Author: rgbryanjr

I’m reading a lot about hormesis and I think it is an interesting lens to look at improving on multiple medical problems.  I’m going to throw out some hypotheses just cause I’m thinking a lot about it.  Would love thoughts on applying the hormetic idea to other issues in the comments.

Hormesis is the stimulation of a beneficial, physiologic response after exposure to mild stress from a source normally thought of as harmful.  The most well known example would be physical exercise.  We go and lift weights and/or run to induce a cellular response to the stress, resulting in a positive impact on the body.  What is routinely glossed over is the stress that exercise places on the body.  Physical exercise results in a 20x increase in respiration in the body’s mitochondria  to produce the energy needed to do work.  This has serious negative implications, increasing the production of harmful substances such as reactive oxygen and nitrogen species, other free radicals, acids, and aldehydes.

The body has to fire up the detoxification system to remove these harmful molecules, repair DNA that has been damaged by the reactive species, and adapt to the exercise stress.  The time of exercise itself doesn’t produce the majority of positive effects (no, those 250 calories you “burned” aren’t the important part,) it’s the body’s overshooting with the repair mechanisms that results in the net gain.  I think so many people think of exercise as a chance to “burn off” calories/donuts/pasta/beer; however, the benefit of exercise comes at the expense of the increase in metabolism.  We fire up the mitochondria and “burn off” calories (a harmful stress) to get the repair benefits at the DNA and protein production level.  The calorie usage (very small for an hour of exercise in comparison to our resting metabolism) is the price we pay to get all sorts of terrific detoxification enzymes, higher levels of the antioxidant system Glutathione, and DNA repair tools created.  This just struck me as a neat way to think about it, exercise as a dose, a means to an end, not an end in itself.

Why is it important to view exercise this way?  Because Michelle Obama and others believe exercise is a tool to create a caloric deficit.  Is the current trend to fight excess with excess in America and the plan to tackle obesity (in children no less) with increased exercise.  I think the hormetic response curve shows why this logic is flawed.  Almost every stress that induces a hormetic response, like exercise, follow this pattern.


As you can see, the red line is the physiologic response to increasing amounts of stress (exercise).  Above the black, x-axis, there is a benefit to the organism.  Below the x-axis there is net harm.  Increasing amounts of the stress are not necessarily good.  There is a narrow range where the benefits outweigh the harm.  In viewing exercise as beneficial because of the caloric deficit created, you ignore the physiologic balance that must be taken into account, and could end up doing more damage than good.

You can apply this same thinking to other stressors.  For example, my grandpa and I have talked a lot about sun.  He has got me thinking about sun energy as a “dose” that follows a similar hormetic response curve.  Sun is great in small doses, even prevents skin cancer to some degree by revving up DNA repair enzymes in the skin.  What have we done? Slop molecules that become reactive species on our skin, let them intercalate into the DNA, and stay in the sun for excess dose anyway.

Take alcohol, I do think that it is a poison.  However, why has it been repeatedly shown that people that drink 1-2 drinks a day live longer with less disease than abstainers?  Hormesis… The moderate dose of alcohol needs to be dealt with, revving up the detoxifying mechanisms in the liver and creating a net positive response.  This tips in favor of harm as you lean towards higher dose, leading to the harmful effects of alcohol.  Once again we see the hormesis response curve.

What else do you think follows this dose response curve?  Short term fasting, cell phone radiation to the head, periodic gorging on food, sugar exposure?  All little stressors at an optimal dose.  I think it is a neat way of viewing human interaction with the surrounding environment, hormetic response.

The trick is to find that sweet spot, the positive hormetic response brought about where the dose is higher enough but not too high.  I think this is where the heart of the n=1, personal hacking, experiential endeavor into finding your best self lies.

 

On February 23rd everyone across the world that is seeking a medical residency in the US had to certify their ranking list in the order of where they would like to to train for residency.  It marks the end of a long residency application process, but now everyone is waiting in suspense for that mythical, March 17th ‘match day’, including me.

It began on September 1st when applicants sent out their ‘e-apps’ to all of the programs they were interested in.  These things house at least 5 years of test scores, grades, people’s opinions of you, accomplishments, essays, and anything else you could think of.  Applicants then sit around and wait for interview offers to come in.  I have to say interviews that were granted to me appeared to follow absolutely no rhyme or reason.  I realized trying to understand their offers/rejections was like trying to find the end of a black hole and I just took what they gave me.

Interviews occurred from Nov-Jan and were actually really fun. I flew all over the country, including trips to Seattle, Hawaii, Dallas, Boston, North Carolina, and Madison getting to see cool cities and meeting really awesome people on interviews. It was odd because I met great applicants and they were simultaneously my competition and my possible coworker since you don’t know how the match will shake out.

After my last interview on Feb. 7th, I started putting together a list of my favorite radiology programs (years 2-6) and favorite internships (year1).  There was a lot of second guessing and alteration right up until the deadline for certifying my list this past Wednesday.  I’m know proud to say I’m contractually obligated to go where I match.

The National Residency Matching Program (NRMP) began in 1952 as a way to fairly distribute labor (residents) to needy programs (residencies). The algorithm is favored towards applicants so if I rank a place #1 and I’m on their list I’m ‘tentatively’ matched there until/if a person with a higher spot on their list bumps me out.  A detailed explanation can be found here.  I found it interesting that the algorithm was developed by game theory economists who were struggling with a classic problem, getting a group of people to pair off in stable marriages! Here.  Hall’s marriage theorem helps a group marry into the best possible combinations so that the most people will be happy.  Why not leverage that, b-school (hugluk) style, to the residency match.

Anyway, the computer holds that information for three sweet weeks until the great unveiling on Match Day. Well technically, the big computer tells applicants who go unmatched the ‘good news’ 3 days early to try to allow them to fill open spots in the “scramble.”  The “scramble” is handled more like a traditional job search, except it happens over the course of a week.

The NRMP holds a national ‘match’ for all of the available residency spots in the US where everyone in the world participating in the match finds out where they are going to be for residency at the same time.  Individual ceremonies are put on at the different medical schools and can get really crazy given their set up.  For example, at our medical school, all the people participating are gathered in a room at 10 am and told to try and socialize.  You can imagine 220 type A people, on a 21 day ‘lack of control’ diet, trying to chit chat and hold liquor at the same time.  Some do better than others.  The pressure gets turned up when the ‘envelopes’ are passed out at 11 am.  There will be shrieks of joy, blood curling screams, moans mixed with tears, just moans, or, hopefully, pure happiness that doesn’t embarrass you or your neighbor.  I would say that at a US medical school its about a 70% solid happiness, 20% happy shrieks, 10% moan/cry/scream mix.  Varies year to year and with the number of people forwarned that they’ve gone unmatched, relegated to scramble.  Match day will be on Thursday, March 17th and I’ll be streaming it live from this blog site through a hidden webcam in my ‘kiss me I’m Irish’ button…….kidding.

And so I wait, stuck in varying levels of the unique residency purgatory.  I am matching in radiology which offers another unique twist, the preliminary year.  I not only ranked 20 radiology programs but also ranked 10 clinical internships in different places around the country.  I could end up on Oahu for the first year and in Boston for the next 5 for my residency.   On the other hand, I could be in Roanoke, Virginia for my first year and Los Angeles the next five for radiology.  The amount of possible variability only adds to the waiting…

It’s all to be able to be elbow’s deep in that ‘sweet earthly paradise’ of 45k/year as an intern…

 

Check out the stats about successful matching below, from Wikipedia and from 2007.  30% of US MD applicants and 94% of DO applicants don’t match…It has only gotten more competitive as more and more people try to practice in the US.  It can get stressful!

Is a calorie a calorie?

The two pills in the picture from The Matrix provide a great launchpad into a discussion on this topic.

So…Let’s see how deep the rabbit hole goes?

The standard nutrition dogma would have you believe that all calories are created equal. In addition, as long as we keep calories at a certain level we can lose (maintain) weight. But is the number of calories the important part of the story? What about the affect of those calories, how does each unit of energy behave once in the body?

Take our two pills, red and blue.  Imagine both undergoing some standard chemical tests to calculate their caloric content.  Both pills are utilized to the tune of 100 calories.  So we know they are isocaloric and theoretically add the same to energy balance.

Being the dutiful Americans we are, we take each pill as part of our daily diet, staying well below our 1800 calorie  daily limit.  However, once in the body the pills are very different.  The red (100 calorie) pill binds to intracellular machinery, decouples cells’ energy production mechanisms, and kills the cells (surprise…it’s cyanide).  The blue (100 calorie ) pill enters cells and is utilized for energy (fat).  The pills act similarly in calorimetry but have very different metabolic implications.

Why is it any different for food products?  Take a given amount of wheat and beef fat, 100 calories of each have a vastly different impacts on hormonal, metabolic, and epigenetic conditions in the body.  Who cares how they act in a chemical test.

I will touch on a few interesting affects the different types of calories (despite equal caloric amounts) may have once active in the body.

Satiety

Protein and fat can make you feel full longer.  Why? Ignoring the appetite stimulation affect of insulin in response to carbohydrate, satiety is mediated, in part, by the affect of cholecystokinin (CCK).  Secretion of CCK by the I-cells in the gut mucosa is stimulated by fat- or protein-rich food (not carbohydrate calories) entering the small intestine from the stomach.

CCK is thought to make you feel full in a few ways. First, it acts on the CCK1 receptor on the vagus nerve which slows the rate of stomach emptying.  More stuff to stretch your stomach lining equals fullness.  Second, CCK acts on the central nervous system by activating the orexin neurons in the hypothalamus.  When orexin neurons fire, they tell your brain that you have enough energy and can stop eating.  Interestingly, excess glucose (carbohydrate) inhibits the orexin neurons making you eat more.  I see why people binge on cookies, pop, and chips and not fatty steak.

Energy level

The CCK – orexin interaction can also explain the “zone-like” state that people get on a low carb diet.  CCK activates orexins which are important regulators of the sleep-wake cycle and energy.  When firing, orexin neurons make you alert, attentive, and active.  When inhibited, you feel sleepy and sluggish.  Remember, excess glucose is the inhibitor and protein/fat the activator.  People that follow low carb will relate to this having said goodbye to the “mid-morning drag” after giving up their morning cereal.  A protein/fat meal hones your energy level and hijacks the CCK-orexin system to ensure you have focus, energy, and a sharpness to your mental activity.

Hormone Response

The type of calories eaten can affect the hormonal environment in the body as well.  An interesting study from 1997 demonstrated the difference in testosterone levels in young men with differing amounts of dietary fat.  As you can see in the graph below, switching the calorie type had large implications on testosterone levels.  This could be from increased production or decreased sex hormone binding globulin.  Either way, I’m for more T.



This is just one example of how the type of calories can affect the body’s hormonal environment.  I’ve left the low-hanging fruit of insulin/glucagon balance and their affect on appetite to people who have done a better job than I could have.  Please comment if you would like my take on insulin, I’d be happy to oblige.

Inflammation

A paper entitled, “Glucose but Not Protein or Fat Load Amplifies the Cortisol Response to Psychosocial Stress” demonstrates how carbohydrate can facilitate an pro-inflammatory state through increased cortisol.   Excess cortisol is tied to chronic hyperglycemia, insulin resistance, decreased GLUT 4 expression (glucose shuttle), high blood pressure, decreased bone formation, decreased sleep, and an impaired immune system.  All around badness…

I’m a believer of some form of the “inflammation-hypothesis,” which holds a chronic inflammatory state responsible for many of the diseases of today including cardiovascular disease, cancer, and degenerative joint disease.

Conclusions

I’ve provided just some examples of why a calorie is a calorie…right up until it enters the body.  It is precisely because calories act differently in the body that I choose to focus on real, natural foods that are high in fat and protein.

Bacon wrapped turducken courtesy of Bacon Today

So go ahead, take the red pill…

Or, the story can end, you wake up in your bed and you believe whatever you want to believe.

Just be careful what that bed looks like.

Until next post…

Sources

Tsujino N et al “Orexin/Hypocretin: A Neuropeptide at the Interface of Sleep, Energy Homeostasis, and Reward System” 2009

Tsujino N et al “Cholecystokinin Activates Orexin/Hypocretin Neurons through the Cholecystokinin A Receptor” 2005

Volek et al “Testosterone and Cortisol in relationship to dietary nutrients and resistance exercise” 1997

Gonzalez-Bono et al “Glucose but Not Protein or Fat Load Amplifies the Cortisol Response to Psychosocial Stress” 2002

Photo: Artificial Heart  from Abiomed

Happy Valentine’s Day to all!  I thought I’d add to the spirit of the day with a heart-related post.

I came across a very interesting study describing the utilization of different nutrients by the heart titled “Carbohydrate-enriched diet impairs cardiac performance by decreasing the utilization of fatty acid and glucose.”  Abstract here.

The study by Porto et al, concluded that “a high-carbohydrate diet can damage myocardial contractile function by decreasing the cardiac utilization of glucose and fatty acids.”  I interpreted this as the heart basically runs less efficiently when given more carbohydrates as fuel.  I took away four key ideas, which I’ll get to in a second, from this study that provide food for thought.

Looking at the composition of the diets given over 9 days, one group (mice) received the “standard” diet of 39.5% carbohydrate, 8% fiber while the high-carbohydrate group got a 58% carbohydrate diet.  This was interesting to me because I’m guessing many Americans eat a diet that is higher in carbohydrate than this every day.  Contrast this with what I learned in medical school cardiac physiology, that free fatty acids (FFAs) were the “fuel of choice” for the heart.

So the main points of interest for me were:

1) The myocardium that was in the high carbohydrate milieu had decreased expression of lipoprotein lipase (LPL) – This is significant but fairly intuitive.  When fed *carbohydrate* cells turn off their fat burning potential. This is powerful for people to realize that a high carb/low fat diet essentially handcuffs any effort to lose fat while exercising through a decrease in LPL activity.

2) Contractility, the squeezing power of the heart, decreases with higher carbohydrate intake. This follows what I learned in physiology, given inferior fuel, it follows that the muscle won’t work as well.  However, taken a bit further, this has interesting implications for all people in athletics and older patients.

First, having played tennis in high school (while very overweight) and then in college (after losing about 100 pounds with a high fat diet) I can give you an interesting viewpoint.  In high school, I followed the conventional wisdom, sitting down to spaghetti dinners before big matches or hockey games.  I would feel sluggish and “doped” when I had to actually play in the next 24 hours.  In college, I had switch to high fat meals pre-event, and I would feel “on-edge” (in a good way) and full of energy.  It will be impossible to know which was responsible for the change in energy, the weight loss or diet change, but I feel it is interesting anyway.  I gained aerobic capacity without significant training within a few months with just a diet change.

Second, the study lends itself to a hypothesis that a high fat diet may improve contractility in patients with Congestive Heart Failure (CHF).  While taking care of these patients in medical school, I observed physicians who had little to do besides manage symptoms by placing patients on toxic/dangerous drugs to increase pumping function, using drugs to try and slow the decline of cardiac function, or ultimately put in a pacemaker to artificially increase contractile function.  I would be interested to see how CHF patients do on a high fat, low carbohydrate diet, with echocardiography to measure cardiac contractility.

Stay with me for the final two, that I find most interesting…

3) The high carbohydrate group showed decreased GLUT4 mass and glucose uptake. Glucose Transporter 4 (GLUT4) is the insulin-regulated glucose transporter found in adipose tissues and striated muscle that is responsible for insulin-regulated glucose transport into cells. GLUT4 is expressed only in muscle (heart and big guns) and fat cells, the major tissues in the body that respond to insulin (James et al 1988).  So extending the thought to all muscles and fat tissue in the body, a higher carbohydrate diet will lead to less GLUT4 in the membrane of the cells –> less insulin effect in total (insulin resistance) –> decreased usage of blood sugar.  Isn’t that interesting that the carbohydrate that is responsible for insulin release and increased blood glucose also down regulates the receptor that is responsible for removal of the blood glucose?  I would argue that the carbohydrate, insulin, GLUT4, and blood sugar system is there to be used only in certain “feast” times, not daily as seen with the SAD (standard American diet).

4) Last, the higher carbohydrate had impaired expression of the peroxisome proliferator-activated receptor α gene. What’s this PPARα thing? Well, it is a transcription factor, basically an on/off switch for getting DNA expressed into active cellular enzymes, that is present in many tissues including the liver, retina, kidney, heart, muscle, and fat tissue.  Interestingly,  a common class of dyslipedemia drugs and triglyceride-lowering agents (Fibrates) activate the PPARα receptor in the tissues listed above (mainly act on the liver).  This activation of PPARα is known to (Barter et al 2006):

• Increase β-oxidation in the liver (Burn Fat)
• Decrease hepatic triglyceride secretion (Lower Triglycerides)
• Increase lipoprotein lipase activity, and thus increased VLDL clearance (Lower triglycerides and small, dangerous LDL cholesterol)
• Increase HDL (The Awesome Cholesterol)

New research (Hiukka et al 2010) also suggest that “PPARα activation attenuates or inhibits several mediators of vascular damage, including lipotoxicity, inflammation, reactive oxygen species generation, endothelial dysfunction, angiogenesis and thrombosis, and thus might influence intracellular signaling pathways that lead to microvascular complications.”   The badness of diabetes (Heart Attack, Blindness, Kidney Failure, and Neuropathy) is avoided when PPARα is fired up.  It seems like higher-carb diets may result in heart disease, diabetes, a whole host of inflammatory conditions, and stroke.  Not saturated fat and high fat diets…(Thanks Minnesota’s own, Ancel…)

Wait, a higher carb diet did what to PPARα???

And wait, the ADA says : “There is no end in sight to the debate as to whether grains help you lose weight, or if they promote weight gain. Even more importantly, do they help or hinder blood glucose management? One thing is for sure. If you are going to eat grain foods, pick the ones that are the most nutritious. Choose whole grains. Whole grains are rich in vitamins, minerals, phytochemicals and fiber. Reading labels is essential for this food group to make sure you are making the best choices.

I’ll argue the end is in sight…this paper provides an interesting hypothesis as to how carbohydrates are responsible for weight gain, vascular complications, and dyslipidemia.  The results suggest, the last thing we should do for high cholesterol (not a true problem anyway) is to lower our fat intake!

And so…Happy Valentine’s Day.  Be good to your heart, eat fat, lower the carbohydrates, and move your muscles once in a while (muscle contraction moves GLUT4 to the surface of the cell to increase glucose usage.)

Have a great night.