The health benefits of hypoxia and living at high altitude

I had the pleasure of attending and presenting at the Ancestral Health Symposium, in Boulder Colorado, August 11-13. My podium presentation was entitled “Living High and Healthy: Why Coloradans and Others Who Live at High Altitude Live Longer, and What Flatlanders Can Learn From Them”.   On several visits to Boulder and the Rocky Mountains, I was surprised that I had lost about 5-10 pounds after returning home to California. Subsequently, I was intrigued to learn that Boulder has the lowest obesity rate in the U.S., and that alpine regions around the world are distinguished by statistically lower prevalence of  obesity and diabetes, and also increased longevity.

My curiosity about this issue spurred a deeper investigation, resulting in this  talk at AHS16. From the scientific literature, I learned that there is a specific hormetic mechanism involving hypoxia (reduced oxygen levels) that probably accounts for the health-promoting effects of living at high altitude.  However, it was particularly exciting to discover that hypoxia is not the only means of activating this hormetic mechanism, which can still be accessed even if you live at sea level!

The Ancestry Foundation is kind enough to produce excellent videos of the talks and release them for free viewing on YouTube.  Enjoy watching!

 

To make the talk easier to digest, I’ve also reproduced my slides here, with a short written synopsis and references:

Slides:

(Click on image below and allow 30-60 seconds for slide show to upload)

 

Overview of the talk.

Overview of the talk.  For ease of reference, here is slide-by-slide “table-of-contents” summary of the presentation.

  1. Title: Living High and Healthy: Why Coloradans and Others Who Live at High Altitude Live Longer, and What Flatlanders Can Learn From Them.
  2. Boulder has very low rates of obesity, diabetes, cardiovascular disease.  Is there a secret we can exploit to live longer?
  3. The obesity rate in Boulder in 2014 was 12.4%, compared with 39.5% for Cabell County, West Virginia.  Could this be due to differences in climate, topography, diet, education and income?
  4. No single cause explains obesity.  亚搏体育客户端下载 , exercise, genetics, and psycho-social factors all likely play a role,and it is difficult to separate cause and effect.
  5. Observational and interventional studies are often hard to interpret.  To identify factors with long-term effects on obesity, it is useful to look at geographic distributions, since they are less transient.
  6. Obesity and diabetes have been on the rise since 1994, but CDC data for the U.S. shows that their prevalence varies significantly state-to-state
  7. In 2004, just a decade later,  obesity rates increased sharply, but unevenly.  The Southeast showed much higher rates compared to the West, and Colorado stood out with the lowest rates in the U.S.
  8. And in 2014, with continued increases in both obesity and diabetes, Colorado and a few other states continued to buck the trend.  But why?
  9. Viewing obesity at a county level provides a sharper, more detailed view.
  10. As does a county-by-county view of diabetes
  11. Apparently, people in regions with high obesity have less access to transit eat an inferior diet
  12. Another explanation is that the obese are less physically active.  That’s supported to some extent by surveys, but are self-reports always reliable?  But inactivity could be as much an effect of obesity as a cause.
  13. It is particularly compelling to see how close a match there is between  obesity prevalence and altitude.  This is evident not only in the high plateau of the Western U.S., but also in how the “low obesity island” of the Appalacian mountains stands out from the surrounding “sea of obesity” of the Southeastern U.S.
  14. It’s not just the U.S.  Maps of Europe show that longevity tracks altitude.  The can be seen, for example in the mountainous regions of northern Spain, Switzerland, Croatia, Greece, Austria, Norway, Iceland, and the Scottish highlands.
  15. Looking at maps is interesting, but it is more convincing to look at statistics.  A survey of 422,603 adults across the U.S. — controlling for age, sex, race, ethnicity, education, employment, temperature, diet, physical activity and smoking — found the odds of being obese for those who live at sea level are 4-5 times higher than for those living at 10,000 feet or higher.  Boulder does better even that predicted, which indicates that altitude is important, but only one of many factors.
  16. A study of obesity among Tibetans strengthens the altitude hypothesis, because Tibetans are relatively homogeneous genetically, culturally and economically. Obesity rates dropped in half at higher altitudes.  Intriguingly, the high altitude Tibetans also consumed more calories and were more physically active.
  17. Why is obesity and diabetes lower at high altitude?  Exercise, ethnic distributions, UV radiation and air quality have been proposed as explanations, but their is countervailing evidence.  The most promising explanation is the drop in oxygen concentration at high altitude, creating a hypoxic environment.
  18. A range of studies show that hypoxia confers numerous health benefits:  reductions in body weight, diabetes, blood pressure, CVD, detention; and increases mitochondrial biogenesis and in measures of cardiovascular fitness, insulin sensitivity and glucose metabolism.
  19. An interventional study of 20 obese males who spent a week at the summit of the Zugspitze in Germany found spontaneous decrease in weight, blood pressure and food intake, and increases basal metabolic rate and leptin signaling, lasting even 4 weeks after return to low altitude.
  20. A comprehensive study of U.S. death certificates found that men and women living above 4900 fit on average had statistically longer lifespan and reduced heart disease, though there were increases in COPD.
  21. A study of athletes found that those who live at high altitude and train at low altitude show increases in strength and endurance, vs. those who live low and train high.  A meta-analysis of 11 similar studies found that spending time at high altitude is only beneficial if sustained for at least 9.5 hours daily for at least 2 weeks. Short term training with “hypoxic masks” appears to be ineffective.
  22. What mechanisms explain the connection between hypoxia and these health benefits?  Three have been proposed:  (1) hormone signaling by leptin and insulin; (2) hormetic sensing by the PGC-1α cascade; (3) inhibition of the mTOR anti-aging pathway via REDD1.  (Note: For an alternative or additional mechanism, involving the elevation of CO2 levels at high altitude, see Comment #5 below by Mark L, and my follow up in Comment #6).
  23. Studies of intermittent hypoxia exposure in rates found a 6-fold increase in plasma leptin and increased leptin sensitivity
  24. Another rat study found that hypoxia increases brain-derived neurotrophic factor (BDNF), spurring neurogenesis and cell proliferation in the hippocampus, and eliciting an anti-depressant effect
  25. Hypoxia also induces production of the REDD1 protein, thereby suppressing the activity of mTOR, a master regulator of protein synthesis and growth processes. While mTOR induced growth is beneficial in youth, overactivity of mTOR is associated with obesity, diabetes and other “diseases of aging”.
  26. Now we get the the core idea of the presentation! I’ve pulled together an overview of these mechanisms in a single diagram, showing how hypoxia improves health by first activating a “stress sensor” called PGC-1α, a protein that binds to the PPAR-γ receptor in our cells.  PGC-1α is the master regulator of mitochondrial biosynthesis.  In turn, it stimulates the hormones FNDC5 and irisin the brain, muscles and adipose tissue, leading to a cascade of beneficial health effects.  For example, secretion of FNDC5 and irisin in the muscles promotes thermogenesis and a shift from inflammatory white fat (WAT) to metabolically active  brown fat (BAT). And in the brain, the secretion of FNDC5 and irisin results in increased BDNF and leptin signaling, insulin sensitivity, appetite suppression, and the urge to exercise.
  27. BDNF, or brain-derived neurotrophic factor is produced in primarily in the brain’s hippocampus and hypothalamus.  It promotes neurogenesis and brain plasticity. Notably, BDNF suppresses appetite and increases metabolic rate and is found at low levels in obese humans and animals.  But despite the name, BDNF is found “peripherally” — outside the brain — in the liver, muscles and adipose tissue.  There it modulates hormones like insulin, leptin and cortisol, and promote thermogenesis and insulin sensitivity.
  28. The PGC-1α cascade similarly activates autophagy, a cellular “housecleaning” process that sequesters damaged intracellular proteins within autophagosomes, digesting and disposing of this waste material, thereby enhancing cellular fitness.  Autophagy has been shown to increase longevity in animal studies.
  29. Autophagy promotes longevity by removing damaged intracellular proteins and pathogens, damping down inflammation, reducing apoptosis, necrosis, senescence and oncogenesis.  It also boosts the innate immune response.
  30. OK, so living at altitude in a hypoxic environment leads to improved health outcomes.  But do we need to move to the mountains or wear hypoxia masks to lose weight and live longer?  Fortunately, not.
  31. To explain why, it is useful to contrast three theories of aging:  the genetic program theory, the damage accumulation theory and the hyperfunction theory. I’ve discussed these in detail in my post, Live Longer!.
  32. The genetic program theory and the damage accumulation theory have serious difficulties.  For example the theory that aging is driven by oxidative damage can’t explain long lived animals like the naked mole rat, that show extreme oxidative damage but live about 10 times longer than lab rats.  One key is that they are able to upregulate their protective endogenous defenses, like the Phase II antioxidant enzymes.  By contrast, the hyperfunction theory embraces the idea that aging results from overactivity of cellular processes like inflammation, cell division, lipogenesis, etc.  These processes are under control of the mTOR pathway.
  33. yabo亚洲 is one of the most useful way to counteract mTOR-driven aging processes.  yabo亚洲 is a set of defense, repair and adaptation mechanisms that are activated by low dose stressors.  Stress must be optimized such that it is high enough to stimulate a response, but not so high as to be damaging.
  34. There are four types of hormesis: structural hormesis, defense hormesis, metabolic hormesis, and psychological hormesis.  I’ve written about all of these in this blog.  But it is metabolic hormesis that concerns us in this talk.  Examples of metabolic hormesis are calorie restriction, exercise, cold exposure and hypoxia.
  35. Returning to our earlier diagram on Slide 26, it turns out that each of these other metabolic stressors — cold, exercise and calorie restriction — also activate the same PGC-1α cascade that is primed by hypoxia.  To me, this is quite a remarkable thing!  We are endowed with a general sensor for external stressors that place demands on our internal energy economy, causing major shifts in our appetite, urge to exercise, insulin sensitivity, and even the metabolic character of our fat stores!
  36.  The universality of the PGC-1α cascade makes sense biologically, but it was a revelation to me when I saw the research that underlies this picture, and how such different activators as exercise, cold and diet can activate the same pathways.  Of course, these external forces are not all identical, because they act to different degrees in different tissues and organs.  But the underlying biochemistry is a common driver.
  37. Of the various effects of the hormesis-activated PGC-1α cascade, one of the most interesting is how it promotes “exercise salience” – the urge to exercise.  It does this by improving mitochondrial function, metabolic rate and thermogenesis, thus enabling the rapid release of energy on demand.  At the same time, this metabolic hormesis is effective in counteracting inflammation. Alistair Nunn and colleagues wrote a brilliant paper, proposing that the epidemic of inflammatory disorders may be a result of a sedentary lifestyle lacking in hormesis.
  38. Nunn contrasts the virtuous cycle of hormesis with the vicious cycle of inflammation.  In the first of these, metabolic hormesis spurs mitochondrial biogenesis, supplies ample energy, encouraging exercise and other hormetic activity, and suppressing appetite.  And hormesis tends to counteract the effect of whatever inflammation is present.
  39. The vicious cycle of inflammation is enabled by a lack of metabolic hormesis.  Inflammation weakens mitochondria, damping energy generation and the willingness to exercise, fast or expose oneself to cold.  The lack of energy results in heightened appetite, particularly for inflammatory “comfort foods”, and leads to a sedentary, pro-inflammatory lifestyle.
  40. Nunn’s brilliant paper encapsulates this view in the observation that hunter-gatherers of yore often went without food, experience extremes of temperature, and were physically active out of necessity.  Inhabitants of the contemporary world, by contrast, suffer from a shortage of hormesis,   giving rise to inflammatory diseases of civilization, and a loss of “metabolic flexibility”.
  41. So you don’t have to live at high altitude to reap the rewards of metabolic hormesis.  Hypoxia is not the only route to taming obesity, diabetes and metabolic syndrome.  Let yourself experience discomfort. Take cold showers, hike and lift heavy things, and eat less frequently.
  42. I have included three slides of references for those wanting to probe this topic more deeply.  References on altitude, obesity and health;
  43. References on hypoxia health effects and mechanisms;
  44. And references on the hormetic control of metabolism and health, particularly the PGC-1α cascade.  In the video, you can also listen to the Q&A that follow the talk.  It starts at the 28:25 minute mark.

Here is a brief summary of the comments, questions and answers:

Q1. How much of the audience lives at high altitude?
A1. Most of the audience raises their hands

Q2. Fetuses in utero compete for oxygen with the mother, experiencing hypoxia like that on top of Mt. Everest. We have evolved to adapt to a hypoxic environment.
A2. Good observation, and I should comment that as with all types of hormesis, one can overdo it.  So hypoxia can represent too much stress, for example with altitude sickness or for individuals with COPD.  So you need to be aware of your health status

Q3. I heard that The Air Force Academy in Colorado was sited here in order to promote physical conditioning due to its high altitude.  Do you know if this is true?
A3. I think there studies supporting this, and Olympic athletes also spend time training at high altitude for this reason.  But as I mentioned, you may need to spend several weeks at high altitude to get the full benefits.

Q4. Can you speculate comparing Boulder to Salt Lake City and Park City in Utah.  They consume less coffee and alcohol.  And among devout Mormons, the practice of fasting once a month. So are these confounding variables to the altitude effect
A4. Yes, they are confounding variables.  As I mentioned, obesity, diabetes and longevity. is multi-factorial. And the map I showed had some pockets around Salt Lake City and maybe Las Vegas, where there is urbanization.  So some factors are working for you, some against you. Altitude is only one variable.  Alcohol is a hormetin.  As with all homeric things, there is an optimum level.Q5.  The CDC maps of the U.S. show that the higher the altitude, the higher the suicide rate.  It peaks in Wyoming, and is high in all the mountain states.
A5.  I had read that too, and I wish I could explain it, but I can’t.

Q6. Have you looked at radiation hormesis?  Low level radiation may be healing. Cancer rates on the east coast were shown to drop where radon levels were higher.
A6.  There is a whole literature on radiation hormesis which I didn’t go into in my talk. It’s more controversial, and it is harder to get conclusive data, but I think there is an effect.

Q7.   I’m interested in the connection between hypoxia and diseases of mitochondrial dysfunction.  Have you seen any data on the effect of altitude on morbidity in general from other diseases related to mitochondrial function like cancer, Alzheimer’s, Parkinson’s, etc.
A7.  There were some studies I saw relating to dementia.  I couldn’t find good studies on cancer.  I cited one study in my talk on the effect of altitude and longevity.

Q8.  Is there a difference between living your whole life at high altitude vs. moving there when you are 40 or 50
A8.  That’s a good question. I don’t know.

Q9.  Ultra-runners recommend that if you can’t arrive at a high altitude race site 2 weeks ahead, it is preferable to arrive just 1-2 days before the race.  Any idea what the mechanism would be and  if that argument is valid.
A9.  Like anything else, hormetic stress start out being a disadvantage and their benefits take time to take hold. Hypoxia initially lowers your VO2 max, but as you get mitochondrial biogenesis, more red blood cells and hemoglobin, you get a net benefit.  But it takes several weeks.  So maybe the advice is right that if you come out just 3 or 4 days before the race you might experience a decrement in performance.

Q10.  In Big Sky, Montana, at 7500-9500 ft, we experience what you showed in your slides.  Maybe the suicide problem results from the cloudy, depressing weather.  People are active in Montana and may get depressed when they can no longer be active.
A10.  The suicide observation is still a paradox to me, particularly in light of the studies  showing that hypoxia elevates BDNF levels.  It still needs some explanation.

At the AHS16 conference in Boulder,  I also had the opportunity to present a more general overview of the biology of hormesis, covering not just “metabolic hormesis” stressors such as hypoxia, but hormesis of the other three types — structural, defense, and psychological.  Several people asked for copies of the poster, so I attach it here as a pdf file.  Feel free to download it:

AHS16 Poster: How yabo亚洲 Works

I think this general topic of metabolic hormesis is fascinating, and quite central to what I write about in this blog.  So I’d love to get further comments, questions and discussions going.


17 Comments

  1. Paul

    Have you considered breath holding as a method to stimulate hypoxia. Simply by holding your breath for as long as possible, or exercising while holding your breath for the fit, you can trigger a hormetic adaptation to low oxygen and increased co2. This will cause a general increase in your bodies ability to deliver oxygen to your cells.

    I go the idea from Patrick McKeown (a Buteyko practitioner) as part of his general breath training method. http://articles.mercola.com/sites/articles/archive/2013/11/24/buteyko-breathing-method.aspx

    Reply
    • Todd

      Good comment, Paul. Wim Hof, the cold enthusiast who I wrote about in my post, “The Iceman“, utilizes breath-holding exercises to improve aerobic capacity and resilience. As a result, he is able to swim long distances under water, even under the ice. His breath holding strategies are described well in Justin Rosales’ book, “Becoming the Iceman“.

      Thanks for the link to the Buteyko method. I’m not sure I follow some of the other elements of the technique, but the breath holding aspect is interesting. The claims that breath holding can improve red blood cell count and EPO levels is supported by some of the hypoxia research I cited in my reference slides.

      Reply
      • Michael

        You might be interested in this comparison article between Wim Hof and Buteyko. http://www.oxygenadvantage.com/wim-hof/

        Reply
        • Todd

          Good article, thanks. I also liked the video interview between Joe Rogan and Wim Hof linked on that page. Wim’s explanations of what he does are sometimes a bit loose on the science (and hence fun to listen to), but you can’t but be impressed by what Wim is able to do with his body and mind.

          Reply
  2. Van

    Hi Todd,

    Great to see another post.

    I spent a few months in the Midwest in the winter. I grew up in the Midwest. But I have lived in San Antonio for years. I sunbathed in boxers for 45 minutes several times a week (in the yard on a chaise lounge). Temperature: 19 degrees Fahrenheit or less. I also rolled around in the snow in boxers for several minutes. Shoveled the drive barefoot. Ran a mile barefoot wearing gym shorts and a thermal V-neck. Nothing else. A guy in a parka lined with fur, and massive gloves/boots said “one of us is not dressed properly for the conditions.

    Does this qualify as cold thermogenesis? I never get cold.

    Reply
    • Todd

      Ha! Love your story, Van. I get similar reactions or looks from people when I “under dress” in the winter or go for February swims in the ocean when all others insist on wearing wet suits. Regular cold exposure is the best way to immunize yourself against the cold and never feel cold. Many of us who do this also find that we rarely if ever get colds or flus.

      Reply
  3. Mark L

    Hey Todd! Thanks for GettingStronger.org. I am interested in hypoxia/breathing for general health reasons and also because in 2 weeks I am hiking a couple 14er mountains in Colorado. After seeing Paul’s comment above, I did some reading on Buteyko Breathing.

    Buteyko explanations state that usually we breathe when we sense that carbon dioxide is too plentiful in our lungs (and not when we sense the need for oxygen); Buteyko instructors believe their exercises create a greater tolerance to carbon dioxide which in turn leads to less breathing, less oxygen in the blood, and more carbon dioxide in the blood. So on the theoretical mechanism of hypoxia benefits in your point #22, you might want to consider adding the following: A greater concentration of carbon dioxide in the blood helps to relax nasal passages and the smooth muscles surrounding blood vessels. -Mark L

    Reply
    • Todd

      Hi Mark,

      Thanks for your explanation of Buteyko. The CO2 mechanism was also mentioned to me in discussions with some of the conference attendees after the talk. What I hadn’t heard before, which you bring up, is that one can adapt to higher CO2 levels. I’ve added a note to the Slide 22 summary to see your comment and this one.

      One of the other talks at AHS mentioned that elevated CO2 levels, which can result either from high altitude exposure, diet or other metabolic mechanisms, can have health benefits. And it explains why hyperventilation is harmful. See this provocative and informative talk by Kyle Mamounis, especially the very interesting section on CO2 from about minute 7:53 to 13:30:

      AHS16 talk by Kyle Mamounis: The Dangers of Fat Metabolism and PUFA: Why You Don’t Want To Be a Fat Burner

      Enjoying hiking your 14ers! The day after the conference I hiked to the summit of Mr. Bierstadt (14,060) with my son and his fiancee. It was beautiful and exhilarating. I did notice some additional exertion required above about 13,000 ft, but it was fun the whole way. And…I dropped about 5 pounds after returning home, and I’ve even lost a couple more pounds in the 10 days since. Definitely there is a sustained appetite suppression effect, at least for me, and my energy level and desire to exercise is good.

      Todd

      Reply
      • Mark L

        On September 11, I too climbed Mr. Bierstadt; at the top it was cold enough to make my nose run and the 40 to 50 mph winds sucked the snot right out of my nose!

        I only had 4 days in Colorado, but I too lost a couple of pounds after returning home.

        Prior to my Colorado trip while home at 600 feet above sea level, my Buteyko “Control Pause” was 30 seconds; while at 8500 feet in Georgetown, CO, my Control Pause was 15 seconds. My resting heart rate at home was about 45, whereas in Georgetown it was about 70.

        Reply
  4. Van

    Hi Todd,

    An interesting presentation by Stephen Phinney MD. What are your thoughts on Histone deacetylase (HDAC)?

    From Phinney’s lecture:

    Suppression of oxidative stress by B-hydroxybutyrate, an endogenous histone deacetylase inhibitor.

    Histone deacetylases (HDAC) – a group of enzymes called gene silencers (do the work of turning the genes in our genome on and off).

    B-hydroxybutyrate, whether caused by fasting or infusion of BOHB, is a potent anti-inflammatory effect, and anti-oxidative stress effect.

    BOHB, at millimolar levels, is an inhibitor of histone deacetylases

    BOHB at 1-3 mM… the range of nutritional ketosis. You are increasing your body’s defenses against oxidative stress.

    HDAC (histone deacetylase) activity turn off your internal oxidative stress protection.

    These enzymes (histone deacetylases) are gene quieting enzymes. They are turning off your internal oxidative stress protection.

    If you want the most potent oxidative stress reduction tool you can find, you want your B-hydroxybutyrate between 1-3. A potent drug like gene signaling effect that protects your body against ROS, oxidative stress and inflammation. “This is huge.” Phinney

    The low carb diets were not always high in anti-inflammatory phytonutrients, which implies the anti-inflammatory effect is due to low carb intake. Simple sugars, particularly fructose, increase oxidative stress. High blood insulin is pro-inflammatory.

    Reply
  5. CS

    Hi,

    From reading Ray Peat’s I think about the advantages of hypoxia as relating to the Bohr effect – that the increase in CO2 concentration is required in order to efficiently deliver oxygen to the tissue (the Buteyko method is also based this effect).

    What to you think of that?

    Reply
  6. Nathan Eliason

    Great talk, Todd. We haven’t heard much from you for some time.

    By the way, I saw this video by someone who improved his vison-he gives you credit:

    https://www.youtube.com/watch?v=DcNDMEGRKcY

    Best wishes,

    Nate

    Reply
    • Todd

      Thanks for the link, Nate. It was good to hear that testimonial about using under-correction to reduce myopia.

      Reply
  7. Dr. Dean Raffelock

    Having had a clinical practice in Boulder, Co for over 25 years (before my retirement), I’m submitting some other points of view to consider: (1) Boulder is a much more affluent community than many other places. Affluent people tend to be able to afford better food, better integrative doctors, and better overall health information.(2) If hypoxia is such a dominant factor, why is it that people with sleep apnea tend to gain weight not lose it? (3) There is a very strong exercise culture in Boulder.People who move to Boulder tend to exercise more frequently and for longer periods of time to do outdoor activities with their friends.

    Dr. Dean Raffelock

    Reply
    • Todd

      You raise a number of good counterpoints to my argument, particularly regarding affluence and exercise culture. However, if you look at the maps of high altitude regions and low obesity regions, they include wide swaths where I daresay the affluence and exercise ethic are not as strong.

      Hypoxia of course has multiple causes and different degrees. So as with any stress or syndrome, it can manifest itself beneficially or detrimentally (as in the case of area). Similarly, exercise, fasting, cold exposure and UV radiation offer benefits in low and intermittent doses, but can be harmful or lethal in excess.

      Reply
  8. zeynep

    My miyop is 3. I haven’t used glasses since one year. Still does this technic work for me

    Reply
    • Todd

      Yes

      Reply

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