The shift from a molecule-first view of biology to an energy-first one feels essential — and long overdue. If mitochondria are at the centre of health, then understanding how energy is produced, distributed, and used becomes the real question.
What I find myself exploring is what sits one level upstream of that.
Energy doesn’t allocate itself. The nervous system does.
And the nervous system is not operating in isolation — it is continuously reading the environment and adjusting energy allocation in real time. Light, sound, air quality, temperature, spatial cues, chemical exposures — these are not passive backdrops. They are inputs into the system that determines whether energy is directed toward repair, growth, or defence.
From that perspective, mitochondrial dysfunction may often be the downstream expression of a system that has been pushed, subtly but persistently, toward vigilance.
Not by a single acute stressor, but by a constant stream of low-grade, misaligned signals.
It raises a slightly different question:
not just how we support mitochondrial function,
but what environmental conditions allow the system to allocate energy well in the first place.
Feels like an important bridge between cellular energetics and the environments we inhabit every day.
Really interesting way of framing it — the idea of cumulative stressors collectively pulling energy away from GMR.
What I find compelling is that many of those “stressors” are not discrete events, but continuous environmental inputs.
Light, sound, air quality, thermal conditions — they’re all signals the nervous system is reading and using to allocate energy in real time.
So in a sense, it’s not just the presence of stressors, but the pattern and consistency of signals that may be shaping allocation over time.
Which raises a question I’d be curious to hear your thoughts on:
To what extent do you see mitochondrial function being influenced not just by internal or acute stress, but by these persistent, low-grade environmental signals that the system is continuously interpreting?
As a family, our 5-minute-at-a-time strategy has empowered us to make realtime-authentic choices. By “checking in” with ourselves, and choosing how we are going to spend the next five minutes, we are often able to navigate around energy traps while we opportunistically fuel up with energy boosts. This strategy has enabled us to build an unexpected and extraordinary quality of life as 5 minute increments have turned into days, days have turned into years, and years have turned into decades.
So many folks, who are aware of the mind-boggling complexity of my family, ask me, “HOW are you doing this?” They think we have some secret supplement we are all consuming! This article, and this discussion here, explains exactly why 5 minutes-at-a-time works for us.
Once again, thank you for your work and your voice!
Yes! And what happens when the nervous system is misreading the environmental conditions via predictive processing? In this situation, it may not be a matter of adjusting the environment, but of recalibrating the nervous system into a state of calm and safety that allows it to better respond to and harmonize with the environment as it is.
Yes, and I’d extend this one more layer: the nervous system itself isn’t reading environments uniformly. Different regulatory architectures parse the “constant stream of low-grade, misaligned signals” with different bandwidths before the trade-off cascade begins.
In the Evolutionary Stress Framework (Hogenkamp, Sanghavi & Natri, Autism in Adulthood 2026), this is the move from parametric heterogeneity (different settings on one regulator) to architectural heterogeneity (different regulator shapes). Two systems reading the same environment can land in very different allocation patterns because the integration architecture is different, not because the inputs are different.
Your phrase “constant stream of low-grade, misaligned signals” maps almost directly onto what we call stress incoherence: signals that fail to predict, track, or resolve coherently, rather than discrete acute stressors.
That sharpens the question you’re raising: not “what environmental conditions allow the system to allocate energy well,” but “for which architecture?” Environments coherent for one regulatory shape can be incoherent for another. In autistic and many neurodivergent populations, that mismatch produces the bandwidth compression that eventually shows up at the cellular level — exactly the downstream-of-vigilance pattern you’re pointing to.
Sterling’s allostasis and Barrett’s body budgeting work do some of this upstream framing too, if those haven’t crossed your desk yet.
The environment is not being read by a generic nervous system. It is being interpreted through different regulatory architectures, histories, thresholds and capacities. So the same signal field can be stabilising for one person and incoherent, costly or overwhelming for another.
That distinction between signal input and integration architecture is very helpful.
It also reinforces why I think the built environment matters so much. We often design for an imagined average body, when in reality bodies differ in how much signal complexity, novelty, noise, light, social demand or sensory load they can metabolise before energy begins to shift toward vigilance.
Your phrase “stress incoherence” is very close to what I describe through Nervous System Design: not stress as one dramatic event, but as a pattern of signals that do not resolve clearly enough for the system to regulate efficiently.
And I agree — the better question may be not simply “what environment supports regulation?” but “what environment supports regulation for this nervous system, with this architecture, in this context?”
That feels especially important for neurodivergent populations, where the cost of poorly matched environments can be much higher and much less visible.
Thank you for bringing Sterling and Barrett into this. Barrett’s body-budgeting work has been especially useful in how I think about environment, prediction and energy allocation.
As a patient who’s navigated illness for over a decade, I see this exact pattern playing out in my own health.. this has sparked so many questions for me as well!
Thank you for sharing. Really impressive work. Wonderful extension of the Constrained Energy Model showing how energy truly drives the entire system.
Your central point that nothing in biology is free and every process carries an energetic cost has powerful implications beyond disease and stress.
Could this be the reason why:
in endurance physiology it helps explain why carbohydrates remain the preferred fuel at high intensities. Converting fat derived substrates into glucose via gluconeogenesis incurs a real energy tax including lipolysis transport activation and gluconeogenesis overhead. With a fixed daily energy budget this cost diverts resources away from other critical processes. For world class runners where margins are razor thin even small inefficiencies in fuel conversion can limit peak power output and surge capacity.
Also in everyday people could this explain why shifting to a high fat diet often leads to higher calorie intake. Because the system is continuously spending energy in fuel conversion processes it may adapt to a new higher calorie constrained energy budget to maintain performance and recovery without trade offs in immunity repair or vitality.
Your energy constraint framework helps explain these metabolic realities.
I find the energy budget model very useful, but I don’t see how we can argue that the real limiting factor behind our fatigue, and behind our inability to cope with everything, is the energetic limit.
To give an example: although chronic mental stress may slightly increase a person’s energy expenditure, this increase is small compared with the increase in expenditure caused by several hours of very low-intensity exercise.
However, while chronic stress exhausts us and makes us ill, going for a walk or riding a bike gently for a few hours helps us feel well.
The type of stressor and the time domain both matter.
There are stressors that seem to activate stress responses, and dig into GMR without producing adaptive long-term responses. That would be the case for chronic low-grade psychosocial stress, perhaps. On the other hand, there are stressors like exercise that vigorously stimulate mitochondrial biogenesis, so over the long-term, the organism lives with more mitochondria, likely in a more efficient state that is beneficial from a health perspective. So you are completely right, it’s not just about the amount of energy. The type of stressor and response matters.
On the time front, stressors that are on for short periods of time (and intense) like exercise seem to produce more robust and adaptive responses than the stressors that drag on for very long periods of time.
A remarkably important framework. What makes it especially compelling is that it reconnects health, disease, and aging to first principles of energy allocation rather than isolated molecular pathways.
One aspect that may become increasingly important as this perspective evolves is not only energy expenditure itself, but the architecture of energy delivery and effective throughput across scales. Two systems may operate under similar energetic budgets while differing profoundly in how efficiently resources can be distributed, accessed, coordinated, and translated into functional work under changing demand conditions.
This may ultimately place greater emphasis on gradients, perfusion, interstitial exchange, membrane dynamics, and the maintenance of functional reserve — particularly in conditions where conventional markers still appear relatively preserved despite declining resilience.
If the thermodynamic perspective on health and aging continues to gain traction, this could represent a profound shift not only for medicine, but for society itself. Because the moment health is viewed through the lens of energetic constraints and recovery capacity, the environments and demands we collectively create become biologically consequential in a very direct way.
Thanks for the work you guys do, it’s fascinating. I’m reminded of the book Transcend, where Scott Barry Kaufman builds on Abraham Maslow’s unfinished work on self-actualization and reframes it as a dynamic sailboat, where its less about moving up, and more of a dynamic interaction.
The hull of the boat represents our basic survival needs (vital functions), and the sail represents our higher needs (skills, vitality, motivation). The wind is life, pressure, demand, and challenge.
Perhaps with your work if our hull isn't stable our sails come down to stabilize the hull. When our hull is stable we can put up the sails and use the wind to our advantage.
Your work brings so many ideas to the surface. Truly exciting stuff.
I realize you are a full-fledged mitochondrial scientist, no doubts there, but I secretly suspect that you’re also a keto-diet adherent (no objections), as well as a Hermetic philosophy adherent (no objections), maybe even a quantum physicist (no objections) because you’ve drawn together too many strands of reality - navigable mitochondria, navigable subconscious, navigable physical reality. It all adds up to a new... I darenot say, not yet.
I have just come across your fascinating posts. I am an ignorant philosopher and not a biologist but came across mitochondria in work by Lynn Margulis on processes of symbiosis. Two questions spring to mind if you have the time. (1)How is her work viewed today? (2)She researched the history of bacteria in what might be called a non-human-centred way. May seem a very silly (philosophical) question but why are humans the focus of your research on mitochondria?
The shift from a molecule-first view of biology to an energy-first one feels essential — and long overdue. If mitochondria are at the centre of health, then understanding how energy is produced, distributed, and used becomes the real question.
What I find myself exploring is what sits one level upstream of that.
Energy doesn’t allocate itself. The nervous system does.
And the nervous system is not operating in isolation — it is continuously reading the environment and adjusting energy allocation in real time. Light, sound, air quality, temperature, spatial cues, chemical exposures — these are not passive backdrops. They are inputs into the system that determines whether energy is directed toward repair, growth, or defence.
From that perspective, mitochondrial dysfunction may often be the downstream expression of a system that has been pushed, subtly but persistently, toward vigilance.
Not by a single acute stressor, but by a constant stream of low-grade, misaligned signals.
It raises a slightly different question:
not just how we support mitochondrial function,
but what environmental conditions allow the system to allocate energy well in the first place.
Feels like an important bridge between cellular energetics and the environments we inhabit every day.
Yes, cumulative exposure to stressors is likely to drive multiple additive responses that collectively steal energy away from GMR.
So many factors call less to allocate energy. And those drivers may be different than different people.
Really interesting way of framing it — the idea of cumulative stressors collectively pulling energy away from GMR.
What I find compelling is that many of those “stressors” are not discrete events, but continuous environmental inputs.
Light, sound, air quality, thermal conditions — they’re all signals the nervous system is reading and using to allocate energy in real time.
So in a sense, it’s not just the presence of stressors, but the pattern and consistency of signals that may be shaping allocation over time.
Which raises a question I’d be curious to hear your thoughts on:
To what extent do you see mitochondrial function being influenced not just by internal or acute stress, but by these persistent, low-grade environmental signals that the system is continuously interpreting?
As a family, our 5-minute-at-a-time strategy has empowered us to make realtime-authentic choices. By “checking in” with ourselves, and choosing how we are going to spend the next five minutes, we are often able to navigate around energy traps while we opportunistically fuel up with energy boosts. This strategy has enabled us to build an unexpected and extraordinary quality of life as 5 minute increments have turned into days, days have turned into years, and years have turned into decades.
So many folks, who are aware of the mind-boggling complexity of my family, ask me, “HOW are you doing this?” They think we have some secret supplement we are all consuming! This article, and this discussion here, explains exactly why 5 minutes-at-a-time works for us.
Once again, thank you for your work and your voice!
Yes! And what happens when the nervous system is misreading the environmental conditions via predictive processing? In this situation, it may not be a matter of adjusting the environment, but of recalibrating the nervous system into a state of calm and safety that allows it to better respond to and harmonize with the environment as it is.
Yes, good point.
Yes — and I think both layers matter.
Practices like breathwork and meditation can absolutely help recalibrate the nervous system and shift state. They’re powerful tools.
But what I find interesting is that the environment is providing signals continuously — whether we engage with them or not.
So if those signals are misaligned, the system is being nudged, subtly but persistently, in a particular direction all day long.
In that context, changing the environment isn’t about replacing internal work — it’s about reducing the load on the system in the first place.
Because one is intermittent and effortful. The other is constant and automatic.
And over time, that difference compounds.
Yes, and I’d extend this one more layer: the nervous system itself isn’t reading environments uniformly. Different regulatory architectures parse the “constant stream of low-grade, misaligned signals” with different bandwidths before the trade-off cascade begins.
In the Evolutionary Stress Framework (Hogenkamp, Sanghavi & Natri, Autism in Adulthood 2026), this is the move from parametric heterogeneity (different settings on one regulator) to architectural heterogeneity (different regulator shapes). Two systems reading the same environment can land in very different allocation patterns because the integration architecture is different, not because the inputs are different.
Your phrase “constant stream of low-grade, misaligned signals” maps almost directly onto what we call stress incoherence: signals that fail to predict, track, or resolve coherently, rather than discrete acute stressors.
That sharpens the question you’re raising: not “what environmental conditions allow the system to allocate energy well,” but “for which architecture?” Environments coherent for one regulatory shape can be incoherent for another. In autistic and many neurodivergent populations, that mismatch produces the bandwidth compression that eventually shows up at the cellular level — exactly the downstream-of-vigilance pattern you’re pointing to.
Sterling’s allostasis and Barrett’s body budgeting work do some of this upstream framing too, if those haven’t crossed your desk yet.
Yes — this is such an important refinement.
The environment is not being read by a generic nervous system. It is being interpreted through different regulatory architectures, histories, thresholds and capacities. So the same signal field can be stabilising for one person and incoherent, costly or overwhelming for another.
That distinction between signal input and integration architecture is very helpful.
It also reinforces why I think the built environment matters so much. We often design for an imagined average body, when in reality bodies differ in how much signal complexity, novelty, noise, light, social demand or sensory load they can metabolise before energy begins to shift toward vigilance.
Your phrase “stress incoherence” is very close to what I describe through Nervous System Design: not stress as one dramatic event, but as a pattern of signals that do not resolve clearly enough for the system to regulate efficiently.
And I agree — the better question may be not simply “what environment supports regulation?” but “what environment supports regulation for this nervous system, with this architecture, in this context?”
That feels especially important for neurodivergent populations, where the cost of poorly matched environments can be much higher and much less visible.
Thank you for bringing Sterling and Barrett into this. Barrett’s body-budgeting work has been especially useful in how I think about environment, prediction and energy allocation.
As a patient who’s navigated illness for over a decade, I see this exact pattern playing out in my own health.. this has sparked so many questions for me as well!
Thank you. I think many of us can relate to the experience of energy constraints.
One dimension missing here is not how much energy is allocated to different functions, but how easily energy flows—meeting with how much resistance.
Thank you for sharing. Really impressive work. Wonderful extension of the Constrained Energy Model showing how energy truly drives the entire system.
Your central point that nothing in biology is free and every process carries an energetic cost has powerful implications beyond disease and stress.
Could this be the reason why:
in endurance physiology it helps explain why carbohydrates remain the preferred fuel at high intensities. Converting fat derived substrates into glucose via gluconeogenesis incurs a real energy tax including lipolysis transport activation and gluconeogenesis overhead. With a fixed daily energy budget this cost diverts resources away from other critical processes. For world class runners where margins are razor thin even small inefficiencies in fuel conversion can limit peak power output and surge capacity.
Also in everyday people could this explain why shifting to a high fat diet often leads to higher calorie intake. Because the system is continuously spending energy in fuel conversion processes it may adapt to a new higher calorie constrained energy budget to maintain performance and recovery without trade offs in immunity repair or vitality.
Your energy constraint framework helps explain these metabolic realities.
Congratulations on a great paper.
regards
Thank you, good thinking. Yes, I believe these make sense, but others may know better.
Hi Martin,
I find the energy budget model very useful, but I don’t see how we can argue that the real limiting factor behind our fatigue, and behind our inability to cope with everything, is the energetic limit.
To give an example: although chronic mental stress may slightly increase a person’s energy expenditure, this increase is small compared with the increase in expenditure caused by several hours of very low-intensity exercise.
However, while chronic stress exhausts us and makes us ill, going for a walk or riding a bike gently for a few hours helps us feel well.
What am I missing?
The type of stressor and the time domain both matter.
There are stressors that seem to activate stress responses, and dig into GMR without producing adaptive long-term responses. That would be the case for chronic low-grade psychosocial stress, perhaps. On the other hand, there are stressors like exercise that vigorously stimulate mitochondrial biogenesis, so over the long-term, the organism lives with more mitochondria, likely in a more efficient state that is beneficial from a health perspective. So you are completely right, it’s not just about the amount of energy. The type of stressor and response matters.
On the time front, stressors that are on for short periods of time (and intense) like exercise seem to produce more robust and adaptive responses than the stressors that drag on for very long periods of time.
This is one of the clearest ways I've seen energy explained.
Living with CRPS has taught me that my body isn't failing - It is carrying a higher load.
I may not be able to cure it, but I can learn to reduce the load and support my system more intentionally and wisely.
This framework connects deeply with that. Thank you!
A remarkably important framework. What makes it especially compelling is that it reconnects health, disease, and aging to first principles of energy allocation rather than isolated molecular pathways.
One aspect that may become increasingly important as this perspective evolves is not only energy expenditure itself, but the architecture of energy delivery and effective throughput across scales. Two systems may operate under similar energetic budgets while differing profoundly in how efficiently resources can be distributed, accessed, coordinated, and translated into functional work under changing demand conditions.
This may ultimately place greater emphasis on gradients, perfusion, interstitial exchange, membrane dynamics, and the maintenance of functional reserve — particularly in conditions where conventional markers still appear relatively preserved despite declining resilience.
If the thermodynamic perspective on health and aging continues to gain traction, this could represent a profound shift not only for medicine, but for society itself. Because the moment health is viewed through the lens of energetic constraints and recovery capacity, the environments and demands we collectively create become biologically consequential in a very direct way.
Thanks for the work you guys do, it’s fascinating. I’m reminded of the book Transcend, where Scott Barry Kaufman builds on Abraham Maslow’s unfinished work on self-actualization and reframes it as a dynamic sailboat, where its less about moving up, and more of a dynamic interaction.
The hull of the boat represents our basic survival needs (vital functions), and the sail represents our higher needs (skills, vitality, motivation). The wind is life, pressure, demand, and challenge.
Perhaps with your work if our hull isn't stable our sails come down to stabilize the hull. When our hull is stable we can put up the sails and use the wind to our advantage.
Your work brings so many ideas to the surface. Truly exciting stuff.
I realize you are a full-fledged mitochondrial scientist, no doubts there, but I secretly suspect that you’re also a keto-diet adherent (no objections), as well as a Hermetic philosophy adherent (no objections), maybe even a quantum physicist (no objections) because you’ve drawn together too many strands of reality - navigable mitochondria, navigable subconscious, navigable physical reality. It all adds up to a new... I darenot say, not yet.
I have just come across your fascinating posts. I am an ignorant philosopher and not a biologist but came across mitochondria in work by Lynn Margulis on processes of symbiosis. Two questions spring to mind if you have the time. (1)How is her work viewed today? (2)She researched the history of bacteria in what might be called a non-human-centred way. May seem a very silly (philosophical) question but why are humans the focus of your research on mitochondria?