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In a previous essay, Obesity and the Physics of Weight Gain, we explored an immutable law of physics related to the epidemic of obesity: if a person expends more energy than they take in, they will lose weight. Because of this certainty, calories in vs calories out (CICO) has long been used as a model for weight loss. While it is not incorrect, it is incomplete, impractical, and ineffective.

1. Incomplete

a. Not all calories cost the same to process. It takes significantly more energy to digest and metabolize protein than it does carbohydrates or fats. This is known as the thermic effect of food, or said another way, the net caloric increase of eating protein is less than fats or sugars because the body has to work harder to make it useful to itself.

b. The source of calories can affect hormones, and hormones control access to fat. Protein, carbohydrates, and fat have differing effects on insulin, cortisol, and thyroid signaling, which in turn affects how your body processes and stores energy.

c. Calories out is not fixed. When intake drops, the body often lowers energy expenditure, meaning the “out” in CICO goes down even as the “in” decreases.

2. Impractical

a. Calories out is also very difficult to measure accurately and it is constantly changing. Wearable devices that estimate calories burned are often off by 10-40%, and sometimes worse.

b. Most people struggle to properly track their calorie intake, even when trying to do it. The general population tends to underreport their calorie intake by 20-30%, while obese and overweight individuals underreport by closer to 40%. Practically, this means if they report 2,000 calorie intake, it was more likely closer to 2,800.

3. Ineffective

a. It’s not that people don’t know about calories in vs calories out. Everyone has heard it. It’s that it’s essentially impossible to accurately track both sides of the equation, the discrepancy in tracking leads to suboptimal behavior because one assumes they have a larger buffer than they actually do.

b. A person can only ignore hunger signaling for so long, regardless of strength of will.

c. Despite all this knowledge, obesity has been steadily increasing, with the exception of the past year and the introduction of GLP1 receptor agonists (Ozempic, Wegovy, Zepbound, etc.)

This is all to say that using the CICO model to pursue weight loss is only minimally helpful at best. Calories are descriptive, but not prescriptive.

So we’re not going to discuss the physics of weight gain/loss, but everything else that affects weight loss in an attempt to reach a useful and effective model for weight loss.

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Hunger as a Signal

The hardest part about losing weight is fighting off feelings of hunger. It’s not easy, but understanding what your body is communicating to you is essential. The key to weight loss is not obsessively counting calories or building up the willpower to constantly push through discomfort, but in learning how to properly manage hunger.

Your body (meaning the collection of cells and more importantly, organs) has limited methods to communicate needs or warnings to the part of your nervous system consciously in charge of executive decision-making. For example, pain is a signal indicating injury of some sort is taking place. What is hunger signaling?

We commonly say, “I’m hungry,” implying that we want to eat. But that is a simplistic mistranslation. Hunger is a far more nuanced and layered signal. It’s the body communicating, in its limited way, that something is lacking.

For starters, in can imply a true energy need. You have expended more energy than your body can easily access, and it’s asking for a refueling. But if your calorie needs have been met, it could be signaling that macro- or micro- nutrient needs have not. You may have enough energy availability, but insufficient amino acid (the building blocks of protein) availability. If you’re hungry right after eating, craving “real food”, or snacking without satisfaction, it likely means your diet is incomplete, not in the amount of energy, but in other nutrients that your body needs to carry out the range of metabolic processes that keep you alive. You are likely missing a significant amount of certain vitamins or nutrients, and eating more of food that lacks those nutrients won’t fill the void. It will, though, result in excess energy being stored as fat in unflattering areas of your body.

Feelings of hunger could also be alerting you to blood sugar instability. Blood sugar rises after eating in proportion with the amount and type of carbohydrates and to a lesser extent, protein. A meal high in simple or rapidly absorbed carbohydrates will cause a greater increase in blood sugar, which prompts your body to deploy insulin, telling liver, fat, and muscle cells to remove the sugar from your blood. Because high blood sugar is harmful and your body wants to get rid of it quickly, it often over-reacts and produces too much insulin, which leads to an ensuing crash in your blood sugar. Simply put, meals high in rapidly absorbed carbs (i.e. refined sugar, especially if it’s dissolved in liquid) leads to greater swings in blood sugar, leading to greater hunger.

High levels of stress can raise cortisol. Cortisol’s job is essentially to get your body ready to survive/escape a life-threatening event. That language may be a little hyperbolic, but it’s preparing you to face some challenging event. Part of cortisol’s action is to raise your blood sugar so you have access to easily available energy if needed. If you’re constantly in a state of stress (physical or emotional), the signal is detrimental, leading to a constant need to increase blood sugar. In addition to psychological stress, poor sleep, over-training, or chronic dieting can lead to persistently high cortisol levels and unending hunger. Hunger late at night, carb or salt cravings, or a calming sense when eating can be clues that your hunger is inappropriately driven by cortisol.

Chronic dieting, excess stress, poor sleep, and persistent inflammation also affect thyroid hormone. Thyroid hormone helps manage your base metabolic rate, or how much energy your body uses to carry out the continual metabolic processes necessary to live. If the thyroid gland is negatively affected by any of the above stressors, your internal processes may be running more slowly than normal.

While cortisol and thyroid are both hormones, two often overlooked hormones that affect hunger directly are leptin and ghrelin. They are integral parts of the systems that regulate appetite, satiety, and energy availability. When dysregulated, they cause hunger signals that don’t match actual energy needs.

Leptin signals long-term energy sufficiency and adequate fat stores, but if the signal is constant over time, meaning you always have access to excess energy, your brain starts to ignore leptin and disregard the presence of extensive energy reserves (body fat).

Ghrelin, on the other hand, rises in anticipation of meals, helping create the feeling of hunger around habitual eating times. Irregular or disordered eating patterns can disrupt this rhythm leading to hunger signals that can appear at inappropriate times. On the reverse side, though, if your body is conditioned to breakfast, mid-morning snack, lunch, afternoon snack, dinner, and a late-night snack, ghrelin is going to rise in anticipation of the timing of all those meals. If you cut back on snacking or to fewer meals a day, ghrelin is still going to rise at 10 am, 3 pm, and 11pm (or whenever your habitual snacking times were), telling you it’s time to eat. Ghrelin will adjust and regulate to a new eating schedule, but it may take weeks to months.

There is also a range of social or emotional cues that can spur hunger, but for now we’ll focus on the other physical aspects of hunger.

Weight Loss Approaches

As you likely know, there is a wide range of approaches to weight loss. But they are not all created equal. The debate over which is “best” is endless, and what is “best” for certain people may not be best for you.

As we’ve discussed, and while technically correct, CICO is one of the least useful approaches to weight loss. If the first step in your diet plan is to “just eat less”, the chances of long term success are low.

Insulin Resistance

The most effective first step is to understand and control insulin. Insulin is a hormone released by the pancreas and is the primary regulator of fuel partitioning, meaning it determines whether energy is stored or released. It’s three main jobs are to move sugar out of the blood stream, tell tissues to store energy, and inhibit fat breakdown. When insulin is elevated, the body is in storage mode. Fat is effectively locked away, inaccessible to meet energy needs.

When organs in your body are repeatedly exposed to elevated insulin levels, most commonly from frequent high carbohydrate meals or snacks, chronic stress, poor sleep or inflammation, they become insulin resistant.

A helpful analogy can be a coach who constantly yells at his team or a parent who constantly yells at their child. At first, the player/child responds and acts as instructed. But if the yelling is constant, the player/child tunes out the yelling. This leads to the coach/parent yelling even more to get a response. Eventually the yellers voice is going to give out.

In insulin resistance, the cells become less responsive to insulin and the pancreas has to produce more and more to achieve the desired response. And when insulin is always at high levels, stored fat becomes increasingly difficult to access. Additionally, if the pancreas constantly has to produce high levels of insulin, it can’t meet demand and the insulin-producing beta cells start to wear out. This is the pathway that leads to type 2 diabetes.

When insulin is high, decreasing calories is minimally effective, because your body can’t access the stored energy sources (fat) to meet its energy needs, resulting in persistent, overwhelming feelings of hunger. In order to burn fat, and thus lose weight, insulin needs to be reduced so cells become less resistant to it, and the body can function as it should.

Rather than lower calorie intake, the first strategic step is to lower the calories that cause the greatest insulin response. Since simple sugars (especially if dissolved in soda or juice) trigger the largest blood sugar spike and largest insulin release, those need to be the first to go.

My unofficial hierarchy of sugars, going from worst to best, is

1. Sugar in liquid form, including fruit juice.

2. Sweets. Usually pretty obvious, like candies or cakes.

3. Ultra-high processed foods: chips, crackers, refined snack foods

4. Processed foods: white bread, white flour, most boxed foods

Note: ultra-high processed and processed foods can be tricky, because they’re often salty. But the carbohydrates in potato chips almost instantly turn into sugar.

5. Fruits. Eat whole, with fiber intact. There is a hierarchy within fruits, but that is beyond our scope at this time.

6. Whole grains: intact grains, high in fiber, sourdough

7. Vegetables: non-starchy vegetables are best

This is obviously not comprehensive, but it’s a good guidepost. The simple rule of thumb is as carbohydrates get further from how they are found in nature, ie more refined, dissolved, and fiber-depleted, they behave more like sugar and raise blood sugar, and thus insulin.

The more of the worst carbohydrates you can avoid, the better. Ideally, and especially if you’re trying to tightly control blood sugar, carbohydrates should come almost exclusively from non-starchy vegetables with maybe the occasional whole grain or fruit.

Proteins and fats have much smaller effects on insulin, so even without reducing calorie intake, shifting your diet to high protein high fat will decrease insulin, decrease insulin resistance, allow your body to more easily access stored fat, and result in weight loss.

There are also a range of supplements that can improve insulin sensitivity. I will leave it to the reader to investigate further, but magnesium, berberine, chromium, alpha-lipoic acid (ALA), inositol, omega-3 fatty acids, and cinnamon can all help restore insulin sensitivity. Drinking apple cider vinegar before a meal can also modulate the post-meal glucose spike.

With the overall goal of managing hunger, controlling insulin directly affects your body’s ability to access stored energy which decreases cravings. It also prevents the large fluctuations in blood sugar that can also drive cravings.

Last, and certainly not least, exercise is essential to improving insulin sensitivity. Exercise improves insulin sensitivity by increasing muscle glucose uptake (without needing an insulin signal to do it) and expanding muscle mass, which acts as a major sink for circulating glucose. Both resistance training and aerobic activity enhance insulin signaling pathways, allowing cells to respond to lower insulin levels. Over time, regular movement reduces baseline insulin exposure, making stored energy more accessible and hunger easier to regulate.

Some benefits of decreasing persistently high insulin will be noticeable quickly, but to truly reset/improve insulin sensitivity is a process that takes place over months.

Hormones

To manage hunger driven by hormonal dysregulation, the primary goal is to reduce the signals that tell the body it is under threat or energy deprived. The most effective levers are often the least intuitive: improving sleep, reducing chronic stress, and avoiding overly aggressive dieting. Adequate sleep lowers baseline cortisol and improves both leptin sensitivity and ghrelin regulation, while consistent sleep and wake times help align hunger with true energy needs. Similarly, dialing back excessive training volume or intensity can reduce cortisol-driven hunger that is often mistaken for a lack of discipline rather than a physiological stress response.

Regular, adequately sized meals also play an important role in calming hormonal hunger. Eating enough protein at meals helps stabilize blood sugar, reducing the need for cortisol-mediated glucose release and preventing stress-induced cravings later in the day. Avoiding constant grazing while maintaining a predictable meal schedule allows ghrelin to recalibrate over time, so hunger becomes more proportional and less intrusive. During this adjustment period, temporary hunger at previously habitual eating times is expected and does not necessarily indicate true energy need.

Finally, improving leptin and thyroid signaling requires patience and consistency rather than restriction. Chronic under-eating, frequent weight cycling, and prolonged inflammation all reinforce the body’s perception of energy scarcity, even in the presence of adequate fat stores. Prioritizing whole foods, maintaining sufficient intake, supporting recovery, and allowing the nervous system to exit a chronic stress state help restore normal hormonal feedback. When these systems are supported, hunger becomes quieter, more predictable, and easier to interpret, making long-term weight management far more sustainable.

Again, anything to do with hormones is not a quick fix. The process of re-regulating dysregulated hormones takes place over a time frame of weeks to months.

Food Quality and Satiety

Food quality plays a central role in satiety because the body does not eat solely for calories, but for nutrients. Highly processed foods are often engineered to be calorie-dense while being low in protein, fiber, and micronutrients, which means they deliver energy without adequately satisfying the body’s nutritional needs. As a result, hunger persists even after sufficient calories have been consumed, driving continued eating in an attempt to meet protein and micronutrient requirements.

Macronutrient balance strongly influences satiety. Protein is the most satiating macronutrient and provides the amino acids necessary for tissue repair, hormone production, and metabolic signaling. Diets that are low in protein relative to calories often lead to persistent hunger and frequent snacking. Carbohydrates vary widely in their effect on satiety depending on their form and fiber content, while dietary fat tends to enhance satiety most effectively when consumed alongside adequate protein and whole-food carbohydrates.

Micronutrient deficiencies further complicate hunger signaling. Inadequate intake of minerals such as magnesium, zinc, iron, and sodium, as well as vitamins involved in energy metabolism, can manifest as cravings or nonspecific hunger that does not resolve with eating more calories. Improving food quality by prioritizing whole, minimally processed foods increases nutrient density, allowing hunger to quiet naturally as both macro- and micronutrient needs are met.

Eating whole, minimally processed foods helps manage hunger because it aligns calorie intake with the body’s true nutritional needs. Whole foods naturally provide adequate protein, fiber, and micronutrients while avoiding the rapid blood sugar swings and low satiety that drive overeating. By improving satiety signaling, stabilizing hormones, and reducing the need for constant insulin release, a whole-food diet allows hunger to regulate itself and weight loss to occur as a consequence rather than a constant struggle.

Conclusion

The most effective way to pursue weight loss is not to count calories, but to manage hunger. This includes managing insulin by avoiding simple carbohydrates that spike blood sugar and result in persistent insulin spikes. It also includes managing stress and sleep, as neglecting important major stressors on the body will lead to dysregulated hormone signaling. Finally, eating whole, nutritious foods give you the best chance of meeting all your macro- and micro-nutrient needs, thus eliminating the confusion between hunger signaling for energy needs compared to signaling for nutrient deficiencies.

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Inflammation is a double-edged sword; necessary for healing from acute injury and disease, but its persistence is the basis for almost all acquired chronic disease.

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Inflammation is a broad term that describes the body’s response to injury at a macro and micro scale. It is necessary for healing, but if it stays around for too long, leads to an array of diseases. The generally accepted responses to inflammation couldn’t be more wrong, though. We overtreat acute inflammation but ignore chronic inflammation and try to treat the secondary effects rather than the fundamental cause.

Examples of acute inflammation include localized swelling at the site of an injury, like a sprained ankle. It also includes systemic responses, like a fever when your body is fighting an infection. In both these cases, inflammation is helpful and necessary to help the body return to its normal state. Unnecessarily reducing inflammation with ice or medication delays healing.

Chronic inflammation is far less noticeable than acute, which is the primary reason it sneaks under the radar. It can be caused by persistent infections or injuries (osteoarthritis), prolonged exposure to irritants (air pollution or toxic chemicals (including those is our food, which some would argue includes sugar)), or autoimmune conditions. Not all causes of chronic inflammation are equal. Some are acquired through lifestyle with varying levels of genetic predisposition, and others (type 1 diabetes, hypothyroidism, and many autoimmune diseases) are essentially genetically predetermined.

While acute inflammation heals, prolonged inflammation injures, which in turn causes more inflammation in a vicious feedback cycle. If chronic inflammation is addressed at all, it’s usually by prescribing medicine to treat downstream symptoms rather than the root cause of the inflammation. The longer inflammation is allowed to persist, the harder it is to heal and reverse the damage caused.

Full essay and accompanying audio file are only available to paid subscribers.

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Inflammation is the body’s response to a stressor. Whether it is a mechanical injury, like a cut or sprained ligament, or a molecular irritant from bacteria, virus, or harmful inorganic chemical, the initial response is one of inflammation. It is the first essential step in healing. It is also the starting point of essentially all chronic disease. It truly is a double-edged sword – beneficial in the short run, devastating if it stays around for too long.

On a cellular level, inflammation involves a complex series of events orchestrated by immune cells, blood vessels, and molecular signals to eliminate the cause of cell injury, clear out damaged cells and tissues, and initiate repair processes. Various cells in the area of the initial injury first detect if the stimulus is coming from damage (i.e. a mechanical injury) or a pathogen (i.e. virus/bacteria/chemical) through pattern recognition receptors on their surface. They then release a range of signaling molecules to initiate the appropriate response.

This response begins with changes in the blood vessels around the active site. The vessels dilate and become more permeable to allow more blood to reach the affected area. (Think of this as if a major disaster happened downtown in a large city, the roads in the area suddenly widened and added extra lanes so the emergency vehicles could reach the site faster.) This accounts for the cardinal signs of inflammation – redness and warmth due to increased blood flow and swelling due to increased fluid in the surrounding tissue. Immune cells also rush to the scene to destroy any encroaching pathogens and clean up dead cells and debris. The release of internal components from the damaged cells can indicate whether skin or other tissue repair needs to start.

Acute inflammation resolves as the body gains better control of the situation. The signaling molecules released in response to the injury naturally start to break down. Neutrophils, a type of immune cell that flock in large numbers to the site of inflammation, die off once their job is complete. Macrophages, another type of white blood cell, are initially activated to drive much of the inflammatory response. As the situation begins to resolve, they undergo a change in gene expression pattern and start signaling for everything to return to normal. This switch in macrophage behavior is important to prevent acute inflammation from becoming chronic.

In the case of an infection, if it is not controlled at the initial site of entry, the body employs further tactics to eliminate it. Everything involved in the initial inflammatory response that we’ve discussed so far is part of what’s called the innate, or non-specific, immune response. If it fails, though, the body’s response moves to becoming systemic (throughout the whole body) rather than local. This includes a fever and greater recruitment of immune cells.

The hypothalamus region in the brain acts as the body’s thermostat. Cytokines, or a type of molecular signal released during a widespread infection, act on the hypothalamus to raise the body’s temperature set point, resulting in a fever. The higher temperature slows down or inhibits replication of the invading pathogens while also increasing the efficiency of immune cells fighting the intruders.

In some cases, this systemic defense response can go too far and develop into SIRS (systemic inflammatory response syndrome) or sepsis.  The primary difference between the two is simply that you call it sepsis if you have a known cause of infection and SIRS if you don’t. This out-of-control inflammatory response involves extremes of body temperature (high or low), rapid heart rate and breathing, and low blood pressure. This can then lead to confusion, dizziness, extreme fatigue and usually death if it’s not treated quickly. In the overwhelming majority of cases, though, your body responds to a widespread infection with a well-regulated systemic response that tilts the battlefield in favor of your body’s defense mechanisms fighting against intrusive microbes.

Acute, or short-term, inflammation is generally uncomfortable. Sprained ankles and cuts hurt. Fevers make you feel miserable. The natural response is to try and mitigate the pain and discomfort, but there is a trade-off between tolerating immediate discomfort and prolonging the healing process.

The typical treatment for a soft tissue injury is called the RICE protocol, or Rest, Ice, Compression, Elevation (which then evolved into more elaborate acronyms such as PRICE and POLICE, but more letters didn’t correlate with any more helpful knowledge). Soft tissue generally refers to either muscle, tendon, or ligament. As a reference point, muscle usually takes 2-4 weeks to heal, tendons 4-6 weeks, and ligaments 10-12. The difference in healing time is related to the amount of blood flow to each tissue type, with muscle generally having the most and ligaments having the least. The severity of the injury also plays a role, i.e. whether it’s a partial or complete tear.

Using a sprained ankle as an example, common knowledge says you should wrap it in an ACE bandage, put ice on it, and lay down on the couch with it propped up on some pillows. Ibuprofen every six to eight hours can help, too.

You should notice, though, that each of these interventions is intended to mute the body’s natural healing mechanisms. Why should you want to override your body’s attempts to fix itself? It’s often not a conscious intention, but rather a short-term attempt to reduce pain.

The RICE protocol was initially published in the “Sports Medicine Book” by Dr. Gabe Mirkin in 1978 (although it was commonly used before then). In 2015, in a stunning act of humility and self-awareness for a doctor, he recanted his long-standing recommendations¹. Ice, rest, and NSAID use (i.e. ibuprofen) all likely prolong, rather than enhance, healing. The jury’s still out on whether compression and elevation make a difference one way or the other.

To be clear, icing an injury has been shown to effectively reduce pain, swelling, and bruising. The problem is that this delays the body’s healing response by limiting blood flow to the area, preventing the release of appropriate cell signaling to initiate healing, and can actually do further damage to the already-injured tissue (usually occurring if ice is left on for too long). And to be fair, the majority of the literature has shown that icing doesn’t help, not that it hurts. It does delay release of cell signaling molecules that initiate the healing process, so it likely slows healing to some degree, but muscles, tendons, and ligaments generally get better somewhere within their expected time frames (as listed at the start of this section).

So how does one most quickly heal from injury, then? If it’s severe enough to need surgery, then it needs surgery, but for everything else early movement is key. The injured tissue does need to be protected, at least for a short time. If you get hurt, stop exercising or playing immediately. Increasing the severity of the injury is only going to delay healing and return to activity. It’s reasonable to take the rest of the day off and start on rehab after 24 hours or so.

For rehab, aim move the injured tissue through the maximal possible range of motion without any load. Again, using an ankle as an example, if you can’t walk, sit on the couch and move it as far forward and back, side to side as you can. Over the next few days, aim to increase the range through which it can move and gradually increase the weight supported by the joint. If you absolutely have to put more load on the joint than is comfortable, for example you have to work, protect the joint with crutches or a brace and limit overstressing it as much as possible. Most studies have shown adhering to a home exercise program is equally effective as supervised physically therapy for rehabbing acute, single joint injuries. The fundamental principles are to gradually increase range of motion and load. One can quibble about various intricacies, but there’s not much more to it than that.

One quick note about rehabbing muscle or tendon injuries. As you are increasing load through exercise, focus on prolonging the eccentric phase of the movement, rather than the concentric phase. The eccentric phase is when the target muscle is elongating, rather than contracting. So with bicep curls, it’s when you’re letting the weight down, or with calf raises, it’s when you’re lowering your heels back down.

What about systemic inflammation, like a fever?

Again, your body’s natural response to an infection is to raise body temperature because it helps the immune system and inhibits the invading pathogens. The technical definition of a fever is 100.4^o F or 38^o C taken in the axillae (armpit). This threshold was initially established in the mid-1800s after Carl Wunderlich reviewed over a million temperature readings from more than 25,000 test subjects. More recent studies in patients presenting to the emergency room have confirmed having a temperature above 100.4^o predicts an infection greater than 99% of the time. (There are various other arguments for and against this definition of fever, specifically lowering the temperature that defines a fever, but not constructive to the current topic.)

Like with localized inflammation, fevers are uncomfortable, and the natural response is to lower body temperature, often with an antipyretic (fever reducing) medication like ibuprofen or acetaminophen. Again, though, this intervention is directly muting the body’s natural attempt to defend itself.

Fever has been recognized as a response to infection since the 6^th century BC. In the 5^th century BC, Hippocrates explained fever by declaring it to be an excess of yellow bile, but it was considered as beneficial, because it meant the body would fight off disease. Fever was generally considered beneficial and necessary for healing until the 1800s. At that time medical personnel began to realize that it also indicated a risk of disease transmission, so feverish patients were isolated and treated to reduce fever. While the practice of isolation to prevent transmission was an important step forward, the pre-occupation with lowering fever was a step backward. (During the Spanish flu pandemic, the 1918 death spike was preceded by increased use of aspirin to toxic levels in a misguided attempt to reduce patient’s fevers.) The perception of fever as being a negative response has persisted until very recently.

Most of the research data again suggests that artificially lowering a fever doesn’t help, not necessarily that it hurts, or delays healing time. Some studies suggest lowering fever can lead to greater disease transmission², but findings are inconsistent, and it definitively does mute the body’s self-defense mechanisms. Medications like ibuprofen and acetaminophen can have negative side effects independent of their antipyretic qualities, but they are generally safe at recommended doses. Aspirin can occasionally cause Reye’s syndrome in children with a viral infection, leading to swelling of the brain and liver, so aspirin should be avoided. If body temperature gets above 104^o F (40^o C), it should be treated. Fever in a newborn is always a concern and should not be ignored.

Fever is also one of the leading causes for pediatric emergency room visits. This is an unnecessary burden on ER facilities, but especially on patients and families who spend an average of 3+ hours at the hospital and can then be stuck with a hefty bill. Fevers rarely require hospital admission and are generally treated with the same medications available at home. Only in rare cases is IV acetaminophen used. Even then, treatment with readily available oral medication is mostly to appease worried parents and to justify an ER visit. Hospital visits for fever correlate with low education and low income, or families that can least afford unnecessary expenses. Part of this is likely due to decreased access to a primary care pediatrician, but this correlation holds true essentially throughout the world, even in countries with universal healthcare (side note: >60% of pediatric ER visits in the US are covered by Medicaid). Both inaccurate and incomplete information contribute to unnecessary visits, and one study in Mexico found that simply owning a home thermometer decreased the rates of hospital visits for fever.

One more point on fever being an unfairly categorized boogeyman: the 1927 Nobel Prize in Medicine was given to Dr. Julius Wagner-Jauregg for treating patients with syphilis by infecting them with malaria. The cyclical high-temperature fevers associated with malaria were enough to somewhat effectively kill the oft-debilitating disease of syphilis, while the patient eventually recovered from malaria. The discovery of penicillin one year later in 1928 quickly put an end to this practice.                               

Chronic, or long-standing, inflammation is a completely different beast from acute inflammation. Chronic inflammation results from either repeated injury or stimulus constantly inciting an inflammatory response, or the failure of acute inflammation to properly resolve after its job is done. Persistent inflammation is at the root of almost all chronic disease. Unlike acute inflammation, which causes significant discomfort, chronic inflammation is easily ignored. It’s similar to the metaphor of boiling a frog in a pot. If you boil the water right away (acute inflammation), the frog hops out. If you turn the heat up slowly (chronic inflammation), the frog doesn’t notice what’s going on and dies. We often don’t recognize the damage done by chronic inflammation until the damage is significant and often irreversible. We habitually overtreat acute inflammation and severely undertreat acute inflammation.

There are multiple mechanisms by which chronic inflammation is harmful. Part of the inflammatory response is ramping up the activity of various immune cells to fight infection and clear away dead or damaged tissue. Certain immune cells die when the acute period is over while others revert to a less active state. If this doesn’t happen, though, the overly zealous leukocytes can attack healthy cells. This can result in a wide array of symptoms, depending on what cells are being attacked.

Acute inflammation also involves the release of molecular signals that promote healing of damaged tissue. If these signals don’t turn off, it results in an overproduction of collagen and other extracellular matrix components, leading to fibrosis and scarring. Fibrosis can affect organ function as seen in liver cirrhosis or pulmonary fibrosis. Functional cells are essentially being replaced by scar tissue, or the tissue becomes too thick to properly perform its function.

Another usually helpful byproduct of acute inflammation are reactive oxygen species (ROS). They perform signaling roles that increase healing and activate immune cells. Some immune cells even use ROS to directly kill bacteria or viruses. The dark side of ROS is that if there are too many, they can start to cause DNA-level damage to healthy cells. Damage to DNA can then lead to the creation of cancer cells. Chronic inflammation is a strong risk factor for cancer development. It can also cause epigenetic changes, or changes that don’t directly affect the DNA, but does change the expression of many genes.

Persistent inflammation also affects fat metabolism and makes it more likely that cholesterol plaques build up in the arterial walls. This can lead to high blood pressure and increases the risk of heart attack or stroke. It also contributes to insulin resistance. Inflammatory cytokines interfere with insulin signaling pathways, which promotes development of type 2 diabetes and metabolic syndrome.

This isn’t a comprehensive summary, but it shows how many aspects of inflammation can be greatly beneficial, but damaging if not properly regulated. We’ve mentioned COPD, pulmonary fibrosis, type 2 diabetes, hypertension, heart disease, and cancer as being direct results of chronic inflammation, but it is just the tip of the iceberg.

The longer immune cells are overly active during inflammatory states, the more likely autoimmune diseases are to develop. There generally has to be an associated genetic component to develop an autoimmune disease, and some will develop in the absence of chronic inflammation, but it is a strong risk factor for development. Autoimmune diseases include lupus, MS, celiac disease, rheumatoid arthritis, Addison and Graves’ disease, Hashimoto thyroiditis, type 1 diabetes, psoriasis, etc. (The Autoimmune Institute lists 160 different autoimmune diseases³.)

There are also strong links between chronic inflammation and Alzheimer’s disease. Inflammatory signaling molecules in the peripheral circulation easily cross the blood brain barrier (BBB) and can affect the brain. As discussed, fever is a result of cytokines produced elsewhere traveling to the brain and acting on the hypothalamus. Chronic inflammation rarely causes fever, but the persistent inflammatory signals can induce the formation of amyloid-beta plaques (abnormal deposition of protein fragments in the brain) and neurofibrillary tangles (abnormal fibrous growths), both of which are hallmark findings in Alzheimer’s disease. There’s also more and more evidence indicating that chronic inflammation affects mood, including depression, fatigue, and anxiety⁴.

Chronic inflammation occurs for one of two reasons: Either there’s something in the body causing a persistent response or the response fails to turn off after the stimulus is controlled. Irritants include infections, environmental exposures, and diet. The more times inflammation ramps up, the more likely it is that one of those times it doesn’t turn off correctly, leading to an autoimmune disease.

An autoimmune disease is when an overactive immune system targets one normal cell type and decides to treat it as an invader. For example, in Hashimoto’s thyroiditis, the immune system targets the cells that create thyroid hormone. Once those cells (or a portion of them) are destroyed, the body can’t make enough thyroid hormone. Hashimoto’s is the most common cause of hypothyroidism in the US, but it usually isn’t specifically tested for because confirming the underlying disease process doesn’t change management of the disease. Type 1 diabetes occurs when the immune system destroys pancreatic cells that make insulin. This is different from Type 2 diabetes, which is not an autoimmune disease. Type 2 diabetes results from insulin resistance. The insulin-creating cells in the pancreas must increase production of insulin to lower blood sugar because the liver and other organs are less responsive to insulin. The pancreas eventually may have to make so much insulin that it gets to the point where the cells burn out and stop producing insulin all together.

 Again, an autoimmune disease can be strongly genetic and develop no matter what, or someone with a predisposition can be pushed over the edge due to recurrent inflammation. Type 1 diabetes, multiple sclerosis, and lupus have stronger genetic components, so they’re likely to develop regardless of lifestyle. Rheumatoid arthritis, inflammatory bowel disease (including Crohn’s and ulcerative colitis), and psoriasis tend to be more dependent on lifestyle. Either way, once an autoimmune disease develops, it’s essentially impossible to get rid of and the goal is to control the symptoms.

Persistent infections can be a cause of chronic inflammation. Viral infections such as Hepatitis B, C, and HIV, bacterial infections like H. pylori, and parasitic infections can all cause chronic inflammatory responses. Prolonged responses to infections like Lyme disease and COVID are less clearly attributable. These chronic infections generally all have lifestyle components that increase the risk of acquiring them, but some are unavoidable. The viral infections are often acquired through sex or IV drug use (very controllable) but could also be passed from mother to child during birth or through an accidental needle stick in a healthcare worker, or contaminated blood transfusion (very rare, but uncontrollable from the patient’s perspective). H. pylori is more prevalent in areas where living conditions are poor, but it is still often seen in developed countries and occurs seemingly at random. Parasitic infections are also more prevalent in hot, humid climates and when living conditions are poor, and while these are lifestyle-related, most people are limited in their ability to change them.

Extended exposure to environmental irritants can also cause chronic inflammation. Air pollution, heavy metals in contaminated food, water or industrial products, pesticides and herbicides, and other industrial chemicals like those found in plastics and some food packaging can all cause chronic inflammation. Many of these are extremely prevalent in modern day society. Once exposed to one of these irritants, such as heavy metals or microplastics, they can stay in the body indefinitely.

Finally, and most importantly since it is the most controllable factor, diet plays a big role in chronic inflammation. Aside from possible contaminants, the nutrients (to use the term loosely) in food put your body in an inflammatory state. For starters, insulin activates the innate immune response similarly to an invading pathogen⁵. Insulin is released from the pancreas when blood sugar levels are high. Skeletal muscle, liver, and fat cells are the most responsive to insulin signaling and increase their uptake of blood sugar. Hyperglycemia, or high blood sugar, is in itself irritating and causes an inflammatory response in the blood vessels. Persistent high blood sugar is a double whammy when it comes to inflammation. Not only is the sugar itself inflammatory, but the body’s response of increasing insulin to lower blood sugar creates an additional inflammatory response.

To know which foods will raise blood sugar, and thus are the most pro-inflammatory, it’s important to understand their glycemic index. The glycemic index of various foods is derived by giving test subject 50 grams of the food and then testing their blood sugar two hours later. The higher the spike in blood sugar, the higher the glycemic index. You could run similar experiments on yourself, either by using a glucose monitoring kit and poking your finger two hours after every meal, or by wearing a continuous glucose monitor (CGM) that constantly monitors blood sugar. The foods with high glycemic indices are generally not surprising, and include sugary food and drinks, processed foods (chips and pretzels), fast food, white bread and other refined flour products, etc. Regular consumption of these foods put your body in a state of constant inflammation. Over time, this constant inflammation and constant presence of insulin cause damage to liver and muscle tissue and make it so they’re not as responsive to future insulin signals. This is called insulin resistance and is the first step on the way to type 2 diabetes and metabolic syndrome.

(*Quick side note: Glycemic load is also important. Glycemic index is standardized to a certain amount of food intake, or the potency of the food in raising blood sugar. Glycemic load takes into account the amount of the food you consume. A single nibble of a high glycemic index food with still have a low glycemic load, and thus a lower rise in blood sugar, because the portion is so small. A giant plateful of a relatively lower glycemic index food will have a high glycemic load and raise blood sugar. Glycemic load is more related to the concomitant rise in blood sugar than glycemic index.)

Since blood sugar is the body’s main source of energy, persistently high blood sugar and persistently high insulin levels lead to increased energy storage, which means increased fat. Fat cells themselves are inherently pro-inflammatory. Obesity is a state of chronic inflammation. You can easily see that chronic inflammation is an ever-increasing feedback loop of inflammation. Unhealthy foods cause inflammation through multiple routes, and result in increased fat, which itself causes inflammation, which leads to further damage to organs and increased inflammation and obesity.

Other “nutrients” that can be pro-inflammatory independent of carbohydrate (sugar) content include omega-6 polyunsaturated fats found in corn, safflower, soybean, and sunflower oils. Saturated fats found in red meat and dairy have also been shown to induce inflammation, although it is through a different pathway than commonly associated with other inflammatory stimuli. It also seems to be related to how immune cells interact with existing fat cells, so saturated fat is likely more inflammatory to those who already have an abundance of fat cells, and less so to those who are lean. It is also odd that out of the most pro-inflammatory foods, they are all highly processed, synthetic derivatives of whole foods, except for saturated fats, which occur naturally in many foods that have been a stable in human diets for millennia. There is also significant evidence⁶ to show a concerted effort to demonize red meat by industries that produce all the other pro-inflammatory foods we’ve discussed in an attempt to cast blame on meat rather than their own products. These vilification efforts have recently been adopted by animal rights and climate activists. It seems apparent that when talking about pro-inflammatory foods, while there are studies that show inflammatory qualities of saturated fat, it is clearly an outlier compared to the other foods in this category and conclusions about its damaging effects should be taken with a grain of salt. (Salt, ironically, is also often unfairly criticized for the negative effects primarily caused by sugar.)

We know very well that chronic inflammation is severely damaging to health and can lead to a range of terrible diseases, including cancer. The problem is it acts very slowly; so slowly that we often don’t feel the need to address it with urgency. We also know very well what causes chronic inflammation. Some of these causes are apparent and avoidable. Some are unavoidable, or far less easily avoidable. Many are ingrained into society and literally would take an act of Congress to prevent future exposure (ie use of pesticides, dangerous food additives, and damaging microplastics). Unfortunately, and for various reasons, America is behind much of the developed world when it comes to banning these chemicals. But even when it comes to avoidable inflammatory triggers, we still respond poorly.

It should be clear that a major source of inflammation in the body is due to diet. Many dietary guidelines are contradictory and confusing. Even foods that should be relatively healthy have so many hidden additives that they are more problematic than they should be. Signs and symptoms of chronic inflammation, i.e. an expanding waistline, skin rashes, gut discomfort, etc., are either ignored or treated with a medication to suppress the symptoms rather than treat the underlying cause (see our article here).

To paraphrase Homer Simpson, “Inflammation is the cause of, and solution to, all of life’s problems.” It is truly a double-edged sword. Acute inflammation is necessary for proper healing and recovery. Chronic inflammation is extremely damaging to our health. Paradoxically, we overtreat acute inflammation and undertreat chronic inflammation. It’s time to hop out of water pot before it boils and address controllable causes of chronic inflammation before it’s too late.

References

1.     http://drmirkin.com/fitness/why-ice-delays-recovery.html

2.     “Population Effects of Lowering Fever” Earn, et. al.

3.     https://www.autoimmuneinstitute.org/resources/autoimmune-disease-list/

4.     “The Role of Inflammation in Depression and Fatigue”; Lee and Giuliani

5.     “Regulation of the Immune System by the Insulin Receptor in Health and Disease”; Makhijani, et. al.

6.     “The Big Fat Lie” by Nina Teicholz (it takes a whole book to outline the deceptive practices of the big food industry)

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Obesity is a dangerous epidemic on an upward trajectory, but management is shrouded in misunderstanding, misinformation, and taboo.

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Obesity rates in the United States have now reached greater than 40% of the population, increased from 15% in the 1970s. By sheer numbers, this means there are 100 million more obese people in America than there was 50 years ago. It’s starting at younger ages and reaching greater extremes, both of which compound the damaging effects.

Obesity is fundamentally a case of energy imbalance. If a person takes in more energy than they use, they will store it as fat for later use. This results in increased body mass. If a person uses more energy than they consume, they will break down previously stored energy for immediate use, resulting in decreased body mass.

The first law of thermodynamics is a universal physical principle which states that energy cannot be created or destroyed, but can only change form. This applies without exception to obesity and weight gain. The equation for weight gain or loss can be as simple as calories in vs calories out, but in reality, a more complex understanding can be helpful.

There are certain genetic factors that play a role, such as basal metabolic rate, which is how many calories the body burns to carry out basic processes necessary to sustain life. This rate is not predetermined, though, and can be affected by body composition, or the muscle to fat ratio a person maintains. The state the body is in when calories are consumed also plays a significant role. Carbohydrates ingested during active exercise will be used for immediate energy needs rather than stored as fat. Foods vary in their nutrient content, which can influence how aggressively the body stores the energy and how satiated, or full, you feel afterward, and how quickly you get hungry again.

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Obesity and the Physics of Weight Gain

Obesity is often referred to as an epidemic, and with good reason. Its prevalence has skyrocketed over the past half century, going from approximately 15% in the 1970s to well over 40% today. Extreme obesity (BMI >40) was essentially non-existent 50 years ago, but now more than 1 in 10 people fit this description. Childhood obesity has grown at an even faster rate, from about 5% in the 70s to near 20% today. This is even more concerning, because the negative health effects of being in an obese state tend to compound over time, so the earlier obesity sets in, the more severe negative effects become. Unlike an epidemic of an acute infectious disease which often causes extensive panic, obesity is an epidemic of chronic disease. Since realization of its symptoms take years to manifest, it doesn’t inspire near the same level of alarm.

America doesn’t have the highest rates of obesity worldwide, but it does stand out significantly among other G7 countries (countries with highly developed economies). Unsurprisingly, our neighbors to the north vie for second place among these countries, with a rate of around 27%, but still significantly lower than our >40%. England, with whom we also have many cultural connections, has rates that hover in the upper 20s as well. Germany’s current rate hangs out just above 20%, France just below, and Italy and Japan are both near 10%. All G7 countries have seen some upward trend in obesity since the 1970s.

Being overweight is defined as a BMI between 25-30, obesity >30, and extreme obesity >40. BMI is a measure based on a person’s height and weight. It’s not perfect, but it does correlate very well with increased risks of metabolic syndrome (the combo of high blood pressure, high blood sugar, high cholesterol, and excess abdominal fat) and death from any cause. It’s important to note that the risk of serious disease doesn’t increase linearly with increasing BMI, but exponentially. Once a person starts to move into and through the obese range, the rate at which they suffer from severe disease increases even faster with each step. The longer time spent at any given abnormal BMI also increases the likelihood of developing a chronic disease.

BMI is oft disparaged, and not just by the body positivity crowd. Again, it’s not perfect, but it’s actually far more likely to tell an unhealthy person that they’re healthy than a healthy person they’re unhealthy. It’s very common for someone who is unhealthy to have a normal BMI (as an extreme example, think of a drug-addicted person who is rail thin but that you’d never classify as healthy). The straw man argument about NFL running backs being obese based on BMI is always brought up, but this is countered with a simple heuristic: “If you can’t see your abs, trust BMI.” Based on body weight, many NFL running backs who are in great shape would be classified as obese, but they are the rare exception due to above average muscle mass. While being at higher weight, even when it’s muscle, still does increase the risk of high blood pressure and other abnormalities, it’s far less for someone with low body fat. So unless you have a 6-pack, you would benefit from losing weight if you fall in the overweight or obese category.

Obesity not only increases the risk of developing a number of diseases, it worsens the outcomes for other issues not necessarily incited by increased caloric intake. Obesity is more than just excess fat cells, but also persistent mild inflammation of these cells. The inflammatory signals released by adipose tissue amplify the effects of the disease beyond just adding excess weight. For example, it became abundantly clear that obesity is a major risk factor for negative outcomes from COVID. In fact, measures of IL-6 (one of the inflammatory signals released specifically by fat cells) in hospitalized COVID patients was one of, if not the best predictor of eventual transfer to the ICU.

Obesity also makes pregnancy much more dangerous. A common statistic paraded around is that maternal death rates are higher in America than other developed countries, and this is then blamed on America’s lack of free health care. First, the mortality rates between the US and other developed countries differ by less than one tenth of one percent in most cases. Second, these numbers don’t account for obesity rates and their negative effects on outcomes. Not only does obesity increase the risk of gestational diabetes, pre-eclampsia, and C-sections, it increases overall maternal mortality rate (chances of the mother dying during or near childbirth) by 2-4x compared to a non-obese person. This increased risk due to obesity and the increased rates of obesity in America more than compensate for the disparities in maternal health outcomes in other developed countries.

At any age, an obese person’s chance of dying from any cause is doubled compared to a person of normal weight. Someone who develops obesity in their 20s or 30s is likely cutting nearly 15 years off their life expectancy, and childhood obesity is new enough that we don’t even have great numbers for what early obesity does to their lifespan. Again, these negative outcomes don’t increase at the same rate as BMI increases, but the rate at which they increase increases with higher BMIs.

Obesity is fundamentally a case of energy imbalance. If a person takes in more energy than they use, they will store it as fat for later use. This results in increased body mass. If a person uses more energy than they consume, they will break down previously stored energy for immediate use, resulting in decreased body mass. Energy intake occurs by eating or drinking. The calories in our food are a measure of heat, or energy. When we talk about calories in food, technically we’re talking about kilocalories. Our body breaks down molecules of food and captures the energy released by the breaking of chemical bonds. This energy is then used as the cells in our body perform the necessary processes to maintain life. (For more about investigating energy from first principles, read our essay on mitochondria.)

The first law of thermodynamics can be simplified to say that energy cannot be created or destroyed, but can only change forms. This is a fundamental physics principle and holds true across the known universe at micro and macro scale. Not too many principles are that broadly applicable, but this law is one of them. Our bodies store excess energy as fat because it’s the most efficient way to hold on to energy. One gram of fat can hold nine calories, while one gram of carbohydrates or protein only hold four. We are predisposed to desperately hang on to every available calorie because humanity has spent most of its time in environments where food isn’t readily available, and it was often necessary to go extended periods of time without access to a good energy source.

To put it simply, fat is stored energy. We store it when we have excess energy (or more precisely, excess substrates that can be converted into energy) at one time and want to save it for later. If we are burning more energy than we’re consuming, we are not storing energy as fat and we have to burn the fat we have to get energy. You cannot gain fat when in an energy deficit, or when you’re burning more calories than you eat. People commonly complain that they’re eating miniscule amounts of healthy food, but still gaining weight. In these cases, the people still must absolutely be eating more calories than they’re burning, because otherwise it is physically impossible to increase or maintain fat stores. Nothing can be said with more certainty in medicine, because it is based on a fundamental principle consistent throughout the known universe: if you are gaining fat, you are eating more calories than you’re burning. Since this is an absolute statement with no wiggle room, it is important to point out a caveat that body weight can fluctuate from things other than fat, such as water weight. Weight may vary day to day or during certain times of the month based on how much water the body is retaining, and this is different from weight due to increased fat. Unless your body is increasingly retaining more and more water, though, body weight will decrease over time if you are in an energy deficit. The body can also break down muscle to gain energy, but it preferentially uses fat, and even if the energy use was coming from muscle instead, it would still lead to weight loss.

This energy balance is very precise. A positive energy balance means you’re taking in more energy than you’re burning, which paradoxically is usually a negative thing. If you’re trying to put on weight or grow taller, as in the case of growing children, a positive energy balance is a good thing, but that’s about it. We want to keep our energy intake and expenditure as close to equal as possible (or a negative energy balance if we’re trying to lose weight). Even something as little as a persistent 1% positive energy balance leads to about a 20-pound weight gain over the course of a decade. This is more than enough to take a healthy weight person into the overweight category, and another 20 pounds could easily move them into obesity. If your total energy expenditure in a day is 2000 calories, this is the difference of only an extra 20 calories a day. That’s not a lot. (20 calories is the equivalent to ¼ of a banana, 1 oz of chicken, or looking too long at an Oreo.)

This energy balance rule holds true no matter what. If you expend more energy than you take in, you will lose body fat, even if it’s low-quality food. The best example is the “Twinkie Diet”, performed in 2010 by a nutrition professor from Kent State. He limited his calorie intake to 1800 calories a day, with at least 2/3 of the calories coming straight from junk food, like Twinkies or Nutty Bars. Over 10 weeks he lost 27 pounds. He was probably hungry for most of the 10 weeks and a diet like this would be very difficult to maintain over a longer period, but it shows that when calories in are less than calories out, even when those calories are trash, your body has to derive its energy from previously stored fat reserves, resulting unequivocally in weight loss. Also, in only 10 weeks, the negative effects of chronically high blood sugars and insulin resistance would not yet manifest.

The body has regulating mechanisms in place to help maintain the energy intake and expenditure balance. It’s impossible to continually track calories burned from exercise compared to calories consumed through diet, so the body has a number of ways to influence the balance in whichever direction is necessary. Unfortunately, since all these internal processes are geared towards survival, and survival depends on access to energy, it is always easier to override the signals in place to stop eating than ignore those that tell us to start eating. In a resource poor environment, during the rare times when food is available, it’s best to eat as much as possible and store it as efficiently as possible. Lack of food will kill you a lot faster than excess food. It’s easier to ignore the feeling of fullness compared to the feeling of hunger. This impulse to eat more than necessary when food is almost always easily available pushes towards an excess energy balance. External forces, such as quality or ingredients of certain foods, can also make it easier to bypass limiting mechanisms. The problem with much of the processed food that is so readily available is that it is calorically dense, but nutritionally poor. It provides a lot of energy, but not much else. This is why they’re called “empty” calories.

In terms of pure energy content, a calorie is a calorie. One dietary calorie contains the same amount of energy regardless of its source. However, in terms of nutrition and metabolism, not all calories are equal due to the differing effects of macronutrients in the body.

For example, proteins have a higher TEF (thermic effect of food), which means your body burns more energy processing proteins than it does carbohydrates or fat. This means it’s a less efficient energy source, which is why your body preferentially uses the other two macronutrients if available.

Carbohydrates, especially highly processed ones, induce the release of insulin. Insulin is an anabolic hormone that triggers the body to hold on to energy even more aggressively than it normally would (aka store more as fat). After a rapid increase in blood sugar there is often a rapid decrease, which triggers hunger. Since this is brought on due to a drop in blood sugar, you often crave something sugary that will bring sugar levels back up quickly, developing a feedback cycle detrimental to your health. Also, chronically high insulin levels due to repeated ingestion of processed carbohydrates is one of the first steps of insulin resistance which then leads to metabolic dysfunction and obesity.

Along with the type of nutrients, the state which your body is in when you eat affects how the food is processed. A body at rest is going to store energy for later, while a body in motion is going to put energy to immediate use. It takes energy both to store energy and then to break it back down to a usable form, so your body will use the most readily available energy source. Working out in a fasted state forces the body to derive its energy from stored resources because there is less easily available energy. This doesn’t necessarily mean that you’ll lose more weight working out before a meal, because most people tend to just consume more calories later in the day in a resting state, and the body quickly replaces the fat burned during exercise with new stores.

Eating carbohydrates right before or during exercise means the energy will be put to good use rather than stored. In this same vein, there is a common practice in Indian culture with ancient Ayurvedic roots to “take 100 steps after every meal.” Even a short walk helps regulate blood sugar as muscles will naturally take sugar out of the blood and ease the insulin-production burden on the pancreas.

It Is often very difficult to rely on exercise to lose weight. You can Is out-eat a good exercise routine. For example, walking for 30 minutes will burn 100-200 calories. Jogging, cycling, or swimming for that same amount of time will burn somewhere between 200-400 calories, depending on intensity. To match calorie expenditure to intake, if you average 300 calories burned in a workout, on the healthy side you get 300 calories from 2 apples, 60 baby carrots, 4oz of salmon, or 1/3 cup of almonds. From unhealthy foods, 300 calories is 10-15 potato chips, ½ of a cheeseburger, 1/3 of a large pizza slice, or our favorite benchmark, 6 Oreos.

This is where nutrient density vs calorie density comes in to play. Your body will get more of what it needs in smaller portions from nutrient-dense foods. Because of this, these foods are generally more satiating. You will fill much fuller after eating 60 baby carrots (probably uncomfortably full and maybe a little orange) compared to 15 potato chips. The chips will also spike your blood sugar and create a feedback loop of cravings and snacking. Sometimes foods can be both nutrient- and calorie- dense. If you’re trying to lose weight, you may try and shift to foods that are higher in nutrients while still being lower in calories ( i.e. baby carrots instead of salmon, or celery instead of steak). If you’re trying to maintain a healthy weight, or just get the most bang-for-your-buck from your food, you’ll probably be ok eating calorie dense foods, as long as they’re also very nutritious (salmon, chicken, steak, eggs, avocados, nuts). Processed foods tend to be more calorically dense with fewer nutrients – a double whammy of negativity. Many of them are specifically manufactured to create a rush of taste that subsides quickly, which induces over-indulgence. (This is the same principle that makes certain drugs more addictive than others: there’s a fast and strong onset followed by a rapid diminishment of the effect.) Aside from vegetables and some fruits, foods with low calorie density but good nutrient density could be something like soup, or other foods with high water content. The water helps fill you up faster and deters over-eating. Nutrient density is generally more important than calorie density. If you’re getting the nutrients you need, your body’s regulating mechanisms can function as designed. When you’re not getting the nutrients, your body will drive you to eat more in an attempt to obtain those nutrients, which, if you’re eating high calorie low nutrient food, will only exacerbate the problem.

Even with regular exercise, it still only accounts for around 10-20% of the daily calorie expenditure for most people. Most of the calories your body uses will be from carrying out behind-the-scenes, everyday functions of living, like breathing, cell growth and division, and maintaining body temperature. This calorie expenditure that is necessary to maintain appropriate bodily functions is called the basal metabolic rate (BMR). Since this accounts for the overwhelming majority of energy usage, it’s important to understand influencing factors, which we will briefly discuss here.

First, the average BMR for women is 1,400-1,500 calories per day, while for men it’s around 1,600-1,800. (This is driven largely by more muscle mass and less fat in men. Muscle is more metabolically active than fat.) The standard deviation of BMR has been reported at 5-8%, meaning that 95% of women will have a BMR between 1,350 and 1,650. The ranges for men would be slightly higher. There’s always outliers, though, and one study in Scotland that measured BMR of 150 different people found a range from 1,027 calories a day at the low end to 2,499 on the high end.

Body composition and size play a large role in setting BMR. Someone who is larger has more cells requiring energy to function, and thus a higher BMR. If the largeness is composed primarily of muscle, then even more energy is required. Fat is still metabolically active, even if it is at a lower rate than muscle. One pound of muscle will burn 6-10 calories a day at rest, while one pound of fat burns 2-3 calories. Even with increasing fat, BMR still increases, so to continue gaining weight in an obese state requires more and more caloric intake.

Age is also another large determinant. BMR tends to decrease with age. Much of this is attributable to change in body composition, (again, more fat and less muscle) but age is also an independent variable. It is reasonable to assume that a person’s BMR could drop about 170 calories a day from age 30 to age 60, assuming weight stayed roughly the same.

There is also genetic variation in BMR that can be difficult to ascribe to specific causes. Genes can regulate hormone production, which is another major driver. Thyroid hormone is integral in BMR, and individuals with low thyroid levels will have lower BMRs. There are a number of other hormones that will have genetic variation and affect BMR, including insulin, cortisol, adrenaline, growth hormone, leptin, glucagon, and sex hormones (testosterone and estrogen). These can also be influenced strongly by environmental factors, so it can be difficult to separate genetics from environment. Either way, 95% of people will be within 10% or so of the mean BMR for their gender.

Out of all the factors above, some can be modified, and some can’t. Body composition can be altered by exercise and appropriate diet. You may not have the genetics to be the most ripped person at the gym, but everyone has the capacity to build muscle. Age is a little tougher to control, but maintaining appropriate body composition as you age will help mitigate the effects. Hormones can also be altered/optimized through various lifestyle changes or medication, which is beyond the scope of this essay.

After all is said and done and you’ve optimized contributing factors to your greatest extent possible, what if you’re still not losing weight? It is an undeniable fact of physics that you must still be taking in more energy than you’re using. Multiple studies on calorie restriction have shown that almost undoubtedly, people in the study not losing weight were underreporting calorie intake and overreporting exercise. The studies also found that this was more common in overweight and obese people. Whether it is due to cognitive dissonance, innocent rationalization, or intentional misrepresentation, one study found that, on average, overweight and obese patients underreported calorie intake by 51% and overreported exercise by 47%. With correct reporting, essentially all patients began losing weight as predicted.

Without precise studies, it’s impossible to know your BMR exactly, and even then it will fluctuate throughout your life. It’s also very difficult to correctly measure exercise calorie expenditure, although wearable devices are making it easier to estimate, although they’re not completely accurate. And it’s unreasonable to track calorie intake every day for the rest of your life. Undoubtedly, some experimentation is in order. If the goal is to lose weight, you can start by cutting calorie intake to 1,500 or 1,200 calories a day. Track your input for a week or two, until you have a good idea of what your input is, and then stick to the same or similar meals. Your weight is a rolling average of this caloric balance, so it may take days to weeks to notice a different in the average, reflected by a decrease in weight on the scale. But if results are still lacking, it means you’re either underestimating your intake or overestimating your output. This is an undeniable law of physics that holds true across the known universe. To make things easier, focus on nutrient dense whole foods and maintain some regular level of activity so your body’s innate mechanisms can function as intended and maintain a healthy weight. This is far from easy and there are numerous organizations across a range of industries with incentives directly opposite of yours. It’s a fight you must fight yourself, but having associates fight alongside you can also be helpful. While you can’t control the outside environment (you may drive past 20 fast food restaurants on your way to work), you can control what you bring inside your home. As Confucius said, “He who conquers himself is the mightiest warrior.” Above all, remember it’s a journey and not a destination. Implementing healthy habits will benefit your life, regardless of numbers on a scale.

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Mitochondria is the powerhouse of the cell. Don’t mess with the powerhouse unless you’re sure you know what you’re doing.

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Energy creation is fundamental to life, and mitochondria are essential to energy production. To understand health from first principles, it is essential to understand how the body fulfills this fundamental process. It stands to reason that in order to optimize performance and longevity, one should optimize mitochondrial function.

To optimize mitochondrial function, it’s important to understand how they do what they do. Mitochondria are organelles, or one of many working parts of a cell. A cell can have varying amounts of mitochondria, depending on its function. Organs that require a lot of energy generally have cells with a lot of mitochondria. Through a complex but elegant process, mitochondria generate ATP, a molecule with high energy bonds that can be used elsewhere in the cell to carry out essential processes.

The first step in ATP production is breaking down or converting the food we eat to glucose. Glucose is then broken in half and enters the Krebs cycle. The Krebs cycle produces a small amount of ATP, but more importantly two types of byproducts (NADH and FADH2) that are then fed into the electron transport chain to produce more ATP. Making sure the mitochondria have what they need to carry out this process is the first step to health.

More importantly, though, is to make sure we’re not unintentionally impeding mitochondrial function. We can extend and specify the Hippocratic Oath in this instance to “Do no harm to mitochondria.” Unfortunately, there are a number of prescription medicines that do exactly that, but very rarely are the direct effects on mitochondrial function considered when prescribing a medicine. This is a very undervalued risk when contemplating the risk/reward benefit of a medication.

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MITOCHONDRIA: FIRST PRINCIPLES OF ENERGY

Energy is essential to life. Mitochondria are essential to energy. Because of this, they are absolutely fundamental to our health. Everyone knows they are the powerhouse of the cell. There is no question about their importance in theory. In practice, though, rather than being the primary focus, mitochondrial health is often ignored. Mitochondrial dysfunction plays a role in a wide range of diseases (maybe even every disease), ranging from metabolic syndromes to likely contributing to mental health issues (which probably have metabolic underpinnings), and are a primary driver of ageing in general. Whenever we talk about “metabolism”, we are talking about mitochondrial function, because they are the fundamental level at which metabolism takes place. In studying health and sickness from first principles, there is no better place to start than with mitochondria.

The reason we eat is to provide fuel for mitochondria, and the reason we breathe is to remove the byproducts of mitochondrial processes. It doesn’t get much more fundamental than this. Mitochondria supply over 90% of the energy our body needs to function, so any wide-ranging impairment in their function will be significant, even if it’s not immediately noticeable. They are present in greater density in energy-intensive organs, such as the brain, heart, skeletal muscle, liver, and kidneys. It stands to reason, then, that these organs would be disproportionately affected if mitochondrial efficiency decreased. Mitochondria do have other functions as well, but we will focus on energy for now.

Adenosine triphosphate (ATP) is the fundamental molecule the body uses to store energy and it is often referred to as the “energy currency” of the cell. When energy to perform a function is needed, the high energy bond holding the phosphates together is broken, which results in a release of energy and a molecule that is now adenosine diphosphate (ADP). Most ATP generated from the breakdown of food takes place in the mitochondria.

Most carbohydrates in our diet can be broken down into the simple sugar glucose, a six-carbon molecule, which is the primary starting point for energy production at the cellular level. There are other simple sugars, but they can either be converted to glucose or implemented into other areas of the energy production cycle. Protein can also be broken down and reconstituted into glucose molecules if carbohydrates are absent from the diet.

The process of turning glucose into usable energy occurs through the Tricarboxylic Acid Cycle, also known as the TCA, Citric Acid, or Krebs cycle. The TCA cycle occurs inside the mitochondria.

Mitochondria are small structures within a cell that are thought to have once been independent organisms, but at some point in our evolutionary past merged with a eukaryotic cell and developed a symbiotic relationship in which mitochondria helped provide more energy for the cell to grow and divide. (When we say merged, we mean eaten, but then somehow avoided destruction.) Mitochondria interestingly have retained some of their own DNA separate from the rest of the cell, but have exported most of their genetic information to the cell nucleus for safekeeping.

Mitochondria have an outer membrane and an inner membrane. Inside the inner membrane is the matrix, and that is where the TCA cycle takes place. If you think of an inflatable kiddie pool, the matrix is where you put the water in the pool. The TCA cycle itself doesn’t produce much ATP, but some of the molecular byproducts (NADH and FADH2) then undergo oxidative phosphorylation to create more ATP.

Oxidative phosphorylation involves breaking apart these molecules and capturing the released electrons. The electrons are then passed along the Electron Transport Chain (which consists of proteins embedded along the mitochondria’s inner membrane) like a game of hot potato. With each passing of the negatively charged electron, a positively charged hydrogen atom is pumped from the matrix of the mitochondria to the other side of the inner membrane. (This would be like the air-filled walls of the kiddie pool.) As these hydrogen atoms and their positive charge build up outside the inner membrane, they naturally want to move back to the matrix to balance out the electrical charge on each side of the inner membrane. You can think about it as water pushing against a dam. And just like a dam, the hydrogen atoms are funneled back to the matrix through a protein that is essentially a turbine, and with each spin a molecule of ATP is created.

This is a very simplified explanation but will suffice for now. It should be noted that ATP creation isn’t 100% efficient (not every proton flowing through the turbine creates one ATP) and efficiency will vary between people. The efficiency level is known as the mitochondrial coupling rate. Also, in addition to producing needed ATP, this process also creates unwanted byproducts called Reactive Oxygen Species (ROS). Much like their near-homonymous RUS (rodents of unusual size), ROS scurry around the cell and cause damage to other structures unless they are properly controlled. Mitochondria have a number of mechanisms to combat this, but it’s not perfect and the slow destruction over time by ROS is implicated in decreasing mitochondrial function over time leading to disease and many of the symptoms which we associated with ageing.

The importance of mitochondria is undeniable, and their importance is evident in the scientific literature. Searching “mitochondria” on PubMed returns over 250,000 papers. 6,000 papers in 2011 alone were published about mitochondria, but mitochondria are quickly forgotten and overlooked in everyday discussions about health and medicine. When’s the last time you talked with your doctor about mitochondrial health? If it’s essential in the fundamental process upon which almost all health and disease is based, it probably should come up once in a while. In medical school, mitochondria are usually discussed during the small first year section of cell biology, and then only reappear later in discussion of rare mitochondrial diseases such as MELAS, MIDD, MERFF, and LHON. It’s also unfortunate that any internet deep dive into mitochondria almost instantly leads down a rabbit hole of pseudo-medicine. Mitochondrial health should be a primary concern of any practical or clinical medical practice.

Mitochondrial Health

Since mitochondrial health is so important to literally every aspect of our life, we’ll go through in some detail about how to improve/optimize mitochondrial function.

Exercise

First and foremost, exercise is essential in both increasing both the amount and efficiency of mitochondria. Regular exercise is the best way to increase overall energy levels, specifically because of its effect on mitochondria. Exercise has been shown to increase mitochondrial density not only in skeletal muscles, but also in the heart and brain^1,2. Any exercise is better than no exercise, but the optimal exercise regimen consists of what is considered Zone 2 training with brief episodes of high intensity exercise.

Exact definitions vary, but zone 2 is generally considered to be around 60-70% of your maximum heart rate. Again, calculations to estimate maximum heart rate differ, but a simple formula is 220- your age. If you’re 40 years old, your estimated max heart rate would be 180 and your zone 2 range is 108-126. Another way to judge if you are in zone 2 is if you were talking to someone on the phone, you could respond in full sentences, but the person on the other end could tell you were exercising. This is also what is considered “moderate” exercise.

The reason zone 2 is important to mitochondrial health is it represents the level at which mitochondria are operating at their maximal efficiency. Zone 2 is also considered the intensity level you could theoretically maintain for a full day. This is because mitochondria are processing lactate, a byproduct of anaerobic exercise, at the same rate as it’s being produced, preventing it from building up in your muscles.

Intense exercise, zone 5, or 90+% of max heart rate, puts the greatest energy demand on the cells, thus signaling to the cell that it needs more mitochondria and stimulating mitochondrial biogenesis. (Inigo San-Millan is the prominent figure in this area of research, and his various appearances of podcasts are always fascinating.) General medical guidelines are 150 minutes of moderate exercise a week, or in other words, 30 minutes 5 days a week of zone 2 training. This should be considered a minimum. Dr. San-Millan’s recommendations (from his podcast with Peter Attia) are 4 days of zone 2 training for 60-90 minutes and one day of zone 5 training, which is shorter, but far more intense.

Fuel

The next step is to ensure the mitochondria have the fuel they need to function and produce ATP. Food that is broken down to glucose is the substrate that enters the TCA cycle and kicks off the process of generating ATP, but this process has its own requirements. We’ll highlight a few of the more important ones below:

Iron

Iron acts as an electron carrier in the Electron Transport Chain (ETC). (It plays the hot potato game passing electrons along.) Studies in iron-deficient (but non-anemic) athletes showed definitive improvement in mitochondrial functioning with iron supplementation³ and generally showed increased endurance. (Their non-anemic status is important, because a common manifestation of low iron is anemia, or too few red blood cells (RBCs). If the subjects were anemic, replacing iron would help increase RBC count and that would also improve performance, confounding the results. Isolating the non-anemic patients helps point towards increased mitochondrial function being the primary driver of athletic improvement rather than just increased RBCs.)  An iron panel blood draw can show your iron status. There’s not much literature on improved energy efficiency in people with normal iron levels, but your internal energy production line is not functioning at full capacity if you are in an iron deficient state. Most meats and seafood are rich in iron, as are dark leafy greens, but absorption from animal products is generally greater compared to plants.

Magnesium

Magnesium is an essential co-factor for many steps in the TCA cycle (and over 600 other processes in the body). Chronic magnesium deficiency is starting to be implicated in the development of many metabolic disorders, including obesity, type 2 diabetes, hypertension, and others. Remember, when you read/hear metabolism, think mitochondria. Again, magnesium supplementation has been shown to increase exercise and muscle performance and in decreasing lactate buildup (indicating mitochondria are functioning efficiently). Unlike iron, simple blood tests don’t give an accurate representation of the body’s magnesium status because <1% of magnesium in the body is in the blood. There are other measurement options, but none of them are great ways to measure magnesium levels. An average diet supplies only about 50% of needed magnesium. This is partly due to food selection, but also magnesium levels in food itself is decreased due to declining soil quality. Foods groups high in magnesium include nuts, seeds, beans, avocados, leafy greens and whole grains.

Since the body’s magnesium status is somewhat of a black box, and it’s very hard to get sufficient magnesium through diet, supplementation is likely helpful. The body generally does a good job of only absorbing the magnesium it needs. If its stores are full, less gets absorbed from the intestine. Some magnesium is excreted through the kidneys daily, so magnesium is regularly needed to replace losses. Exercise also increases the need for magnesium. Again, the body manages magnesium levels well, so your job is to make sure enough magnesium is available to be absorbed when needed. (Quick side note: One side effect of magnesium can be loose and/ or urgent bowel movements, and the less that is absorbed, the more remains in the gut to cause these side effects. So, if you’re overdoing the magnesium, it can be uncomfortable.) Magnesium recommendations are 400-420 mg daily for men and 300-320 mg for women. Making sure you are getting plenty of magnesium is a good way to make sure your mitochondria have what they need to function.

Coenzyme Q10, aka CoQ10, aka Ubiquinone

CoQ10 also acts as an electron carrier in the ETC and has antioxidant properties, which protects the mitochondria from the pesky ROS they are constantly producing. It has many other roles, and the name ubiquinone was given because of its ubiquitous presence throughout the body. Like magnesium, it’s difficult to assess the body’s overall CoQ10 state through blood testing. While it is essential to mitochondrial function, supplementation of CoQ10 has inconsistent benefits in any measurable outcomes when it comes to exercise performance, VO2 max (a measure of maximal exercise capacity), or recovery. Some studies showed benefit, but the majority did not⁴. It can be helpful in mitigating side effects of statin medications (more on this below), but in an otherwise healthy person, it probably doesn’t provide much value.

 The body can synthesize CoQ10, but not in sufficient quantities for optimal functioning. Foods high in CoQ10 include meats and fish, especially organ meats. It is found in some vegetables, but most vegetarians will likely be CoQ10 deficient⁴. If you choose to supplement CoQ10, ubiquinol is much better absorbed than ubiquinone.

Glutathione

As discussed earlier, the energy production process results in toxic byproducts that can wreak havoc within the mitochondria. Mitochondrial damage will be discussed in more detail below, but glutathione is the most important molecule in helping neutralize the toxic ROS and protecting mitochondrial function. Glutathione is rarely tested for in the clinical setting and is primarily reserved for research studies. Glutathione is synthesized in the body, and its precursors include glycine and cysteine. Studies have shown that supplementation with these building blocks with glycine and N-acetyl cysteine (GlyNAC) did increase glutathione levels in the blood and it did correlate with increased exercise capacity, strength, and gait speed (in older adults) and decreased inflammatory markers.

Manganese, vitamins B1, B2, and B3, carnitine, riboflavin, and niacin are all also necessary for mitochondrial function, but play lesser roles, so we’re not going to dive into them here.

In conclusion, to optimize mitochondrial function, iron levels need to be in a normal range, supplementing with magnesium and glutathione precursors is probably helpful, and although CoQ10 is essential, supplementing likely won’t produce measurable benefit except in the case of taking statin medications.

Mitochondrial Damage

Mitochondrial dysfunction is demonstrable in a wide range of diseases including all metabolic diseases (obesity, type 2 diabetes, hyperlipidemia, NAFLD, etc.), Alzheimer’s, Parkinson’s, autism, cardiomyopathy, and chronic kidney disease. There are specific mitochondrial diseases, such as MERFF, MELAS, and LHON, which although sound like they could be names of your multiethnic neighbors in a Boston apartment building, are serious crippling diseases. They come with a range of symptoms, but consistent with the logic that cell types with the highest number of mitochondria will be affected the most, they tend to affect the brain, eyes, muscle, and heart.

Decreased efficiency of mitochondrial function can come from genetic causes or acquired over time from accumulated damage. Mitochondria are essentially inherited only from the mother. Egg cells have far more mitochondria than sperm, so when the two fuse to form an embryo, the mitochondria present are almost solely from the mother. Because of this, genetic mitochondrial diseases pass from a mother to her children.

Because of the hazardous waste products (ROS) emitted by the ATP-generating process, mitochondria inevitably sustain damage. There are several protective mechanisms, but they are imperfect. This gradual accumulation of damage is considered a fundamental aspect of the overall process of aging, in addition to development of specific diseases. It’s also important to note that these ROS emissions aren’t all bad. Their presence can trigger beneficial changes, mostly in helping the body adapt to stress, and are used by immune system cells to kill invading bacteria.

To maintain our focus on the energy-producing and fundamental importance of mitochondria, we won’t delve deep into any of those processes at this point. The purpose here isn’t to discuss each individual disease, but in future essays about each condition, mitochondrial function will be a primary focus.

In the same way we try to optimize mitochondrial function, we should avoid unnecessary inhibitors of their functions. Avoiding harm is actually far more important than anything that can be done to optimize their function. Many medications, both prescription and non-prescription, have unintended effects on mitochondria and these effects are often overlooked or ignored. Again, since mitochondrial function is absolutely essential to life and health, medication effects on mitochondria should be our foremost concern and an essential consideration in any risk/benefit discussion.

Statins

Statin medications are commonly prescribed for dyslipidemia, or high cholesterol, with the intent to reduce risk of heart attack or stroke. By commonly prescribed, we mean that atorvastatin (Lipitor) is the most prescribed medication in the United States and the highest grossing prescription drug of all time, generating over $163 billion in sales for Pfizer as of 2021.

Statins directly affect mitochondria by inhibiting an enzyme called HMG-CoA reductase, which is involved in cholesterol synthesis. It’s also involved in the production of CoQ10. Without CoQ10, the ETC doesn’t function as it should and ROS build up in the cell, increasing levels of damage. The drug also appears to affect the complexes of the ETC and decrease mitochondrial biogenesis, or the creation of new mitochondria.

Because of this direct action, statins have high rates of side effects. These side effects are generally mild and preferrable to a heart attack, but there are undeniable incentives to both minimize perception of its harms and overstate the risk reduction. Starting a statin should be a conversation with your primary care doctor, but any method or lifestyle intervention to reduce cardiovascular risk should first be implemented. Sure, starting a medication to lower cholesterol is far easier, but it comes with its own risks, which are often understated.

Consistent with the theory that organs with high levels of mitochondria will be most affected by injuries to mitochondria, the most common side effects of statins are joint and muscle pains, brain fog and insomnia, and elevation of liver enzymes. (Muscles, brain, and liver all have high mitochondrial density.) A medication that directly impairs the functioning of mitochondria, the fundamental driver of energy and life, should be treated with the upmost caution.

When starting a statin for primary prevention of cardiovascular events, the rationale is based off the levels of total and HDL cholesterol (and the subsequent calculation of LDL based off those two numbers), blood pressure, and other lifestyle and genetic factors. This information is plugged into a risk calculator, which then provides a 10-year risk assessment of the patient’s likelihood of severe cardiovascular event, like a heart attack or stroke. The guidelines for starting a statin are based off total LDL levels and this risk assessment.

Put another way, the risk you’re trying to decrease stretches across the next decade. The annual risk (year by year risk) is weighted towards the back end of that decade, since age itself is a major driver of the heart attack risk. (If your 10 year risk is 10%, that’s about 1% per year, but it’s less than one percent in the first years, and slightly greater in the last years.) Spending the next 6 months to a year trying to lower cholesterol levels by lifestyle interventions and reduce risk naturally is not playing with fire and risking your life, like some would have you believe. You’re talking about maybe dealing with a 0.5-2% increased absolute risk over the time while you’re trying to fix yourself. It’s a very reasonable, low time preference approach to your health. The alternative is taking a medication that directly impairs the most important cellular function necessary for life.

On this same note, strong recommendations for starting a statin are when that 10-year cardiovascular risk rate reaches 10%. For some people, 10% may be an acceptable risk level compared to starting a statin. 15% may be an acceptable risk level. Everyone will have a different personal preference and risk tolerance level. Guidelines are helpful, but not imperative to enforce on everyone. Most people are willing to start a medication based on guidelines without ever really knowing the basis for the guidelines because they’re never told. Most doctors don’t have a strong knowledge of the reasonings and especially statistical calculations behind recommendations. Pharmaceutical companies like it that way. In fact, pharmaceutical companies, along with other big industry players, provide significant funding for the various organizations making these recommendations. In 2020-2021 the American Heart Association received over $180 million in funding from pharmaceutical companies and other corporate entities⁵. This is in addition to the almost $357 million dollars spent by the pharma lobby in DC over the same period. Do you think these dollars are being spent to make sure Americans get the best information regarding their health? Keep in mind, Goldman Sachs (a large investment firm that holds significant influence over many of these companies) stated in their most recent industry report that curing disease is not a sustainable business model. Creating disease is very profitable, though. That’s the quiet part they don’t say out loud. Not to cast aspersions, but this may be why the AHA’s heart healthy check mark appears on some of the most sugar-filled and unhealthy cereal boxes and other foods in the grocery store.

Metformin

Metformin is a widely prescribed drug for the treatment of diabetes. It is the 8^th most prescribed drug in America. It also directly acts on mitochondria, but this is part of its primary mechanism of action for its glucose lowering effects, rather than a side effect, as with statins.

Briefly, metformin disables the first step in the ETC, which significantly impairs energy production. Because the cells are then low on energy, they start to pull more sugar out of the blood stream in an attempt to generate more, and also start to use fat for energy production. This produces positive overall affects in people with chronically high blood sugar. Since the ETC is not properly functioning, metformin also results in less ROS in the cell, and less chance for damage to DNA or other organelles. Metformin may also increase mitochondrial biogenesis, increasing the density of mitochondria in certain tissues, which is generally beneficial.

While the goal of health, and essentially the definition of life, is to maintain self-regulated homeostasis, not all drugs are equally bad. The first step in treatment should always be via negativa, or removing the cause of harm, but if something must be added to restore equilibrium, it is essential to understand risks and benefits. It’s probably not surprising to find that metformin comes from the compound guanidine in the Galega officinalis plant, which has been used for centuries to treat symptoms now known to be associated with diabetes, like frequent urination. We also don’t completely understand the actual mechanism of action by which metformin works. This is an excellent encapsulation of the theory behind Medicine Across Space and Time. Empirical knowledge of the beneficial qualities of this drug have been known for centuries, rigorously tested through the gauntlet of time, and does so with an elegant complexity that evades our scientific investigations.

Metformin is far from perfect. Its active compound was discovered in a flower, isolated, synthesized, and now mass manufactured. Taking a tablet of metformin is far more potent than chewing on some goat’s rue (the common name for Galega officinalis), but metformin has several negative side effects as well, most commonly gastric discomfort and diarrhea, and the extremely rare but severe lactic acidosis. Again, treatment should be through removal of the cause, but when additive intervention is needed, it shouldn’t necessarily be done with the strongest medication, but with the one with the fewest negative side effects.

Compare metformin to statins, which were discovered in the 1970s in a lab in Japan. It was a systematic, top-down approach screening thousands of fungi that allowed Dr. Akira Endo to identify compactin, a compound that inhibits HMG-CoA reductase, an enzyme that is essential in the synthesis of cholesterol in the body. As discussed above, this also inhibits the production of CoQ-10 and has other deleterious effects on mitochondria. Based on this discovery, Merck & Co. soon identified a similar compound and proceeded to mass manufacture. While potent, it unquestionably does harm, and the high rate of reported statin side effects don’t even include all the second order effects associated with impairing the body’s fundamental energy production process. A top-down process will never properly account for unintended second order consequences in the way that a bottom-up process will.

NSAIDs and Others

Although many NSAIDs, such as Advil and Aleve, are available over the counter in the US, they are far from benign. NSAIDs are anti-inflammatory medications and primarily work by inhibiting cyclooxygenase enzymes and decreasing prostaglandin synthesis, but they also affect mitochondria. NSAIDs are a broad category of medications, so these effects are generalizations, but they can inhibit complexes in the ETC, increase ROS, and even directly damage mitochondrial DNA.

There are many other medications that affect mitochondria but are far less common. These medications include tetracycline antibiotics (doxycycline), anti-seizure medications (valproic acid), antipsychotics (haloperidol, olanzapine, clozapine, risperidone), anesthetics, and other.

Conclusion

Production of energy at a cellular level is essential to life, and mitochondria are central to this process. Working from first principles, in order to maintain health and vitality it is imperative to optimize mitochondrial function, and even more importantly, avoid impeding their functioning. For something so important to life, we spend very little time truly thinking about how substances we ingest affect them. Because mitochondria are so fundamental, the second-order effects of damage are widespread and underappreciated. Many of the effects of their malfunction are generalized, ambiguous and difficult to pin to an exact cause, i.e., “feeling tired”. You don’t need to understand in great detail how mitochondria work, but it you do need to understand what can be damaging to them, and in turn, your health.

Citations

1.     Exercise and Mitochondrial Function: Importance and Inference- A Mini Review, by Vaishali et. al.

2.     Exercise training increases mitochondrial biogenesis in the brain, Steiner, et. al.

3.     Iron supplementation improves endurance after training in iron-depleted, nonanaemic women; Hinton, et. al.

4.     Coenzyme Q10 and Its Impact on Exercise and Sport Performance in Humans: A Recovery or Performance-Enhancing Molecule?; Drobnic

5.     AHA website https://www.heart.org//media/Files/Finance/21_22_Pharma_Funding_Disclosure_0323.pdf

"Via negativa," also known as the "negative way", is a theological concept and philosophical approach that seeks to describe God, the divine, or other ineffable concepts by specifying what they are not, rather than attempting to define what they are. This approach acknowledges the limitations of human language and cognition in grasping the full essence of such concepts. By eliminating attributes or qualities that are not appropriate for the subject, it helps to clear away misconceptions and create a more precise understanding, even though this understanding remains incomplete.

In the context of theology, via negativa is often used to describe the divine by negating attributes that are seen as inadequate or inappropriate when applied to a transcendent being. For example, one might say that God is not limited, not changeable, not confined to time, etc.

Via negativa is also used more broadly in philosophy, where it’s applied to various concepts that are difficult to pin down or define positively. This approach is especially popular in certain Eastern philosophical traditions, such as Zen Buddhism, where it is used to point towards a direct experience of reality that transcends linguistic or conceptual categories. To put it more simply, via negativa is a way to approach ideas or systems of extreme complexity. Second and third order effects of altering a complex system can be difficult, or even impossible, to predict.

In the context of health and medicine, we are always dealing complex systems with complex interactions. It is impossible to fully grasp the overwhelming interconnectedness of processes that go on in the human body and relation to their immediate environment. Thinking it can all be completely understood is utter hubris.

To sustain life, billions of cells and all their component parts must interact with each other and maintain an appropriate balance. This balance is called homeostasis. Homeostasis is not static, but dynamic. So while the body as a whole must maintain an equilibrium, the variables are always changing and moving through various levels of imbalance. Ideas in ancient medicine, such as “humors” in Western Medicine and “qi” in Eastern, tried to encapsulate this idea of a dynamic balance.

As a quick and simple example, think about energy availability. Throughout the day, sources of fuel (food) are intermittently added to the system. First, the food needs to be broken down and turned into a fuel the cells can use, and that fuel needs to be regulated so that it can be available over the next few hours or longer to continue to maintain necessary cellular functions. There’s a constant imbalance of fuel availability, but your body is able to maintain an appropriate balance so that all organs can continue functioning properly.

In general, the body does a fantastic job of maintaining this constant imbalanced balance through countless methods of cell signaling and response. Some cell signals are meant for those in the immediate vicinity and induce immediate action, while other signals are meant for cells far away within the body with responses that take months to years to enact. Think of all the conversations that may be had across New York City in a typical business day and how complicated it would be to try and track them all.

Our bodies are resilient and able to handle the varying imbalance caused by both internal and external stressors, but the balance is delicate. Medicine has always tried to help maintain this balance, and most of the time this involves intervening in some way. Obviously if you see something wrong, you should fix it. If an artery has been cut and is gushing blood, it should be sewn back together. If a bacteria has spread systemically through the body and is causing septic shock, antibiotics are necessary to push the body back into balance. For serious, acute problems, intervention is necessary, and modern medicine is better at this than it’s ever been. Rapid imbalances can be fixed with rapid intervention.

Chronic diseases have to be managed differently. Chronic diseases include heart disease, hypertension, type 2 diabetes, etc. These diseases are the result of imbalances that developed over months to years, not overnight. As with all imbalances, the initial impulse is to intervene in a way to fix the problem, and with the current paradigm of modern medicine, this is usually with a medicine. There are countless medicines that can be used to lower cholesterol, blood pressure, or blood sugar and restore a semblance of balance. All these medications, though, cause greater disruption to the dynamic balance of the human body. By adding a medication, you are adding an extra variable that needs to be integrated into the balance, and the variable is often a foreign, synthetic substance that the body has no prior experience or reference about how to properly manage. Adding a medicine disrupts the immense complexity of all the cellular interactions, the second and third order side effects cannot be predicted. Medication doesn’t cure the cause of the imbalance, it just gives the illusion of balance while the actual cause of the imbalance continues to progress and strengthen.

Written in about the 5^th century BCE (2,500 years ago), the Hippocratic Oath has been reduced to a very simplified form of “Do No Harm.” Many inconvenient parts, such as medical education being free and abortion being antithetical to the purpose of medicine, have been taken out. We barely even pay lip service to what little remains of the Oath. Every additive intervention (ie medication) will cause harm. We justify it, though, because the idea is it does less harm than the disease process it’s trying to fix. As we’ve extensively discussed in other essays, it doesn’t fix the problem, but masks it.

While sometimes necessary for severe acute issues, prescribing medications to manage chronic diseases is the lowest form of medicine. It often actually would be better to have an inattentive, lazy doctor that did nothing than one that over-prescribes medications to micromanage even the smallest lab abnormality. The doctor that prescribes a statin as soon as your calculated 10 year ASCVD risk (risk of severe cardiovascular event, like a heart attack or stroke) equals 7.5% or prescribes an anti-hypertensive when your blood pressure is 136/90 at two separate occasions is not the best doctor if your goal is to live a long and healthy life. (Both of these interventions would be the recommended management based on medical society guidelines.) Even worse, it has become somewhat fashionable among “longevity doctors” to prescribe statins, metformin, and other drugs in a completely prophylactic manner, regardless of any signs of disease progression.

The highest form of medicine is to understand that the body is perfectly well equipped (barring significant genetic incapacity) to maintain an appropriate balance, or self-sustained equilibrium, and that chronic disease simply represents a persistent imbalance. The doctor’s job, then, is to identify what substance or practice is disrupting the balance, and help to remove it. This is Medicina via negativa, or medicine by removal. This is also the only way to practice medicine and truly follow the Hippocratic Oath, since adding medication or other intervention will cause harm.

There are appropriate times and places for medication, such as when the chronic condition has gotten so acutely severe that it poses an immediate threat to life. Short-term medication in this case would be warranted. (But even acute illnesses, such as those caused by viruses, are often overly and inappropriately treated with antibiotics. Even in acute cases, use of medicine needs to be thoroughly evaluated.) Also, some people may have sustained damage to an organ or other regulation mechanism, either from a traumatic event or due to persistence of a chronic disease, that is beyond repair and prevents the body from properly regulating itself. Medication may also be necessary here as well.

As you can see, this highest form of medicine, Medicina via negativa, involves the patient making appropriate lifestyle changes to heal themselves. As with all chronic diseases, they are not healed by the doctor, but by the patient. Intervention by the doctor is more likely than not to lead to greater harm down the road. This seems to minimize the doctor’s role, and in a sense it’s not a bad thing. This style of medicine actually makes the physician’s job much, much harder. Rather than taking five seconds to write a prescription, it involves thoroughly discussing the patient’s lifestyle, identifying the problem, and working with the patient to develop a plan to make appropriate changes. It involves emotionally investing in the patient and persistently encouraging them. It involves identifying unhealthy habits and disease processes early, because the earlier it is addressed, the easier it is to fix. It involves dealing with setbacks, monitoring even the slowest of improvements, and developing the mental fortitude to accept increased short-term risks for the benefit of long-term reward.

In Hippocrates’ time, food was considered medicine. Different herbs or soups were recommended at different times based on the patient’s physical condition. More importantly, certain foods were often abstained from during times of illness. In our current culture, food has become a poison. The vast majority of chronic disease is due to our diet, or an imbalance of persistent excessive energy availability. This means the intervention is often dietary change, or removing the type or amount of food causing the imbalance. This is difficult because of habit, addictive qualities of the food, and a cultural paradigm that promotes indulgence.

The body positivity movement has been extremely damaging to population health. While it may have had some good intentions, the results are devastating. Celebrating obesity is a uniquely western thought, developed to coddle the most fragile egos. In most Asian or South American countries, people won’t hesitate to mention if you’ve been putting on weight. In America that is considered hate speech. When a Taiwanese a’ma (grandmother) asks if you’ve been eating too much rice lately, it’s not fat shaming, it’s a gentle reminder that she is concerned about your health and that you should practice some medicina via negativa, and remove excesses from your diet.

This cultural perception doesn’t make the doctor’s job easy, especially when the American Heart Association’s approval is stamped on countless sugary cereal boxes. The body positivity movement has persisted, not because of its positive effects on mental health, nor despite its extreme negative effects on public health, but because it involves increasing profits to pharmaceutical and large food manufacturers whose marketing budgets allow for bribing governmental and medical institutions and providing much more appealing commercials to eat their literal poison. As always, the poison is in the dose, but many of our foods today (mostly highly processed carbohydrates and oils) are literal slow-acting poisons that gradually destroy our organs.

In a culture that celebrates excess, it is a doctor’s job to preach austerity. It is easy to get caught up in various movements, and simply parrot lines of body positivity and self-acceptance. There is a strong belief in “nutrition” circles that patients shouldn’t be told to avoid foods, and that there’s no such thing as unhealthy foods. This outrageous claim also has the support of Presidentially-appointed health experts. It is almost unbelievable how promotion of dangerous practices can be so widespread and supported and it leaves physicians fighting a Sisyphean uphill battle. But doctors that don’t point out this blatant misinformation are doing their patients a disservice.

Health is valuable, maybe the most valuable attribute a person may have, and as such it is not cheap. In a world where so many influences push towards unhealth, or disease, the price for health is even higher. Good health comes at a price, and not just a higher bill at the grocery store. Yes, there is an abundance of cheap unhealthy foods, but being healthy doesn’t have to be costly just in the monetary sense. The poorest communities in the world often have the fewest chronic diseases.

In Bitcoin, “proof of work” is a prominent concept. It is also a lightning rod for haters and governments trying to cling to their authoritarian fiat currencies. Proof of work refers to the fact that in order to mine a block, obtain the block reward (a certain amount of bitcoin that varies from block to block), and further secure the blockchain ledger, an input of capital is required. There is no reward without first spending the money to purchase bitcoin miners (computers that solve the algorithm to mine a block) and supplying the electricity for them to run. Compare this to the US Dollar, or any other government fiat currency, in which the supply of available money can be increased dramatically with a vote or sometimes just by the decision of unelected officials. Fiat currency rapidly and consistently loses value because it can be created without any input or sacrifices. It can essentially appear out of thin air, and when currency is cheap, the things it is used to buy become expensive. If there is an unlimited amount of dollars, goods and services that are limited due to time or other natural constraints then become expensive. We call this inflation, and we’re told it’s a good thing. Proof of work, or the input of scarce resources, is what gives bitcoin its value. Anything that requires sacrifice is going to be more valuable than that which doesn’t, but the application of this principle is more stark, apparent, and controversial in Bitcoin than other areas of life.

Obtaining good health is the same in that it requires proof of work, or sacrifice of resources. It’s not cheap, and it requires physical, emotional, and mental inputs. You won’t achieve long term health through over-indulgence. There must be a balance. If a doctor’s job is to promote health and help ensure the long-term vitality of their patients, they must also fight against the cultural tidal wave of extravagance and help patients realize the true keys to health. Yes, it hard, but it is necessary. Obesity and other chronic diseases run rampant through our population, and continuing to uphold the current paradigm of masking symptoms of disease with medication without fixing the underlying problem will only propagate the current problems and create greater and greater profits for the corporations that benefit. Health requires sacrifice – there’s no other way about it. The doctor’s job is to help their patients know what appropriate sacrifices need to be made and support them in that path. Sacrifice can include types of food, amounts of food, not immediately ceding to hunger and eating, and increasing activity and exercise. Waiting a couple hours to eat when you feel hungry doesn’t, and isn’t going to, make you anorexic. The lowest form of medicine is to simply prescribe a medication, while the highest form, Medicina via negativa, involves insightful diagnosis and persistent persuasion, and is far harder, but the only true way to do the job well.

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SENTENCES:

Treating the symptoms of a disease rather than the disease itself hides the effects of unhealthy lifestyle choices. It enables, rather than heals, and has led to an overall sicker population.

PARAGRAPHS:

The way medicine is practiced today has led to a sicker population. While there has been success in treating acute issues, the framework through which we view chronic disease is misguided and harmful.

The use of medication as a crutch masks the symptoms of chronic disease, giving the appearance of healing, while the disease process continues unabated. We are enabling rather than healing.

Healing is a return to self-sustained equilibrium. Healing is a process, not a medication. The longer we can maintain a self-sustained equilibrium, the better chance we have of living a long and healthy life. Chronic disease develops overs years to decades, and symptoms are often not apparent until late in the disease process. In frustrating but elegant symmetry, healing occurs on a similar time frame.

Because of this symmetry, the earlier a disease is found, the easier it can be treated. Preventing disease by focusing on the pillars of health, specifically diet, exercise, sleep, and mood (mental health) is even better. Unfortunately, all the incentives imposed on physicians limit their ability to appropriately treat chronic disease.

There is a role for medication in medicine. Congenital disease can result in the complete malfunction of a vital function, such as in type 1 diabetes. Medication is often necessary in this case. The body has a remarkable ability to heal itself, but sometimes irreversible damage occurs, either from untreated chronic disease or a severe traumatic accident, and medication may be necessary in these cases. And while a disease process may be reversible, medication may be indicated to help mitigate further damage while healing takes place. Americans, though, are prescribed far more medications than in other countries, but without measurable benefit in key indicators, such as life expectancy, and this is because of the paradigm forced upon us by corporate and political influence.

The symptoms of disease are not the disease and focusing on treating the symptoms allows the disease process to progress while masking the outward manifestations. The paradigm of modern medicine fails because treatment starts too late and it focuses on the superficial manifestations of a disease rather than the underlying cause. Rates of chronic disease and their personal and societal costs will continue to increase unless we make significant changes in our approach to treatment and healing.

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The way medicine is practiced today has led to a sicker population. The use of medication as a crutch masks the symptoms of chronic disease, giving the appearance of healing, while the disease process continues unabated. The current paradigm of modern medicine enables unhealthy behavior rather than heals.

Obesity rates are the most obvious manifestation of declining population health. In the early 1970s, 15% of the population was obese. Today, it’s almost 50%, with 75% of adults being overweight. Obesity is just one sign of metabolic dysfunction – it just happens to be the most readily apparent. Rates of type 2 diabetes have quintupled over that same period, from 2% to over 10%. Healthcare expenditures in the US have gone from $74 billion in 1970 to $1.4 trillion in 2000 to over $4.3 trillion in 2021, and one out of every four of those dollars is spent on diabetes care. In children, rates of non-alcoholic fatty liver disease (NAFLD) are estimated to be between 5-10%. This was almost non-existent only a few decades ago and this is permanent liver damage that will stay with them their entire lives. In 2023, 29% of Americans report they have been diagnosed with depression. Diagnostic criteria have changed over the decades, but in 1970 the rate was around 5%. The largest increases have been in women and teens.

If so much more money is being spent on healthcare, why are disease rates so high? Is capital M Medicine (as an institution) really contributing to worsening health, or are they doing their best fighting an unwinnable battle against unstoppable social and lifestyle factors?

Obesity, type 2 diabetes, and NAFLD are all related to excess calorie intake. Most of the acquired chronic diseases with which we struggle are. Metabolic dysfunction may also contribute to depression and many other mental illnesses. The availability (it’s everywhere) and accessibility (it’s cheap) of high calorie foods is unprecedented. A longer discussion on this specific issue is warranted, but for now it should not be controversial to simply state this as a fact. Modern life also comes with myriad constant stressors aided and exacerbated by the overwhelming unavoidability of the news and social media. This is devastating to mental health.

Strategies to fight these new and everchanging foes are necessary. The question is, though, is Medicine fighting for us, or deceptively siding with the opposition?

The concept of a doctor and their role has varied throughout time and across cultures. From shamans in almost all indigenous cultures, curanderos (Latin America), sangomas (Africa), and hakims (Middle East and SE Asia), healers have always played an integral part in their communities. Attempts to understand the nature of illness has ranged from humors in ancient Greece (ambiguous bodily fluids whose abnormal flow results in sickness), qi in traditional Chinese medicine (even more ambiguous energy channels dependent on unimpeded flow), to simply ascribing ailments to evil spirits. Abundant useful knowledge has emerged from the trial-and-error process of using available plants and natural materials in search of various cures. Since chronic illness was rare in these communities, most of the healing efforts were focused on acute disease, and because many acute illnesses are self-limiting, less useful medical knowledge also persisted due to overvaluing anecdotal evidence.

 “Doctors” in the West had much more inauspicious beginnings than the traditional village healers. Rather than being integral parts of the community, many were snake oil salesman promising miraculous cures only to be constantly on the move as their fraud became apparent.

The 1800s brought about germ theory and the establishment of medical schools. The idea that infections were caused by unseen organisms and could be limited by proper hygiene or appropriate antibiotics has been the single greatest leap forward in medicine and the biggest extender of human life. While positive advances were made towards actually helping people, medicine was still far from a respected profession. It was dirty, gruesome, and often did more harm than good. Lack of trust in the medical establishment persisted for decades, but over time physicians became the most trusted profession in the United States. Like the indigenous village healer, the quintessential nostalgic view of the doctor who hung up their shingle and started their own practice was an integral part of the local community.

In 1966, 75% of Americans had “great confidence in medical leaders.” Today that number is 34%. While that number surely took a large drop over the past few years with inconsistent and ineffective recommendations around the COVID pandemic, trust has been gradually eroding over decades as physicians have slowly but surely withdrawn from the community to the corporate world.

One of the first important but underappreciated steps in this process came from a landmark Supreme Court ruling, Goldfarb v. Virginia State Bar, in 1975. This ruling specifically targeted the practice of law, but was quickly applied to other professional organizations. The ruling reduced law, medicine, and other learned professions to “ordinary purveyors of commerce” and revoked much of their ability to self-regulate as independent professional societies. Simply put, the Federal Trade Commission would regulate medicine rather than an internal code of ethics.

Within five years the FTC sued the AMA over aspects of its ethical standards on the grounds of preventing free market competition. The suit alleged that two sections of the AMA’s Principles of Medical Ethics violated Sherman Antitrust laws, specifically the section that prohibited advertising, explicitly stating that the ban seriously inhibited the growth of HMOs (the horror!). The suit also attacked restrictions on physician’s contractual opportunities with corporations. The AMA had opposed such contracts on the ethical standards that fees for physician services should accrue to the physician and not a corporate entity, and that if a physician was employed by a corporation, they may find themselves under undue pressure to prioritize corporate goals over patient well-being.

The FTC won the lawsuit, breaking down the ethical walls surrounding medicine and allowing a flood of corporatism into an industry that previously prided themselves on maintaining the upmost respectability. Further regulatory burden and increased administrative costs have continued to pull doctors from the community into the corporate world, resulting in a climate where physicians are ultimately accountable to their company rather than their patients.

Around this same time, as healthcare was being invaded by corporate oligarchs, the US came off the gold standard backing its currency. A full examination of the effects of this move are both impossible and unnecessary here, but US dollars were no longer backed by gold and could thus be more easily created. As with any commodity, an increase in supply leads to a decrease in value. The supply of US dollars was then constrained only by an arbitrary debt ceiling set by Congress which eventually always gets raised, giving only the illusion of financial prudence. While dollars have maintained their strength relative to other countries’ currencies because of American economic prowess and strategic alliances, their purchasing power has plummeted compared to real goods. This is why a hamburger that used to cost 25 cents is now at least $5.00. Even with advances in technology that should result in cheaper costs of production, prices on essentially all goods continue to rise.

The most illustrative example of the dangers of debased currency is the propagation of endless wars. When going to war, countries or rulers would need to rely on the funds acquired from their respective citizens. The war could only last as long as money could be raised. Medieval wars mostly consisted of short raids to restock the coffers to fund the next raids. Even in World War I, American war bonds were issued and US citizens chose to invest to support what they saw as a worthy cause. But war is no longer dependent on the support of the respective populations. Rather than raise money from the populace, governments can simply issue debt to pay for needed expenses. This is money essentially created out of thin air and the reason why unfathomably expensive wars can continue indefinitely. For the first time in history, there is no constraint on war funding. Of course, this debt eventually comes due, so in order to pay it off, the government simply creates more money to pay it, devaluing the currency further.

War is extremely profitable for the defense contractors involved in supplying its necessities. If the price of human life is ignored, there is significant incentive to find endless battles to drive perpetual income streams. While not as absolutely horrific as war, in the same way the military industrial complex profits from human suffering, the medical industrial complex unquestionably profits from illness. Both hospital corporations and insurance companies benefit from increasing medical costs, and sick people generate much more revenue than healthy. Public companies (which includes most hospital systems and insurance providers) exist with the primary injunction to increase shareholder revenue. There is absolutely no question that corporate incentives are not aligned with the average person’s desire to live a long and healthy life. There is also no question that these same groups have infiltrated public health organizations and exert undue and insidious influence on policy. There is no coincidence that chronic disease, or illnesses requiring lifelong treatment and thus consistent revenue streams, also began skyrocketing in the 1970s. Healthcare costs as a percentage of GDP in the US have gone from 7.3% in 1970 to 19.7% in 2020. Endless disease, like endless war, is extremely profitable to small groups of individuals, while devastatingly detrimental to the population at large.

So where does this leave your local doctor? Are they fighting valiantly against the endless deluge of modern life that unavoidably leads to chronic disease? Or are they silently or unknowingly complicit in perpetuating a corrupt system that benefits from poor public health? Do they truly have your best interests at heart, or are they conflicted in their responsibilities to their corporate employer? Are they integrated into the community or an employee ID number in a faceless corporation? Are they doing their best within imposed constraints or burned out from misguided purpose? Are they a healer or an enabler?

Physicians operate under a number of constraints, and we will focus here on primary care physicians, who are the first line contact with the healthcare system.

First, most employment arrangements are fee-for-service, meaning the doctor gets paid for how much work they do. Seems reasonable, right? But it does create the incentive to see as many people as possible in a day, which results in shorter appointment times, less discussion, hastier diagnoses, and prescribing the easiest effective solution.

Second, physicians are paid for what they can bill. The patient may have a copay associated with their insurance that they pay prior to a medical visit, but the bulk of physician compensation comes from billing the insurance company after the visit. This is an arduous and complicated process and primary driver for why administrative costs to run a medical practice have skyrocketed. As a general rule, you work for whoever pays you. You are not paying your physician -- your insurance company is. This third-party payor also contributes to price obfuscation when it comes to medical services, but that is a topic for another day.

At the end of a visit (or during, if they’re trying to be especially efficient) the physician will input the various diagnoses into the medical record and the treatment plan, which will then be sent to the patient’s insurance company. Each diagnosis is associated with a code, and there must be a code to be billable. The current iteration of billable codes is ICD-10 and are assigned by Centers for Medicare & Medicaid Services (CMS). These codes are essentially all focused on treatment of existing disease rather than prevention. Insurance companies generally pay for one “preventative” visit a year, but the rest of billing is based on disease treatment. Again, this makes some sense, but alternatively incentivizes delayed monitoring or attention to early signs of burgeoning disease because addressing it before it is billable is uncompensated. In only paying for treatment of disease rather than prevention, insurance companies impose their priorities onto the doctor-patient relationship. No matter how good of a person your PCP is, they’re probably not going to expend too much energy for free.

Third, physicians are influenced by legal liability. Just like the other two constraints, this should generally be a good thing because you don’t want a careless doctor prescribing dangerous treatments or ignoring warning signs. But this also incentivizes “defensive” medicine, though, which results in ordering excessive tests and imaging, which quickly becomes expensive in order to not miss a potential diagnosis for which the physician could be sued later. Even with a miniscule chance of an obscure pathology, from a physician’s point of view, it’s advantageous to order the extra tests to minimize the chance of future legal issues. Hospitals and companies providing these services obviously love this for their bottom lines. Insurance companies generally benefit as well because they can push increased costs to their broad consumer base without causing too much of a fuss. Insurance companies will occasionally push back on testing and require a prior authorization, but as mentioned earlier, both healthcare institutions and insurance companies benefit from rising costs. (In bizarre reasoning, part of the reason insurance companies are ok with high prices is because, by law, insurance company executives can only be paid a percentage of their company’s incoming insurance premiums. Increasing medical costs can be passed on to consumers, which increases the overall incoming premiums, allowing these executives to pay themselves more.)

Legal liability also incentivizes doctors to prescribe medications more quickly. For example, if lab work reveals that a patient has high cholesterol and meets the recommendations for starting a statin, the doctor prescribes the medication and probably rechecks cholesterol levels in 3-6 months. In a situation like this, a risk calculator may show that the patient has, say, a 10% risk of severe cardiovascular event (ie heart attack or stroke) over the next ten years. The risk calculator also says that under ideal conditions, this risk could be decreased to 6% over those same 10 years. In their current condition, there’s about 1% chance per year of a serious event. (It’s actually slightly lower than 1% in the first year and slightly higher than 1% in the tenth year because increasing age brings increasing risk.) Ideal conditions would result in a 0.6% annual risk, or a 0.4% per year decrease in risk. This is a relatively small risk benefit, and once a patient is started on a medication like a statin, they are likely to be on it the rest of their lives. Statins do come with a range of side effects, and while they are generally less severe than a debilitating heart attack or stroke, it’s important to remember that no intervention is benign, or without risk. With so little benefit, it would seem reasonable that an alternative strategy would be to talk with the patient about possible lifestyle interventions and recheck cholesterol after implementation and see if risk can be reduced in that way, without introducing the added risk of a medication. The problem is, though, if that unlucky patient hits on that 1% per year risk and dies of a heart attack, the grieving family members could easily sue the negligent doctor that ignored medical society guidelines to start a statin medication. (The topic of misguided or absent risk/reward conversation will be in a future essay.)

To summarize, physicians are incentivized to see as many people as possible, only treat established disease and largely ignore preventative measures, treat said diseases with medication, and disregard costs. There is no incentive to keep a patient healthy. Generally being good people, most physicians try to reasonably balance these forced incentives with their true desire to help patients, but only have so much room to work within these set parameters.

This removal of physicians from the community to the corporate world, misaligned incentives, and imposed constraints all bring into question whose side the physician is truly on. It’s obvious that the goals of big healthcare and the general population do not align, and doctors are caught somewhere in the middle. But intentional or not, physicians have fallen into the trap of being enablers rather than healers.

Healing is a return to self-sustained equilibrium. Healing is a process, not a medication.

With an acute illness, such as a bacterial infection, medication can be used to help the body fight off the invaders and/or control symptoms while it does so on its own. These illnesses generally do not last very long, and the body quickly returns to its normal state of health. Healing is achieved.

Chronic illness (type 2 diabetes, fatty liver, COPD, depression, etc.) is a completely different animal. Where symptoms of a bacterial illness generally manifest within hours or days of the infection taking hold, chronic illness can build for years and decades before the first symptoms become apparent, and many of these symptoms are non-specific, or don’t necessarily point directly to the disease process causing them.  Symptoms, though, are the body’s feedback mechanism, letting you know something is wrong. They are an internal organ’s cry for help.

When medications are prescribed for chronic diseases, they just interrupt this feedback mechanism and mute the distress signals. Medications don’t heal chronic disease. They can prevent progression of the disease, or they can mitigate damage while healing takes place, but they don’t heal the disease. They don’t help the body return to its state of self-sustained equilibrium. A medication may improve various measurable indicators, such as blood glucose levels or blood pressure, but that shouldn’t be considered healing. Sometimes so much damage has been done that healing isn’t possible, and medications are required to maintain a new steady state, but that is a far rarer case than we are led to believe. The danger with quickly prescribing a medication at the first sign of a disease, when it’s not actively threatening life or serious organ damage, is that it hides the effects of the disease and gives the illusion of healing, but allows the actual disease process to progress and gain a stronger foothold. It’s like pulling the leaves off a weed in your garden without getting to the roots. It may look like the weed is gone, but its roots are continuing to grow and become stronger.

The longer a person can maintain a self-sustained equilibrium, the greater their chances of living a long and active life. Once medications enter the picture, it is a slow decline from there. Of course, if a disease has become severe, declining medication treatment could lead to an earlier than necessary demise. In frustrating symmetry, in the same way that a chronic illness develops over years, healing often takes a similar amount of time. It’s not a quick resolution, so sometimes medications can help manage risk while lifestyle changes are implemented. Medication should always be started with the intent to stop them as soon as possible. While they do mask symptoms and in so doing diminish the urgency of making healthy changes, they are sometimes necessary.

Modern medicine has fallen into the trap of high time preference. Time preference is the value a person places on a reward received in the present vs receiving it in the future. Someone with a high time preference wants the reward now, while one with a low time preference is willing to wait.

The famous Stanford marshmallow experiment provides a good illustration of this concept. A child was placed in a room with a marshmallow. The child was then told that if they waited to eat the marshmallow until the researcher came back (after about 15 minutes), they would get a second marshmallow. The children who ate the marshmallow would be described to have a high time preference, while those who waited would have a low time preference. One of the conclusions from this study discovered decades after the initial experiment was that low time preference correlated with success and achievement later in life. Specifically, children that waited tended to have higher SAT score, lower levels of substance abuse, better social skills, and better responses to stress. Another heuristic is a “spender” is high time preference and a “saver” is low time preference.

Quickly prescribing medication once a chronic disease is diagnosed provides the immediate satisfaction of improved lab results or symptom relief. (Again, sometimes symptoms are severe enough that medication is necessary to mitigate harmful side effects.) This isn’t healing the disease, though, and leads to persistence of the underlying process. A moderately high blood sugar doesn’t immediately need metformin. A statin medication isn’t needed right away for elevated cholesterol. SSRIs aren’t urgently necessary for depression, and usually take weeks to even become effective in improving mood.

High time preference medicine involves prescribing a medication for the immediate reward of improved metrics rather than investing the time and energy necessary to figure out and fix the actual problem. This is what pharmaceutical corporations want. They want us to buy into the charade that improved symptoms is the same as healing. With any intervention there is a risk/benefit calculation to be made. It’s naturally easier to see the possible benefits of intervention and ignore the possible risks. The most underappreciated risk is that treating the symptoms of disease just leads to continued progression of the disease. Once a medication is started, it is far more likely that a patient will eventually need either increased doses of the medication or additional medications rather than eventually needing less or none. The disease process that caused the symptom is marching onward, even though the symptom, the bodily organ’s cry for help, was muted.

Medications enable unhealthy lifestyles. When we think of “enabling”, we generally think of dangerous addictive substances such alcohol or drugs. The “enabler” implicitly supports the addict’s behavior by ignoring or covering up for their mistakes and preventing the addict from facing the consequences of their actions. When a bodily organ starts to get overworked, signs and symptoms start to show up. Some are subtle and are only detected on blood work. Others, such as an expanding waistline or constant thirst and urination in the early development of diabetes, are less subtle. Medications often blunt and distort these feedback mechanisms. Disease symptoms are the body’s way of telling you something is wrong and using medications to suppress symptoms enables continued unhealthy lifestyle. The dangers of enabling something like unhealthy eating habits isn’t as acutely dangerous as enabling a heroin addiction, but it does encourage a person to continue down a dangerous pathway.

The thinking is often that the risk of an abnormal finding on lab work (or by some other measure) needs to be mitigated immediately. Without fixing the underlying problem though, this just pushes risk down the road and allows it to increase. It is often better to tolerate some risk in the short term while working towards healing, rather than immediately intervene, but encourage the disease process to grow and result in likely greater damage in the future. The only way to truly eliminate risk is to eliminate the disease process.

What, then, is the doctor’s role? How does a doctor return to the role of a healer? The current amount of people suffering from chronic disease is unprecedented. Doctors of old didn’t have to deal with this. Because we are facing an unprecedented challenge, this requires a complete re-imagining of a doctor’s role. The current system obviously isn’t working. There are myriad outside forces pushing increased chronic disease and it’s essentially impossible to eliminate the forces. As discussed above, there’s also multiple constraints within which a doctor must work.

First, a doctor must resist the urge to practice high time preference medicine and prescribe medications too quickly. A physician’s role is to educate, encourage, and help their patients reach their individual health goals.  It can include warning of the dangers of unhealthy lifestyles that are becoming more and more accepted. (Of course a company that manufactures fattening foods wants to normalize obesity.) A doctor needs to be able to cut through the corporate and political interventions and give their patient clear and concise medical advice. This requires intensive critical thinking skills on the part of the doctor, because even generally accepted medical society guidelines are not free from outside subterfuge. In the same way investors may have different risk appetites when it comes to their investment portfolios, patients will have different risk preferences when it comes to their health. A patient may be ok with the 10% decade risk of a heart attack compared with starting a medication, while another cannot tolerate any increased risk that could be mitigated with a statin. Or it may just be that the patient can’t make the appropriate changes and openly uses a medication as a crutch to support their desired lifestyle. But again, the high time preference paradigm of modern medicine underemphasizes intervention risks, overstates their benefits, and subtly imbeds this paradigm into doctors from the very first day of medical school. Doctors are to follow society guidelines and any deviation leads to quackery.

Most important is recognizing that a doctor doesn’t actually heal anyone of chronic disease. Prescribing a medication is enabling, not healing. Healing comes through lifestyle changes, and these must be made by the patient. More often than not, these lifestyle changes involve removing the offending action or substance. It’s the doctor’s job to understand and point out what needs to be removed and develop individual strategies to work towards that goal. The practice of medicine which involves the removal of dangerous influences, or medicina via negativa, is the only way to truly follow the Hippocratic Oath. Any additive intervention will have some harmful consequences. To be fair, the Hippocratic Oath also purports free medical education and decries abortion, so we gave up on it long ago, but we still barely even pay lip service to its maximally condensed form of “Do No Harm.”

 A patient must ultimately heal themselves. The new paradigm through which a doctor should be viewed is as a guide and confidant along the pathway to healing. This sounds mushy, but it’s important to recognize that a doctor’s role in chronic disease is to educate and encourage, and burdening the physician with the responsibility to heal is misinformed and can lead to dangerous over-intervention.

Many people are fighting uphill battles against unfair genetic pre-dispositions to disease, but the result isn’t foreordained. The cure is a change in lifestyle. Regardless of the malady, healing happens from the inside out. Healing can only take place after one accepts responsibility and resolves to change. The responsibility can’t be outsourced onto someone else. It doesn’t have to be done alone or without help, but there is not a single medication that can heal someone against their will. Putting the burden of responsibility on the patient is often considered naïve or hopeless, and maybe it is, but it is the only way to fix progressively worsening public health.

In classical literature, heroes were more commonly praised for their efforts rather than their outcomes. Heroes could, and often did, lose, but the glory was in the fight. Over time, the view of heroism gradually shifted to results, rather than process. The hero was the one who won. This view is harmful and encourages high time preference thinking and valuing short term outcomes over long term ones. Modern medicine focuses too often on achieving short term results at the expense of investing in long term health. Healing is a process. We already know we’re in a losing battle. We will all undoubtedly die. The longer we can keep our bodies close to the self-sustained equilibrium, though, the more prepared we are to deflect the various maladies that come our way. The glory and heroism, then, is in the fight. It’s a Quixotic endeavor full of unstoppable forces and immovable objects, but it is a fight worth fighting, and it doesn’t need to be fought alone. A doctor must resist the constraints of the medical system and become the helpful squire supporting the knight in their fight against the ravages of modernity that have sent so many down a road of ill health and unfulfilled potential.

Sentence:

Medicine Across Space and Time is a search for true principles of health and wellness that have persisted over time and across cultures to provide context and answers to the myriad chronic health issues we face today.

Paragraphs:

Dr Charles Burwell, cardiologist and Dean of Harvard Medical School from 1935-1949, once famously told an incoming class that “half of what we are going to teach you is wrong, and half is right. Our problem is we don’t know which half is which.”

Being only half wrong may be generous.

One place to start figuring out which half is which, though, is with the idea of the Lindy Effect. This theory states that the longer an idea has been around, the longer it’s likely to continue to be around. The keys to health and wellness that have persisted for the last hundred years will probably be true over the next hundred years. In that same vein, those ideas that have been adopted across cultures are more likely to have value and staying power.  Be wary of fantastic new findings that seem to overturn generational wisdom.

Modern medicine has made major advances in treating acute conditions, like illness from infectious disease and traumatic injuries. It has struggled with chronic conditions such as obesity, heart disease, diabetes, cancer, depression, and dementia. The prevalence of many of these diseases is increasing.

These conditions develop over many years to decades and have innumerable interconnected variables affecting their progression. Their complexity is such that study through traditional scientific processes is insufficient. Experiments that are insufficient in duration or focus on only one variable without properly accounting for confounders are just as likely to produce a harmful result as a helpful one. As systems increase in complexity, bottom-up iterative knowledge tends to outperform top-down authoritative knowledge.

When it comes to health and wellness, this bottom-up knowledge is embedded in the cultural practices that have persisted through generations. This knowledge is often so subtly ingrained in societal norms that its importance is overlooked and quickly disregarded in favor of exciting new findings.

Medicine Across Space and Time is a search for true principles of health and wellness. Truth is a knowledge of things as they were and as they are. True principles persist over time and are adopted across cultures and multiple domains. Understanding health and disease from first principles and in broad context helps us better apply them to the unique health issues we face today and will face in the future.

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Full Essay

Dr Charles Burwell, cardiologist and Dean of Harvard Medical School from 1935-1949, once famously told an incoming class that “half of what we are going to teach you is wrong, and half is right. Our problem is we don’t know which half is which.”

Being only half wrong might be generous.

Even if we give medicine the benefit of the doubt, it often takes decades to sort through and separate the correct information from the incorrect, and sometimes the harmful recommendations persist due to profit-based incentives, political bias, or cultural influence.

It shouldn’t be difficult to find straightforward information about the best ways to live a long and active life. It’s a universal desire, but diving into the massive amounts of available data often leaves one feeling confused and frustrated. The space is filled with both the well-intentioned and the grifters.

Guidelines from governmental agencies and consensus statements from medical associations in consult with your personal physician are a good place to start. It’s reasonable, though, to be concerned about corporate dollars insidiously influencing public policy. And as anyone who has watched the sausage get made knows, consensus statements don’t have near the support and agreement that the final product conveys. Asking any one of the involved “experts” their personal opinion would result in different advice than what’s written. And it is impossible to have a thorough conversation on such a broad and wide-ranging topic with your doctor in the 7-10 minutes they have to spend with you.

Less official information channels can also have significant value. Whether it’s in a book, an article (in or out of a scientific journal), or social media, there are plenty of knowledgeable people sharing their thoughts on health. Quality varies wildly, both positively and negatively.

Although Dr. Burwell was probably being humbly hyperbolic, if a highly curated medical school curriculum is only half right, imagine the accuracy of the troves of publicly available information!

But why is it so hard? Why don’t we have definitive answers on preventing heart disease, curing diabetes, and healing major depressive disorder? Why is there so much variance and conflicting information?

Significant progress in many areas of medicine has been made since Dr. Burwell’s statement. Capital M Medicine (as in the institution as a whole) has done well in raising the average lifespan by treating acute trauma and illnesses that have historically lowered the mean age of death. It has struggled, though, in the fight against chronic diseases, such as metabolic syndrome (obesity, diabetes, hypertension, etc.), dementia, cancer, and mental illness.

Chronic disease is, by definition, a disease that develops and persists for an extended amount of time. It doesn’t pop up overnight, and it can’t be cured overnight. It often percolates under the surface without detection for years before any symptoms appear. These are the types of problems modern medicine has struggled with.

These are wickedly difficult problems to solve due to the immense complexity of the disease process. There are innumerable and unmeasurable factors with undetermined influence throughout this process and affect individuals based not only on genetics, but epigenetics as well. (Epigenetics are factors that influence expression of genes encoded in DNA but are not part of the DNA itself.)

Proving causation is the holy grail of clinical studies. In a scientific study with the goal of proving causality (clinical trial), one independent variable is changed, and an outcome is measured. If the outcome is significantly different, then it’s reasonable to say the thing you changed caused it. Significance, in this sense, is statistical, which means there has been enough trials or participants that the outcome is unlikely to be due to chance alone. It does not mean the desired outcome happened every time.

In physics, hypotheses can be confirmed and proven over and over again. In chemistry, this happens most of the time. In biology, with all its inherent complexity, findings often barely meet the minimum standard for statistical significance and can be very difficult to reproduce in subsequent studies. When you hear the term biology is “squishy”, it doesn’t mean you can poke the things you’re studying. It means biology is complex, variable, and unpredictable.

A 2005 study titled “Why Most Published Research Findings are False” suggests that over half of published findings might be exaggerated or blatantly false due to deficiencies in study design, multiple comparisons, “p-hacking” (statistical manipulation to produce the desired response), or the pursuit of novel, rather than confirmatory findings. To get published, a study must show something new and cool; it can’t just confirm what is already known. It would also be terrible to spend tens (or hundreds) of thousands of dollars of grant money and years of study only to find that the desired outcome barely missed the threshold of significance. There is obvious incentive to maybe just play around with the data a little bit, but definitely not in a bad way, to make it show a statistically significant result. There are lies, damned lies, and statistics. A 2015 experiment attempted to replicated 100 psychological studies and found that only about 36% of the replications yielded significant results. When it comes to medical research, psychology is the squishiest of the squishy, but the low reproducibility of the findings is still concerning.

Another difficulty in studying chronic disease is the length of time necessary to track the development and progression of a disease. The Bogalusa Heart Study performed autopsies on young people ranging from ages 2-39 that died from traumatic causes (accidents, murders, suicides) and surprisingly found fatty streaks in coronary arteries, an early sign of heart disease, in many of the children. When it comes to heart disease, fatty streaks develop into fibrous plaques, which can then increase in size, impairing blood flow through the coronary arteries (the arteries the supply blood to the heart muscle itself). Decreased blood flow can result in chest pain with activity (or at rest, if it’s bad enough), when the heart muscle needs more blood to meet energy demands and make heart attacks more likely.

The point here is that the first signs of heart disease were found in children, but these were hidden except via autopsy, and symptoms likely wouldn’t show up until middle age at the earliest. How then can the disease course truly be studied?

Studying diseases with undetectable beginnings that take decades to develop is near impossible. Longitudinal studies are attempts to follow the same group of people over many years to study disease progression. Aside from the time required often exceeding the career length of the investigators, these studies are also expensive, have high rates of participant drop out, and have innumerable confounders. Artificial end points or time periods are sometimes used to make the studies more manageable. Examples include measuring bone mineral density when study osteoporosis rather than the actual endpoint of interest, which is a bone fracture. Another example is measuring change in glycated hemoglobin, or A1c, when studying diabetes, rather than waiting for the development of kidney disease, peripheral nerve disease, or death.

When using these surrogate end points, the risk of developing the true endpoint can usually be inferred, but it leaves significant room for error. In studies for cancer treatment, change in tumor size is often used as an artificial endpoint in order to get cancer drugs approved more quickly (which for the most part is a noble goal). The problem is, though, that there is often correlation between change in tumor size and prolonged survival, the true important end point. Avastin for metastatic breast cancer was approved by the FDA in 2008 because of its rapid effect on tumor size, but the indication for its use was removed in 2011 when further studies showed it did not contribute to extended or improved lifespan.

In addition to using artificial endpoints as surrogates for the true endpoints, sometimes arbitrary time periods, rather than outcomes, are used. New medications generally go through pre-clinical and then 3 phases of drug testing, with each successive step including more people. If approved, “Phase 4” is continued surveillance after the drug is widely available. It is expected that some side effects will emerge in this phase, but the hope is that the risks for serious negative outcomes have been identified and mitigated in the earlier trials. A study must end at some point.

In the 1980s, observational studies showed that hormone replacement therapy (HRT) reduced the risk of heart disease in post-menopausal women. HRT was then widely recommended on this basis. When the results of the much longer Women’s Health Initiative were released in 2002, though, it showed that HRT actually increased risk of breast cancer and heart disease. The study focusing on HRT with estrogen and progestin replacement was stopped early after about 5 years because of the 26% increased relative risk of invasive breast cancer and 29% increased risk of heart attack. This equates to 8 and 9 extra women respectively out of 10,000 suffering from the negative side effect, but these are not minor side effects. Since this number is fairly small, it is also why HRT is still often used to help with moderate to severe symptoms of menopause but is no longer widely recommended.

The most egregious example of drawing conclusions from too short of a time frame were the initial claims that slow-release opioid medications like OxyContin were not addictive. This assertion was initially based on a 1980 letter published in the New England Journal of Medicine that patients given slow-release pain medication over 5 or less days in a hospital setting had very low rates of addiction. It’s difficult to overstate the monumental negative outcomes of such a short-sighted conclusion. It’s less difficult to understand how corporate greed and inept regulatory oversight led to the opioid crisis. But even with a claim so obviously false, prescriptions for the drug increased year over year from 1995 to 2010.

In contrast to the OxyContin example, the Framingham Heart Study is one of the most renowned and longest-running epidemiological studies in medical history. It was initiated in 1948 by the National Heart Institute to identify the common factors or characteristics that contribute to cardiovascular disease. The study initially enrolled over 5,000 men to follow throughout their lives to determine what factors might contribute to the risk of heart disease. The trial has since enrolled second and third generation participants and continues today. The wealth of data generated by this study (it pioneered the idea of identifying “risk factors”) has contributed enormously to the current understanding of cardiovascular disease.

Despite its valiant effort, this study faces the same challenges that any epidemiological study faces. An epidemiological study, unlike other types of research studies that might focus on individual-level factors or lab-based experiments, analyzes larger population-level data to uncover trends, risk factors, and outcomes over time. It seeks to understand the patterns, causes, and effects of health and disease conditions in specific populations.

Drawing meaningful conclusions from epidemiological studies can be challenging because they rely on observational data, which can show associations, but cannot prove cause and effect. They can be influenced by many confounding factors, such as lifestyle or genetic differences that are difficult (impossible) to control for. But there is no practical way to study chronic disease other than longitudinal epidemiological studies, and we are left wanting any hard scientific evidence. To quote Nietzsche, “causes are fictions we ourselves invent”.

The scientific process is insufficient to properly study chronic disease. It is too complicated and interconnected. This may sound heretical, but it is impossible to sufficiently control and measure all the contributing factors over a long enough period of time to draw significant conclusions. Each variable involved in the disease process is so intertwined with others that trying too hard to isolate it is just as likely to produce a misleading outcome as a true one.

Evidence-informed recommendations are the best we can hope for, which leaves room for a lot of ambiguity in ensuing recommendations. Unfortunately, official recommendations generally give the impression that the science is settled and there should be no further arguments against the edicts handed down from governing medical bodies. And this is before so many powerful competing corporate and political influences undoubtedly try to put their hand on the scale.

This doesn’t mean disregard science. Important advancements have been made in the treatment of chronic diseases due to diligent research efforts. It means understand the complexity and variability and take recommendations with a grain of salt. It means not all that glitters is gold, and the newest hot research finding or medication may not be all it’s made out to be. For anyone who has watched the sausage being made, consensus statements and recommendations from medical associations are generally a collection of compromises that don’t have near the strength and support the final product conveys.

So where does that leave us in the search for how to live a long and healthy life? Are we at the mercy of biohackers or gym bros on social media, or the medical organizations and journals that subsist solely on donations from large corporations?

Humans have actually really flourished as a species for centuries, even before modern medical breakthroughs. Childhood diseases, bacteria, and accidents took too many people too early, and modern interventions have helped save a lot of those people. In many ways, though, Americans (and much of the world population) is unhealthier than it’s ever been. Obesity, diabetes, depression, many cancers, and dementia (and others) are all increasing, worsening quality of life and raising both individual and collective healthcare expenditures.

Medicine Across Space and Time is a search for true principles of health and wellness. Truth is a knowledge of things as they are and as they were.

The Lindy Effect, made popular by Nassim Nicholas Taleb, states that future life expectancy of an idea or technology is proportional to its current age. More simply put, the longer something has been around, the longer it’s likely to continue to be around. In that same vein, those ideas that have been adopted across cultures are more likely to have value and staying power. Be very wary of “new findings” that miraculously invalidate widespread generational practices.

To help answer Dr. Burwell’s question and determine which half of medical knowledge currently being taught is correct, start with what has been taught the longest. The keys to health and longevity that have been known for one hundred years will probably be the keys to health and longevity over the next hundred years. The ideas developed over the last one to two decades may be helpful, but the chances are far lower. (Think of the major shift in dietary recommendations in America in the 1970s compared to the typical diet of the preceding 100 years and the obesity epidemic that almost immediately followed.) This is especially important when it comes to overall health and vitality, as these concepts can be difficult to quantify and investigate with scientific rigor.

There are other ways to develop and progress societal knowledge other than formal research studies. There is much to be learned from the health practices that are imbedded in cultural traditions. This isn’t necessarily explicit knowledge packaged neatly with an abstract, methodology, discussion, and conclusion. It’s implicitly passed from generation to generation to help ensure continuing success. It’s so subtly imbedded in everyday life, it’s easy to disregard. It has stood the test of time and consistently produced results.

In contrast to institutional research studies, cultural norms around health develop from the bottom up, rather from the top down. There’s no central director dictating the exercise and dietary choices of the individuals. The habits developed are emergent properties of a population that gradually proved to produce the healthiest individuals and were thus adopted by others in the group. Their persistence helps diminish the effects of confounders and randomness just through the unyielding filter of time. It doesn’t have the appeal of authoritative declaration, but it has the significance of producing robust positive outcomes. And while authors of research studies may have the incentive to massage their study outcomes to produce publishable results, the inherent cultural knowledge has no other motive than to encourage survival of the species.

There is a sweet spot in taking the knowledge passed down over centuries that has helped humanity thrive, while also incorporating new medical knowledge. Modern technology has greatly increased our knowledge of how things are, often down to the most minute cellular detail. New discoveries can theoretically invalidate previous knowledge, but more often than not, they simply add context. For example, it is extremely unlikely that any new knowledge about the intricacies of lipid metabolism or atherogenesis will invalidate ancestral diets that have persisted for centuries. True principles persist over time and are adopted across cultures and multiple domains. Understanding these principles of health in a broader context helps us better apply them to the unique health issues we face today.

By embracing multi-generational health practices, we are relying on the longest, most robust longitudinal epidemiologic studies available. Any study that seemingly overturns decades of acquired wisdom should be bulletproof. The burden of evidence is far greater on the new information than it is on the old.

In the 1977 “Dietary Goals for the United States”, which famously condemns animal-based products and recommends a monumental nationwide dietary shift to grains, Dr. D.M. Hegsted, another Harvard physician and the driving influential force in the new guidelines, writes that “the diet we eat today was not planned or developed for any particular purpose…The question to be asked, therefore, is not why should we change our diet, but why not?”

This statement is first and foremost an excellent example the overwhelming rise in hubris in medicine in the 30 years between Dr. Burwell and Dr. Hegsted. Unfortunately, medicine has continued this trajectory over the last 50 years. “The Science” of medicine has become an unassailable monolith where dictates are handed down from on high to be unquestionably followed. (If further evidence is needed on this point, read almost anything Anthony Fauci has said over since 2020.) The recent efforts to label anyone questioning official health guidelines as a radicalized conspiracy theorist is reminiscent of medieval Catholic church practices.

Secondly, the fundamental basis and logic of Dr. Hegel’s statement is categorically false. The standard American diet at that time was developed over decades solely for the purpose of the flourishing and survival of the human species. True, it wasn’t authoritatively directed by an omnipotent governmental organization, but rather by assimilating best practices. The question should always be “Why should we deviate from generational knowledge unless we have a really, really, really good reason to do so.” Not “Why not?”. It was not long after these new 1977 guidelines that obesity and overall rates of chronic disease began to skyrocket.

Adhering to cultural practices of health and wellness is not a reductionist view clung to by Luddites unable to comprehend the magical brilliance of modern medicine. It is rather accepting that the primary factors of health -- specifically diet, exercise, sleep, and mental health-- are extremely complex and are resistant to the study of individual variables over arbitrary timelines. Yes, medical knowledge has grown substantially, and our natural inclination is that new knowledge should lead to intervention. This is not always true, especially when all the ancillary effects cannot be fully accounted for. New medical developments often help treat or manipulate diseases that are a result of straying from the robust existing knowledge in the first place.

Medicine Across Space and Time is a study of health from first principles and how this knowledge has progressed over time. Medical guidelines will always have inherent uncertainty, whether this is openly portrayed or not. Given the ambiguity, understanding the issues in as broad of context as possible is imperative. Best practices, or the “right” answer, is most likely the one that has been preserved over generations and adopted across cultures.

The focus is not only on curing the disease (the negative side of health), but also strengthening good health habits (the positive side) to preserve health and prevent disease. The pillars of health include diet, exercise, sleep, and mood (mental health). Focusing on strengthening these pillars, rather than treating disease symptoms of an illness, is the more productive focus and one area where the current paradigm of modern medicine falls short. Since these pillars are the keys to health, longevity, and survival of the species, the keys to strengthening them are embedded into cultural practices passed down through generations. Observing how the practices relating to these pillars developed, evolved, and propagated is supremely useful.

Modern life, of course, brings challenges with it that previous generations didn’t face, such as the wanton availability of calorically dense food, sedentary lifestyles, and the constant stressors of social media. Modern medical advances can be helpful, but even more helpful is understanding and applying ancient principles to the new challenges. Long-held practices around cultural staples such as diet, exercise, and socialization are often disregarded because they are thought to have developed only out of necessity, but now that there are other options, these practices can be forgotten. This is a dangerous presumption.

Most of the major health issues we face today are not new, even though it may seem that way given their rise in prevalence. Understanding these issues and their solutions in the broadest context possible is imperative. What has changed to lead to skyrocketing levels of chronic disease and why is it so hard to treat? What healthy practices have stood the test of time and been adopted across cultures? How can the insidious influence of corporate and political bias be weeded out? Answers to these questions can help you make the right health decisions for you and your family, and this is the goal of Medicine Across Space and Time.

References

1.     Sugar Industry and Coronary Heart Disease Research: A Historical Analysis of Internal Industry Documents; JAMA, 2016

2.     Is There a Correlation between Dietary and Blood Cholesterol? Evidence from

Epidemiological Data and Clinical Interventions; NIH, 2023

3.     Statin Safety and Associated Adverse Events: A Scientific Statement from the American Heart Association

4.     William Castelli, Concerning the Possibility of a Nut, Archives of Internal Medicine, 1992

5.     Minnesota Coronary Experiment