ENERGY SCIENCE

Full-Text Link to Primary Source

Our TSEE guest writer Caroline Trumpff is an Associate Professor in the Department of Psychiatry at Columbia University and a member of the Mitochondrial Psychobiology Group.

In this post, she shares the story of several years of research on cell-free mitochondrial DNA across different biofluids. She also describes results from a new paper examining the rhythmic dynamics of this potential stress signal.

Most of us think of stress as a feeling. A racing heart before a presentation. The knot in your stomach before difficult news. The mental exhaustion after a conflict with someone you love.

But beneath those experiences lies a fundamental biological challenge: stress costs energy.

Every time we adapt to a challenge, our bodies must rapidly mobilize resources: heart rate increases, hormones are released, immune cells shift behavior, and the brain becomes more alert. All of this requires energy.

Because mitochondria transform nutrients and oxygen into usable cellular energy, they sit at the center of the stress response.

For decades, scientists have studied hormones like cortisol to understand how the body responds to stress. But over the past ten years, our group and others have been building a body of evidence focused on a different character in the stress signaling story.

We’ve seen that mitochondrial signals are measurable in blood, saliva, and other biofluids, in the form of cell-free mitochondrial DNA (cf-mtDNA).

What is Cell-Free Mitochondrial DNA?

Unlike most cellular structures, mitochondria possess their own genome. This mitochondrial DNA (mtDNA) is inherited almost exclusively from our mothers and contains genes that help mitochondria perform the important task of transforming energy.

Mitochondrial DNA is mostly contained within mitochondria, but it can also circulate freely throughout your body through your body fluids. When outside of cells, it is known as cell-free mitochondrial DNA (cf-mtDNA).

We used to think it existed as little piece or circles of naked DNA, but we now know it’s mostly surrounded by membranes—many of which could be fragments of mitochondria.

Researchers initially viewed cf-mtDNA primarily as a marker of injury, inflammation, or disease. Elevated levels were reported in trauma, infection, aging, cancer, and psychiatric disorders.

But over time, a different picture began to emerge. Rather than a static marker of damage, cf-mtDNA is surprisingly dynamic.

Stress Can Change cf-mtDNA Within Minutes

In 2019, our group reported that a brief psychological stressor increased circulating cf-mtDNA within minutes. Participants performed a short task that most people find stressful. They had to give an impromptu speech while being judged by an evaluator wearing a white coat.

Within 5 to 30 minutes, cf-mtDNA levels in the blood increased substantially. This suggests that mitochondria are signaling in response to stress.

After this initial study, we wanted to scale up. Would the findings hold if we studied more people, across biofluids, and built in the controls the first study lacked?

To test this, we had to build a fast, inexpensive method that could break apart membranes to allow us to measure cf-mtDNA. We called this approach MitoQuicLy. It can quantify cf-mtDNA from just 10 microliters (less than one drop) of blood or saliva, and it is cheap enough to run on thousands of samples.

That scalability made new studies below possible.

Putting It to the Test: MiSBIE and MaPS

The MiSBIE (Mitochondrial Stress, Brain Imaging, and Epigenetics) study that followed exposed participants to the same kind of likely stressful speech task. We enrolled healthy adults plus people with rare mitochondrial diseases. Saliva, serum, and plasma were collected for analysis.

Saliva cf-mtDNA rose fast and dramatically. There was a 280% increase within 10 minutes.

Blood told a quieter, messier story. Serum took a full hour to show any change. Plasma barely moved before quietly declining below baseline by two hours. The response in saliva was 20-fold larger than in serum and 18-fold larger than in plasma.

In people with rare mitochondrial diseases, the saliva response was blunted, most dramatically in those with a large mitochondrial DNA deletion. This suggested the magnitude of the response depends on having healthy, intact mitochondria.

The second study, MaPS (Mitochondria and Psychological Stress), was conducted by our collaborator Anna Marsland at the University of Pittsburgh. It was designed to interrogate our own findings.

Participants completed a real stress visit where they completed the same speech task. And they did a separate resting control visit where they sat quietly with an IV catheter for the same length of time. The stressor worked as intended, raising anxiety, heart rate, blood pressure, and cortisol relative to rest.

But blood cf-mtDNA did not follow suit. Serum levels showed no significant change in either visit. Plasma levels rose and fell over two hours in a nearly identical pattern regardless of whether people were stressed or resting. This told us the signal was tracking the visit, not the stress.

We concluded that saliva, collected non-invasively, gives a fast, large cf-mtDNA stress signal. On the other hand, the cf-mtDNA response in blood was harder to interpret, likely because the process of drawing blood may be an added stressor.

A Mitochondrial Signal in Saliva

Blood collection is useful but not always practical for repeated sampling. And as results from the MaPS study suggest, the draw itself might be a confound. Saliva, in contrast, can be collected at home, relatively conveniently, without a needle, across many days.

When we first looked for cf-mtDNA in saliva, we did not know whether it would even be detectable. It was, and it displayed remarkable day-to-day dynamics.

Most strikingly, there was a robust awakening response. Similar to cortisol, salivary cf-mtDNA increased dramatically in the first 30 to 45 minutes after waking, in some cases by nearly two orders of magnitude.

We recently confirmed this pattern in a larger study. Hourly saliva samples were collected across a weekday and a weekend day in 25 healthy adults.

We found that cf-mtDNA rose 2.5-fold within 45 minutes of waking, climbing to a 5.7-fold peak around three hours later, before settling into a stable plateau. It tracked closely with cell-free nuclear DNA, hour by hour, but its relationship with cortisol was much weaker.

These findings indicated that cf-mtDNA isn’t just mirroring the pattern of the classic stress hormone. It follows its own rhythm.

That study also suggests this rhythm is influenced by individuals’ states of mind. People who reported more daily hassles, less social support, and greater anxiety, fatigue, or depressive symptoms tended to show higher cf-mtDNA at waking, a blunted rise afterward, and a flatter profile across the day. This echoes how chronic stress flattens cortisol rhythms and reduces heart rate variability.

The Cost of Waking Up

Why does waking up increase cf-mtDNA?

From an energetic perspective, waking is a major physiological transition.

Think about it. When you transition from sleeping to awake, your body temperature rises, heart rate increases, attention sharpens, and metabolism accelerates. All of this requires energy provided by mitochondria.

cf-mtDNA may reflect this shifting energetic landscape. It may be an anticipatory signal preparing the body for the day ahead.

Does This Hold Up Outside the Lab?

A lab stressor is controlled and time-locked. Everyday life is messier. So we asked whether saliva cf-mtDNA tracks stress and mood as people actually live it, using two intensive, real-world sampling studies.

In the first study, young adults, half with major depressive disorder, collected their saliva four times a day for four days. They also reported nightly on stressful events.

Diagnosis alone did not predict cf-mtDNA levels. What mattered was the interaction. On stressor days, cf-mtDNA in participants with major depressive disorder dropped by 68% relative to stress-free days, falling further as stressors grew more numerous and severe. Healthy controls showed a similar but weaker, non-significant dip in cf-mtDNA.

In the second study, we collected hourly saliva and mood ratings across two days in 25 healthy adults. Our results showed that momentary positive emotions, like happiness, energy, calm, and feeling in control, were each linked to higher cf-mtDNA levels. Conversely, stress and frustration tracked with lower levels.

The cf-mtDNA increase from positive emotions weakened as negative emotions rose, showing their interplay matters for cf-mtDNA signaling.

Together, these findings complicate the simple story about what cf-mtDNA does.

Real-world, sustained stress seems to suppress cf-mtDNA rather than increase it, perhaps because chronic stressors call for energy conservation rather than rapid mobilization.

cf-mtDNA may behave less like a fire alarm and more like a gauge of adaptive flexibility, similar to heart rate variability. From this viewpoint, a narrower range of movement, not one elevated reading, signals strain.

What Does cf-mtDNA Actually Mean?

For me, this remains one of the most important open questions. cf-mtDNA may function as a signal communicating energetic demand, a marker of mitochondrial activation, a by-product of remodeling, a molecule involved in immune signaling, or a component of broader adaptation and tissue-repair processes. Or it could be more than one of these things depending on the circumstances.

One possibility deserves special mention. Not all of what we measure as cf-mtDNA in blood is naked, fragmented DNA. some of it appears to be packaged inside whole, intact, cell-free mitochondria. This was discussed in a prior post.

That matters, because separate research shows cells can transfer intact mitochondria to one another. Perhaps at times to rescue the bioenergetic transformation capacity of struggling cells. If some circulating cf-mtDNA is inside cell-free mitochondria in transit, part of what we measure may be less of a debris signal and more of a resource transfer. In other words, the cf-mtDNA measure we’ve been using may include energy being shared cell to cell.

Most likely, several of these mechanisms operate simultaneously. There is mounting evidence though that cf-mtDNA should not be viewed solely as cellular debris. It appears to be part of a dynamic biological language linking mitochondria, stress, energy, and adaptation.

Looking Ahead

For decades, stress biology has focused largely on hormones, such as cortisol. Those hormones remain important, but mitochondria may offer a complementary perspective.

If stress is fundamentally an energetic challenge, mitochondrial signals could reveal aspects of adaptation that hormones alone cannot capture.

cf-mtDNA gave us one of the first ways to observe those mitochondrial responses directly in humans. And we watched them during the flow of daily life, rather than only in the lab, using nothing more than saliva samples collected at home over time.

Research on cf-mtDNA still has real limitations, including open questions about what it is measuring and how to interpret it across biofluids and contexts. But it suggests that the next generation of stress research should ask how our mitochondria respond to stress, and how flexibly they recover. How efficiently our mitochondria mobilize and recover from stress could shape our long-term health and resilience.

Our TSEE guest writer Matt Bernstein, MD, is a psychiatrist, Co-founder, CEO, and Medical Director of Accord Mental Health, Chief Medical Officer of Ellenhorn, and a Lecturer in Psychiatry at Harvard Medical School.

In this article, Matt shares clinical insights from his time treating individuals with mental health conditions. Through his work and personal experiences that shaped him as a clinician, Matt has learned that examining the role of energy may help clinicians better understand the problems patients face, and provide more effective solutions.

Patients tell me they have no energy. They have been telling me this for twenty-five years.

It is one of the most common sentences spoken in a psychiatrist’s office, and for most of my career I did with it what I was trained to do. I wrote it down as a symptom, checked the box for fatigue or loss of pleasure, and moved on to the parts of the interview I could do something about.

But it troubled me.

I was trained to treat energy as something the diagnosis explains, rather than as a problem in its own right. The patient offers a report about their bioenergetic state; psychiatry converts it into evidence for a diagnosis. Depression explains the low energy, the low energy confirms the depression, and the vital communication originating in that person’s mitochondria never gets heard.

The Gap I Couldn’t Explain

I trained in psychiatry at Massachusetts General and McLean Hospitals in the early 2000s and spent the first eight years of my career working in an inpatient unit for patients with schizophrenia and bipolar disorder. I’ve seen antipsychotics, mood stabilizers, and electroconvulsive therapy save lives. Some of my patients do well on medication and will likely use it for the rest of their lives.

Many of the same patients became chronically ill. We would address symptoms, but they still could not return to their usual lives. That gap, between symptom reduction and functional recovery, has never stopped bothering me. It never felt right to say: “they’re having a good outcome with their severe mental illness” when in fact they were miles off their previous life trajectory.

Well before any of this became personal, I also thought that the diagnostic system had a problem at its foundation. Since 1980, when the modern diagnostic system took shape (DSM-III), psychiatry has been optimizing for reliability—whether two clinicians examining the same patient reach the same conclusion—rather than validity, whether the label names something real. Reliability was a genuine crisis in the 1970s, and the field solved it.

But a system optimized for agreement between observers has no place for a variable that is invisible in the interview room. Cellular energy availability is exactly that kind of variable.

I carried that discomfort for a decade and did not change how I practiced.

What I Had to Learn When My Sons Got Sick

Then, two of my sons became seriously ill. The most dramatic symptoms were related to their mental health.

I am not going to tell that whole story here. It belongs to them. They are adults now, and they are deciding for themselves what part of it they want permanently attached to their names.

What I want to share is what it did to me as a physician.

Standard psychiatric treatment did not help. In stretches, it clearly made things much worse. This was very hard to say out loud, given what my career had been built on.

The eventual explanation for what afflicted them was not “psychiatric” in origin. What finally helped them was a long, expensive, exhausting bundle of medical and alternative treatments that one would put in the category of functional or environmental medicine. More than 15 years out of my medical training, I learned about immunology, infectious disease, endocrinology, cell biology, and metabolism to vet the treatments proposed for our boys.

The treatment bundle helped in a way that far surpassed anything psychiatry had offered them.

But how can I say that it was definitely these treatments that helped them? The strongest clue is in the trajectory of their recovery. They did not drift up and down over years the way a waxing-and-waning illness does. They remained in very rough shape when we transitioned from traditional psychiatric treatments to the most common integrative interventions. Their condition only began to improve when the intensity of the treatments was vastly stepped up and many were running at once.

That timing is why I don’t think we were watching the natural course of their illness. What I cannot tell you is which components mattered. The physician treating them believed every one of them was necessary. I think it’s impossible to know for sure.

What I Offer Patients Now

If I do not know which element worked, the responsible move is not to reproduce the whole bundle for other people. Every person is unique.

The right thing to do is to ask which interventions are worth offering under uncertainty?

Trial evidence is one factor. But in this field, the trials are thin–and each case is so unique. So I ask two more questions: 1) Is it safe enough that being wrong costs the patient very little? And 2) does it act on physiology that is shared across conditions, rather than on one presumed cause?

That is a much shorter list than the one our family endured.

• Nutrition, especially a whole foods ketogenic diet.

• Exercise.

• Sleep and circadian structure.

• Mind-body practices and psychosocial support.

I can defend each of these interventions to a skeptic on its own evidence.

I can also defend the combination of them based on mechanism: they converge on insulin signaling, inflammation, oxidative stress, and mitochondrial health.

We also carefully reduce medication when appropriate, being mindful not to induce withdrawal syndromes.

With this approach, I have since watched dozens of people who are not my children recover. It doesn’t happen for everyone, and I have patients who have not benefitted. But I have seen people who had been through every reasonable version of standard care—good care, from good clinicians—recover levels of function that nobody expected.

These human experiences motivate me to keep doing this.

Of course you need to weigh that against an obvious bias: I have an ownership stake in a program that provides this intervention, and I stand to benefit financially if it succeeds. That is the kind of interest that could make you discount an uncontrolled clinical observation, and I would rather name it than have you find it out later.

I cannot separate the ketogenic diet from the rest of the program: the exercise, the mind-body practices, and the work on circadian rhythms and relationships. I don’t see that as a problem. If metabolic state is the target, then everything that improves it is an intervention.

So what happens when someone leaves?

That is the problem the recent trial by Gao and colleagues (described below) ran into. Benefits were correlated with adherence, and adherence fell once the dietitian support stopped. The residential piece is not the whole treatment. It is where the treatment gets learned. A lot of what we do is teach people to cook, to sleep, to move, and to notice how their own behaviors and symptoms track together, so they can keep doing it at home.

A program where people improve on site and relapse at home has not done its job.

What I Think the Evidence Actually Shows

The first randomized controlled trial of a ketogenic diet in treatment-resistant depression (88 participants) found a real but modest advantage over a well-matched control diet at six weeks. The benefits faded by week twelve.

The most dramatic results in the literature come from uncontrolled studies: a retrospective inpatient case series and a small pilot with no comparison group. These studies and others provide much-needed hope for individuals and families who have hit a wall with standard treatment approaches.

The observational picture is much stronger. In a longitudinal birth cohort study, children on a persistently high insulin trajectory from age nine had markedly elevated odds of both a psychosis-risk state and psychotic disorder at twenty-four.

The insulin signal predates the psychosis by about fifteen years. Insulin resistance and mitochondrial abnormalities show up consistently in people in their first episode of psychosis who have never taken an antipsychotic. People with serious mental illness die twelve to fifteen years earlier, overwhelmingly of cardiometabolic disease and not suicide. The medications amplify metabolic problems they did not create.

Moreover, a recent study following tens of thousands of people for over a decade also showed that another energy-based blood marker, GDF15–which signals energy shortage–predicted new cases of depressive and anxiety disorders, dementia, and other neurological disorders.

What Needs to Change

I am not arguing that psychiatry should trade neurotransmitters for mitochondria.

I am arguing that we have been treating a downstream signal as though it were the disease. However, the metabolic physiology underneath has been measurable for decades, and we haven’t been paying attention.

This is also why the solution is not simply to add a diet. If you improve the underlying condition, then you often need to adjust the pharmacology, and that is a skill my field has largely lost.

Some patients do best on standard doses of medication. Some do best on much less. Some do best off of medication entirely. Knowing which is which is the actual job of a prescriber, and we have been training doctors as if only one of those three answers is possible.

With clinical trials, we largely have a science of averages—but every patient is an individual, nobody is the average.

When someone tells me they have no energy, I no longer log it and move on. I treat it as a window into their physiology—one I can often improve. I would rather have learned this from the literature than the way I learned it. But the thing I took from those difficult years with my own family was not a set of answers. It was learning to ask what the body is doing underneath the symptoms we observe.

And none of this is expensive in principle. There is no proprietary molecule here. It is expensive now because it is rare and delivered in private settings like mine to the families who can find it and afford it. That’s a problem with how care is organized, not with what the treatment costs to provide.

The patients most likely to benefit are often the ones least able to reach me, and most of them have already been told more than once that they are treatment resistant. I would like ours to be one of many programs rather than one of a few. In that world, my field might finally retire the phrase “treatment resistant.”

This week on The Science and Experience of Energy, we explored how mitochondrial biology and energy metabolism may shape two seemingly distinct challenges: neurodegeneration and chronic inflammation.

In our first piece of the week, Beyond Brain Energy, neurologist Matthew Phillips considers metabolic flexibility as a dimension of brain resilience. The question is not only whether the brain has sufficient fuel, but whether it can shift between different metabolic states as conditions change.

In the second piece, Inflammation as an Energy Problem, physician Pascal Mensah examines whether inflammatory signals may reflect a deeper problem in how cells manage energetic stress, and the role mitochondria may play in restoring balance.

These pieces put into perspective a bigger picture question: could our resilience in part depend on the capacity to transform and use energy under changing conditions?

What might change if we viewed metabolic flexibility as a feature of resilience, rather than simply a response to illness?

We would love to hear what you think about this?

With gratitude,
Martin

Thanks for reading The Science and Experience of Energy.
Know someone who may be interested in an energetic view of life?

Share The Science and Experience of Energy

ENERGY SCIENCE

Our TSEE guest writer Pascal Mensah is a physician specializing in Clinical Immunology, Immunometabolism, and Integrative & Regenerative Medicine at Juaneda Hospital (Mallorca, Spain). In this post, he draws on fifteen years of treating autoimmune disease
to argue that inflammation may be better understood as a problem of energy flow
than as a problem of immune signaling alone.

In a single week of clinic, I may see a woman with lupus, a young man with Crohn’s disease, and a patient whose rheumatoid arthritis is changing the shape of her hands.

Three diagnoses. Three specialties. Three sets of guidelines.

And yet inside them I keep finding the same thing: inflammation that will not resolve.

The Question That Keeps Coming Back

I have been working on autoimmune disease for nearly fifteen years. Across conditions that look nothing alike, inflammation has been the common thread.

We have not been idle. Medicine has developed a myriad of treatments. Corticosteroids, immunosuppressants, and monoclonal antibodies that block a single cytokine (signaling protein) with a precision that would have seemed like science fiction when I started. Some have been genuine successes. I have seen patients recover lives they had given up on.

But I have never been convinced that we could solve inflammation with one product, or two.

Blocking a cytokine treats the immediate message. It often does not treat the reason the message is being sent.

Patients respond, then, at some point, stop responding. We switch targets, escalate, and combine. The inflammation moves rather than resolves. I began to suspect we were describing the fire by its smoke.

Why I Started Bringing Physics Into Immunology

If we want to understand inflammation, I think we have to bring physics into biology—and especially into immunology.

My reason is simple. Mitochondria determine the fate and function of an immune cell, including which cytokines it can produce. And, among their various functions, mitochondria are energy-transformers. Importantly, their energy transformation activities are bound by physics.

In doing so, they shape how cells transform energy, move electrons, and maintain the conditions required for life. Biology is not reducible to physics, but it unfolds within physical constraints.

That is what drew me to the Energy Resistance Principle described by Picard and Murugan in a previous post. It treats a cell as an electrical–energetic circuit: electrons from our food flux through the carbon wiring of metabolism toward oxygen, the terminal acceptor.

Energy resistance (éR) is whatever impedes that flow. Some resistance is necessary for useful work to get done. Without any resistance, an electron’s potential could never become cellular fuel in the form of ATP (adenosine triphosphate).

But when resistance climbs too high, energy stalls and dissipative losses rise: oxidative and reductive stress, heat, molecular damage, inflammation, and lost information. These are the hallmarks of disease and aging.

This changed the question I ask in the clinic. Instead of “which cytokine is too high?”, I began asking what is the cause of excess resistance in this patient, and why?

Cytokines as Alarms, Not Villains

In this framing, the immune system both reports energy resistance and corrects it. Pro-inflammatory cytokines are the reporting arm. They are the alarms that let your body know resistance has risen.

The trigger is mitochondrial. When the electron transport chain is impeded, electrons back up, membrane potential becomes abnormal, and reactive oxygen species leak from Complexes I and III, the structures that carry out energy transformation. Those leaked species are a recognized “signal 2” that drives pathways that raise pro-inflammatory output. The cytokines we measure in blood report on the impedance underneath.

High energy resistance → more reactive oxygen species leaked → more inflammatory cytokines released

The same logic extends to endocrine signals. The cytokine GDF15 carries word of energetic distress to the brainstem. There, high circulating GDF15 levels serve as an index of high resistance. This “alarm” prompts the body to conserve energy through loss of appetite and fatigue. The balance between alarms like GDF15 and anti-inflammatory correctors conveys the net resistance of the system.

The Role of Mitochondria in Maintaining Balance

This is where the framework stopped being a metaphor for me. Mitochondria are not merely permissive for regulatory cytokine production. They are required.

The clearest evidence comes from regulatory B cells, or Bregs, a subset of B cells that produces interleukin-10 (IL-10), a powerful anti-inflammatory cytokine central to this story. Unlike conventional B cells, they differentiate appears to depend on intact mitochondrial electron transport and tightly regulated, homeostatic levels of reactive oxygen species.

So what happens if we inhibit Complex I or Complex III with a drug? The mitochondrial membrane depolarizes, and there is a sharp, selective drop in production of anti-inflammatory cytokines like IL-10.

Inhibiting Complex I or Complex III does not directly affect production of the pro-inflammatory cytokines. Only the anti-inflammatory, resistance-lowering arm collapses.

What is lost is the ability to answer the alarm, not to set it off. A cell cannot make IL-10 unless its electron transport chain is already healthy—by definition, a low-resistance state.

There is a clinical echo. In patients with lupus who have depolarized Breg mitochondria, elevated reactive oxygen species, and fewer thioredoxin-producing B cells, giving the antioxidant thioredoxin restored both membrane polarization and Breg numbers.— This suggests thioredoxin may help regulate the éR set point.

What It Costs to Run a Cell

This is where physics becomes important in the story.

For an electron current (I) flowing through resistance (R), the power dissipated as heat is P = R·I².

That is Joule’s law. It’s why a wire warms up when current fights its way through. Resistance is the term that converts useful flux into wasted heat and entropy. Loosely, entropy is the disorder in a system. Energy resistance is the biological version of that term.

The mechanism by which IL-10 would lower it is well defined. In immune cells called macrophages, IL-10 signalling results in the breakdown and recycling of damaged mitochondria leaking reactive oxygen species and dissipating heat. And respiratory capacity is restored. Both reduce the back-up of electrons—the I²R term—lowering the cost of running the cell.

I have a prediction that has not yet been tested. Because entropy production is related to aging dynamics and lifespan, chronic IL-10 signalling should measurably reduce the entropy produced per unit of ATP.

It is also falsifiable: in cells engineered so they cannot break down damaged mitochondria, IL-10 should not lower energy resistance at all. If it does, my prediction is wrong.

IL-10 as a Thermostat, Not a Brake

We usually describe IL-10 as the anti-inflammatory brake. I have come to think of it as a thermostat that calms inflammation by improving how the cell handles energy.

It does this in at least two ways. The first is the mitochondrial clean-up just described. The second involves fats. IL-10 supports production of monounsaturated fatty acids, the flexible fats that keep membranes fluid. When IL-10 is lost, stiffer saturated very-long-chain molecules called ceramides accumulate instead. This hampers mitochondrial respiration and keeps inflammation switched on through a gene-control protein called REL. Restoring the monounsaturated fats reverses it—a metabolic correction, not an immunological one.

It also reframes what happens when IL-10 fails altogether, for example, in the severe enterocolitis (inflammatory bowel disease) caused by a non-functional IL-10 receptor. The problem is not only a missing brake; it is the lost control over energy resistance itself. A shortage of IL-10 can lead to unrestrained mitochondrial resistance. The downstream signature is the “cytokine storm”: a dangerous reaction, driven by the release of too many cytokines at once. It can cause high fever, organ failure, and death.

What This Changes in the Clinic

Reading inflammation as a disorder of energy-resistance control shifts the logic from “add an anti-inflammatory drug” to “lower the resistance.” Those sound similar, but they are not.

Rather than flooding the body with IL-10 from the outside, the better strategy may be to support the cell’s own thermostat.— Supplying a thermostat’s output is not the same as repairing it.

There are two potential approaches: adopt a diet favouring monounsaturated fats over the stiff ceramides that impair mitochondria, and repair of the control points that let cells produce IL-10 and respond to it.

It is also where the framework becomes measurable The GDF15 to IL-10 ratio, alarm over correction, is a plausible clinical index of net energetic resistance.

Measures That Could Reflect Energy Resistance

Energy resistance cannot be measured directly, so clinicians would need a panel of multiple measures rather than just one marker.

The panel could include:

• plasma GDF15 against the IL-10 signalling reserve in a patient’s B cells;

• spare respiratory capacity, membrane potential and mitochondrial reactive oxygen species by extracellular-flux respirometry; and

• the thioredoxin set point as a proxy for metabolic reserve.

All thresholds would be illustrative, and the panel would be best measured repeatedly over time. Still, these markers only hint at energy resistance—they do not measure it directly.

What I Still Do Not Know

This is a synthesis, rather than a direct demonstration. Each component is experimentally supported: mitochondrial function is required for IL-10 production, reactive oxygen species can amplify inflammatory signalling, and this response engages downstream lipid programs. What remains to be tested is the unifying idea that cytokines may, in part, report on a shared energetic state.

Several questions remain open. Does this set point differ across autoimmune diseases, or does a common underlying problem manifest in different tissues? Can it shift with something as ordinary as sleep, meal timing, or exercise? And when a patient no longer responds to a monoclonal antibody, have we quieted the signal while the underlying resistance continues to rise?

What fifteen years in autoimmune medicine has taught me is that we have become very good at silencing the alarms. Whether we can lower the resistance that sets them off is, to me, the far more interesting question.

If it is, then inflammation is not only an immunological problem. It is an energetic one, and it may need to be treated as such.

ENERGY SCIENCE

Our TSEE guest writer Matthew Phillips is a Neurologist and Director of Neurology at Waikato Hospital in New Zealand. In this post, he discusses how metabolic dysfunction and mitochondrial biology may contribute to neurological conditions. Training our brains to have greater metabolic flexibility could be a useful treatment approach to explore.

“The only constant in life is change.”— Heraclitus.

In 2021, a 64-year-old man and his fiancée walked into my office. He had been experiencing 18 months of slurred and slowed speech, difficulty swallowing, fatigue, and weight loss.

After a thorough workup, I made the unfortunate diagnosis of amyotrophic lateral sclerosis (ALS). ALS is a devastating neurodegenerative disorder in which motor neurons progressively degenerate and die. This man had the bulbar-onset form of ALS, which typically progresses rapidly and often leads to respiratory failure and death within 2-4 years.

After discussing the diagnosis and available options—which are largely supportive—his fiancée asked whether there were any other possibilities. She had heard of our work using ketogenic metabolic therapies in other neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease. She wanted to know: Could it help?

Despite the promising findings in those disorders, I was uncertain—and perhaps even a little skeptical—that a metabolic approach could help someone with ALS. I had seen too many patients succumb to this disorder, and I was not aware of anyone attempting this approach. Still, after discussing the potential benefits and risks, as well as the inherent uncertainty, we agreed to try.

I guided him through a time-restricted ketogenic diet. He was instructed to eat two meals per day, while substantially increasing dietary fat and minimizing carbohydrates. He maintained this approach for the next 18 months, during which we regularly assessed his functional status, breathing, swallowing, quality of life, fatigue, blood markers, and other measures.

And he did remarkably well. Over those 18 months, rather than the expected progressive decline, his function, breathing, swallowing, quality of life, and fatigue generally stabilized or improved. Moreover, despite extensive fasting, his previously pronounced weight loss slowed.

Since this study involved just one patient, we cannot draw definitive conclusions. However, the outcome was certainly unusual and encouraging. Although the ALS continues to slowly progress, he is still doing ok and remains living at home.

What happened?

The Metabolic Iceberg

At first glance, neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and ALS look very different. Clinically, Alzheimer’s typically announces itself through cognitive impairment; Parkinson’s through movement problems; and ALS through progressive weakness of the limbs and the muscles involved in speech, swallowing, and breathing. Based on these different presentations, neurologists are trained to “split” these disorders by their clinical features, as well as by the characteristic brain regions and proteins involved.

Yet beneath these obvious differences lies a shared vulnerability that enables neurodegenerative disorders to be “lumped.” This is not always apparent to the clinician, radiologist, and pathologist. One way of conceptualizing this common ground is through what we call the metabolic iceberg, composed of a tip, a bulk, and a base.

- The visible tip represents what we recognize clinically. This includes the neurological symptoms, as well as the degenerating brain regions and protein aggregates.

- The hidden bulk represents what may be a deeper biological problem. In this case, it may be impaired mitochondrial biology throughout the body, involving multiple interconnected processes.

- The underlying base encompasses factors that, over years or decades, shape the trajectory of impaired mitochondrial biology. These include exposure to modern industrial toxins, dietary patterns, cognitive, physical, and psychosocial behaviours, and genetic susceptibility.

The idea is that a particular suite of factors influences mitochondrial biology over years or decades, disproportionately affecting the “mitotypes” in certain brain regions. These effects eventually surface as the distinctive clinical features that we recognize as the disorder.

The metabolic iceberg gives us a way to think more deeply about Alzheimer’s, Parkinson’s, ALS, and other neurodegenerative disorders. Rather than isolated diseases of different brain regions, they may be different manifestations of a shared disturbance of energy metabolism, centered around impaired mitochondrial biology.

It may also help explain what happened to our patient.

Metabolic Flexibility

Although mitochondria have traditionally been portrayed as cell “powerhouses,” they are, of course, more than that. Perhaps owing to this enduring metaphor, the energetic impairment in neurodegenerative disorders is often framed primarily as a problem of energy deficiency. Put simply, the thought is that neurons and their mitochondria do not have enough energy, therefore we need to provide them with more (or a better) fuel.

This has helped motivate the application of ketogenic metabolic therapies, such as intermittent fasting and ketogenic diets, to these disorders. Both approaches increase the availability of ketones, which provide an alternative energy substrate. The metabolic properties of ketones are different from glucose, the dominant brain fuel under typical dietary conditions.

The basic idea, then, is straightforward. Essentially, neurodegenerative disorders involve an energy deficit, and ketosis may help by providing more (and a superior) fuel. While there is likely some truth to this, there may exist a deeper problem that has not received as much attention.

Crucially, these disorders also involve impaired metabolic flexibility—the ability of neurons and mitochondria to switch between fuels and metabolic pathways according to environmental circumstances. A metabolically inflexible brain is largely limited to glucose. However, it can be “trained” to increase its use of other fuels. During fasting or carbohydrate restriction, for example, it can be trained to increase its use of ketones. And during exercise, lactate becomes another important fuel source.

The problem, then, may not simply be that the brain has too little energy. It may also be that it has become constrained in the ability to change how it transforms energy. This reframes neurodegeneration as a problem not only of energy deficiency, but also one of energy rigidity, a concept that aligns with the Energy Resistance Principle.

Prolonged reliance on a particular energetic pathway may contribute to a state in which the system becomes increasingly resistant to using energy effectively.

Given this perspective, metabolic therapies may do more than provide more energy through a superior brain fuel. Perhaps some of the benefit of ketosis comes from repeatedly asking neurons and mitochondria to operate under a different set of metabolic conditions—to switch fuels, engage different pathways, and adapt.

In other words, the therapeutic signal may lie not only in ketosis, but in the transition between metabolic states.

Brain Adaptability

If this is true, one of the most underappreciated features of ketogenic metabolic therapies may be that they restore metabolic options for the brain.

For example, if neurons become less able to effectively use glucose - as can occur with insulin resistance - ketones can provide an alternative substrate that enters energy metabolism through a different route. In this sense, ketones can function as a metabolic back-up fuel for the brain. But perhaps that framing can be expanded even further.

Ketones are not exotic molecules. They are a natural component of human metabolism and would have been routinely available during periods of food scarcity in our evolutionary past. Our hunter-gatherer ancestors ate intermittently and did not have continuous access to carbohydrate-rich foods. Thus, transitions between fasting and feeding were likely commonplace. And ketones may have been the brain’s primary fuel—perhaps utilized even more than glucose.

The ability to switch fuels may therefore be less of a therapeutic method than a fundamental feature of healthy physiology, one that raises a broader possibility.

Metabolic flexibility itself may be a form of brain resilience.

The healthy brain can use glucose; it can increase its use of ketones during fasting and carbohydrate restriction; and it can also increase its use of lactate, particularly when circulating lactate rises during exercise.

By this view, ketones do not just increase brain energy. Their availability - and, in a broader sense, the repeated transitions between metabolic states associated with them - may train mitochondria, neurons, and the brain as a whole to adapt. This is where “mitohormesis” becomes interesting. Modest metabolic challenges may provoke adaptive responses that ultimately improve mitochondrial resilience.

Viewed through the metabolic iceberg, these adaptive signals occur in the hidden bulk. If they improve mitochondrial biology, their effects may eventually trickle upwards to the visible tip, potentially influencing neurological symptoms.

Multimodal Therapies and Brain Health

This perspective changes how we think about metabolic therapies. If brain adaptability is important, then perhaps the goal should not simply be to maintain a particular metabolic state. Instead, we might deliberately train the brain to transition between metabolic states.

Fasting and ketogenic diets already do this to some extent. In addition to creating a series of transitions between catabolic (breaking things down) and anabolic (building them up) states, both strategies increase the brain’s exposure to ketones, encouraging it to operate on an alternative fuel rather than relying predominantly on glucose.

Exercise adds yet another dimension. As exercise intensity increases, lactate production rises. Lactate is not merely a waste product; it can be transported to the brain and used as an energy substrate, among other functions.

This raises an intriguing possibility. Perhaps the next generation of metabolic therapies should be primarily designed not as monotherapies, but as multimodal interventions that deliberately expose the brain to fluctuating metabolic conditions and stimulate mitohormesis.

The most obvious way to do this is to integrate two or more interventions—intermittent fasting and a carbohydrate-restricted diet, for instance, as in our patient with ALS.

Another possibility is to alter existing interventions. Rather than maintain ketosis indefinitely, for example, a “cyclical” ketogenic diet could be used to periodically introduce modest amounts of carbohydrate. The goal would not simply be to maximize ketone levels, but to repeatedly engage the metabolic machinery required to transition between glucose and ketone metabolism.

Similarly, prolonged periods of lower-intensity exercise activity, such as brisk walking, could “cycle in” brief periods of higher-intensity functional exercise. The latter increases lactate production to introduce another metabolic challenge.

While the findings to date are promising, multimodal metabolic therapy protocols have not (yet) been definitively proven as treatments for neurodegenerative disorders. For now, they simply illustrate a different way of thinking about metabolic therapy by reframing the question from “How can we give the brain more energy?” to “How can we give the brain more ways to transform and use energy?”

This reframing may be crucial for enhancing brain health.

Beyond the Brain as a Battery

Despite accumulating evidence, many people continue to think about brain energy as though the brain were a battery. If energy is insufficient, give it more fuel and recharge it. But a battery is not a particularly good metaphor for a living biological system.

Perhaps the brain is more like an improvised jazz ensemble. It has multiple functional units (separate instruments), which appear to predictively process information in parallel (play music in concert). And like the ensemble, it can change its performance depending on its external circumstances.

A metabolically rigid brain may know only one state (composition), but a metabolically flexible, healthy brain can switch between them. Importantly, a healthy brain can transition between metabolic states without losing its ability to function.

Ultimately, brain health—perhaps health more generally—is probably not simply about having more energy, maintaining a static threshold of energy sufficiency, or even possessing a surplus of energy at all. Perhaps it is about having more possible ways to transform and employ the finite energy that is available.

A healthy brain is not merely an energy-rich brain—it is an adaptable brain. And perhaps the fundamental currency of metabolic and mitochondrial health is not energy abundance, but a dynamic adaptive capacity to changing circumstances in the environment. A capacity to adapt to—and ultimately, thrive on—change itself.

Which might lead to some important therapeutic implications… maybe even in a disorder as challenging to treat as ALS.

This week on The Science and Experience of Energy we explored two unexpected windows into the dynamic biology of energy, adaptation, and repair. Each invites us to look a little more closely at the world around us to inspire our curiosity.

In the first piece, we describe a new paper examining the mysterious mitochondria-like particles found in blood and saliva using high-resolution electron microscopy. This new research suggests new directions for thinking about the stuff that floats about in our blood that helps us heal.

In the second piece, guest writer Julia Wallis, an experienced electrologist, shared a striking clinical observation. After electrolysis treatment of white hairs, she has repeatedly seen neighboring follicles regaining color. Energy-induced reversal of greying hairs?

Together, these pieces encourage us to think of energy as a force that informs how living systems respond and recalibrate. Circulating blood stuff and hair follicles are little windows that teach us new things about how cells communicate, adapt, repair, and perhaps even share resources.

What else is there to learn? Please share your thoughts.

To you, what feels like the most important thing or idea our team or other researchers should explore?

With gratitude,
Martin

Our TSEE guest writer Julia Wallis is a wife, mum of 3, grandparent, and an accredited electrologist based in the UK with over 35 years of experience in the beauty industry. She is the founder of Julia Wallis Natural Skincare, and she specializes in electrolysis, advanced cosmetic electrolysis, and holistic skincare.

Combining clinical expertise with a holistic approach to wellbeing, Julia developed her own natural, cruelty-free skincare range to support clients before, during, and after electrolysis treatments. She is passionate about sharing a multi-faceted approach to health and wellbeing, integrating effective, circadian-aligned, and nature-inspired solutions that support both skin health and overall wellness.

In this article, she shares insights from her observations of hair pigmentation changes with electrolysis and how these observations relate to what we know about energy, biological repair, and healing.

What if the smallest observations we make in clinical practice are quietly pointing us towards biology that we don’t yet fully understand?

For more than thirty years I have looked through magnification at thousands of hairs. Over time, patterns begin to emerge—patterns that are rarely discussed in textbooks. One observation has stayed with me.

After treating white hairs with electrolysis, I repeatedly saw neighbouring hairs emerge with colour again. During their next growth cycle some hairs appeared with the top half white and the bottom half to the root pigmented again.

I wasn’t expecting to see this, and at first, I assumed it was a coincidence.

But the pattern continued with a variety of clients.

By nature, I have an enquiring mind. My role as an electrologist is not simply to remove unwanted hair, but to observe carefully, ask questions, and better understand the biology unfolding beneath the skin. Every new observation becomes an opportunity to learn—not only to improve outcomes for my clients, but also to contribute to a wider understanding within the electrolysis profession.

The observations I share here do not prove a new biological mechanism. Instead, they raise a question that I believe is worth exploring.

Could the local healing response initiated by electrolysis temporarily create an environment that supports renewed pigment production in neighboring follicles?

Recent discoveries in melanocyte stem cell biology, wound healing, and mitochondrial science suggest this may be an important question to ask.

The Hair Follicle: A Remarkable Mini-Organ

Hair follicles are often thought of simply as structures that produce hair. They are among the body’s most biologically active mini-organs.

Each follicle contains stem cells, melanocytes (cells that make and contain the pigment melanin), immune cells, blood vessels, nerves, and sebaceous glands (structures that secrete an oily substance called sebum).

Throughout life, hair follicles repeatedly cycle through four stages; growth (anagen), regression (catagen), rest (telogen), and shed (exogen). They are continuously regenerating themselves.

Producing a pigmented hair is an energy-intensive process. Melanocyte stem cells must mature into functioning melanocytes, synthesize melanin, and transfer that pigment into the developing hair shaft. This requires healthy cellular communication, an adequate blood supply, oxygen, nutrients, and efficient energy transformation in the mitochondria.

Hair pigmentation is therefore not simply about colour. It reflects the health and energetic capacity of the follicle.

What Happens When a Hair Turns White?

From a clinical perspective, white hairs differ markedly from pigmented hairs.

The term “grey hair” describes the overall appearance created when pigmented hairs become mixed with white hairs. Hair itself is not actually grey. Rather, the combination of coloured (pigmented) hairs alongside white hairs that have lost their melanin creates the visual impression of grey.

Pigmented hairs contain melanin within the thick middle layer of each strand usually possess a well-defined root sheath, and often appear dense and biologically active. White hairs lack melanin, frequently present with a thicker, more opaque root sheath, and can appear coarser in texture.

These differences are more than cosmetic. They reflect changes within the follicular environment and how the melanocytes function.

For decades, it was believed that white hair resulted from the irreversible loss of pigment-producing cells. However, recent research has challenged this view. Studies from researchers at New York University demonstrated that melanocyte stem cells may not disappear entirely. Instead, they can become immobilized or stuck within the follicle, preventing them from maturing into pigment-producing cells.

Martin Picard’s group has shown that stress-induced greying—as in my own case below—can, in some circumstances, be partially reversible. This suggests that hair pigmentation is far more dynamic than we once believed.

Rather than viewing white hair simply as an inevitable consequence of aging, we may instead consider it a reflection of changes in the follicle’s biological environment.

Electrolysis: Initiating an Energy-Dependent Healing Response

Electrolysis is widely recognised as the only permanent method of hair removal. Yet biologically, far more is taking place than the destruction of a single follicle.

My approach is to treat hair follicles where the hair has become genuinely problematic and unwanted, rather than treating simply for the sake of treatment. I recognize that hair and its follicles are living, biologically active structures with important roles in skin function, sensory communication, thermoregulation, and the wider skin ecosystem, including its relationship with the microbiome.

A sterile probe the diameter of the hair delivers carefully controlled electrical energy into the follicle, creating a controlled localized micro-injury. The treated follicle is permanently disabled, but the surrounding tissue immediately initiates a sophisticated wound-healing response.

Blood vessels dilate to increase circulation. Histamine and inflammatory mediators coordinate the early stages of repair. Immune cells migrate into the area, fibroblasts begin producing collagen and elastin, new capillaries form through angiogenesis, and the space surrounding the cells is remodeled as healing progresses over several months.

Every part of this process requires energy.

From a biological perspective, electrolysis does not simply remove unwanted hair—it initiates one of the body’s most sophisticated energy-dependent repair programmes. Beneath the temporary redness visible on the skin, thousands of cells are communicating, adapting, and responding to restore tissue integrity. The human body is just amazing in its ability to respond to the signals it receives.

My Clinical Observation

Over many years of practice, I have consistently observed an intriguing pattern in clients with white facial hair.

Following electrolysis treatment, neighbouring follicles—not the treated follicle—often produce hairs that are no longer completely white. You can see some examples in the photos below.

During their next anagen growth cycle some emerge as two-toned hairs. The upper portion remains white while the newly formed lower shaft contains pigment.

Importantly, these hairs arise from adjacent follicles already programmed to enter anagen. This should not be interpreted as electrolysis stimulating new hair growth. Rather, it suggests that the local follicular environment may have changed in a way that influences pigmentation.

As clinicians, we often reassure clients that new hairs appearing after treatment are part of the normal hair growth cycle. My observation concerns not the appearance of new hairs, but the unexpected return of pigment within those neighboring follicles.

Biological Energy: Looking Beyond ATP

Traditionally, biological energy has been described in terms of ATP (adenosine triphosphate), the cell’s energy currency. ATP is produced largely through the transformation of energy in the mitochondria. However, emerging research is revealing a much broader and more dynamic understanding of biological energy and how it influences cellular function, communication, adaptation, and repair.

Mitochondria are increasingly understood as dynamic signaling organelles that integrate metabolism, stress responses, circadian rhythms, inflammation, and cellular communication.

Biological energy is therefore not simply fuel. It is the capacity of living systems to adapt, communicate, and repair.

This perspective resonates with what I observe clinically.

Healing is an energy-dependent process. Tissue repair demands increased mitochondrial activity, enhanced blood flow, coordinated immune signaling, and communication between neighboring cells.

The question that naturally follows is whether this temporary increase in biological activity could influence neighboring follicles that are approaching their next growth cycle.

A Clinical Hypothesis

At present, there is no evidence that electrolysis directly restores hair pigmentation.

However, my observations suggest that the local wound-healing response initiated by electrolysis may temporarily influence the biological environment surrounding neighbouring follicles. I do not know how long any renewed pigmentation persists following electrolysis, as I continue to treat these surrounding follicles as new stimulated problematic hairs emerge during subsequent growth cycles.

If melanocyte stem cells remain present but functionally dormant, as recent research suggests, could the enhanced cellular signaling, vascular support, and metabolic activity during tissue repair temporarily favour renewed pigment production?

This remains a hypothesis.

Nevertheless, it is a hypothesis born from repeated clinical observation rather than one isolated anecdote.

Throughout history, careful observation has often preceded scientific understanding.

Why This Matters

Hair follicles are among the most metabolically active structures within skin, the largest circadian organ in the body. Pigment production itself is energetically demanding and influenced by ageing, stress, circadian rhythms, nutrition, mitochondria, and the local tissue environment.

Perhaps pigmentation is not a fixed characteristic but a dynamic reflection of the follicle’s biological resilience.

Whether future research confirms or refutes this hypothesis, I believe these observations can offer reassurance to both clients and practitioners by helping them understand what they may see during the course of electrolysis treatment. They also deserve further investigation, as they raise important questions about tissue communication, wound healing, and the biological capacity of neighbouring follicles to adapt.

Lessons From Follicles to Stimulate Future Research

Every day, electrologists closely observe one of the smallest yet most biologically active organs in the human body.

My observations do not prove that electrolysis restores pigmentation, nor do they establish a new mechanism in hair biology. They do, however, invite a different way of thinking.

If biological energy is the capacity of living systems to adapt, communicate, and repair, then perhaps the healing response initiated by electrolysis offers a unique window into that process.

Science often begins in the laboratory, but sometimes it begins in the treatment room—with a practitioner who notices something unexpected and is curious enough to keep asking why.

Perhaps that is one of the greatest lessons electrolysis has taught me.

Every hair follicle tells a story—not only about hair, but about healing, adaptation, and the extraordinary intelligence of living systems.

My hope is that by sharing these observations, they may encourage further discussion, inspire future research, and deepen our understanding of the remarkable biology that unfolds beneath the skin every day.

Full-Text Link to Primary Source

Blood and other fluids are essential for life. While scientists and physicians have studied blood for centuries, we’re still making new discoveries about what is in our blood and how the contents of our blood support our biology and our health. In this article, we cover a new paper that gives us a closer look at different types of particles found in blood and saliva, including particles that resemble mitochondria.

Blood flowing through your body is like a mass transit system that delivers oxygen, nutrients, and chemical messages to all of your cells. It also plays an important role in moving waste products and mobilizing your defenses when your body is injured or is experiencing an infection.

There are many well-known passengers in this transit system. Red blood cells carry oxygen and some carbon dioxide. White blood cells have specialized immune functions. And billions of platelets travel along.

White blood cells and platelets contain mitochondria. Red blood cells don’t.

Recent work by our group highlights some more mysterious passengers. We still need to investigate further before drawing any conclusions, but some of them look remarkably mitochondrial.

Challenging Our Assumptions About Mitochondria and Mitochondrial DNA

In addition to serving in delivery, clean-up, and protection roles, blood is the bridge between your breath and the transformation of energy in your mitochondria. It carries both the electron-giving food substrates, and the oxygen that accepts electrons in your mitochondria.

Mitochondria are multifaceted organelles. They perform a wide range of functions beyond transforming energy from food and oxygen into forms that your cells can use. For example, they produce signals that can influence inflammation, stress responses, gene activity, and cell survival. They are the processor of the cell.

As you may know, they also have their own separate genome—the mitochondrial DNA, or mtDNA.

Scientists have known for years that mtDNA can be found outside of cells, circulating in blood, saliva, and other bodily fluids. Circulating mtDNA is often called cell-free mtDNA (cf-mtDNA). The name brings to mind loose fragments of mtDNA drifting freely through the bloodstream.

Five years ago, we wrote a grant to study the effects of mental stress on cf-mtDNA. And the pro-inflammatory effects of cf-mtDNA. Turns out that most cf-mtDNA in our blood isn’t naked DNA capable of triggering inflammation.

Our hypothesis was wrong.

But what if some of that mtDNA is not actually free? What if it is packaged up inside pouch-like vesicles, fragments of mitochondria, or intact mitochondria traveling between your cells and tissues?

Mitochondria are usually described as structures that live inside our cells. But they do not always remain confined to the cells where they originated.

Work by Al-Amir Dache a few years ago suggested that normal human blood contained about one million mitochondria per milliliter. Mitochondria, interestingly, that could respire and contained intact mtDNA.

A growing body of research also suggests that different cell types can release mitochondria or mitochondrial components into the surrounding environment, which can then enter other cells. Mitochondria transfer to other cells via direct connections between the cells, inside extracellular vesicles, or possibly as free-standing extracellular structures.

Through these transfers, mitochondria may directly participate in communication between cells and tissues, or even transfer energetic resources from one cell to another.

So, we wanted to know, if we looked closely enough at what is in blood and saliva samples that contain cf-mtDNA, could we actually see evidence of mitochondria in transit?

To answer this question, I had the chance to work with Alexandra Volos, Soah Grace Franklin, Jeremy Michelson, Shannon Rausser, and Jonathan Brestoff, co-authors on the new paper. This project started as one of Jeremy’s PhD thesis projects.

Exploring Blood and Saliva at Microscopic Scales

Jeremy and Shannon collected blood and saliva from ten healthy adults, processing the samples using established methods (check out our paper for all the details). This left us with the small particles from samples of plasma, serum, and saliva.

In each sample, we quantified how much mtDNA they contained with quantitative polymerase chain reaction (qPCR).

To get high-resolution images of the tiny particles in the blood and saliva samples, we used transmission electron microscopy. This involves shooting an electron beam through very thin slices of each sample.

With electron microscopy, the dense things, like DNA and proteins with metals, stop the electrons. The electron-lucent structures like the watery inside of the mitochondrial matrix let most electrons pass through. The contrasts reveals the cellular and sub-cellular structures in detail.

There was a lot to see. We collected thousands of single images, some stitched into large, high-resolution tiles. From these images, we classified particles into 14 different types based on their size, structure, and electron density. Plasma, serum, and saliva samples each had a distinct mix of particles.

Some particles were large, membrane-bound structures containing smaller vesicles. Others were diffuse and irregular or small and granular. The image below shows the wide range of particles that likely float around in your blood.

While we can’t say with certainty what each of these kinds of particles are or what they do from the images alone, it’s likely that we’ve captured cellular debris; biological packages carrying proteins, lipids, and other molecules; and particles involved in signaling.

Of particular interest to us, some of the particles had features consistent with extracellular mitochondria.

Why Mitochondria-Like Particles Matter

In each of our cells, the mitochondria and nucleus are the only organelles with a double membrane. Unlike the nucleus, the inner mitochondrial membrane folds inward to form cristae.

Several particles from our image catalog appeared to have this same general architecture. They had an outer boundary, an inner membrane, and, in some cases, internal folds resembling cristae. These particles were present in plasma, serum, and saliva, but they were more common in plasma.

Here are some from healthy participants (two on the left, one on the right):

The images are compelling, but it’s important not to jump to conclusions. Until further studies can be done to determine if these particles are actually pieces of mitochondria, whole mitochondria, or something else entirely, we’re calling them mitochondria-like particles.

Whether mtDNA is exposed or enclosed inside a membrane-bound particle can change the kinds of biological effects that the mtDNA can have.

When released during injury or stress, mtDNA activates immune and inflammatory pathways. As a result, elevated cf-mtDNA is often interpreted as a sign of cellular damage or physiological stress. But mtDNA sealed inside a vesicle or an intact mitochondrion may serve different purposes and have different biological effects.

Stepping back to look at the big picture, cf-mtDNA may not be just one biological signal.

When we measure cf-mtDNA using typical methods, we are likely capturing the mtDNA that is truly cell-free and released from damaged cells, as well as mtDNA that is within vesicles or mitochondria-like particles. And a mitochondrion likely carries much more information than just mtDNA would.

Separating these potentially distinct sources of mtDNA is important because one may signal injury, while the others may be involved in communication, adaptation, or repair and healing.

If we confirm that the particles are mitochondrial in nature, we should examine if they are able to perform some of the many important tasks that mitochondria do. For example, can they maintain a membrane potential and transform energy?

Also, where do the particles come from and where are they going? Future research could track labeled mitochondria from their original cells to follow their movement and identify their destinations.

We could then evaluate whether the transfer of mitochondria changes things like energy resistance (éR). If so, incoming mitochondria could alter metabolism, inflammation, resilience to stress, and tissue repair. How might the nature or dynamics of these mitochondria-like particles change with exercise, aging, sleep, stress, infection, injury, or disease?

Through this study, we created an open-access catalog of high-resolution electron microscopy images that anyone in the world can use for free. This will serve as a resource to guide future studies of mitochondrial transfer, extracellular mitochondrial biology, and cf-mtDNA.

We don’t yet know if these intriguing particles are cellular debris, distress signals, delivery vehicles, a mode for reallocating metabolic capacity, or perhaps all of these things depending on the context.

For now, these mitochondria-like particles remain mysterious travelers whose journeys remain to be further explored.

This week on The Science and Experience of Energy, we explored why the human experience deserves a more central place in how we understand health and practice medicine.

In the first piece, we examined how the mind shapes health through behavior, mental states, and energy metabolism. Bringing subjective experience into biomedical research could help medicine understand how health is maintained and restored.

In the second piece, , Lluc Montull, and Maria Antonia Lizarraga explored whether changes in perceived energy can help us recognize when energetic demands are becoming unsustainable. Can we anticipate exhaustion and respond before strain becomes prolonged?

Together, these pieces invite a more complete view of healing. One that brings lived experience into the conversation with physiological measurement of energy. What people feel carries meaningful information. Rigorously approached, this will contribute to a more preventive, personalized, and human-centered medicine.

We leave you with a question to carry into the week: When do you feel energized? When does effort begin to feel unsustainable? What might the difference reveal about what supports your health?

With gratitude,
Martin

Thanks for reading The Science and Experience of Energy.
Know someone who may be interested in an energetic view of life?

Share The Science and Experience of Energy

ENERGY SCIENCE

We are excited to introduce you to our TSEE guest writers: Natàlia Balagué and Lluc Montull are Professors of exercise physiology at the National Institute of Physical Education of Catalonia in Barcelona, and La Seu Spain. Maria Antonia Lizarraga is a Professor of Human Nutrition and Dietetics at the University of Barcelona.

In this article, they discuss how we perceive our body’s internal states and how our subjective perceptions of energy states may help us better monitor our health and potentially intervene to prevent disease.

Sensation and Perception, and the Complexity of Interoceptive Awareness

Sensations emerge when physical signals (particles of light, air pressure, chemicals, temperature, etc.) are transduced into neural activity by specialized cells (sensory receptors like photoreceptors, mechanoreceptors, chemoreceptors, thermoreceptors, etc.).

Raw sensory inputs are converted into meaningful, interpretable experiences, and coherent mental impressions. How that activity becomes subjective experience remains one of science’s biggest open questions.

Contemporary neuroscience often describes perception as a process in which the brain continuously generates predictions about sensory inputs. It also continuously updates these predictions based on incoming information, amplifying, attenuating, or bringing sensory signals into conscious awareness.

Current research on awareness increasingly suggests that conscious experience cannot be fully explained by localized brain mechanisms alone. Rather, it emerges from dynamic brain–body–environment interactions.

Growing evidence indicates that physiological systems often register and respond to environmental contingencies before these processes reach conscious awareness.

For example, the autonomic nervous system controls involuntary body functions such as changes in heart rate and sweating. Autonomic activity, which can be measured by heart rate variability or skin conductance, may precede explicit recognition of external stimuli. These findings suggest that what is often described as anticipation or “intuition” may correspond to non-conscious processes that integrate these signals and guide behavior prior to explicit cognitive awareness.

Interoception refers to the sensory system that allows us to perceive signals from inside our bodies, such as feeling your heart beat.

Interoceptive awareness fuses signals coming from multiple levels and communication pathways, including electrical and molecular signaling, to shape our moment-to-moment psychobiological state and our capacity to adapt. It provides us with an outstanding potential to dynamically and rapidly integrate massive amounts of internal and environmental information.

This is key for facilitating our self-regulation of health and performance of tasks in our everyday lives.

Perception is Dynamic

The integration of sensory information with psychological and contextual inputs (e.g., sense of purpose, prior experiences, beliefs, expectations, motivation, behavioral goals, emotions, attention) shapes perception. This is why two individuals—or even the same individual at different times—can perceive the same sensation quite differently.

As shown below, the psychological and contextual inputs operate at different timescales, and therefore carry different weights in shaping perception. Some of them are more stable or change more slowly (e.g., sense of purpose, prior experiences, beliefs, motivation) with respect to others. Consequently, they exert longer-lasting effects and have a greater impact than those that are less stable or change more rapidly (e.g., acute fatigue, emotions, attention focus).

The relationship among the different psychobiological constructs is bidirectional—from top to bottom and from bottom to top—indicating that perception is constrained by their continuous interaction.

For instance, the perception of bodily signs can be amplified by prior experiences (e.g., previous injuries), as demonstrated in studies of interoceptive awareness in injured young football players. Perception can also be attenuated when interoceptive signals are interpreted as unimportant and receive little value and attentional focus.

Valuing and providing education on subjective monitoring seems crucial for enhancing interoceptive awareness and promoting self-consciousness, autonomy, and self-regulation of health and performance.

Perception of Energy

Expressions like “I am low on energy,” “My battery is drained,” “This kid has a lot of energy,” or even “This room has good energy,” are commonly used.

But what do they really mean?

The sensations of energy and fatigue have been traditionally conceptualized as opposite poles of a single bipolar continuum. However, some research indicates that they are better considered as two separate constructs with different underlying neurobiology.

Energy is thought to have evolved as an “approach-oriented” sensation with feelings like arousal and vitality that encourage an organism to move toward positive stimuli. On the other hand, fatigue is considered an “avoidance-oriented” sensation that promotes rest and recovery through different neural and inflammatory pathways.

Mitochondrial processes likely modulate brain–body interactions that contribute to the subjective experience of energy and related affective states. Consequently, changes in how we perceive our energy may provide critical insight into our internal experience of things like vitality, mental clarity, calmness, and adaptive capacity.

Monitoring and regulating energy can be challenging because we don’t currently have biological sensors or measurement scales to easily quantify changes in our energy levels or allow us to rate our energy. A similar problem is found when monitoring perceived fatigue, because it is often difficult to quantify fatigue in absolute terms.

In contrast, we can monitor shifts in perceived exertion. Individuals can successfully identify, for example when exercise feels more or less effortful, without having to specify exact amounts.

Although it is hard to perceive and quantify energy in absolute terms, we do sense when energy availability becomes insufficient relative to task demands.

This sensation drives, for instance, our decisions to continue or stop tasks.

Potential Links Between Perceived Exertion, Energy, and Exhaustion

Exhaustion has been conceptualized as a form of task disengagement: we decide to “give up” (i.e., disengage from the task) when continuation of exercise, for example, is perceived as impossible.

The dynamic psychobiological model of exercise-induced fatigue points out that although exercise performers are conscious of task disengagement this does not mean that stopping is voluntary.

From a dynamic perspective, perceived exertion is conceived as an emergent product of the interaction among body, brain, and environment. In a similar manner, we can hypothesize that the shortfall or abundance of perceived energy, playing a relevant role in exercise tolerance, may reflect the flexible trade-off among these interacting components.

The figure below shows the fluctuating dynamics of perceived exertion (PE) with workload accumulation. We can speculate that perception of energy with respect to the task fluctuates as well, increasing—perceiving exertion as heavier—and decreasing—perceiving exertion as lighter—over the course of the continuous exercise.

Assuming that there is no single site or process causing fatigue, the dynamic psychobiological model of exercise-induced fatigue proposes that it is the weakening of the strength of couplings between the brain, the body, and the environment that finally produces the task disengagement.

The loops at the bottom of this figure represent renewed psychobiological synergies that enable us to continue the task. When new synergies cannot be formed, increases in PE stabilize. These nonlinear dynamics (from fluctuating to non-fluctuating dynamics of PE) are also observed in psychological and kinematic variables.

Perceiving Energy Return on Investment

Another common subjective experience that is easy to perceive is whether an energy investment was “worth it.”

The concept of Energy Return on Investment (EROI), used as a unifying principle in biology, economy, and sustainability, can explain this phenomenon. EROI is defined as the ratio between the energy obtained and the energy invested.

The changes in the EROI ratio (e.g., more or less energy obtained with respect to the energy invested) are particularly related to the perceived efficiency. When movements or actions feel smooth, coordinated, or “fluent,” it results in a higher perception of energy efficiency. The reverse is also true.

The flow state can be interpreted as a high EROI condition, in which the energy invested feels matched by performance outcomes. For example, during a competition, a player may perceive high EROI when actions feel effortless, energy is conserved, and performance results are positive.

The graphic below connects the energy production with its perception, the estimated energy return on investment, and the corresponding behavioral outcome.

How Monitoring Your Energy Perceptions Could Be Useful for You

Great progress has been made in identifying energy-related biomarkers, such as Growth Differentiation Factor 15 (GDF15). GDF15 is a cytokine of mitoception now considered a signal that informs the brain about the organism’s energetic state.

However, although quantifiable, this biomarker provides limited dynamic information over short timescales and is not yet available for routine clinical use or accessible to most individuals in everyday settings.

In contrast to objective energy monitoring, subjective monitoring of energy perceptions allows for the real-time integration, synthesis, and reduction of multiple converging sources of information. Furthermore, because people can assess it themselves, it may allow us to capture the dynamics of energy resistance, including its potential nonlinear changes over time and overlaid with our personal experiences and circumstances.

Monitoring the dynamics of energy perception could serve as a convenient and accessible way to anticipate and identify transitions between states of low-, mid-, and high-resistance to energy flow.

Because energy perception draws on information from prior experiences, it is anticipatory and predictive.

As a result, changes in perceived energy could prompt interventions, such as increased rest, improved nutrition, or modifications to the physical or social environment. This could potentially prevent prolonged exposure to detrimental energetic conditions that could lead to disease.

Our physiology is shaped by our perceived and anticipated reality, as well as genetic, social, and cultural factors. In biology and medicine, substantial focus has been placed on monitoring, quantifying, and evaluating one or a few physiological markers in isolation. This approach fails to consider how these physiological markers are related to relevant psychological, emotional, or social variables that integrate subjective experiences.

Monitoring energy perception may also contribute to developing self-awareness, autonomy, confidence, and self-regulation. These are all essential qualities for an effective preventative approach to health.

In this context, the promotion of educational programs that emphasize the value of energy perception and enhance self-awareness and self-regulation may help prevent accumulation of allostatic load and promote health.

What this all means

In summary, monitoring the dynamics of perceived energy is not merely an accessory variable of subjective monitoring, but it could serve as a central axis for protecting health and ensuring sustainable performance.

Perceptual cues that indicate whether a situation constitutes a threat play a critical role in regulating the allocation of limited energy resources. Integrating this perceptual dimension into clinical and training models could enable a more prevention-focused, human-centered, and coherent approach to health, thereby supporting longevity and improved quality of life.

The human mind can be both the greatest ally and obstacle in achieving individual health. As a result, grasping how our mind shapes our health is key to fulfilling the promise of personalized medicine. This article explores limitations with our current medical model, and how bringing the mind—or human experiences—into our conversation about health and healing is essential for medicine to shift into its next stage of evolution.

The Paradox of Medical Advances and Declining Health

Thanks to progress in diagnostics, pharmacology, and surgery, medicine has acquired a formidable ability to treat previously-elusive symptoms and disorders. However, disease incidence, particularly non-communicable diseases, hasn’t been declining.

Modern children and adults get sick more often with chronic diseases, receive more expensive treatments than ever before, and spend more time in disability and poor health.

As a result, healthcare spending in the United States has risen to a quarter of the gross domestic product (GDP). Despite the investment, the U.S. population doesn’t live much longer than 10 years ago. In fact, in the last decade the average U.S. lifespan has continued to fall behind that of other developed countries, urging us to reconsider the premise and our approach to the modern medical enterprise.

We have gotten better at fixing broken parts, but not at keeping people healthy.
What are we missing about health?

Intrinsic health is a field-like state that drives our ability to optimally adapt to challenges. It manifests as the intrinsic capacity of an individual to reach their full physical and intellectual potential. As medicine attempts to fulfill its mission and support public health, it needs not only to fix problems, but also to promote health to avoid sickness in the first place.

Examining the Mind-Body Connection

Of the factors that can tilt the delicate balance between good and poor health states, an understudied, poorly integrated, and rarely leveraged factor is the mind.

The human mind encompasses the subjective dimension of the lived human experience. It includes thoughts and emotions that release powerful hormones and shift systemic metabolism and pathophysiology.

It also includes more subtle and less acutely salient inner experiences, such as our sense that the world is coherent and meaningful, our desire and ability to entertain social connections, and the overall emergent sense of well-being. All of these experiences—as ineffable as they are—shape human health.

The mind is also the “organ” of the human organism that gets injured by early life trauma and abuse. Once damaged, it becomes excessively vulnerable and easily triggers abnormal physiology that manifests as severe, medically-unexplained mental and physical health disorders. Traumatized minds increase the risk for most age-related diseases to arise over a person’s lifetime.

How can we be sure that we have much to gain by integrating the mind into medical training, practice, and research?

How the Mind Can Influence Health

Three major domains of human health are naturally under the control of the mind: behaviors, mental health, and energy metabolism.

Understanding how the mind connects with the biology of health at different levels cements the importance of bringing the mind into medicine.

1) The mind shapes health behaviors.
The pillars of health promotion include physical (in)activity, diet, sleep, and other modifiable behavioral strategies well known to mitigate disease risk. The effects of behaviors are particularly well-established for cardiovascular health and increasingly recognized for other chronic illnesses, including diabetes, neurodegeneration, and mental health.

Some behaviors increase disease risk. For example, overeating causes metabolic oversupply. Acutely, this leads to obesity and insulin resistance. Chronically, it damages neurons in the nervous systems and other tissues. Smoking increases cancer risk through well-defined carcinogenic mechanisms, whereas social isolation increases the risk of neurodegeneration through mechanisms that still elude us.

Nevertheless, health and social behaviors are directly under the control of one’ states of mind.

2) The subjective experiences of the mind, over time, crystalize into mental health.
Mental health is your ability to entertain positive, realistic interactions with your environment and other individuals. This involves brain-based perceptions of our external environment through the senses, but also of our internal physiological environment through interception.

This explains why our microbiome and its metabolic products influence our acute emotional tone and mental health. The mind also underlies our ability to accurately perceive the external environment and to consistently distinguish imagined from real occurrences.

The mind is the subjective interface between our inner biology and our outer environment.

3) The mind regulates energy metabolism.
Energy is the force that brings the otherwise inert genomic and molecular hardware of our cells to life. Energy metabolism fuels all cellular activities, from neuronal action potentials, production of immune cytokines and antibodies, to the dynamic expression of longevity-promoting genes that shape lifespan.

States of the mind–emotions, perceptions, and expectations–cause the release of hormones and neuropeptides with powerful metabolic effects. For example, acute psychosocial stress triggers cortisol release from the adrenal glands, and the neurotransmitter norepinephrine from sympathetic nerve terminals. Acting on target tissues, cortisol, norepinephrine, and other chemical messengers engage intensive energy-consuming cascades that increase cellular respiration, heart rate, and neural activities.

Through its brain-based signaling effects on cellular and systemic metabolism, the mind regulates energy expenditure and possibly cellular aging.

Because it’s connected to all of our being—behaviors, how we feel, and energy metabolism—the mind is both the greatest ally and obstacle in achieving individual health.

Our Vision for the Future of Modern Medicine

The defunct medicine of past centuries lacked proper biological grounding. As a result, it focused on occult concepts and brought little relief for real human suffering.

Now anchored in remarkable biological details, modern medicine effectively reduces all aspects of human suffering to physical and molecular events. But reductionism has long been recognized as an incomplete approach to make sense of life.

As our major analytical lens, reductionism leaves the mind outside our field of view and consistently fails to produce actionable healthcare strategies. To fulfill its evidence-based, personalized, and effectiveness aspirations, our medicine of the future needs to bring the human mind into the picture.

Advancing a robust science of mind-body processes has the potential to shift pieces of the health puzzle from the periphery of molecular medicine to the core of person-centered medicine.

Our goal as biomedical scientists should remain focused on building increasingly accurate models of human health. And I am increasingly convinced, focused on building a science of the healing process—Healing Science. We won’t be able to do this without integrating the full spectrum of human experiences that fill our minds.

Upon close inspection, we soon realize that all aspects of life that normally operate in healthy organisms and that falter in disease–from energy metabolism to information transfer–are naturally under the control of the human mind. The mind and body unfold together from energy transformation. They also evolved in tandem over millions of years to promote survival.

As a result, they are wired together, reflecting two important facets of the energetic process that you are.

Our scientific landscape is ripe for a new generation of translational mind-body, mind-mitochondria, and mind-molecule science. We need to build robust evidence bridges at the intersection of disciplines, and across levels of analyses.

If successful, this effort has the potential to reveal novel bioenergetic mechanisms through which the mind, and the fabulously individual experiences it holds, shapes health and aging trajectories over periods ranging from minutes to decades.

Once discovered, validated, and implemented, new mind-body principles could rapidly illuminate a new generation of scientifically-informed, energetically-inspired interventions designed to help people flourish—to fulfill their psychobiological potential.

Evidence suggests that if we help people flourish, we can also keep people healthy for longer. And thus help fulfill the much-needed promise of modern medicine.

This week on The Science and Experience of Energy, we explored how energy is sensed, communicated, and coordinated, from mitochondria and individual cells to the social environments that can shape our health.

In the first piece, we introduced a framework called mitoception that covers how mitochondria may communicate energetic strain to our brain using the signaling molecule GDF-15. Mitoception could help explain experiences like fatigue as adaptive responses that allow us to conserve and reallocate limited energy resources.

In the second piece, described how we can view the body as an energetic collective. Through the lens of social physiology, he discussed how energy flow can be shaped by our biology, environment, and society, and how this view could impact our approach to medicine.

Together, these pieces emphasize the important roles of communication and coordination in managing and supporting our energy for optimal health.

Thank you for joining us on this adventure.

With gratitude,
Nirosha and Martin

Thanks for reading The Science and Experience of Energy.
Know someone who may be interested in an energetic view of life?

Share The Science and Experience of Energy

Our TSEE guest writer Jameel Barkat Lone is a Basic Life Science Research Associate in the Svensson Lab at Stanford University. In this post, he describes parallels between our cells and societies that are relevant for fighting disease and promoting health. He advocates for a shift in how we think about our cells—from individual, autonomous units to cells as an interconnected, energetic collective.

Our social structure has deep impacts on how we understand and describe cellular life. I grew up studying the cell, and we were told the nucleus acts as a command center. The organelles suspended in the cytoplasm are manufacturing, shipping, and packaging units. We were inundated with the concept of selfish genes in books and papers.

These metaphors perhaps reveal more about our society than the true nature of our cells. They fail to capture the complexity of human biology and how our biological systems are affected by our experiences. And, importantly, these metaphors have shaped how we approach scientific questions about health and the policies we’ve created to protect public health.

Seeing Cells as Social Structures

Despite knowing that eukaryotic life is fundamentally a cooperative process that started with a landmark cooperative event of endosymbiosis, we continued to view the cell as a factory. Paradoxically, alternative models inspired by cooperation that framed the cell as a collective have received far less attention and recognition.

Rudolf Virchow described the human body as “a republic of cells” and viewed diseases as disturbances in the cellular organization. Virchow produced the famous report of the typhus epidemic outbreak of Silesia (1847-1848) and blamed the negligence of the elites for their detrimental social and economic policies that led to the epidemic. His early insights into the collective nature of cells and his view of medicine as a social science helped bridge medicine and politics.

How an Epidemic Revealed the Role of Social Medicine

In parallel, across the North Sea, tuberculosis (TB) was sweeping through the cities and towns of the United Kingdom, where the recorded mortality figures reached tens of thousands of people per year and likely still underestimated the devastation.

In 1882, Robert Koch identified that tuberculosis is caused by Mycobacterium tuberculosis. This discovery set the stage for developing treatments and preventative measures that focused on killing the bacteria and preventing infection. Interestingly, by the time the antibiotic streptomycin was introduced in 1947 and the BCG vaccine for TB was made available in 1955, TB mortality rates had already decreased significantly in England and Wales. But why?

In 1975, McKeown, Record, and Turner reported interesting and startling statistics. They plotted the proportional relationship between rising wages and declining TB mortality. McKeown’s thesis perplexed the ‘overconfident’ medical community by clearly showing that rising wages led to better nutrition, which significantly reduced the TB mortality rates.

McKeown’s thesis was later refined and critically re-examined by many experts, including Simon Szreter, who, by his diligent scholarly work, found that preventive health reforms at local levels—sanitation, better housing, and quarantine of TB patients—were also instrumental in decreasing mortality rates.

However, Szreter does not exclude or diminish the role of nutrition in decreasing TB mortality. Instead he argues that economic progress (rising wages) does not always translate into ‘health-enhancing properties. Objectively analyzing both McKeown’s and Szreter’s work, I find them complementary, and they further supportVirchow’s thesis that epidemics are social in origin.

The Metabolic Health Conundrum: Examining Biological, Environmental, and Societal Factors

The evidence from public health history shows that clinical interventions complemented by systemic, population-level changes are most effective in fighting diseases. This is especially true for diseases that have an unambiguous socioeconomic structure.

What is paradoxical is that we are so efficient at giving emergency treatments for metabolic conditions like obesity and type 2 diabetes in the form of targeted clinical interventions, but we lack the foresight to achieve lasting victories.

How and why do we reach such metabolic health emergencies? Undoubtedly, a part of the blame rests on the politics that shape the socioeconomics of society. But also, the self-imposed intellectual constraints adopted by the scientific community through a reductionist approach to disease.

Once the cumulative effect of factors that shape the social, ecological, and biological structure of disease breaches a critical threshold, urgency overwhelms us. Stepping back to question the underlying superstructure becomes a luxury.

According to recent research published in JAMA, the prevalence of diabetes in US adults from 2013 to 2023 has not significantly changed, and glycemic control in those diagnosed with diabetes has worsened. This coincides with a period during which we have seen a remarkable number of new drugs for obesity and diabetes, predominantly in the form of GLP-1 agonists, entering the market. This indicates the complexity of disease management and the limitations of clinical interventions in achieving the desired health outcomes.

Pharmacological treatments alone cannot solve the problem of widespread metabolic disease.

Another eye-opening but not surprising finding came from India, where a study conducted by the University of Hyderabad found that 84% of Indian IT sector employees have Metabolic dysfunction-Associated Fatty Liver Disease (MAFLD), driven by obesity, inadequate sleep, sedentary lifestyle, and stress. This is about 2.5x the estimated global prevalence of MAFLD of 32.4%. These findings emphasize the importance of lifestyle and environmental factors, our societal roles, and our everyday experiences on our metabolic health.

How Energy Contributes to Our Social Physiology

In particular metabolic disorders, disease is marked by disturbances in the foundations of eukaryotic life: bioenergetics.

Bioenergetic flow and efficiency are key to upholding the sanctity of the “republic of cells.”

We need a more comprehensive framework for understanding how the disruption of energy flow in our bodies impacts our cellular collective. And this framework should incorporate a social-physiology perspective.

Examining cellular activities in isolation from their environment does not capture the complex interactions that underpin life and human health. Sociality goes sub-cellular as the state of the cells and organs in a person’s body can convey information about the person’s role and position in society, the environments they are regularly exposed to, and their access to certain resources.

For example, the lungs play a vital role in supplying our cells with the oxygen they need to transform energy into useful fuel. It should be easy to recognize the lungs of a coal mine worker from those of a CEO of a multinational corporation. And it is easy to imagine how damaged lungs from occupational hazards can increase resistance to energy flow and thus increase disease risk for people who work in coal mines.

It is critical not to restrict our view of metabolic disorders to biochemical changes only, but to understand how social physiology (and energetics!) shapes our biology.

Accumulation of cellular stress signals by low- and high-intensity conflicts marked by lack of optimum energy flow may erode and fragment the cellular collective. These stressors may increase the cost of living for each cell. When individual cells receive signals that the world is a dangerous place, they likely have to concentrate their limited energy budget on surviving another day (self-preservation), rather than engaging in activities that support optimal

cooperative behaviors that sustain metabolic health. Taking a step back, this moves the organism away from a holistic state of health towards a state of individualism and fragmentation of the cellular collective that may lead to disease.

This takes us back to the social origins of diseases and social determinants of health. While it is necessary to ramp up our scientific endeavors to meet the challenges of metabolic disorders, taking a step back and looking at human physiology as social physiology is a prerequisite for sustaining the health gains and achieving the goal of a healthy society.

Social Physiology and Aging

The lens of social physiology can shift the paradigm of approaching diseases, and even the process of aging, from reductionism to holism, thereby challenging conventional wisdom based on assumptions about the human body.

As we age, damage accumulates at the molecular level, and our cells have to use more energy to perform their usual activities. Despite the increase in energy expenditure of our individual cells, collectively, our whole-body energy expenditure stays stable or decreases with age.

The brain–body energy conservation (BEC) model of aging describes how the brain likely plays a key role in managing our energy allocation overall to keep us on-budget. The energy-saving strategies focus on diverting energy away from growth, maintenance and repair processes to focus energy resources on processes that are most essential for survival.

Let’s look at the example of blood pressure rising with age. Higher blood pressure costs more energy, and chronic high blood pressure (hypertension) can lead to a heart attack, stroke, heart failure, and kidney disease. In general, as humans age, blood pressure tends to elevate. However, this does not occur in the foraging community of the Kalahari Desert, where blood pressure increases till puberty and then stabilizes and levels off.

This raises philosophical questions that are important for medicine. Are increases in blood pressure over time an inherent feature of the human body as it ages, or do these changes occur as a function of society and environment? Do the energy conservation strategies the brain uses to combat the increased energy demands of aging differ across populations and societies?

Invoking Rudolf Virchow’s famous recommendation of “full and unlimited democracy” in the typhus epidemic outbreak of Silesia report, we should revisit our approach to metabolic disorders and aging by making the ‘cellular democracy’ the centerpiece of health.

However, cellular democracy cannot be ensured without democracy at the societal level. Because stressors like insecurity, domination, and exclusion may induce stress responses that increase the cost of living for our individual cells, societies that cultivate these environments may reproduce the same pathologies in our bodies.

Full-Text Link to Primary Source

Could the feeling that we are “running out of energy” begin as a biological message from our mitochondria? In this article, we share a new framework that suggests how the body communicates energetic strain to the brain—in part through that the molecular messenger growth differentiation factor 15 (GDF15)—so we can reallocate energy to where it’s needed most.

Being healthy and feeling great isn’t just about having enough of an energy supply. Your cells have to continuously match their energy demands with sufficient capacity to transform nutrients and oxygen into usable energy.

Meanwhile, your brain has the important task of sensing and coordinating processes across the whole organism. That ensures that our limited energy budget is directed where it’s needed most. But what happens when your overall energy demands exceed your body’s ability to transform energy?

How do we perceive when energy resistance creeps up and our cells can’t flow energy fast enough?

In a recent paper, we introduce the concept of mitoception. Mitoception is a framework for understanding how the brain monitors cellular energy strain through GDF15, a stress-related cytokine or hormone. Mitoception connects mitochondrial biology with stress physiology, fatigue, emotion, behavior, disease, healing, and aging.

What Does “Mitoception” Actually Mean?

To keep us alive and healthy, our bodies depend on different kinds of internal sensory signals that allow our brains to recognize and locate threats to our physical well-being. This internal sensory system is called interoception. (There is a great recent book on interoception called Inner Sense.)

For example, when a tissue is damaged, we feel pain. That’s nociception.

Following this naming scheme, we refer to our internal sensory system related to metabolism as metaboception.

Metaboception

Metaboception, or the perception of our metabolic state, describes how our brain monitors and controls energy supply, demand, and transformation capacity.

For example, when there is plenty of food in your gut, your brain must know that. The gut signals the presence of food through GLP-1 and other hormones. And when GLP-1 hits the brain, you feel full.

Metaboception helps you be aware of how much energy is available.

Mitoception

Going one level deeper, mitoception is a more specific part of this metaboceptive system. It involves the brain’s monitoring of the balance between cellular energy demand and the capacity of our mitochondria and metabolic circuitry to transform energy.

In this case, we’re not talking about monitoring whether we have enough energy supply or reserves. There can be plenty of nutrients and oxygen, but a limit to how well or how fast our mitochondria can transform those inputs into usable cellular fuel, like ATP (adenosine triphosphate).

That’s what we call an energy gap.

A more dynamic way of thinking of this is excess energy resistance (éR). Excess energy resistance reflects a mismatch between energy demand and transformation capacity. Problems arise when a cell can’t transform energy quickly or efficiently enough to meet current energy needs.

Energy gaps or excess energy resistance happens when demand rises, like during infection, tissue repair, strenuous exercise, chronic psychosocial stress, or other energy-expensive activities. They also can arise when mitochondrial energy transformation capacity is impaired by inherited defects, toxins, drugs, aging, or other factors.

But how does this kind of mitoceptive communication between your mitochondria and the brain happen?

GDF15 as a Signal From the Body to the Brain

The more we’ve learnt about the protein GDF15, the clearer it’s become that it is a key player in mitochondrial signaling and health.

GDF15 is a small cytokine secreted by different cells in our body that is often described as metabokine–a metabolically-regulated cytokine.

GDF15 has also been called a mitokine, because it is strongly induced by metabolic stress and mitochondrial disorders. So, even if it doesn’t come from mitochondria directly, it’s a sensitive and specific enough biomarker of mitochondrial defects that some researchers feel it’s earned that name.

Where does GDF15 come from?

The GDF15 gene is expressed across nearly all of our organs and tissues. Except one… the brain. In the brain, GDF15 gene expression is extremely low.

Where does GDF15 signal to?

Only in one organ… the brain. Indeed, the best-characterized GDF15 receptor, GFRAL (glial derived neurotrophic factor receptor alpha-like), is concentrated in a small part of our brainstem. Although we know now that other ways of signaling outside the brain likely do exist.

This area of the brainstem is well-suited for monitoring signals in the blood because there are many blood vessels there with tiny pores that allow larger molecules to pass through. Other areas of the brain are harder for circulating signaling molecules to reach due to tighter regulation of what can pass through those blood vessels.

Every Cell is a Metaboceptor

One new concept we introduce in this piece is that any cell can, in theory, act as a metaboceptor: a sensor and signaling agent of metabolic states.

Cells sense local energetic conditions and release GDF15 to signal energy gaps to the rest of the body—to the brain in particular. GDF15 travels through the bloodstream to cells in the brainstem that have GFRAL receptors.

This raises the question: how are energy gaps sensed locally?

Integrating evidence from a decade of research, we show how the cellular sequence of mitoception begins with reductive stress.

When mitochondrial energy transformation capacity is not enough to meet demand, electron flow encounters resistance. With enough resistance, electrons effectively begin to flow backwards. The electrons start to pile up and attach to molecules like NAD+ (nicotinamide adenine dinucleotide), switching them over to their “reduced forms”. That’s why it’s called reductive stress.

An increase in the reduced forms of NAD+ (NADH) activates the integrated stress response (ISR). The ISR is a cellular program that suppresses some expensive activities while activating stress-adaptation genes, including GDF15.

Elevated energy demand → Energy gap → Reductive stress → ISR → GDF15 → Brain

In this body-to-brain component of mitoception, a problem with energy transformation in your cells is converted into a circulating signal the brain can detect.

What Happens When the Brain Receives the Signal?

Let’s go back to our earlier example of tissue damage. When our nociception system detects signals from damaged tissues, the signals travel to our brain. Then, the brain sends a message to our body to take action to protect itself and prevent further damage.

That response typically involves both a subjective experience (pain) and a physical reaction (moving our body in a way to reduce pain).

If we apply this to mitoception, an energy gap or excess energy resistance prompts the release of GDF15 from a set of cells, circulating GDF15 travels to the brainstem, and this tells the brain there is a problem with energy transformation somewhere in the body.

Brain sensing of GDF15 triggers two two downstream protective actions: energy mobilization and energy conservation.

Energy mobilization recruits and diverts fuels from some parts of the body to the areas that need it most. Research in mice shows that GDF15 signaling via GFRAL receptors can activate systems that increase circulating glucose and fatty acids. This process promotes fuel delivery to tissues in need.

Energy conservation reduces activities that are energetically costly and not immediately essential. For example, GDF15 reduces appetite and induces nausea. This makes sense because fasting frees up the energetic resources that would normally be spent on seeking and digesting food. And that’s not a trivial amount of energy. Digestion alone makes up about 5-10% of our total daily energy expenses.

So, mitoception in mice triggers an energy-saving and energy-mobilizing state that slows down their behavior, drops their body temperature, and induces various metabolic changes.

In humans, this may be analogous to how shitty we feel when we’re sick. Fatigue. Feeling weak and unmotivated. Or inclined to rest. These feelings reduce our physical, mental, and social activities. That limits energy demand, allowing energy to be redirected toward higher-priority processes.

This does not mean that fatigue is always caused by issues with mitochondrial energy transformation, or that GDF15 is the cause of every experience of low energy. However, fatigue may sometimes be an adaptive, brain-mediated response to signals that your body is approaching its energetic limits.

Evidence Connecting GDF15 with Human Health

Several studies connect GDF15, health, disease, and the aging process.

For example, people with mitochondrial disease have exceptionally high levels of blood and saliva GDF15—up to 10 times normal levels. We recently found that their physical and mental fatigue correlates with circulating GDF15 levels.

The higher the GDF15, the more fatigue people feel.

GDF15 also rises steeply with age. It has been identified in large proteomic studies as one of the most consistently elevated proteins across many chronic diseases. These include cardiovascular disease, kidney disease, cancer, Alzheimer’s disease, and autoimmune diseases.

Research has also shown that GDF15 can predict who will develop chronic diseases in the future. Even cognitive dysfunction and dementia, within the next 10-20 years, is better predicted with GDF15 than many other protein biomarkers.

New research also links GDF15 to mental health.

Across several studies, blood GDF15 levels were 40-78% higher in people with major depressive disorder, bipolar disorder, or psychosis than in individuals without a psychiatric diagnosis. And in more than 52,000 participants in the UK Biobank, GDF15 was the protein most strongly associated with reported social isolation and loneliness.

GDF15 was also the most upregulated protein in relation to anxiety. Stressing out seems to have an energetic toll on the body.

Mental Stress and GDF15

In line with this, our group also found that acute psychosocial stress increases GDF15.

When we exposed healthy people to an acutely stressful situation that involved giving a speech, blood and saliva GDF15 shot up within 5-10 minutes. These findings suggest that mental stress can produce rapid changes in mitochondrial and metabolic strain.

And work-related stress may also be related to how much a person’s GDF15 levels increase in response to a mental stressor.

The research done to date does not establish that GDF15 directly causes psychiatric illness, loneliness, or fatigue. Age, disease burden, medications, diet, environmental exposures, socioeconomic status, and other factors all converge to influence our energetic state—which we sense through metaboception and mitoception.

The science of GDF15 in general, and the concept of mitoception in particular allows us to see how physical diseases and psychosocial stress may converge on common energetic pathways.

Future Directions

In our mitoception paper, we highlight questions that remain unanswered.

For instance, we need to more clearly define the role of GDF15 as a potential link between psychosocial factors, fatigue, and energetic challenges. To do this, we’ll need large-scale epidemiological studies, long-term observational research, clinical studies that measure GDF15 at time scales of minutes to hours.

Some evidence also suggests that GDF15 biology may be related to sleep, wound healing, and other restorative processes. How do chronic stressors such as loneliness, workplace stress, adversity—which we know can undermine our health—affect mitoceptive signaling?

Do interventions that improve well-being and promote deep rest reduce GDF15 levels?

Measuring and interpreting GDF15 levels comes with some challenges. GDF15 varies with age, may show daily rhythms, rises dramatically during pregnancy, and can be underestimated by some assays in people carrying a common genetic variant. Emerging biosensors, microneedle patches, and other continuous-monitoring technologies could soon provide more precise data on how GDF15 fluctuates over time.

Mitoception offers a different way to interpret fatigue and the states of dis—ease (the lack of ease) we experience in our lives.

It also provides a testable framework that bridges mitochondrial energy transformation, cellular stress signaling, brain activity, and lived experience. It’s helping us understand how the science and experience of energy converges within our cells.

The emerging science of mitoception may help us understand more holistically how the body manages its finite energy budget, and how those decisions shape health and healing across our lives.

This week marks six months of TSEE. Thank you for sharing this milestone and being part of this journey!

Nirosha and I previously shared why we care so much about bringing together the science and experience of energy, and you along with it.

We continue to hold this dear to our hearts.

What is Flourishing?

We’re on a mission to support human flourishing.

“But what is flourishing?,” we’ve recently been asked a few times.

To flourish is to fulfill the unique potential you alone have to offer the world. Like every living organism, it requires continuous healing, growth, and transformation.

Healing, growth, and transformation require energy.

Without energy, there is no life. And when energy does not flow efficiently, we cannot be at our best. We feel tired and drained. We rely on stimulants. We get sick more often. We recover less easily from challenges. Life feels heavier.

When energy is properly patterned in your mitochondria, you feel energy. You have vitality. You still go through shit, but somehow you have the capacity to grow and transform—to become a better version of your unique self. You can flourish.

So, to flourish and achieve our collective potential, we have to understand energy.

And to understand the role of energy in our health, we have to use the two greatest instruments in the universe that allow us to understand how things work: science and the human experience.

TSEE is a vehicle for that journey.

To spend time with our families and prepare for the second half of the year, we’ll be taking a short summer pause in July.

We’ll be back in August with new papers, some beautiful mitochondria, fresh ideas from guest contributors, and new reflections from the biophysics side of our world.

With gratitude,
Martin and Nirosha

On Thursday, a podcast from The Diary of a CEO was published. On this podcast, Martin shared our understanding of energy and health, aging and hair graying, and some stories that have shaped us.

Thank you again for joining us!

To help grow this community, please share with someone you love.

Share The Science and Experience of Energy

Full-Text Link to Primary Source

The Energy Resistance Principle (ERP) has changed how we think about life, biological energy, and the human experience. In this post, we share with the TSEE Community what inspired the ERP and a new video about how it applies to health, disease, and to our everyday lives.

The Missing Variable

Nothing is free in biology. Everything costs energy.

To stay alive and thrive, cells require the continuous flow of electrons towards oxygen—the ultimate electron acceptor in your mitochondria.

The food you eat provides the electrons. Your metabolism sequentially rips them off the carbon backbone of fats, carbs, and proteins one by one. And it’s in your mitochondria that the final step takes place: electrons meet with oxygen, turning into water.

Yes, your mitochondria ooze water. Cooling down the fire of metabolism that burns within you.

When energy—here, electrons—flows efficiently, biological systems function efficiently. But when energy flow becomes constrained, the organisms experience stress, dysfunction sets in, disease risk increases, and aging accelerates.

People living with mitochondrial diseases illustrate this clearly. For example, when someone’s mitochondria can’t keep up with energy demand, electrons accumulate in the body (called reductive stress), people tend to experience debilitating fatigue, and to die earlier than people whose mitochondria flow energy efficiently.

Science has brought us to a place where we understand that energy isn’t just a nice-to-have thing. Any scientist would agree that energy flow is fundamental to life. It’s not like a vitamin you can skip eating for a few days while you fast. Energy flow and transformation is a vital process that takes place every second.

Your metabolism burns like an uninterrupted flame. It’s been passed on from generation to generation, since the beginning of life.

That’s why you must breathe continuously. It’s why your life started with a first breath. And why it will end with a last one.

Every breath we take ultimately serves one purpose: precious oxygen rushes through your cells, drawn by an irresistible concentration gradient, descending into your mitochondria to keep those electrons coursing through the metabolic circuitry of your body.

All this flow to keep life going.

That uninterrupted process has sustained life on Earth for billions of years.

Yet despite decades of research into metabolism, we have lacked a simple framework for thinking about how energy behaves inside living systems. How is the balance between energetic demand and energetic supply maintained?

And what happens when that balance is lost—not only in cells and organs, but across the organism as a whole?

The Energy Resistance Principle, or ERP, was developed to explore those questions.

The Energy Resistance Principle (ERP)

At its most fundamental level, energy is the potential for change.

For energy to be transferred or transformed in a system, it needs to flow through some sort of conductive material. Think about how electrical energy flows through conductive copper wires to power the lights in your home.

What is the equivalent conductive media in your body?

Our bodies are a network of about 5,000 trillion metabolically-connected mitochondria. Our breathing mitochondria and other metabolic enzymes bridge your digestive tube to cytochrome c oxidase—the final enzyme in the mitochondrial electron transport chain. This is what enables energy metabolism.

Metabolism is your body’s conductive media—like the copper wire in electrical circuits—that allows energy to flow and transform in your cells.

Ultimately, we are fleshy energetic circuits with electrons flowing through our metabolism. That diagram from the ERP paper illustrates this:

The Circuit Analogy, Thinking Beyond Molecules

Typical conductive materials don’t just offer a path for energy to flow, they also provide resistance. That’s true of simple electrical circuits.

In simple, resistive electrical circuits, if resistance is zero, it doesn’t matter how many electrons flow, the power is going to be zero. There are two simple formula predicting this, called Ohm’s Law and the Power Law.

And by tweaking resistance in more complex circuits, you can direct where electrons flow.

It turns out that biological systems also use resistance to direct energy, for example, the energy carried by your blood. If the body wants to send more blood or energy to your muscles when you run, it closes off (i.e., increase vascular resistance) the arteries to your gut, and loosens off (i.e., decrease vascular resistance) to those of your legs.

And voilà! Energy diverted from one place to another, by tweaking vascular resistance.

From this idea, we began to conceive of a generalizable principle—one that reframes energy metabolism not simply as molecular process with enzymes and metabolites, but one where electrons flow from food to oxygen—as if in a circuit, also regulated by resistance.

For more details about the underlying science behind the ERP, check out our prior post. But the central idea was applying the Power law in the context of energy metabolism.

In a funny way, we also noticed in discussion with our good friend Judyann McNamara that the Power Law and consequently the ERP matched in structure the simplified version of Einstein’s famous mass-energy equivalence principle: E=mc².

This is likely a meaningless coincidence. But it helped us think about the general principle—it was useful food for thought. So we included it in the paper in case it sparked something useful.

The basic ERP-inspired equation EP/f₂=éR isn’t meant to be an all-encompassing explanation of exactly what is happening in biological systems. Instead, it’s meant to be an accessible heuristic—a useful starting point for people to think about biological energy in a dynamic way.

The Energy Resistance Principle and the formula it inspired need to be further tested and refined. For now, it provides a coherent, unifying structure grounded in physical laws and in what we know of biology.

It serves as a springboard for scientists and any of us to start testing and exploring the science and experience of energy.

What Does Energy Resistance (éR) Feel Like?

A few common situations illustrate what it might feel like when energy resistance creeps up in our bodies.

Brain fog

The first is when blood flow to your brain decreases. Have you ever experienced getting up too fast and feeling light-headedness, or feeling faint?

What happens in this situation is that blood flow to your brain decreases. Less blood flow, less oxygen for your mitochondria to flow electrons, so electrons quickly start to stall—flux, the denominator in the ERP-inspired formula, drops.

So in this case, decreased blood flow (lowers f) despite sustained work (EP, given the brain’s constantly high metabolic rate), which rapidly increases éR. The light-headedness could be many things.

The ERP suggests that the brain fog or light-headedness you experience may be the experience of elevated brain éR.

Burning muscles

Another situation where éR increases is during strenuous exercise.

Here, the contracting muscle increases EP. If the contraction is intense enough, and in particular if blood flow is occluded, the increase in workload isn’t followed by a proportional increase in oxygen and electron flux (f).

The result is a rapid increase in éR. And this might feel, or be experienced as discomfort—in the worse cases, if you don’t let up, that burning sensation of the last few reps in the gym.

Angina (chest pain)

And perhaps the worse, most acute we know of, when the heart mitochondria are oxygen deprived.

An analogous situation to the brain and muscles occurs when a coronary artery becomes partially occluded by a narrowing of coronary arteries, or a blood clot.

In this case, blood flow (f) stops to it cannot sustain the metabolic cost of cardiac tissue (EP). Again, éR must then increase precipitously.

The resulting sensation in the ischemic heart here is one of pain, pressure, and deep discomfort. Not because of some mechanical injury or damage—simply, it seems, because energy can no longer flow.

The ERP helps us think about a new possibility: might we experience the flow of energy directly? Or rather, the resistance or blockages to energy flow?

Do we experience energy resistance (éR) directly?

Why Temporary Resistance Helps Us Adapt

Another generally accessible experience of high éR is running out of breath.

Consider what happens when you hold your breath for an extended period of time. Try it now, if you wish.

At first nothing happens. Then a gradual dreadful feeling emerges. Where is the sensation? This time, the sensation is more diffuse than that in the oxygen-deprived brain, contracting muscle, or starving heart—it is generally in the chest area.

Running low on oxygen (and high on carbon dioxide, CO₂) directly increases the resistance to flowing electrons in mitochondria. This drives éR up. And because we evolved to dislike and avoid excess éR, our animal instinct is to breathe.

Breathing relieves the discomfort of energy resistance.

If you’ve been holding your breath throughout this paragraph—breathe! Feel the relief of lower éR. Enjoy breath and the release of resistance in your mitochondria.

The schematic below is pulled from the paper. It shows what happens to the three terms of the ERP-inspired formula over time, as someone exercises at a mild, medium, and maximal intensity.

Notice that skeletal muscle éR only creeps up to uncomfortable level during the maximal intensity, as the mild and medium intensities didn’t overwhelm the system’s capacity to flux oxygen.

Sleep, on the other hand, evidence suggests although we still need to confirm this, likely lowers energy resistance across different organs and tissues.

Diseases as Consequences of Excess éR

We have decades of research showing how certain things increase disease risk, while others decrease risk. The ERP provides a framework to help us think about this.

Based on several factors converging on either energy demand or supply, behaviors like eating less, sleeping, resting, relaxing, and meditation are predicted to reduce éR by decreasing energy potential (EP).

Based on factors converging on oxygen and electron flow through our metabolism, increasing the number of mitochondria, increasing oxygenation, growth of new blood vessels, ketosis, and other factors reduce éR by increasing flux (f).

Conversely, risk factors like hyperglycemia, immune activation, infection, trauma, damage accumulation, cell proliferation, and exercise are predicted to increase éR by increasing EP. While decreased blood flow, low oxygen, toxins, mitochondrial defects and mutations, protein aggregates, and other factors increase éR by reducing flux.

Evidence from clinical and epidemiological studies of the proposed energy resistance and reductive stress marker GDF15 (Growth Differentiation Factor 15) support these connections.

In the previous post introducing the ERP, we discussed what happens when energy resistance is too high for too long. Your body adapts to protect itself during brief increases in éR, but sustained high levels of energy resistance without sufficient recovery leads to degradation and disease.

All of the cellular hallmarks of disease appear to be mechanistically linked to energy resistance. Excess energy resistance could be a major upstream driver of disease and aging.

What Changes When We Think in Terms of Energy Resistance?

Every disease has its own molecular signature, so we’ve been thought to understand through a molecular-centric view. Cancer is not Alzheimer’s disease, and depression is not diabetes.

Yet many seemingly unrelated diseases share common energetic challenges: altered metabolism, impaired mitochondrial energy transformation capacity, inflammation, impaired perfusion, or increased energy demand. What is going on?

The Energy Resistance Principle does not replace genetics or molecular biology. It provides another level of description—one that asks how different biological processes ultimately influence the balance between energetic demand and the body’s capacity to transform energy.

Viewed through this lens, molecularly unrelated diseases become connected by a common feature: energy constraints and energy resistance.

Disease Snapshots

CANCER is often described as a disease of mutated genes and uncontrolled cell growth. From the perspective of ERP, those mutations also create an energetic problem. Rapidly dividing cells dramatically increase the work being performed by a tissue, often (but not always) raising energy demand.

Tumors respond by rewiring their metabolism, recruiting new blood vessels, and competing aggressively for nutrients and oxygen. Recent studies suggest this competition may extend even further, showing that cancer cells can physically acquire mitochondria from neighboring immune cells through tunneling nanotubes, effectively drawing energetic resources away from the very cells attempting to eliminate them.

These are familiar hallmarks of cancer. The ERP simply frames them as different ways of managing the elevated energy resistance. GDF15 is also commonly elevated in people with cancer.

DIABETES is traditionally viewed through glucose and insulin signaling. ERP reframes diabetes as a problem of energy resistance.

Overly abundant blood glucose (hyperglycemia) pushes electrons onto the delicate biological circuitry of the body, increasing EP beyond what f can support, chronically increasing éR.

As a protective mechanism, muscle and other cell become “resistant” to taking in glucose, which is stimulated by insulin. Cells become insulin resistant. Insulin resistance is a protective mechanism against excess éR.

The result is not simply high blood sugar. It is a progressive increase in éR across all organs, which accelerates damage accumulation in vulnerable tissues.

NEURODEGENERATION is the progressive loss of brain structures and function. The brain has one of the highest energetic demand in the body. The demented brain seems to engage in excess protein synthesis, activates stress response pathways, and sustains neuroinflammation (activated microglia)—all converging on increasing energy demand, or EP. In parallel, long before neurons die in Alzheimer’s disease, researchers observe a decline in glucose metabolism, impaired blood flow, and impaired mitochondrial energy transformation capacity—indicating decreased flux f.

If the brain increases EP but decreases f, that’s bad news because it increases éR.

The ERP suggests that these brain changes represent different paths toward the same energetic state: increasing resistance. New studies show that GDF15 isn’t only elevated in Alzheimer's, but that it predicts Alzheimer’s disease over a decade ahead of time.

Excess energy resistance is bad news for the brain.

SEVERE MENTAL ILLNESSES are among the most biologically complex conditions we know. No single molecular pathway explains depression, bipolar disorder, or schizophrenia.

Yet many of these disorders are associated with altered mitochondrial energy transformation capacity, inflammation, oxidative stress, and changes in brain metabolism. In particular, recent studies demonstrate the existence of excess éR in the brain of people with schizophrenia and bipolar disorder. There is superb work by my colleagues Virginie-Anne Chouinard and Dost Ongur on this topic.

Many more studies of mental illnesses show elevated GDF15 in these diseases. And we recently found that acute mental stress increases blood and saliva GDF15.

The ERP does not reduce mental illness to energy alone. It suggests that diverse biological disturbances may converge on a shared energetic landscape that influences how the brain functions, and how we feel and experience life.

HYPERTENSION illustrates elevated resistance in perhaps its most literal form. Tighter blood vessels that make it harder for blood to flow increase the hydraulic resistance against which the heart must pump—every beat.

The cardiovascular system compensates by performing more work (EP), increasing energetic demand while simultaneously altering tissue perfusion. Over years, this imbalance contributes to damage throughout the body.

From an energetic perspective, hypertension is not only a disease of blood pressure—it is a disease of altered energy distribution, driven by excess resistance to flow.

Bridge to Therapeutics

One of the most interesting implications of ERP is that therapies that have different molecular targets may nevertheless converge on a common energetic outcome.

Exercise, meditation, sleep, ketogenic diets, psychedelic-assisted therapy, photobiomodulation, vagus nerve stimulation and patterned electromagnetic stimulation certainly act through distinct biological pathways.

Yet many appear to improve metabolic efficiency, tissue perfusion, inflammation, and/or enhance mitochondrial energy transformation capacity.

Rather than investigating whether these interventions share the same molecular mechanism, leveraging the ERP may help us explore whether they ultimately reduce energy resistance by lowering energetic demand, increasing energetic flux, or both.

This principle provides a framework for comparing therapies that have traditionally been studied in isolation and may help explain why interventions with very different mechanisms can produce overlapping or potentially new clinical benefits.

How the Energy Resistance Principle Can Inspire Future Research

Since the ERP paper was published in November 2025, we’ve heard from other dozens of scientists and clinicians interested in applying the principle to their own work.

This principle provides a new way for people to think about how health and disease emerge. What if diseases like cancer or diabetes, and even poor mental health were driven by excess energy resistance?

What if biophysical treatments can help restore the balance of energy resistance to improve health?

Perhaps, then, interventions of behaviors that decrease energy resistance—like exercise training, not eating too much and/or cutting sugars, and learning to relax with meditation—could have broad trans diagnostic effects.

Different biophysical therapies can also be explored through the lens of the ERP. That may help us better understand how they work, and how they can be optimized for each individual based on their unique energy status.

Some interventions work well for some people, some not so much. The ERP could become a fruitful path to design and evaluate personalized health-promoting interventions.

This framework may also inspire new technologies and therapeutics designed to modulate energy flow more directly, from ionic potentials, electromagnetic patterning, to mitochondrial flux and tissue-level transport.

By making connections between the physical energetic perspective and a biological view of health and disease, the Energy Resistance Principle has sparked interdisciplinary conversations that are already inspiring new research projects.

At its very core, this principle is rooted in connection.

We hope the ERP continues to bring people from different backgrounds together with the goal of advancing our understanding of the science of human health and flourishing.

Want to hear more on this topic?
We shared some thoughts in the video below from the TSEE YouTube channel.

This week on The Science and Experience of Energy, we were fortunate to feature two guest writers bringing distinct perspectives on energy, physiology, and lived experience.

In the first piece, , a postdoctoral fellow in the Caltech/UCLA Cardiovascular Engineering Training Program, explored how meal timing may help synchronize mitochondrial activity across tissues, suggesting that metabolism is organized not only by fuel availability, but by time.

In the second piece, Peggy Arnold (), a speech and language therapist and independent systems thinker, offered a deeply personal and systems-level view of health and disease as patterns of energy accessibility, resistance, and distribution across scales.

Together, these two pieces suggest that health may be like a murmuration of starlings: not a consequence of individual parts acting alone, or how much energy is transformed, but of how that energy is coordinated across the organism in the right place, at the right time, and in the right pattern.

Thank you for joining us,
Martin

Thanks for reading The Science and Experience of Energy.
Know someone who may be interested in an energetic view of life?

Share The Science and Experience of Energy

This week’s TSEE guest writer Peggy Arnold is a speech and language therapist, mother of two, and independent systems thinker. Her curiosity and interest in physiology, metabolism, and complex biological systems connects clinical observation and personal experience around the kind of unexplained physiological instability that affects hundreds of thousands of people. In this post, she explores how energy flow, transport, and accessibility shape biological function across scales. We hope you find her perspective valuable.

---

I turn fifty this year. Outwardly, I appear healthy, but my body tells a different story. Seventeen years ago, a severe infection marked the beginning of a long chain of diagnostic dead ends. My laboratory values remained largely normal—apart from persistently elevated liver enzymes—even as my functional capacity steadily declined.

Seeking Answers for My Own Medical Mystery

Over the years, I immersed myself in metabolic research, searching for explanations that could reconcile my lived physiological experience with the reassuring picture presented by standard diagnostics. I explored nutritional interventions, glucose regulation, insulin resistance, fasting, ketosis, and metabolic health. Many of these frameworks offered valuable insights, yet none fully accounted for the patterns I observed.

At the onset of menopause, I followed prevailing endocrinological recommendations and began hormone replacement therapy (HRT). Rather than improving my condition, this coincided with a progressive deterioration that culminated in a profound systemic crash. This forced me to consider that the primary problem might not reside within any single hormone, signaling pathway, or organ system.

The diagnostic dead ends, metabolic experiments, and conceptual framework that emerged from these experiences have been explored elsewhere. Here, I want to focus on the observations that eventually led me toward a biophysical interpretation of metabolism.

By then, many of the pieces were already present. The framework had taken shape over several years as recurring observations, patterns, and unresolved questions. What I lacked was the language capable of connecting them.

Physics entered my life only eighteen months ago.

One evening, after an intense jump-rope session, I rushed to my husband with a sketch of a few cells and pointed to the space between them—the interstitium.

“Only here, again and again,” I told him. “Whenever I create a deep gradient between the inside and the outside, regardless of the absolute value on my CGM (Continuous Glucose Monitor), is when I feel well.”

My husband, a physicist, studied the drawing.

“Well, that sounds like diffusion,” he said.

Following that thread led me to Adolf Fick and the laws governing the passive transport of matter down concentration gradients.

Fick’s laws of diffusion gave meaning to patterns I had been observing for months.

In the conversations that followed, I described the physiological patterns that had puzzled me for years.

My worst episodes occurred not when my CGM readings fluctuated, but when they became unusually flat. This state of physiological stasis, in which concentration gradients seemed to vanish, brought blurred vision, brain fog, overwhelming thirst, and profound energetic collapse. Eventually, the system would undergo a major physiological shift, often accompanied by intense heat.

His response was immediate.

“From what you are describing, you need to look into entropy.”

The word hung heavily in the room, but that conversation changed how I thought about biological architecture.

Biological resistance is not a static barrier but a dynamic, multiscale transport constraint determined by the physical structures through which energy and matter must travel.

No biochemical analysis of fuel selection—whether carbohydrates, ketones, or lipids—is complete without considering the transport conditions that determine whether these fuels can reach the metabolic machinery that depends upon them.

Fick explained why gradients mattered. But he did not explain why movement could repeatedly restore my sense of energy and physiological function. For that, I eventually found myself exploring the work of Peter Mitchell.

The Arnold Resonance Model (more on this in a moment) quietly took shape over roughly two years as a series of disconnected observations, recurring patterns, and unresolved questions.

The philosophical essays I published are an attempt to weave these fragments into a coherent narrative and offer them as a conversation with science about a biophysical interpretation of metabolism.

The Preclinical Corridor: Compensation Before Collapse

What became increasingly apparent to me was that disease does not begin when a biomarker crosses a clinical threshold.

Long before diagnosis, biological systems may enter what could be called a preclinical corridor—a prolonged phase in which function deteriorates while conventional measurements remain normal.

Stability, in this context, does not necessarily indicate health. It may be compensation. The organism preserves the appearance of equilibrium by expending regulatory capacity. Hormones, autonomic responses, vascular adaptations, behavioral changes, and cellular stress responses work together to maintain function despite rising resistance within the tissue microarchitecture.

This observation led me to a question that extends beyond classical metabolism: What if many forms of dysfunction don’t primarily arise from a lack of energy, but from increasing difficulty in accessing and distributing energy where and when it is needed?

What began as an attempt to understand my own physiology gradually evolved into a broader inquiry: are living systems fundamentally organized around the continuous coupling of demand, transport, and accessible energy across scales?

The Principle of Transport–Demand Coupling Across Scales

Living systems may be defined by the dynamic coupling of transport and demand. While biology often treats supply as the primary variable of interest, organisms frequently behave as though demand helps shape supply. For example, delivery of fuel molecules and metabolic demand are reciprocally coupled, driving the continuous remodeling of the networks for transporting these molecules.

Demand is not fixed. It depends on context and arises from function.

Whether mounting an immune response, performing muscular work, adapting to cold, processing information, forming memories, repairing tissue, or responding to environmental challenges, transport systems continuously reorganize around changing metabolic requirements.

When this logic functions well, resources are directed where metabolic flow is needed, from local capillary recruitment to mitochondrial respiration. When demand declines, stasis can degrade the transport networks themselves. Our bodies are designed to address the same challenge across levels: moving matter and energy through a resistant medium.

Intracellular scale: Mitochondria and gated channels match energy production to demand, maintaining life-sustaining gradients.

Tissue scale: The architecture and fluid dynamics of the interstitial space shape nutrient access and waste removal across the capillary–interstitium–cell interface.

Hemodynamic scale: The vascular network continuously adjusts pressure, flow distribution, and exchange capacity, shaping the gradients that drive downstream transport.

From Networks to Flow Fields

Recent years have seen growing scientific interest in the interstitium, suggesting that a previously underappreciated aspect of physiology may be coming into clearer focus. Yet much of the prevailing language still reflects a structural view of interstitial spaces and fluid transport.

Classical physiology emphasizes branching pathways of fluid-filled spaces, while newer network-based descriptions focus on connectivity of these spaces throughout the body. Both perspectives may understate the variable conditions that govern exchange within an organism.

From my perspective, it may be useful to consider a different lens.

Rather than viewing the interstitium primarily as a distribution system—or even as a network of interconnected spaces—it may be more informative to think of it as a dynamic flow field shaped by gradients, geometry, and time-dependent patterns of exchange.

This shifts attention away from predefined pathways and toward the conditions that make transport possible. Movement emerges not simply from anatomical connectivity, but from the interaction of local gradients, physical constraints, and changing metabolic demands. In this view, transport, resistance, and demand are different expressions of the same underlying dynamics.

If virtually every cell exists within an immediate exchange environment, then the interstitium may be less usefully understood as a discrete anatomical compartment and more as a continuum of exchange processes across multiple levels of biological organization.

What appears structurally fragmented may function as a coordinated field emerging from countless local interactions.

Viewed through this lens, the interstitium becomes interesting not merely as a transport space, but as a possible site of physiological coordination. Gradients are continuously created and dissipated. Local demand alters energy accessibility, energy accessibility influences transport, and transport reshapes the energetic landscape from which new gradients emerge.

This perspective invites a comparison with dissipative structures.

Living systems maintain their organization through continuous flows of energy and matter while operating far from thermodynamic equilibrium. If this principle extends into the exchange environment surrounding cells, then the interstitium may participate in the formation of accessibility patterns through which energy and matter are distributed across scales.

Whether this view ultimately proves useful remains an open question. Nevertheless, it offers a framework in which the interstitium can be considered not simply as a passive space between biological structures, but as a dynamic context through which energetic and metabolic requirements may become coordinated across scales.

To visualize the shift from traditional branching networks toward a flow-field-based description, it is helpful to return to the fundamental physics of diffusion.

Resistance as a Necessary and Dangerous Property

An important insight emerging from recent work on the Energy Resistance Principle (ERP) is that resistance is not inherently pathological.

As Martin Picard and Nirosha Murugan write, living systems require a finite level of resistance because “without resistance, no work can occur.” Resistance is therefore not merely an obstacle to energy flow, but a necessary condition for biological transformation and organization.

This perspective resonates across physical systems. A river without friction cannot shape a landscape, an electrical circuit without resistance cannot perform useful computation, and a biological system without energetic constraints and thermodynamic gradients cannot generate structure or maintain order.

The question is not whether resistance exists, but whether it remains proportionate to transport capacity. When resistance exceeds a system’s ability to compensate, energy accumulates upstream while downstream regions experience functional scarcity.

This pattern appears across scales. Glucose may accumulate in the bloodstream while cells remain energetically constrained. Fluid may accumulate in tissues while local exchange deteriorates. Information may accumulate in networks while effective communication declines.

In each case, abundance and scarcity coexist within the same system, separated not by supply, but by resistance to flow.

From this perspective, health may depend not on eliminating resistance, but on maintaining a dynamic balance between resistance, transport capacity, and demand. Too little resistance permits no meaningful transformation. Too much impairs flow and fragments access to resources. The challenge for living systems is the continuous regulation of resistance across scales.

Beyond Biology: A Different Way to Think About Disease

At a certain point in my journey, I began to wonder whether my diverse symptoms might reflect a common underlying problem rather than multiple unrelated dysfunctions. By comparing CGM patterns with my subjective sense of energy and well-being, I gradually developed an intuitive picture of fluctuating accessibility within the system. In my mental model, this often appeared as changing degrees of openness and resistance at the level of my cells.

Because the symptoms affected many functions and organ systems, I eventually stopped thinking in terms of isolated organs and began thinking in terms of architecture. The question was no longer which organ was failing, but whether a common transport problem might manifest differently across the entire system.

Only later did I discover that others had explored similar ideas from very different directions. Reading the work of Philip Ball, I had a surprising moment of recognition.

Concepts that had emerged from my personal observations seemed to resonate with broader discussions of pattern formation, physical organization, and emergent order in living systems.

The most unexpected consequence of this journey was not a new way of looking at disease, but a new way of looking at the world. The actors, materials, and scales differ, yet the underlying challenge remains similar: how can complex systems maintain coherence while energy, matter, and information move through constrained pathways?

As evidence accumulates, many chronic disorders—from diabetes and cardiovascular disease to neurodegeneration, menopausal symptoms, Long Covid, and cancer—appear to converge on disturbances of metabolism and energy regulation.

This raises the possibility that health and resilience reflect a common organizational principle: the continuous coupling of demand, transport, and accessible energy across scales.

If so, many medical specialties may be observing different manifestations of the same underlying challenge. Rather than beginning by looking for problems with individual structures or physiological systems with the usual diagnostic categories (e.g. hormonal, mitochondrial, inflammatory, vascular), perhaps we should start with a more general question. Are energy and resources able to reach the right place, at the right time, in amounts sufficient to meet demand? The familiar categories do not disappear; they become possible explanations for why our adaptive capacity succeeds or fails.

Viewed through this lens, the challenge for medicine may be not only to discover isolated mechanisms, but also to consider the recurring architecture that connects them.

This framework does not attempt to specify the molecular mechanisms underlying every transport constraint. Instead, it begins with observable patterns of gradients, accessibility, compensation, and flow, and asks whether these patterns reveal common organizational principles across biological scales. The underlying mechanisms remain an empirical question.

What fascinates me most about this perspective is its simplicity. In everyday life, especially while learning to navigate insulin therapy, my task is often reduced to a surprisingly simple goal: restoring flow and accessibility.

In that sense, it is striking that concepts of flow have existed for centuries in many Asian traditions, expressed in a language that is intuitive and directly observable. Whether these traditions describe the same phenomena remains an open question. Yet they remind us that complex systems are often experienced long before they are fully explained.

Perhaps most importantly, this perspective invites dialogue between disciplines that rarely speak to one another. Physiology, metabolism, systems biology, ecology, physics, and even the social sciences may be asking related questions from different vantage points.

Rather than a conclusion, this perspective is best understood as an invitation.

Full-Text Link to Primary Source

Our TSEE guest writer Dylan Sarver is a postdoctoral fellow in the Caltech/UCLA Integrated NIH T32 Cardiovascular Engineering Training Program. In this post, he shares new research that highlights the role of mitochondria as timekeepers within our bodies. Their findings support the presence of complex coordination of mitochondrial activity across tissues.

Every day, organisms transition between sleep, feeding, and activity. These transitions are not simply behavioral—they require coordinated physiological and metabolic changes across the entire body.

When an animal wakes, the brain alters firing patterns, the liver shifts glucose production, muscles increase energy utilization, the heart increases its workload, and adipose tissue changes how it stores and releases fuel. Countless processes must adjust together to support a new behavioral state.

We often think about these organs independently, but life depends on their ability to work as a coordinated system.

Tuning in to Our Bodies’ Rhythms

Circadian biology has taught us a tremendous amount about biological clocks within individual tissues. We know the liver has daily rhythms. So do the heart, skeletal muscle, adipose tissue, intestines, and brain. But much less is known about how these rhythms are coordinated across tissues to support transitions between behavioral states.

How does the body maintain metabolic coordination across dozens of organs simultaneously? This question has fascinated me for years. And because all these physiological processes ultimately require energy, I began wondering whether part of the answer might lie within one of the cell’s most important metabolic organelles: the mitochondrion.

The Role of Circadian Rhythms in Mitochondrial Biology

Most people know mitochondria as the “powerhouses of the cell.” While not entirely wrong, this description misses much of what makes mitochondria so interesting.

Mitochondria do not simply produce energy. They help cells sense nutrients, regulate metabolism, respond to stress, and adapt to changing environmental conditions. Importantly, mitochondria also keep time.

Many mitochondrial-associated genes rise and fall in predictable patterns across the day. These rhythms help coordinate cellular metabolism with recurring environmental events such as waking, feeding, fasting, and sleeping.

Over the last decade, researchers have learned a great deal about mitochondrial rhythms within individual tissues. But a question remained largely unanswered: What if the most important aspect of mitochondrial rhythms is not what happens within a single tissue, but how those rhythms are coordinated across the entire body?

Imagine an orchestra preparing for a performance. Each musician may be highly skilled. The violinists know their parts. The percussion section knows theirs. The brass section performs beautifully on its own.

But without coordination, there is no symphony. The same challenge exists within the body. Individual tissues can maintain their own metabolic rhythms, but healthy physiology requires organs to work together. This idea motivated our recent study.

Examining the Coordination of Rhythmic Activity in Mitochondria

To investigate how mitochondrial rhythms are organized across the body, we analyzed gene expression patterns from 22 different mouse tissues collected throughout the day and night.

Rather than focusing on individual tissues, we asked whether mitochondrial-associated genes displayed coordinated timing across organs. We then compared two feeding schedules. In one condition, mice could eat whenever they chose. In the other condition, food access was restricted to a consistent daily window—a dietary intervention known as time-restricted feeding or time-restricted eating.

Time-restricted feeding has attracted considerable scientific interest because it often improves metabolic health, even when calorie intake remains unchanged. Most explanations have focused on what happens within individual tissues. We wanted to know whether feeding time might also influence coordination between tissues. The results revealed a striking pattern.

With unrestricted feeding conditions, many mitochondrial-associated genes displayed daily rhythms within individual tissues. However, relatively few showed synchronized timing across large portions of the body.

Under time-restricted feeding, that picture changed dramatically. Many more mitochondrial-associated genes began oscillating together across tissues.

Organs that normally appeared to operate more independently now seemed to follow a more coordinated daily schedule. It was as though the orchestra had become more synchronized, and thus, one could finally hear the symphony.

Evidence of Strategic Synchronization of Mitochondrial Activity

What fascinated me most was when this coordination occurred. Many of the strongest synchronization events appeared around major behavioral transition points—when animals moved from rest to activity, from activity to rest, or between fasting and feeding states.

This observation suggests that mitochondrial-associated programs may be particularly important during periods when the body must rapidly reorganize itself to meet changing physiologic demands.

From an evolutionary perspective, this makes intuitive sense. Animals live in environments filled with reoccurring patterns. Food tends to arrive at predictable times. Activity and rest often follow regular cycles. Rather than constantly reacting to the world moment by moment, biological systems may benefit from anticipating what comes next.

One of the most intriguing observations from our study came from a mitochondrial-associated gene called Coq10b. Under normal conditions, expression levels of this gene were closely aligned with feeding schedules.

When feeding time was shifted, however, the rhythm of Coq10b shifted as well, regardless of whether food was provided during the animals’ active or inactive period. This suggested that the gene was highly responsive to the timing of food availability.

We then asked what would happen if food failed to arrive. Surprisingly, when mice experienced an unexpected fasting challenge, the rhythm persisted.

Rather than immediately disappearing, Coq10b continued to oscillate according to the schedule established by previous feeding patterns. This observation suggests that mitochondrial timing programs may be shaped by more than the immediate presence of nutrients.

In some cases, they may reflect an organism’s prior experience with recurring environmental events. In other words, mitochondrial-associated systems may not simply react to predictable behaviors such as feeding—they may help prepare the body for them.

While this finding emerged from a single gene, it echoes a broader pattern observed throughout our study. Across many tissues, mitochondrial-associated programs appeared to become synchronized around major behavioral transitions, such as feeding, fasting, activity, and rest.

We do not yet know what mechanisms generate this coordination. It is possible that the synchronized patterns may arise from shared hormonal, neural, nutritional, and/or circadian signals.

It’s important to be clear that our findings in this study do not demonstrate direct communication between mitochondria in different tissues. Nevertheless, the results suggest that mitochondrial-associated programs across the body may be responding to common organizing cues.

What Our Findings Mean in the Context of Metabolism and Health

The results from our research on the coordination of the expression of mitochondria-associated genes across the body reflects a broader shift in how I think about metabolism.

Traditionally, we study organs one at a time. We ask what the liver is doing, what the heart is doing, or what the brain is doing. But organisms are not collections of isolated tissues. They are integrated systems.

Our findings suggest that understanding metabolism may require us to study not only what happens within organs, but also how organs remain coordinated with one another across time and space.

Intriguingly, the synchronized patterns we observed often emerged around major behavioral and environmental transitions—periods associated with initiating waking, feeding, fasting, or rest.

This raises the possibility that mitochondrial timing programs help align physiology not only across tissues, but also with predictable events occurring in the external world.

With this view, metabolism is not simply a collection of biochemical reactions responding to immediate demands. It is part of a larger adaptive system that prepares organisms for recurring patterns in their environment.

This study represents important progress, but many questions remain.

What signals help synchronize mitochondrial rhythms across tissues? Does aging gradually fragment these patterns of coordination? Do metabolic diseases disrupt them? And could some of the benefits of behavioral interventions—such as exercise, meal timing, or light exposure—arise because they help restore temporal organization across the body? We do not yet know.

What our work suggests is that biological energy systems may be organized not only in space, but also in time. And understanding how the body’s mitochondrial orchestra stays in tune may reveal new insights into health, disease, and the remarkable coordination that makes complex life possible.