see whether there is a chronic anaerobic shift, and we check lipid peroxide markers to measure baseline oxidative stress.

Dr. Scott Sherr (11:05): Once we have those baseline cellular health markers, we establish our Do This on Monday protocol.

If a patient is a healthy, active individual currently taking metformin off-label for longevity, we transition them off the drug entirely. Instead, we optimize their natural insulin sensitivity and mitochondrial efficiency through a phased protocol.

Phase one is circadian and autonomic safety. We anchor their circadian rhythm with early-morning sunlight exposure and optimize sleep hygiene to support cortisol and melatonin curves naturally.

Phase two is orthomolecular cofactor support. We supply the direct raw materials for mitochondrial electron transfer: magnesium glycinate, coenzyme Q10, and active B vitamins guided by their metabolomics data.

Phase three is phytochemical pulsing. Instead of a daily Complex I inhibitor, we use natural glucose-sensitizing epigenetic modulators like berberine or quercetin. But we enforce a strict rule: never take these on exercise days. We only pulse them on rest days to allow exercise-induced oxidative-stress hormesis to signal mitochondrial biogenesis unblunted.

Dr. Jup Kuipers (12:10): That’s right. If they need targeted, non-toxic electron support, we use compounds like methylene blue, for example, Troscriptions Tro+ Blue, which serves as an alternative electron carrier, donating electrons directly to cytochrome c and bypassing Complex I blockages entirely without neurotransmitter depletion.

Dr. Ted Achacoso (12:30): Exactly. This is where HOMeHOPe differs from lifestyle medicine. HOMeHOPe does not prescribe lifestyle from disease markers. It prescribes lifestyle from cellular health markers. When you measure organic acids and organic metabolites, you can see exactly where the mitochondrial machinery is stalling. You can support it with the precise orthomolecular cofactors your cells evolved to use rather than introducing a synthetic drug to poison your enzymes.

We are not here to prevent diseases like diabetes either. That is preventive medicine. Again, disease. We are here to optimize cellular health, and disease prevention is a beneficial side effect.

Dr. Scott Sherr (13:09): Let’s steelman the opposing case. What is the strongest argument a conventional endocrinologist or anti-aging doctor would make for keeping healthy adults on metformin for longevity? Allen, why don’t you take the lead here?

Dr. Allen Bookatz (13:22): Metformin is one of the most studied, cheapest, and safest drugs we have. We have 60 years of clinical data behind it. Let’s look at the population we are treating in most of medicine. The majority of adults are sedentary, overweight, and have some degree of insulin resistance that they do not know about.

For that population, metformin is a cheap, effective layer of protection. Let’s be honest: Who is getting 150 minutes of exercise a week? Most people are not. I barely meet that.

Mild Complex I inhibition still lowers the advanced glycation end products that we are so worried about. That is where the harm comes in. It calms and quells systemic inflammation and mimics some of what caloric restriction would do. For a sedentary patient, the glucose benefit outweighs the theoretical hit to whatever adaptation they would receive from exercise. But there is no exercise adaptation happening in the first place, so where is the harm?

Dr. Jup Kuipers (14:33): That is an excellent steelman, Allen, and I have heard it a couple of times in my practice. We fully agree. If an individual is sedentary, has poor metabolic control, and refuses to engage in physical activity, metformin is a highly effective, safe intervention to prevent diabetes and reduce glycation.

But our target audience is not the sedentary pathogenic cohort. We are talking about metabolically active, physically optimized individuals. For someone who is already actively exercising, lifting weights, and eating clean, adding a Complex I inhibitor is a profound biological mismatch.

We refine our position: Metformin is a useful pathogenic tool for managing metabolic decline in sedentary individuals, but it is a metabolic detractor for those pursuing health optimization.

Dr. Scott Sherr (15:23): Let’s deliver our take-home three for today. Jodi, give us the first one.

Jodi Duval (15:27): Number one: Metformin is a mitochondrial Complex I inhibitor, not a longevity supplement. While it lowers blood glucose in diabetes, in healthy individuals, it creates a mitochondrial blockade, blunts cardiorespiratory fitness gains by up to 50%, and prevents muscle hypertrophy.

Stop taking a metabolic poison to optimize when you have a healthy cell.

Dr. Scott Sherr (15:54): Takeaway number two: The 21-year DPPOS follow-up study published in JAMA proves that lifestyle, not metformin, prevents chronic multimorbidity. Intensive diet and exercise slash long-term multimorbidity risk by over 20%, while metformin showed no statistically significant benefit over a placebo.

Lifestyle is the ultimate longevity intervention.

Dr. Ted Achacoso (16:15): Takeaway number three: Never take glucose-sensitizing phytopharmaceuticals on exercise days. Natural compounds like berberine and quercetin are powerful tools, but they must be pulsed strictly on rest days. This allows exercise-induced oxidative hormesis to signal mitochondrial biogenesis completely unblunted.

Dr. Jup Kuipers (16:35): As we close today’s discussion, let’s tie this back to the foundational principles of Health Optimization Medicine and Practice. Prevention is the prevention of disease and remains disease-centered. Health optimization is health-centered. When we use off-label medications to force a single numeric biomarker like fasting glucose, we are operating in a pathogenic framework. We are trying to prevent disease by manipulating a disease marker.

Dr. Ted Achacoso (17:03): Exactly. In HOMeHOPe, our goal is salutogenesis: building and sustaining cellular coherence and metabolic safety. We do not want to poison an enzyme to lower glucose. We want to supply the mitochondria with the exact orthomolecular cofactors, vitamins, and minerals they need to produce ATP efficiently.

We detoxify heavy metals like mercury or arsenic that block the ATP production cycle. We focus on neotenization, meaning the youthful, highly efficient, and adaptive cellular energy production of a healthy 21- to 30-year-old.

Health is A plus B plus C: an optimal physiological state characterized by A, the absence of disease; B, the maintenance of the balance between anabolism and catabolism; and C, the cycle of life of the organism.

When your cells have bioenergetic harmony and the exposome is optimized, your body naturally regulates glucose, manages inflammation, and sustains cellular safety without synthetic interference.

Dr. Allen Bookatz (18:06): That was a genuinely eye-opening look at what real cellular bioenergetics looks like. If you are a healthcare practitioner listening, a physician, a health coach, or simply interested in improving your own health, head over to homehope.org.

Our clinical metabolomics and bioenergetics certification will give you the frameworks, testing protocols, and orthomolecular guidelines to optimize your patients from the cell up. Again, that’s homehope.org. Join the health optimization movement. We’ll catch you on the next episode.

Dr. Ted Achacoso (18:38): Bye.

Dr. Scott Sherr (18:39): Bye, everybody. Have a great day.

Dr. Allen Bookatz (18:40): Thank you for listening, everyone.

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