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The First Mars Marathon: Part 3

Martian nutrition: How runners will fuel

Carb-loading for the Red Planet marathon might prove more difficult than simply gorging on a pre-race pasta dinner. Since they will be shivering and burning a lot more calories not only during, but before the race, runners will simply have to eat more on Mars during the pre-race period to fully saturate their muscles with glycogen.

Just getting plates of pasta to Mars will be a major issue. After years in transit, many of the nutrients in any food shipped to Mars will have been lost, and deep-space radiation will have degraded much of a food’s chemical and physical structure. Preparing and shipping food to Mars for the runners to eat requires special methods. Anyone care for high-pressure processed, microwave sterilized, freeze-dried spaghetti and meatballs…anyone?

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Use of critical fuels such as carbohydrate and fat will drastically increase on mars due to the extreme cold

Mid-race nutrition is equally important. As stated earlier, the drastically cold temperatures will result in a higher rate of glucose use and glycogen depletion, so the runners will need to fuel more often to keep glucose stores elevated in the face of increased use of these from shivering, coupled with the metabolic demand of running. Marathoners, who rely heavily on their glycogen stores into the later miles of the race will need to ingest glucose during the race at a rate exponentially higher than the recommended 25-60 grams per hour to avoid hitting the dreaded wall around mile 20 of the Red Planet marathon. This drink will likely have to be specially formulated with a higher glucose content.

Authors of a 1998 paper in Experimental Physiology provide evidence that providing a drink containing 15% carbohydrate was able to maintain blood glucose levels better than one containing just 2% during a cycling test to exhaustion (1). For this reason, Martian aid stations will need to occur at regular intervals and provide runners with carbohydrate-rich gels, drinks, or tasty freeze-dried space snacks.

What they’ll wear

Until we evolve into actual Martians, humans won’t get away with running unprotected on the surface of Mars. For now, technology will prove vital to success as runners on this new planet. Newly minted Martian sports scientists and gear technologists will be recruited to design a top of the line marathon-specific spacesuit.

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Theoretical concept of the Mars runner suit. Source: News.mit.edu

This suit will provide a sealed, pressure-controlled environment, help maintain some warmth and control body temperature, riding a fine line between protection and optimal range of motion. A protective suit is necessary: in the low atmospheric pressure environment of Mars, bodily fluids would boil. This is known as the Armstrong limit of pressure, which Mars sits well below.

Additionally, runners will develop severe impairments in blood pressure maintenance due to the reduced atmospheric pressure. This drastic reduction in blood pressure was demonstrated in a Journal of Physiology study from 2015 (2). Studying astronauts on the International Space Station, researchers noted a reduction in blood pressure of 8-10 mmHg, mainly due to central volume expansion.  The marathon gear will resemble something of a wet suit– a design which is able to solve the low-pressure problem by using super tight wrapping  (instead of gas-pressurization, it uses mechanical counter-pressure) (3). This leaves the body mobile. Wrapping the lower limbs in this counter pressure “fabric” will allow full range of motion at the ankles, knees, and hips,

The suit will require an enclosed helmet with breathing apparatus for runners to get their oxygen which is lacking in the Martian environment and dispense of the large amount of atmospheric as well as metabolically produced CO2. But don’t even think about attempting a snot-rocket.

Additionally, features of the suit crucial to completing our space-race might include an airtight hole in the mask so that runners can ingest their mid-race fluids and gel packs.

One final, and perhaps most vital feature will be the shoes. Just as elite runners have custom shoes designed to their unique gait pattern and foot size, Mars marathoners will need footwear tailored with the same precision and comfort in mind. As it turns out, the painful condition of onycholysis (separation of the finger/toe nail from the nail bed) is not just a problem among ultra-endurance athletes, but astronauts too. Ill fitting gloves combined with the intra-suit pressure can spell disaster (and pain) for anyone carrying out activities in space, and this would surely apply to the feet as well. After 26 miles of running in cramped space-boots, it can only be expected that runners might lose one or more toenails. To prevent this, it will be necessary for runners to have Mars boots fit to their particular foot size, strike, and biomechanics.

Can They Do It?

Just as Opportunity Rover completed its own Red Planet marathon, so too will humans eventually cover 26.2 miles on foot over the dusty red surface of the fourth planet from the Sun.

Will it be fast? Probably not – but let’s hope we break the current standing record of 11 years, 2 months. Evolving a new, skipping gait required for efficient running on Mars will take some time, just as did the adaptation of lower limbs and body structure of Australopithecus to that of the modern Homo erectus, a body ideally formed for endurance running. Tendons and ligaments will have to adjust to the new microgravity environment, and it will take time for muscle fibers to regain their strength and capacity. The deconditioning of the cardiovascular system (due to fewer hemoglobin molecules, reduced ability to both supply and utilize oxygen, and decline in heart and lung function) will take some time to adapt to. Along with the various environmental factors (extreme cold, hypoxia, and dangerous levels of radiation), runners will certainly have a slow marathon debut.

We will eventually design equipment and training protocols that allow us to traverse 26.2 in record times on Mars. Remember, the first marathon run by Pheidippides resulted in his keeling over in death upon arrival. Since then, we have perfected running tactics, advanced our knowledge of performance, and unlocked human physiology such that it is now possible for man to run 26.2 miles at an astonishing 4 minutes and 41 seconds per mile, something once thought impossible.

Perhaps, some day, the elusive 2-hour barrier will be broken, not on a curated and well-paced course in Italy, but near Endeavor crater, some 54.6 million kilometers away.

References:

  1. Galloway et al. The effects of substrate and fluid provision on thermoregulatory, cardiorespiratory, and metabolic responses to prolonged exercise in a cold environment in man. Experimental Physiology. 81 (1998); 419-430
  2. Norsk et al. Fluid shifts, vasodilatation, and ambulatory blood pressure reduction during long duration spaceflight. The Journal of Physiology 593.3 (2015); 573-584
  3. Shrink-wrapping spacesuits. Jennifer Chu, MIT News Office. September 18, 2014. http://news.mit.edu/2014/second-skin-spacesuits-0918

 

The First Mars Marathon: Part 2

By Brady J. Holmer, @B_Holmer

Unlikely or not, it is interesting to ponder the physiological and technical challenges of a Martian marathon. Read our post from last week to learn why runners will be moving in giant leaps. Stride aside, how will the freezing cold, lack of oxygen, calorie requirements, and protective clothing affect the runners?

Cons of the Mars environment:

Temperature: beyond chilly

Race day conditions can be quite unpredictable even on Earth, and Mars will be no exception. Temperatures can vary from a moderate 70˚ F (20˚ C) around noon to an unbearable -195˚ F (125˚ C) at night. For the sake of this thought experiment, let’s assume that race day temperatures hover around the average of -67˚ F (-55˚ C).

At this temperature the blood vessels in many organs and leading to the skin will undergo profound constriction, reducing blood flow to areas where the runners don’t need it (that is, everything but the legs, brain, lungs, and heart). This conserves heat and maintains core body temperature as close to normal as possible.

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Average race day temperatures at select endurance races.

Authors of a classic 1998 paper in Experimental Physiology demonstrated that this constriction can occur even at a “mild” temperature of 45˚F (7˚C) for just 90 minutes (1).

Exaggeration of this physiological response in instances of extreme cold (i.e. Mars) would occur due to a condition called non-freezing cold injury (2). Symptoms include damage to vascular tissue and heightened constriction of blood vessels. This means runners will have trouble providing oxygen-rich blood to their working muscles which will be in competition with the core to maintain a survivable temperature. Frostbite on Mars sounds disproportionally painful.

Another main concern of extreme cold exposure will be the detrimental effects of shivering thermogenesis, the body’s involuntary quivering of muscles to produce heat in an attempt to maintain core body temperature. To do this, the body must use fuel sources such as carbohydrate and fat. This also occurs at even relatively “mild” cold temperatures.

A study appearing in a 2005 issue of The Journal of Physiology exposed a group of men to a temperature of 41˚F (5˚C) for just 90 minutes and showed that utilization of glucose and glycogen increased five-fold from normal resting conditions (3). Muscle glycogen, our stored form of carbohydrate, contributed up to 60% of the total increase in heat production during just moderate-level shivering.

Exposure to Mars level cold would exacerbate these effects in runners and lead to a sacrifice of valuable fuel stores in an attempt to stay warm, leaving little for the marathon effort. In a race over 2 hours such as the marathon, fuel partitioning is key, and glycogen stores become important late into the race. Without fuel to provide energy for muscle contractions, performance will inevitably suffer, even if proper nutrition and “carbo-loading” are implemented.

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Solar particle events will lead to a destruction of valuable red blood cells in space.

Oxygen deprivation in the air

Given the vast difference in the composition of the air, breathing on Mars will also be difficult.  The atmosphere of Mars is 95% carbon dioxide (CO2), meaning there is very little oxygen. Normally, CO2 is produced during high intensity exercise such as marathon running, but is counteracted by expiration, preventing accumulation of acidifying ions and the ensuing unpleasant burning feeling in the lungs and legs. In this regard, Mar’s atmospheric gas composition presents an ideal situation for the lung-torching turmoil that all runners fear late into the end miles of a marathon, although now, this will occur from the start. Even the most rigorous altitude training regimen won’t prepare Martian runners for the low-oxygen conditions they will experience. Well-designed spacesuits will need to be implemented to allow runners to inhale a gas composition that resembles one on Earth, while simultaneously helping to expire CO2 at a higher rate than usual.

Wreaking havoc with red blood cells

Let’s not forget about the radiation. Mars’ atmosphere is less dense than the Earth (approximately 100-fold less so), and radiation from the sun is much more potent. Spontaneous and largely unpredictable solar flares that decide to pop up during the marathon will send charged helium nuclei, neutrons, protons, and other dangerous and highly energetic particles coursing through the runner’s bodies. Exposure to one of these solar particle events during the Mars marathon would lead to the destruction of red blood cells (hemolysis) and along with it, the all-important, oxygen carrying hemoglobin molecules, oxidative stress, and damage to muscle fibers.

Runners will likely fall victim to a condition we might call “space anemia”. A study in Physiological Reports from 2017 investigated the response of the circulation to a head down tilt bed rest condition – used to simulate microgravity encountered in space – and found that it resulted in a loss of hemoglobin  (4)! Hemoglobin is necessary to carry oxygen to sites of active muscle during running, and a reduction  is associated with a lower exercise capacity.

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Aerobic capacity and power will both decline after just 15 days in space.

Reduced circulation

Circulatory changes may be further exacerbated by the well-known detrimental effects that microgravity has on aerobic capacity. Indeed, researchers have used a model of sustained bed rest further compounded by low-oxygen space environments such as Mars, to investigate the effects on cardiovascular capacity.

Keramidas et al. demonstrated in a 2017 Experimental Physiology paper that just 10 days in this space-simulating condition impaired whole-body peak oxygen uptake (VO2peak) by 8% with an accompanying reduction in peak power output during an exercise test (5).

Furthermore, in 2018, Salvadego et al demonstrated in The Journal of Physiology that 21 days of hypoxic bed rest led to an 8% reduction in V02peak, a reduction in thigh muscle volume, and impairments in the body’s production of energy (mitochondrial respiration and aerobic metabolism) and an ability to match oxygen supply to demand during leg exercise (6).

These changes lead to a reduction in aerobic performance – and Mars runners will fight against all of these pathological changes as they try and complete the race as they find themselves starved of the ability to get crucial, oxygen rich blood to their working muscles during the race. This means that runners will be less capable of performing at their max capacity on race day.

So far, the prospects are looking quite grim for the runners. Will nutrition or protective suits be their saving grace? Find out on Friday in the final blog of our series.

References

  1. Weller et al. Physiological responses to moderate cold stress in man and the influence of prior prolonged exhaustive exercise. Experimental Physiology. 83 (1998); 679-695
  2. Tipton M.J. Environmental extremes: origins, consequences, and amelioration in humans. Experimental Physiology 101.1 (2016); 1-4
  3. Haman et al. Partitioning oxidative fuels during cold exposure in humans: muscle glycogen becomes dominant as shivering intensifies. The Journal of Physiology 566.1 (2005); 247-256
  4. Trudel et al. Hemolysis during and after 21 days of head-down-tilt bed rest. Physiological Reports. 5.24 (2017)
  5. Keramidas et al. LunHab: interactive effects of a 10-day sustained exposure to hypoxia and bedrest on aerobic exercise capacity in male lowlanders. Experimental Physiology 102.6 (2017); 694-710
  6. Salvadego et al. PlanHab: hypoxia does not worsen the impairment of skeletal muscle oxidative function induced by bed rest alone. The Journal of Physiology 000.00 (2018); 1-15

The First Mars Marathon: Part 1

By Brady J. Holmer, @B_Holmer

Humans have successfully conquered herculean feats of endurance in some of the most unbearable conditions on Earth. Such conquests as the Badwater Ultramarathon, 135 miles (217 km) through Death Valley, where temperatures can reach 130˚ F (54˚ C), or the 100k Antarctic Ice Marathon (average wind-chill -4˚F (-20˚ C)) not only require a certain amount of mental fortitude (some might call it insanity), but also careful consideration of human physiology and its inherent limits. Unpreparedness for such harsh climates can spell disaster; Mother Nature isn’t merciful to those who are ill-prepared. In tests of extreme endurance, environmental conditions, and the body’s response to those conditions, can be the dividing line between successful completion of the race and  a certain meltdown.

It is unlikely that humans will ever lose their aspiration to push the limits of human physiology through feats of endurance. Given humanity’s recent interest in colonizing planets other than our own, it seems likely that our sporting and recreation habits will make their way out into the cosmos.

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Images from http://alpacaengine.com/mars-landscape/ ; https://runningmagazine.ca/elite-qa/eliud-kipchoge-loves-running/ Photo: Nike 2018, Bejo Creative Theme 2018.

Indeed, Tesla CEO and Mars colonization proponent Elon Musk thinks that exploring new planets isn’t just a choice we have, but a necessity, and projects that the first manned trip to Mars will leave no later than the year 2020 (1).  Should we colonize Mars, humans will have stay active to prevent muscular atrophy, deconditioning, and boredom. Eventually, someone will have the crazy idea to try a marathon on the newly colonized Red Planet.

However sci-fi this situation may seem, it is interesting to ask what physiological and technical challenges a Martian marathon would provide. Will the vast climactic differences between Mars’ atmosphere and our own prove insurmountable? Will the elite road runners of our modern time be reduced to hobby joggers in the extreme climate? Or, perhaps even more tantalizing, will this novel atmosphere allow us to finally run a marathon under two hours? Let’s explore the physiology of humankind’s first marathon on Mars.

It may be important to note that the first Mars marathon has been completed, although not by a human. On Tuesday, March 24, 2015, Mars exploration Rover “Opportunity” completed the 26.219-mile (42.195k) journey across the Red Planet’s surface (2). Opportunity’s performance was quite mediocre, finishing in approximately 11 years and 2 months (a speedy pace of 222,000 minutes per mile). Let’s hope humans can improve on the current record.

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The first marathon route completed on Mars. Source: Mars.nasa.gov, Nasa 2015

Fortunately, thanks to Opportunity, we have a perfectly measured course, and the Red Planet marathon will follow the same route, putting the finish tape at the rim of Endeavor crater. On this journey, how will environmental conditions be different, and what adjustments will be required to nutrition and protective clothing? Stay tuned to find out.

The Martian environment

Will the environment on Mars be conducive enough to run, much less perform well in, a marathon, even for the most battle-hardened endurance veterans? Various factors about the climate, both positive and negative, affect physical capacity and physiological response.

Pros: A giant leap for mankind

One benefit, taking nothing else into account, is that runners will be lighter on Mars. Martian gravity is a little less than one third that of the Earth, so a man or woman weighing 154 pounds (70 kilograms) on Earth will weigh a mere 51 pounds (23 kilograms) on Mars. Many of the top-100 world class marathon runners typically weight around 123 pounds (56 kg) – so if we forget about the danger of “floating away” for a moment– this puts Martian runners way below the “elite” weight class.

Weight reduction will dramatically increase V02max (maximum oxygen use, which measures exercise capacity) relative to body weight without any training required! The transition to partial gravity will cause an immediate 67% increase in relative V02max. Compared to changes seen in an Experimental Physiology study in which V02max increased only around 9% after 6 weeks of aerobic exercise training (3), this is quite the shortcut.

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Source: Wikimedia Commons, NASA/JPL/Cornell

 

Another beneficial change upon arrival to Mars will have to do with the biomechanics of running.  Even if we design aerodynamic spacesuits which provide ample range of motion and reduce mass as much as possible, human locomotion will differ substantially; our running will look more like skipping, in fact. Apollo astronauts discovered the benefits of skipping on the Moon. A bouncing gait in the low-gravity conditions on Mars will also be preferred to walking and running since it leads to a threefold reduction in cost of movement. In addition to reducing work, skipping enhances grip control, which will be helpful on Mars’ surface. Covered by in “lunar dust”, it provides little in the way of friction.

Stride rate, typically 150-160 steps per minute for a marathon runner, will dramatically fall on Mars. This is mainly due to the large vertical displacement and increased time spent in the “flight” phase while skipping. Airborne time while running will be 80% longer in duration than on Earth, and stride length approximately 3 times as long. On Earth, the average stride length is 54 and 74 inches (1.3 to 1.8 meters) for men and women, respectively. This means that Martian marathoners will travel around 13.5 to 18.5 FEET (4 to 5.5 meters) per stride. Compare that to Usain Bolt, who has a stride length of about 7 feet (2 m). Talk about a “giant leap for mankind.”

The above changes, resulting in only a decrease in work and slight increase in biomechanical efficiency, may be the only beneficial alterations in running physiology on Mars – and it might look quite funny. Indeed, where gravity gives runners a benefit, the other environmental factors on Mars will all work against running a fast marathon.

Check back next week to learn how the freezing temperatures, and lack of oxygen impact the marathoners, as well as how they’ll fuel up and what they will wear.

References

  1. Elon Musk Has a New Timeline for Humans Living on Mars. June Javelosa. February 19, 2017. https://futurism.com/elon-musk-has-a-new-timeline-for-humans-living-on-mars/
  2. NASA’s Opportunity Mars Rover Finishes Marathon, Clocks in at Just Over 11 years. NASA release 15-049. March 24, 2015. https://www.nasa.gov/press/2015/march/nasas-opportunity-mars-rover-finishes-marathon-clocks-in-at-just-over-11-year
  3. Montero et al. Haematological rather than skeletal muscle adaptations contribute to the increase in peak oxygen uptake induced by moderate endurance training. The Journal of Physiology. 593.20 (2015); 4677-4688

Can ketones lower blood sugar, and thus help diabetes?

By Jonathan Little (@DrJonLittle) and Étienne Myette-Côté, University of British Columbia

Low-carbohydrate, high-fat ketogenic diets are gaining popularity as a treatment option for type 2 diabetes because when someone eats less carbohydrates their blood sugar remain low. The diet is named after ketone bodies, compounds that the body produces when someone restricts their carbohydrate intake to very low levels.

Now, new ketone supplements that come in liquid or powder form claim to offer some of the benefits of a ketogenic diet without having to follow such a strict diet. Essentially, they allow you to drink ketones instead of relying on your body to produce them naturally. The appeal is obvious: lifestyle interventions like a ketogenic diet are hard to stick to over the long term. However, these supplements are also interesting for us physiologists because when someone eats a ketogenic diet, so many metabolic changes happen at the same time that it’s difficult to pinpoint which change caused which effect. Using ketone supplements can allow us to study the effects of ketones specifically.

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Image from- https://www.prevention.com/food-nutrition/a20483336/keto-diet-facts/

Unfortunately there is very little research on ketone supplements, particularly their impact on blood sugar or outcomes relevant to diabetes. To begin to fill this gap in knowledge, our recent research in The Journal of Physiology studied the effect of ketone supplements in healthy adults.

Introducing the ketone star: β-OHB

The most abundant and important ketone body produced by the liver during a ketogenic diet is called beta-hydroxybutyrate (β-OHB). β-OHB can be used as an alternative fuel to carbohydrates by some parts of the body including the brain, heart and muscles. In recent years, β-OHB has garnered substantial media and research attention: studies in cells and animals have shown that β-OHB has glucose lowering, anti-inflammatory, anti-oxidant, and even lifespan-extending effects (1, 2, 3, 4).

In humans, it is difficult to determine the effects of β-OHB itself due to the myriad of physiological and hormonal changes that occur when somebody follows a restrictive ketogenic diet. The first answers come from studies where researchers have infused ketones directly into the blood of participants – like with a drip feed. Several of these studies conducted over the last few decades have consistently observed that when you infuse β-OHB directly into the bloodstream of humans, their blood sugar drops (5, 6).

Although the infusion method provides insight, it lacks therapeutic application: it would be impractical to keep patients with diabetes on a ketone drip in an attempt to lower their glucose. With the blood sugar-lowering effects of β-OHB infusion having been consistently observed in the past, we became interested in studying whether the newly-developed ketone supplements might lower blood sugar levels in humans.

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It would be impractical to keep patients with diabetes on a ketone drip.

Do ketone supplements lower blood sugar in humans?

Given that this was the first study (to our knowledge) to directly test this, we started by studying young healthy individuals. We recruited 20 healthy participants (10 males and 10 females, aged between 21 and 29 years) who underwent two oral glucose tolerance tests. This test involves drinking a large quantity of sugar (pure glucose) and measuring blood sugar at several time points afterwards to assess changes in blood sugar level. This test can also be used to diagnose diabetes.

One oral glucose tolerance test was performed 30 minutes following the consumption of the ketone supplement and one was performed after consuming a masked placebo. The order was random – some took the ketone supplement first and some the placebo first – and both the participants and study personnel performing the laboratory analyses were blinded, meaning that they did not know whether the participant had taken the ketone supplement or placebo.

The ketone supplement raised blood β-OHB to just over 3 mM within 30 min, levels normally seen after many weeks on a ketogenic diet or several days of fasting. This suggests that the supplements might be a good method to get β-OHB into the blood, without the hassle of a drip. When we then looked at the spike in blood sugar in response to the oral glucose tolerance test, it was much lower after drinking the ketone supplement compared to the placebo condition. Specifically, when plotted on a graph the area under the curve was decreased by ~16% when participants had the ketone supplement. Additional metabolic benefits of the ketone supplement were a reduction in levels of fatty acids circulating in the blood and an improvement in insulin sensitivity. Thus, consuming a ketone supplement was able to improve aspects of glucose regulation in healthy humans.

This study in healthy humans raises the obvious question of whether the same effects could be seen in individuals with elevated blood sugar, such as individuals with type 2 diabetes, prediabetes, or obesity.

It is not clear if our results will carry over to people with these diseases. However, a major reason for high blood glucose in type 2 diabetes is that the liver is constantly “leaking” too much glucose into the circulation. If the ketone supplement prevents this, which is what we think happens, then ketone supplements might indeed be helpful for diabetes; it’s now up to future studies to build on our findings and hopefully find the answer!

References:

  1. Madison, L. L., Mebane, D., Unger, R. H., & Lochner, A. (1964). The hypoglycemic action of ketones. II. Evidence for a stimulatory feedback of ketones on the pancreatic beta cells. The Journal of clinical investigation, 43(3), 408-415.
  2. Youm, Y. H., Nguyen, K. Y., Grant, R. W., Goldberg, E. L., Bodogai, M., Kim, D., … & Kang, S. (2015). The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease. Nature medicine, 21(3), 263.
  3. Shimazu, T., Hirschey, M. D., Newman, J., He, W., Shirakawa, K., Le Moan, N., … & Newgard, C. B. (2013). Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science, 339(6116), 211-214.
  4. Edwards, C., Canfield, J., Copes, N., Rehan, M., Lipps, D., & Bradshaw, P. C. (2014). D-beta-hydroxybutyrate extends lifespan in C. elegans. Aging (Albany NY), 6(8), 621.
  5. Mikkelsen, K. H., Seifert, T., Secher, N. H., Grøndal, T., & van Hall, G. (2015). Systemic, cerebral and skeletal muscle ketone body and energy metabolism during acute hyper-D-β-hydroxybutyratemia in post-absorptive healthy males. The Journal of Clinical Endocrinology & Metabolism, 100(2), 636-643.
  6. Miles, J. M., HAYMOND, M. W., & GERICH, J. E. (1981). Suppression of glucose production and stimulation of insulin secretion by physiological concentrations of ketone bodies in man. The Journal of Clinical Endocrinology & Metabolism, 52(1), 34-37.
  7. Taggart, A. K., Kero, J., Gan, X., Cai, T. Q., Cheng, K., Ippolito, M., … & Jin, L. (2005). (D)-β-hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. Journal of Biological Chemistry, 280(29), 26649-26652.
  8. Reaven, G. M., Chang, H. E. L. E. N., Ho, H. E. L. E. N., Jeng, C. Y., & Hoffman, B. B. (1988). Lowering of plasma glucose in diabetic rats by antilipolytic agents. American Journal of Physiology-Endocrinology and Metabolism, 254(1), E23-E30.
  9. Ferrannini, E., Barrett, E. J., Bevilacqua, S., & DeFronzo, R. A. (1983). Effect of fatty acids on glucose production and utilization in man. The Journal of clinical investigation, 72(5), 1737-1747.
  10. Balasse, E. O., Ooms, H. A., & Lambilliotte, J. P. (1970). Evidence for a stimulatory effect of ketone bodies on insulin secretion in man. Hormone and Metabolic Research, 2(06), 371-372.
  11. Senior, B., & Loridan, L. (1968). Direct regulatory effect of ketones on lipolysis and on glucose concentrations in man. Nature, 219(5149), 83.

 

Tight squeeze: a new way to get larger drugs into the brain

by Michelle Pizzo & Robert Thorne, University of Wisconsin Madison, USA

The brain and spinal cord are a difficult body parts to fix. Only seven percent of drugs for diseases of the brain and spinal cord succeed, whereas fifteen percent of drugs for other parts of the body do (1). New research published in The Journal of Physiology may have found part of the solution: a method for getting bigger drugs into the brain.

The issue is, in part, that we still lack a detailed understanding of the complicated structure and physiology of the brain’s cells and fluids, including the communication between the cells and fluids (2). This limited knowledge has further compromised our understanding of the delivery and distribution of drugs in the central nervous system (brain and spinal cord, abbreviated as CNS), particularly for large-molecule drugs (bigger than about one nanometer) which are unable to cross the blood-brain barrier to reach the brain tissue.

A tight fit: getting big antibody drugs into tiny brain spaces

Among the best examples of promising large-molecule therapeutics are antibodies, the weapons of our immune system. They work by recognizing a part of a molecule (called an antigen). Indeed, five of the top ten drugs by revenue are antibodies (3).

Besides being great potential drugs, antibodies are very abundant in the fluid that bathes the brain and spinal cord (called cerebrospinal fluid, or CSF) (4). Antibodies in the CSF may play an important role in the brain’s immune system and contribute to central nervous system autoimmune disorders (like multiple sclerosis) that cause our immune system to attack our own body.

Because antibodies (and other large-molecule protein therapeutics) are 10 times the size of small-molecule drugs, it has long been thought that their distribution in the brain will in most cases be much more limited than small-molecule drugs (5).

However, a recent study published in The Journal of Physiology from the University of Wisconsin-Madison by Michelle Pizzo, Robert Thorne, and their colleagues (6) has uncovered an unappreciated key mechanism governing antibody transport within the CNS that may ultimately allow these big proteins to access much more of the brain from the CSF than previously thought.

This has important implications as there are numerous clinical trials that are ongoing in the United States for treatment of brain cancers with antibody drugs.

Go with the flow: using the fluids of the brain for antibody drug delivery

Injecting antibodies of two different sizes into the CSF of rodents, the researchers found two main mechanisms of transport—1) slower movement (called diffusion) in between the tightly packed brain cells, and 2) quicker transport along tubular spaces around blood vessels, (called perivascular spaces) (6).

As expected, they found that the slower movement of these large molecules by diffusion was quite limited, whereas the smaller antibodies penetrated further. Aspects of the quicker transport around the blood vessels appeared to be independent of size; both the smaller and larger antibodies could reach deep into the brain along the walls of blood vessels in a short amount of time.

This is great news for the CSF delivery of biotherapeutics, including protein drugs like antibodies. The quicker perivascular flow along these tubular pathways is thought to exist in humans, so such flows are likely translatable/scalable to the clinic. Slower, diffusive transport, on the other hand, does not scale across species. In other words, if effective drug diffusion is limited to a distance of one mm in the rat brain, it will also be limited to one mm in the much larger human brain. This distance may not be enough to treat most brain diseases.

Pizzo1

A large, full-size antibody protein (green) infused into the fluid bathing the brain (cerebrospinal fluid) reaches deep into the brain along the spaces around blood vessels (red). Nuclei of all the brain/blood vessel cells are labeled in blue. (Photo credit: Michelle Pizzo)

They also found that the smaller antibody was able to get into more of these tubular perivascular spaces compared to the larger antibody, which meant a significantly poorer overall delivery was obtained for these full-sized antibodies. Two questions arose from this finding—1) what barrier is causing this size-dependent entry into the perivascular space, and 2) can the barrier be altered to improve delivery?

Let me in: identification of a new barrier between the CSF and brain and a strategy to open it

Pizzo and her colleagues found that a layer of cells wrapping around blood vessels on the surface of the brain, between the CSF and the perivascular spaces, is a likely candidate for the size-dependent barrier.

They suggested that pores or openings in these cells may contribute to a sieving effect, allowing smaller molecules into the perivascular space but making entry more difficult for larger molecules. A method that has previously been used to open cell barriers is to administer a hyperosmolar (which more or less means, concentrated) solution that makes these cells give up their water to dilute the surrounding solution. Thus the water exits the cells (by osmosis) and causes them to shrink, allowing gaps between cells and pores in the cells to open. Pizzo and colleagues then reasoned that if they were to administer this solution into the CSF, the larger antibodies would enter the perivascular spaces better.

This is essentially what they found; the larger antibody had significantly greater access (about 50%) to the perivascular spaces when it was delivered into the CSF with a hyperosmolar solution.

Numerous studies of protein drugs administered into the CSF are ongoing for brain cancer and childhood metabolic diseases that affect the brain (called neuropathic lysosomal storage disorders). Thus, an improved understanding of how these large molecules move through the brain is critical.

This new research has shed light on how these antibodies use different types of transport to move between the CSF and the brain in rodents, revealing that fast perivascular transport can reach deep into the brain and may offer the best hope for translation to humans.

Even more exciting is their new hypothesis for the cellular barrier that may regulate entry into these perivascular spaces. Manipulating this ‘barrier’ could lead to improved methods for delivery of drugs to the brain and spinal cord.

References

  1. Pangalos MN, Schechter LE, Hurko O (2007) Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov 6(7):521–32.
  2. Thorne RG (2014) Primer on Central Nervous System Structure/Function and the Vasculature, Ventricular System, and Fluids of the BRain. Drug Delivery to the Brain: Physiological Concepts, Methodologies, and Approaches, eds Hammarlund-Udenaes M, de Lange E, Thorne RG (Springer-Verlag, New York), pp 685–707.
  3. Lindsley CW (2015) 2014 global prescription medication statistics: strong growth and CNS well represented. ACS Chem Neurosci 6(4):505–506.
  4. Davson H, Segal MB (1996) Physiology of the CSF and blood-brain barriers (CRC Press).
  5. Wolak DJ, Thorne RG (2013) Diffusion of macromolecules in the brain: implications for drug delivery. Mol Pharm 10(5):1492–504.
  6. Pizzo M, et al. (2017) Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport, and osmotic enhancement of delivery. J Physiol:Accepted manuscript.

Exercise, stress and Star Wars: Best of 2017 roundup

Happy New Year! In 2018, we look forward to more physiology fun, and to giving you an insight into the exciting new developments in the Science of Life!

Physio-what, you ask? Take a look at our animation below introducing physiology! Scroll down to find out more about a centuries-old shark patrolling the deep Arctic Ocean, how being active gives children’s hearts a head start for life, and why it’s time scientists took back control from exercise gurus, in our best of 2017 roundup!

1. Exercise scientists should fight the exercise gurus

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Exercise gurus build strong rapports with their audience to encourage commitment, but they will often simplify a large body of scientific evidence to back up their advice.

In this post, Gladys Onambele-Pearson and Kostas Tsintzas discuss the risks of letting exercise gurus disseminate exercise science to the public, and why it may be time for scientists to become the actual celebrities.

2. The Myth of a Sport Scientist

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There is a mismatch between the perceptions and reality of what a sport scientist is and what skills this career entails: just because exercise scientists use models of sport performance, exercise bouts or physical activity sessions, doesn’t mean that there aren’t complex scientific skills, theories, analytics and techniques behind the work.

Read more from sport scientist Hannah Moir in this post.

3. Shark Diary, Episode I: On the trails of the Greenland shark

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How do you keep lab chemicals cool when there’s no fridge in your room? Well, if you’re in chilly Denmark, you could just hang them outside your window.

Holly Shiels did just that in Copenhagen, on her way to Greenland to join a team of physiologists on a shark research mission. Their aim was to gather data on the physiology of the Greenland shark. Clarifying how these animals reach hundreds of years of age without developing diseases associated with human ageing, like cancer and heart disease, could lead to new therapies down the line, and understanding shark physiology is also important for their conservation.

Read more about the mission in this post, and check out watch below to see the researchers braving the icy waters of the North Atlantic and releasing a tagged Greenland shark.

4. Breath of the Sith: a case study on respiratory failure in a galaxy far, far away

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Have you always wondered what actually is going on behind the mask? Darth Vader’s acute respiratory failure appears to be the consequence of a number of factors, including direct thermal injury to the airways, chemical damage to the lung parenchyma caused by inhalation of smoke and volcanic dust particles, carbon monoxide poisoning, as well as secondary effects to his severe third degree burns, which seems to cover ~100 % of his total body surface area.

Read on as Ronan Berg and Ronni Plovsing make a tongue-in-cheek diagnosis of the numerous respiratory ailments of everyone’s favourite Sith Lord.

5. Exercise now, thank yourself later

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Exercise is good for the heart, but the benefits fade soon after we stop training… or so we thought. Studies so far have focused on adults, but research published last November in The Journal of Physiology reveals that exercise in early life could have lifelong benefits for heart health.

This is because young hearts are able to create new heart muscle cells in response to exercise, an ability that is mostly lost in adulthood. Glenn Wadley, Associate Professor at Deakin University and author of the study, explains the findings in this post, and makes the case for children to get active!

As if that wasn’t enough reason to exercise, being active is one of three tips that can help relieve the stress we feel for instance at the approach of exams. Watch our animation below to find out more about what stress does to our bodies, and start making good on those New Year resolutions!

Exercise now, thank yourself later

by Glenn Wadley, Associate Professor, Institute for Physical Activity and Nutrition (IPAN), Deakin University, Australia.

Endurance exercise and healthy hearts

A wealth of evidence shows that physical activity helps prevent heart disease and all causes of mortality (1) and has benefits for the heart at any age (2): aerobic exercise – often referred to as ‘cardio’ – and in particular endurance-training, is beneficial to the heart. But these effects – in adults – are only temporary and lost soon after training is stopped (3-5). Because of this, it has been assumed until now that the beneficial effects of exercise for the heart are also temporary for young and adolescent mammals, including humans.

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The athlete’s heart – when big is beautiful

Moderate levels of endurance exercise training improve the structure and function of the heart, and makes it grow larger, resulting in what is called athlete’s heart, or physiological cardiac hypertrophy (3-5). This larger heart is beneficial and quite distinct from the enlarged hearts observed in disease, which display reduced function, and increased scarring and molecular and structural differences, in addition to heart failure and increased mortality (6). In contrast, athlete’s heart can improve quality of life, since people with a physiologically healthy, bigger heart will pump more blood and thus can train harder at any given age (7). This effect is of particular benefit as adults get older.

The workhorse cells of the body – cardiomyocytes

 In the heart, specialised muscle cells do the heavy lifting: they are called cardiomyocytes, and are highly resistant to fatigue. The adult human heart contains several billion cardiomyocytes and their coordinated contraction produces around 100,000 heartbeats per day, every day.

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Cardiomyocytes up close.

Until recently, we thought that the number of cardiomyocytes in mammals’ hearts was fixed shortly after birth. Adult cardiomyocytes don’t get renewed or multiply much, so we thought that the heart grew larger in response to training because the existing cardiomyocytes grew larger, rather than because there were more of them.

However, our recent study has established that an increase in cell number also plays a considerable role in cardiac growth in response to just four weeks of moderate intensity exercise, if the training is conducted during juvenile life, which is 5-9 weeks of age for a rat. This training period would be equivalent to late childhood and puberty in humans. We also found that this effect of exercise on cell number diminishes with age and is lost by adulthood. Indeed, when the same exercise training program is conducted in adolescent rats (11-15 weeks of age, or around the time of late puberty and reproductive maturation in humans), there is a much smaller impact on cardiomyocytes multiplying. In adult rats, heart mass and cardiomyocyte size still increase following exercise training, but without any increase in cardiomyocyte number. Clearly, endurance exercise is beneficial for the heart at any age, but it appears that a window of time exists in the younger heart whereby exercise might be able to grow more cardiomyocytes.

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With regards to the benefits of juvenile exercise for the heart, perhaps the most compelling finding is that the increased heart mass and around 40% increase in cardiomyocyte number remain well into adulthood. What’s more, this increase in cell number is sustained despite the rats being couch potatoes for a prolonged period of time – the equivalent of 10 years in humans! Having more cardiomyocytes potentially makes the heart better equipped for the structural and functional challenges of adult life. For example, in the UK, the 915,000 survivors of heart attack (8) are left with a heart containing up to 25% fewer cardiomyocytes (9) that are not replaced, along with a large degree of scarring and fibrosis. Thus, having more cardiomyocytes saved up for a rainy day could be a handy reserve if you are unfortunate to suffer a cardiac event.

There are already plenty of good reasons to exercise regularly and we know exercise is beneficial for heart health at any stage of life. However, should these recent findings translate to humans they would provide a new reason to ensure there are sufficient opportunities for children to engage in regular physical activity in school curricula. Importantly, our research suggests that there may be long-term cardiac benefits of physical activity for all children, even if the children do not continue with regular exercise in adulthood. Unfortunately, we know the majority of children do not meet physical activity recommendations (10) and therefore their hearts may be missing out on the best start to life.

References:

  1. G. Erikssen, Sports medicine (Auckland, N.Z), 2001, 31, 571-576.
  2. S. Lachman, S. M. Boekholdt, R. N. Luben, S. J. Sharp, S. Brage, K. T. Khaw, R. J. Peters and N. J. Wareham, Eur J Prev Cardiol, 2017, DOI: 10.1177/2047487317737628.
  3. O. J. Kemi, P. M. Haram, U. Wisloff and O. Ellingsen, Circulation, 2004, 109, 2897-2904.
  4. R. C. Hickson, G. T. Hammons and J. O. Holloszy, Am J Physiol, 1979, 236, H268-272.
  5. D. S. Bocalini, E. V. Carvalho, A. F. de Sousa, R. F. Levy and P. J. Tucci, Eur J Appl Physiol, 2010, 109, 909-914.
  6. B. C. Bernardo and J. R. McMullen, Cardiology clinics, 2016, 34, 515-530.
  7. R. J. Shephard, British journal of sports medicine, 1996, 30, 5-10.
  8. British Heart Foundation, BHF CVD Statistics Factsheet – UK, https://www.bhf.org.uk/statistics
  9. M. A. Laflamme and C. E. Murry, Nature, 2011, 473, 326-335.
  10. Australian Bureau of Statistics, Australian Health Survey: Physical Activity, 2011-12. 2013. http://www.abs.gov.au/AUSSTATS