Hormesis (exposure to a stress to create a benefit), is proving to be an incredibly valuable tool in our health arsenal. From cold exposure to psychedelic micro-dosing and everything in between, the field has a lot of promise. Part 2 in our 7 part series addresses exercise, perhaps the most important and effective strategy, one that is incredibly popular, but not popular enough.
For a full introduction to Hormesis read part 1 of this Hormesis series.
Physical exercise is one of the most important and critical habits that everyone who is able in any capacity should utilize to take control of health and longevity. While there are many workout strategies, active debate on the most effective strategy, and the best routine for a myriad of different goals, in this article we will only focus on exercise as a hormetic agent and where various intensities fit into different, specific, hormonal responses.
For any of my readers quick to defend their chosen passion, this article is not meant to rate any activity over another overall. As Doug McGuff M.D. and John Little put it in the opening paragraph of the first chapter of Body by Science
“Strange as it may sound, fitness is a state that lacks a precise definition. Most of us use the term without really knowing what it is we’re talking about. The fitness industry offers no definitions, nor does the medical industry.”
I intend to write a full analysis of various strategies to remain “fit”, as defined by each reader’s intent, so stay tuned.
PGC-1α and irisin share this section, as they are connected. In fact, it is hypothesized that increased expression of PGC-1α in muscle tissue during exercise leads to irisin production,iii a fairly recently discovered myokine, referred to as the “exercise hormone”.ivv Myokines are a type of cytokine, which are small proteins critical for cell signaling, that are released during muscle contraction.
This has contended, however, and a recent systematic review has brought up issues with detection methods, concluding
“The effects of physical activity on the link between PGC-1a, FNDC5 mRNA in muscle, and UCP1 in white human adipocytes has attracted little scientific attention. Current methods for Irisin identification lack precision and, therefore, the existing evidence does not allow for conclusions to be made regarding Irisin responses to physical activity”.vi
It is worth noting that this review was published two years after Bruce Spiegelman et al., the team that originally ”discovered” irisin, declared they had quantified it in blood work.vii It is important to consider these controversies and not publish absolute declarations in catchy headlines, such as the often infuriatingly inaccurate but wildly popular and followed pop-science blog IFLS or “I Fucking Love Science” did here.viii
What does this mean? Simply put, we have some evidence that exercise leads to irisin, however, the testing for it is inadequate and thus we need to refine methods and test further. This means we cannot state “exercise increases irisin” and cannot state that “exercise does not increase irisin.” I think it is likely that it does, however, the implications are far less important than the media or highly excitable bloggers and antiaging practitioners would lead you to believe.
What Does Increased Expression of PGC-1α Mean?
PGC-1α is the “master regulator” for mitochondrial biogenesis and a key regulator in bioenergetics or the flow and creation of energy through our cells and bodies. Mitochondrial biogenesis is the process in which our cells increase mitochondrial mass. More mitochondria mean more energy, and it has been implicated to assist in weight loss, athletic performance, and overall health. While we have linked a decrease in mitochondria and reduced mitochondrial biogenesis to aging and correlated it to heart disease and diabetes, it is currently unclear if restoring mitochondrial function on its own would dramatically alter longevity or healthspan. Likely, it is an important piece of the puzzle, but not the only piece.
What are the Supposed Benefits of Irisin?
Irisin is relatively new on the scene, and our understanding of it is still lacking. I often talk about the limitations we have regarding communicating the benefits of molecular hydrogen due to how green the science is. Irisin has been studied far less, for a far shorter period of time. On top of this, as mentioned above, there are still concerns about our ability and methods to even test for it. To give context, irisin was first “discovered” in 2012. Psychology Today has a succinct introduction on its discovery, and the interest surrounding it.i x
“In 2012, Bruce Spiegelman, Ph.D., a cell biologist at Dana-Farber Cancer Institute in Boston dubbed the hormone "irisin," after Iris, a Greek messenger goddess. Spiegelman foresaw the role of irisin as a ‘messenger’ saying, "There has been a feeling in the field that exercise 'talks to' various tissues in the body. But the question has been, how?" His ongoing research—along with that of others around the globe—continues to solve the irisin riddle.
At the time of irisin's initial discovery, Spiegelman believed that it was an important first step in understanding the biological mechanisms that translate physical exercise into beneficial changes throughout the body—both in healthy people and in preventing or treating disease. A variety of studies released since 2012 continue to show that the “exercise hormone” irisin (also known as FNDC5) has wide-ranging health benefits.”
So what are these health benefits? Irisin has been linked to converting white adipose tissue to brown adipose tissue and driving thermogenesis,xxixii which may be significant for human weight management. Although, I am much more cautious of the potential than many others, and detail why in part 1 of this series that was released last week here.
In a study published in the journal Cell just a few months ago (Dec 2018),xiii Bruce Spiegelman et al. discovered a molecular receptor for irisin, which allows it to bind to and activate osteocytes, the most abundant cell type in adult human bones. The Harvard Gazette discussed with Spiegelman the implications of this for conditions such as osteoporosis, although the research is still incredibly green and only in mice and cell cultures.xiv
Irisin may be neuroprotective and a recently published Nature Medicine study (early 2019) indicates it may stave off synapse failure and memory decline in a rodent model of Alzheimer’s disease.xv Although, mitochondrial biogenesis and PGC-1α expression have been implicated in neuroprotection,xvixvii and impaired PGC-1α function has been implicated in Alzheimer’s/dementia pathology.xviii As discussed, irisin is created downstream via increased expression of PGC-1α, the master regulator of mitochondrial biogenesis. Due to this relationship, it is premature to attribute causation re: irisin and neuroprotection. As usual, media has jumped the gun in creating excitement, contributing to distrust in science (since we keep curing everything, why are we getting sick?). I will credit the New York Times for being restrained in their article here, using language more cautious than others would and maintaining some intellectual honesty.xix
Does all Exercise Drive Increases in Irisin?
While there is data for irisin increases in low-intensity aerobic exercise,xx high-intensity exercise, including HIIT, has shown to drive an increase in controlled studies where aerobic has not.xxi Similarly, resistance training has increased irisin levels in comparative studies where aerobic has not.xxii Due to the lack of data, and limitations in testing for irisin levels, it is too soon to draw any definitive conclusions from this.
How is this Linked to Other Known Hormetic Agents?
There were clues that H2 could have similarities with other hormetic agents. In fact, what we know about PGC-1α is that it is activated or deactivated by a host of stressors, including every single topic of this series. In fact, the established literature in 6 of 7 parts of this series has it being activated, with the lone “deactivator” being the stressor with the ‘narrowest’ J curve, coupled with the highest chronic exposure. As irisin research grows, it will be important to look for its increase via other hormetic agents. We have previously identified that cold exposure releases irisin in a similar fashion to exercise, which I wrote about in part 1 of this series.
Myokines and the Interesting Role of IL-6 as an Anti-Inflammatory
As noted above, irisin is a myokine. Other myokines released during muscle contraction also play important roles, the very nature of how they are created and what they are, being an important factor in exercise-induced hormetic stress. Interleukin 6, or IL-6, has caught my attention. In disease models, IL-6 is one of *the* targets where research aims to lower in terms of preventative aging and disease.xxiiixxivxxv In fact, it is one of the most commonly shown benefits of hydrogen therapy and hydrogen water.xxvixxviixxviiixxixxxxxxxixxxii
In fact, where IL-6 is a marker of chronic inflammation in disease models, regarding its role as a myokine, IL-6 is actually a potent anti-inflammatory. Exercise-induced release of IL-6 can acutely elevate levels in serum by 100x,xxxiii which leads to a powerful anti-inflammatory response via activation of other anti-inflammatory cytokines, such as IL-10.xxxiv
Where IL-6 is signaling matters. We now understand that when IL-6 is signaling within muscles, it creates an anti-inflammatory effect.xxxv When IL-6 is elevated and signaling outside of muscle tissue, within a type of cell called macrophages, or within white blood cells, our understanding of it being a devastating pro-inflammatory signaling molecule (when chronic and elevated) remains accurate.
This is why the reports of elevated serum IL-6 being lowered in H2 research is a good thing- and I am interested in researchers exploring the nature of increased IL-6 levels in muscle tissue concurrent with hydrogen water or hydrogen therapy in the future, although more on that later in this series.
Exercise, Vasodilation and Nitric Oxide and VO2 Max
Nitric oxide (NO) is an endogenous source of oxidative stress and a free radical, meaning it has an unpaired electron and as such is highly reactive. Historically, the media has told us that free radicals are bad and as such marketers have tried to shove exogenous antioxidants down our throats. Our understanding of this has been changing over the last several decades (although many marketers and influencers are slow to get the message), and in 1998 the Nobel Prize in Physiology or Medicine went to the team that discovered nitric oxides critical role in as a cardiovascular signaling molecule.xxxvi
It is of interest to recreational athletes worldwide that exercise increases nitric oxide.xxxvii “Nitric oxide supplementation”, or rather supplements designed to elevate NO levels (e.g. nitrates, citrulline, etc.), may improve exercise performance and tolerance in healthy, but untrained or moderately trained individuals. Concerning highly trained and elite athletes, however, no benefit has been observed.xxxviii
Vasodilation is an important function in our bodies, nitric oxide playing a critical role, which results in a “widening” of our blood vessels as a result of the relaxation of muscle cells within our vessel walls. The inability to vasodilate leads to high blood pressure/ hypertensionxxxix and can lead to grave health concerns.xl Exercise likely plays an interesting role in vasodilation, however, our understanding of this is still expanding.xli We do know that exercise is as good as most drugs in lowering blood pressure.xlii Impaired NO can also lead to hypertensionxliii and orally administered NO supplements can acutely lower blood pressure.xliv
VO2 max is an interesting subject. We know that our fitness increases our ability to reach a higher VO2 max, and exercise will increase subnormal VO2 max over time regardless of the intensity.xlv We also know that VO2 max declines with age in a very closely related progression to muscle decline.xlvi In fact, while our ability to reach a VO2 max declines with age, our ability to take on oxygen does not seem to be impaired, pointing to the decline in muscle as the likely culprit.xlvii
Further to this point, master athletes lose their ability to reach a VO2 max at roughly half the rate of sedentary individuals their own age.xlviii While an exercise-induced increase in nitric oxide leads to an increase in VO2 max,xlix an increased VO2 max does not seem to have any effect on nitric oxide levels, availability, or dose-response to supplementation.l This likely leads us down the same path as most other discussion topics, in that coaxing out a benefit by maintaining a homeostatic function is ideal, and more is not necessarily better.
While IGF-1 is a “hot topic” for many biohacking bloggers and mentioned on numerous podcasts by antiaging or integrative doctors, the verdict is still out on if and when altering its expression has benefits. In fact, there are two factions: one group that believes upregulation comes with negative consequences, and the other that believes is comes with positive health implications. None of the data is consistent, either, and both up- and down-regulation are proving to be more complex than we originally believed.
To be absolutely frank, I am not sold on the benefits of either IGF-1 up- or down-regulation, and when there are such contradictions in the research I suspect it will end up being something that should be tightly regulated. With specific conditions caused by both increased and decreased expression, I do not think we have enough data to be wading into the debate over altering levels in humans at this time or encouraging eager biohackers to think about the pros and cons. In fact, I do not think we have data to even discuss the pros and cons yet.
While the overall outcomes of alteration in IGF-1 levels remain a mystery, there are a few facts that we do know about IGF-1. First, many hormetic agents seem to play a role in regulating it, both up and down. Second, it declines as we age. Whether that is a correlative or causative factor, we do not know. Third, the administration of IGF-1 in models where we expect to see an impact has come back with conflicting results, with human clinical trials failing on all accounts.
Perhaps IGF-1 is more complicated than simplified conclusions of needing to up- or down-regulate it. It could be a situation like inflammation or reactive oxygen species (ROS), where, in certain cases, they can be beneficial and are needed functions, but increased expression can be harmful. Until we know more, biohackers should not be searching for ways to specifically alter this. That said, considering the known beneficial effects of the various hormetic agents showing to regulate it, there should also be limited or no concern over its altered expression in these situations.
Heat Shock Proteins
While the name implies “heat shock”, we now know that heat shock proteins (HSPs) are released in response to many stressful conditions and are a factor in numerous topics of this series. Also, as is the case with many items we detail, there are pros and cons associated with HSPs. Very rarely is a biological function “always good” or “always bad” regardless of the specific instance, with most functions having a beneficial role when functioning homeostatically. Regarding HSPs and other functions that we do not completely understand, the best we can do is make educated predictions based on overall health outcomes.
HSPs act as a “supervisor” or “chaperone” during protein folding, ensuring proper folding occurs. Basically, proteins start out as a long and random “coil or string”, and to function properly they need to fold into a specific 3D shape. Imagine taking a rope stretched out and twisted in random ways, and coiling it into a tighter and specific pattern. Misfolding proteins may simply not function properly or in some cases, may operate in modified functions, not as intended, or even in a toxic manner. In fact, misfolded proteins have been implicated in many neurodegenerative diseases,li and also in many allergies and even cancer.liiliiilivlv
Exercise is, as we know, a stress, and as such, increases HSPs.lvi As logic follows (but is not always the case in our physiology), misfolding proteins lead to neurodegenerative diseases and stresses that increase HSPs, in this case specifically exercise, decrease the risk of neurodegenerative diseases, such as Alzheimer’s.lvii Lack of leg strength and exercise has been linked to increased risk of neurodegenerative issues.lviii In addition, so has sarcopenic obesity and just sarcopenia, or the condition of muscle frailty, especially when combined with increased fat mass.lix Exercise is also linked to a decrease in cancer risklxlxi and encouraged while undergoing cancer treatment.lxii
In fact, aerobic exercise has actually shown to improve repair following traumatic issues, such as stroke.lxiii It has also shown to increase adult neurogenesis in our hippocampuslxivlxv and the subventricular zone in mice.lxvilxvii
If relationships like this throughout our entire system had not been becoming more and more prevalent and clear each year, the dangers of elevated HSPs would seem paradoxical with what I have just presented. In fact, elevated HSPs have been linked to increased risk of both Alzheimer’s and cancer,lxviii perhaps by increasing DNA damage and protein crosslinking.lxix
In fact, it is some of the very same HSPs, such as HSP90 (they are titled based on their molecular weight), that exercise specifically increases and are linked in the strongest matter to increased carcinogenesis.lxx There are actually anti-cancer drugs and vaccines currently in development to inhibit HSPs as a form of cancer prevention and treatment.lxxilxxiilxxiii The role of HSPs in cancer, and their inhibition, remains a hot topic of research.lxxivlxxv
What does this mean for exercise enthusiasts? Don’t worry about it, but don’t overdo it. There is such thing as “too much of a good thing.” This brings us to our next sections, where exercise, like any hormetic stress, can have negative consequences.
Dangers of Overtraining, Rhabdomyolysis
By definition, exercise is a stress. Like any hormetic stress that elicits a positive response, too much can cause serious damage. While I am hesitant to categorize exercise as a potential addiction similar to other hormetic agents, like alcohol, the results of overdoing it are comparable. Part of this has to do with culture and the growing cultures of glorifying inhuman like training methods.
Overtraining, or acute bouts of high-intensity exercise, especially in those undertraining, can lead to chronic inflammation.lxxvi As a stress, acute training in untrained women can lead to (reversible) menstrual disorders, which is telling regarding momentary health.lxxvii Overtraining can also lead to a higher risk of muscle tears and injuries and can lead to health issues such as decreased sleep, fatigue, and ironically lower capabilities for athletic performance.lxxviii
Perhaps most frightening is the increased occurrence of rhabdomyolysis., a condition where your tissue actually starts breaking down and is through your urine. This is a potentially life-threatening condition in which your organs will begin to fail. It is usually associated with trauma or serious muscle damage, but an increasing trend has occurred where fitness enthusiasts develop it because they do not know when to rest and recover.lxxix Fitness trends need to self reflect on their purpose when instances of rhabdomyolysis begin happening. The entire point is for life-changing health benefits, not to endanger participants due to this ever-increasing narrative of “more intense, more hardcore is better”.
Hormesis - Exercise Conclusion
Exercise is perhaps the most important health consideration you can take. There is no pill, no surgery, no protocol that will protect your health span and longevity to the same extent of regular, moderate exercise. That said, exercise is a stress, an assault on our bodies and momentary health. Overtraining not only negates the benefits, but could potentially cause greater risks. A healthy lifestyle full of physical activity is something to strive for. A cult like obsession over constant improvement on subjective fitness is something that can be dangerous. Incorporate physical activity, in whatever method brings you the most enjoyment, that you can maintain a healthy long term routine and remember to get enough rest and recovery. Train smarter, not harder.