The Yin and Yang of Homeostasis
As you may recall, homeostasis is a word we use in biology, molecular biology, and cellular medicine to describe when a person is in a normal – or balanced – state of health. As humans, this innate drive for homeostasis drives almost every process in the body at the cellular level.
Redox offers us a good example of how homeostasis works. As we’ve discussed numerous times in masterminds, rabbit holes, office hours, and, of course, in my second book, The Redox Promise, energy metabolism, cellular functioning, and immune system modulation all depend on redox balance. The constant interplay between reduction and oxidation activities comprises an ongoing effort that all cells participate in – to both generate energy for optimal functioning and protect these same systems from stressors that either upset the balance or overwhelm the immune system’s capacity for protection.
I sometimes refer to this quest for balance as the yin yang effect: we need both oxidation and reduction processes for cell metabolism and functioning. When one gets compromised or is dysregulated, the other suffers and vice versa. There are always stressors that threaten the equilibrium of cell environments, thereby undermining energy production, TCA metabolism, beta oxidation metabolism, and amino acid metabolism. For example, if the body is exposed to a virus, the cell system has some decisions to make about how to direct its energy. A first defense will be a call for antioxidants to handle the increase in reactive oxygen species produced by the cell in reaction to the stressor (i.e., the virus). If, however, the individual has been sick with a virus – something like COVID – in a two-or three-month prior period, their antioxidant system may be depleted. Without a strong antioxidant response, oxidative stress will increase, perhaps exacerbating lingering inflammation. In short, the innate immune response is less than energetic because of a low availability of reducing agents (such as superoxide dismutase, catalase, glutathione) to handle the pathogen’s direct and indirect causation of cellular ROS, so the body becomes ill, falling out of homeostasis.
And yet, despite these less-than neutral conditions, the body persists in its drive for homeostasis. The mechanism at the heart of this drive?
Adaptation.
Adaptation is not merely a term to describe the evolution of species and traits within species; it also refers to a continual activity that all cells and tissues engage in in response to any kind of stressor – whether endogenous or exogenous – that can threaten its status quo and push it into a disrupted state. Adaptation begins like an automatic impulse responding to a stressor – lack of sleep, exposure to a toxin, alcohol inundation, viral contagion– prompting the cells to figure out how to get themselves back into a steady state.
Again, let’s look at redox. If in the case of a viral overload and a depleted antioxidant system, what else will the body do to get itself back into balance, whereby reducing agents and oxidizing agents can be restored and once again work in more or less harmony?
Let’s imagine you're a cell that’s been knocked out of balance. You will ask yourself, How do I get back to that state of homeostasis? How do I adapt to what I've just been presented to me? What can I do to manipulate the situation and get back to that homeostatic pattern?
First, you will naturally produce more energy to handle the cellular changes necessary to drive the production of cytokines chemokine and proteases to deal with the virus. This will also demand the cell to adapt to this increase in energy requirements and increase production of antioxidants.
Or you might take matters into your own hands and take a high dose of Vitamin C ( a scavenger antioxidant) and go to bed to rest – this proactive step being another reminder for all of us healthcare providers to help our patients become aware of the importance of nutrition, supplements, and peptides that can benefit them when they get sick. Talking about such situations explicitly with patients also helps them understand the big picture dynamics of cellular adaptation.
The next time the cell is under attack by a similar virus it will be more resilient to infection because it adapted to the insult before and is now more on alert and ready to act in concert with the immune system.
Building Cellular and Systemic Resilience: Stepping Stones to Optimal Healthspan
In this way, adaptation is a process that can be harnessed to build cellular and systemic resilience and work toward optimal healthspan. If we make a cell more resilient to any number of factors that have the potential to set things off the pace of homeostasis, then we're doing things to make the cell adapt better to those stressors – and maintaining that equilibrium in the cell environment.
How can we be more proactive? In some ways, these strategies are quite simple: getting sufficient sleep; regular exercise; and meditation – are all productive ways that have immediate, beneficial cellular effects. You might be surprised that I, of all people, recommend meditation – probably because you can't imagine me sitting cross legged on a yoga cushion. But keep in mind that meditation comes in many forms – for you that may be walking for twenty minutes, for another person it may take the form of a tai chi class; for me, it might be skiing at high speed down a double black diamond. Regardless, the effects on the nervous system are similar: a restoration of balance (which means a balance in sympathetic and parasympathetic signaling), a calming of the excitatory neurotransmitters like cortisol and adrenalin, and an upregulation of the calming neurotransmitters like dopamine and serotonin.
So let’s go back to how homeostasis works at the cellular level with redox. Again, the imperative of cellular redox is about how the cell signaling and metabolism maintain balance under stress, in particular, under oxidative stress and how they respond to any increase in reactive oxygen species (ROS) when the cell environment changes due to increase mental stress, lack of sleep, radiation, disturbance in metabolism such as chronically high circulating glucose, an exposure to heavy metals or pesticides – any of these exogenous stressors change the equilibrium of the cell environment.
An initial call to action in redox is the call for the appropriate antioxidant response at the right time in the right compartment of the cell. Adapting to the loss of equilibrium in the cell environment, the cell makes antioxidants to control those reactive oxygen species that, without such interference, can cause inflammation, which can then trigger changes often in the form of maladaptations.
If the viral contagion persists, and the individual cannot restore homeostasis through production of sufficient antioxidants and does not take steps like resting or supplementing with Vitamin C and Zinc, for example, the cells will nonetheless begin to adapt, but in negative ways. The cell, still driven to respond and make decisions, now begins to do so in maladaptive ways. For instance, if the cell environment is becoming overwhelmed by oxidative stress, mitochondrial biogenesis will become disrupted, which will in turn disrupt mitochondrial metabolism, pushing the cells to over-rely on glycolysis and eventually down-regulating beta oxidation of fat and decreasing oxidative phosphorylation. And that, of course, is a slippery slope.
Exercise: The Eustress of Optimal Adaptation
But here’s the very good news: not all stress is bad stress – there’s a concept called eustress, which is moderate type of stress that produces positive adaptations that enhance cellular function and lead to resilience. I like to think of the effect of exercise on the cellular environment as a form of eustress. And for those of you who are physicians and healthcare providers who are looking for ways to motivate your patients to incorporate more exercise into their daily lives, using exercise provides a perfect illustration for its powerful adaptive potential.
Let’s consider resistance exercise in particular: when you perform a bicep curl, you are asking your muscles to adapt. If you do a bicep curl in eccentric motion the stress will be different than if you perform it under a concentric motion. If you increase the repetitions (reps), you intensify the stressor. You can also manipulate the impact of the stressor by increasing the load, meaning the weight involved. Or you can increase the rate of speed. Or the degree of contractility or the stretching of the muscle. Each of these methods of exertion puts a positive stress on the body and helps prepare the cell to adapt so that the next time that you go through the exercise, your muscles are more capable of working with that weight, speed, or stretch.
In response to these stressors, there is a window when the muscle cells react by breaking down from the exertion. But in its adaptive capacity, these same muscle cells move into a reparative process to recover and then rebuild the muscle, making it stronger, which also is part of its resilience-building mechanism. When cells go through those stages and repair themselves, they enable the cell environment to recover homeostasis, they literally build resilience in real time.
It’s for this reason that I think exercise provides us with an excellent opportunity to help our patients understand how a cell can adapt to positive sources of stress and help build resilience. When cells go through those stages and repair themselves, recovering from the stress of exercise (i.e. the exertion and increased demand for energy), the cells are actually setting themselves up to be more capable of handling that next onslaught of stress . . .or bout of exercise. Each round of exercise then makes cells more agile at repairing and adapting.
Further, understanding that the tissue breakdown of the muscle is followed by repair and restoration and then improvement can be a huge motivator for people – not just athletes or gym rats who are into performance, but your average Jake and Jill who want to feel sharp in their minds, energetic throughout the day, and look and feel their best.
These mechanistic effects of exercise make a lot of sense, and have been studied over and over, establishing irrefutable evidence that shows the cellular modifications of exercise on the cell. And considering this powerful effect of making muscle tissue more resilient, we can use it as an illustration of how adaptation can be progressive.
The Skinny on VO2 Max and Exercise
It should be no surprise that exercise is a great way to improve this function of mitochondrial efficiency, which inevitably will lead to the sought-after improvement in VO2 max. It’s this turn to cellular respiration that people confuse with VO2 Max as a measurement of fitness. I often hear people say you need high VO two max to be the best athlete and to live longer. Okay. But it’s worth understanding what that means first, and the answer lies in the capacity of the mitochondria to stay efficient and how well they can adapt to utilizing oxygen and other nutrients to make ATP – the energy needed by the cell in this increased activated state.
VO2 max offers us a macro look at what’s happening inside the cell, especially as it relates to mitochondrial efficiency, increasing respiratory capacity, and improving oxygen consumption, along with vascular adaptations – which, together, enable muscles to utilize oxygen more efficiently during exercise. As a result, each time you exercise, those muscles are going to be using oxygen a little bit better, a little bit more efficiently, and that results in enhanced aerobic capacity, endurance, and performance – all of which are reflected in VO2 max. Let’s not get too caught up in maximizing VO2 max to an ultimate level. Remember a Porsche running on the Autobahn at 210 miles an hour may be at maximum performance but not necessarily efficiency!
These constructive adaptations stem from the activation of key signaling pathways, especially AMPK and PGC1 alpha, which enable improved mitochondrial biogenesis and functioning. With improved cell signaling, the resulting metabolic changes also increase mitochondrial density and improve oxidative enzyme function.
At the same time these pro-adaptative activities are happening during exercise, there is a first breakdown of muscle protein, which activates AMPK and inhibits mTOR until the cell is ready for protein synthesis with AMK deactivation and mTOR activation; as mTOR gets activated, there is increased ribosomal biogenesis. When this happens, there will be an upregulation of other anabolic genes, an enhanced uptake of amino acids, and then an end stage of muscle fiber hypertrophy that occurs from increased protein synthesis.
While exercise comprises all these stages of cell adaptation, it also creates oxidative stress, which then triggers the cells to adapt again, this time in recovery mode to protect the cells from oxidative damage. And yet, keep in mind that exercise disrupts the homeostasis of the cell. It triggers an adaptive response to improve not just resilience, but also performance of the cell. And because the cell's adapting, it's becoming better at handling all that stress, which makes it perform better under those stressful situations. What are the different levers that can call up this adaptive response in exercise? Change the intensity, duration, frequency, and recovery periods.
So what's the relevance to cellular medicine with all of this?
If we understand how and why exercise induces adaptations and how they improve major processes including cardiac function, immune function, insulin sensitivity, the reduction of inflammation, and mitochondrial function, it opens the door to the management of chronic disease.
Using the Adaptation Lens to Think about Disease States
Understanding the metabolic pathways and molecular mechanisms of adaptation pushes us to think about disease states and disruptions of metabolism in a more expansive way. We can start applying this lens of adaptation to all disease states – from cancer to diabetes to neurodegenerative diseases – to better understand how these pathways can change under certain stressors. Through observation of certain cellular shifts in energy regulation, metabolism, and signaling, we then may be able to predict how pathways or processes may begin to make decisions - to either adapt or maladapt.
A cell’s ability to communicate and be flexible as it encounters endogenous or exogenous stressors always comes back to cellular redox, which is why I often use redox as an anchor for illuminating the mechanism and importance of cellular medicine: when we appreciate that redox balance is essential for cell resilience and survival, we can learn how to make the cell better at adapting to daily life.
So we've talked about cellular adaptation and how the cells need to be able to respond and adjust to changes in order to maintain homeostasis. You can also look at this drive for homeostasis as a drive for cell survival so that it doesn’t lose its functionality. Another component to keep in mind related to the body’s eternal quest for homeostasis is that there can be different levels of adaptation going on at the same time within the body system: how does the kidney react to a lack of salt? How does muscle tissue adapt to an overload of lactate production?
All of these shifts within the cell environment create changes in energy production, cell signaling and work through various molecular pathways that can change gene expression, change protein synthesis, and cause metabolic adjustments in response to the stimulus that's presented.
When it comes to disease states, we want to keep in mind the adaptive mechanisms that cells use to stay in homeostasis. We know that signaling pathways are involved in gene expression, protein synthesis, and various metabolic processes. We also know that the cell will have to deal with some oxidative stress and that as a result the cells are going to form reactive oxygen species, which at first act as signaling molecules to activate antioxidant defenses and repair mechanisms that are important in making the cell adapt to the stressors.
Then we have mitochondrial adaptation, which cause metabolic changes, and then stress protein activation like autophagy (activation of autophagy sets the cell up for protein synthesis) or heat shock proteins – other adaptive mechanisms that come into play to protect cellular structures while we are recovering and taking full advantage of protein synthesis.
Again at the cellular level, any stress is a form of oxidative stress, pushing the cell environment out of redox balance. And we know that when redox is disrupted, a complex cascade of cellular reactions typically occurs:
- Formation of ROS, which act as signaling molecules to activate antioxidant defenses and repair mechanisms
- Mitochondrial adaptation
- Metabolic changes
A stressor can be psychological in nature, too. Mental stress or post-traumatic stress also act as stressors pushing cells out of redox balance. There are also significant environmental stressors that can upset redox homeostasis. In response, oxidative stress ensues, which in turn induces the antioxidant defense and repair mechanism that allows the cell to regain homeostasis and then build capacity to adapt to stressful conditions in the future.
It’s also important to keep our eye on mitochondrial adaptation, which is one of the keys in understanding cellular homeostasis and how a cell adapts. In order for homeostasis to be maintained, the mitochondria have to stay efficient at meeting the energy demands of the body. The body needs to be able to regenerate more mitochondria (through mitochondrial biogenesis) in response to stress in order to meet the needs for more energy, and this generative work has to be done efficiently. In response, the mitochondria work to optimize these metabolic pathways, in particular by increasing respiratory capacity. The mitochondria adapt by regulating the proteome to meet the needs of the cell; this requires redox homeostasis to maintain protestasis.
As we encounter patients with certain disease conditions, we can use this insight into homeostasis to create pro-adaptive interventions. As physicians and healthcare practitioners, it’s crucial that we build in opportunities to educate our patients about lifestyle behaviors that can support their cellular health – so they will not only live longer they will live better. How? By supporting our patients in making simple but powerful behavior modifications. In addition to peptide therapy, I also suggest that all patients consider my three pillars of optimal healthspan:
- Dietary modifications that focus on fresh foods that highlight macronutrients with a de-emphasis on processed or pre-packaged foods;
- Physical activity that encourages people to incorporate regular exercise, with an emphasis on strengthening;
- Sleep sustenance that regulates sleep to reset and restore the cellular mechanisms that protect the brain and body and restore their circadian clock.
So when your patients come to you motivated by their goals of optimizing their healthspan, encourage them to be intentional about these three pillars. In my next blog, I will share both the science that supports these behavioral modifications, as well as some tips for helping patients make these important changes. Most of us did not receive this kind of information in our training, and yet it’s a huge missed-opportunity to help prevent disease.
To help our patients thrive, we must help them understand and appreciate how to make daily choices that impact their healthspan so they can live their best lives – now and into the future.
AGING: Adaptation vs Maladaptation
Let’s consider aging. Understanding the mechanisms of cellular adaptations that we can achieve with exercise points to the potential to work against some of the age-related declines that are associated with loss of mitochondrial functioning and oxidative capacity. When we proactively harness the power of cellular adaptations, we are really getting to the heart of how to improve our healthspan. Again, using exercise as a model example, we can fight or defend against what many assume are inevitable declines associated with aging when we target those cellular pathways that:
- Improve insulin regulation
- Improve glucose utilization
- Improve energy production, TCA, Beta-oxidation, and protein metabolism
- Improve insulin sensitivity
- Improve microbiome diversity and stability
These proactive results from regular exercise should not be overlooked. However, without exercise as a buffer; without other healthy lifestyle habits that positively influence cell pathways and support redox and mitochondrial metabolism, oxidative stress and the resulting inflammation go unchecked. What happens as a result? Type 2 diabetes. Metabolic Syndrome. Cancer. Neurodegenerative conditions. The downstream effects of a disrupted cell environment caused by a lack of homeostasis is very real and happens all the time.
But it doesn’t have to happen.
Leverage Against Disease (aka Prevention)
If we're enhancing mitochondrial function and energy metabolism, that can be leveraged against metabolic diseases like type two diabetes. As I've talked about ad nauseam, type 2 diabetes can be managed by simply walking 10-20 minutes after you eat to reduce the postprandial hyperinsulinemia and triglyceridemia.
And that’s my point: if we look at cellular adaptation, we can discover and harness straightforward methods of maintaining homeostasis and building cellular resilience – which is the essence of optimizing your healthspan. There's nothing better than exercise to give us all that information that we should be taking advantage of, understanding all the molecular pathways and how we can improve health and how we can interfere with age related changes, how we can treat chronic diseases, and how we can work against metabolic disorders.