Biohacking Lite
Throughout my life I never paid too much attention to health, exercise, diet or nutrition. I knew that you’re supposed to get some exercise and eat vegetables or something, but it stopped at that (“mom said”-) level of abstraction. I also knew that I can probably get away with some ignorance while I am young, but at some point I was messing with my health-adjusted life expectancy. So about halfway through 2019 I resolved to spend some time studying these topics in greater detail and dip my toes into some biohacking. And now… it’s been a year!
Now, I won’t lie, things got a bit out of hand over the last year with ketogenic diets, (continuous) blood glucose / beta-hydroxybutyrate tests, intermittent fasting, extended water fasting, various supplements, blood tests, heart rate monitors, dexa scans, sleep trackers, sleep studies, cardio equipments, resistance training routines etc., all of which I won’t go into full details of because it lets a bit too much of the mad scientist crazy out. But as someone who has taken plenty of physics, some chemistry but basically zero biology during my high school / undergrad years, undergoing some of these experiments was incredibly fun and a great excuse to study a number of textbooks on biochemistry (I liked “Molecular Biology of the Cell”), biology (I liked Campbell’s Biology), human nutrition (I liked “Advanced Nutrition and Human Metabolism”), etc.
For this post I wanted to focus on some of my experiments around weight loss because 1) weight is very easy to measure and 2) the biochemistry of it is interesting. In particular, in June 2019 I was around 200lb and I decided I was going to lose at least 25lb to bring myself to ~175lb, which according to a few publications is the weight associated with the lowest all cause mortality for my gender, age, and height. Obviously, a target weight is an exceedingly blunt instrument and is by itself just barely associated with health and general well-being. I also understand that weight loss is a sensitive, complicated topic and much has been discussed on the subject from a large number of perspectives. The goal of this post is to nerd out over biochemistry and energy metabolism in the animal kingdom, and potentially inspire others on their own biohacking lite adventure.
What weight is lost anyway? So it turns out that, roughly speaking, we weigh more because our batteries are very full. A human body is like an iPhone with a battery pack that can grow nearly indefinitely, and with the abundance of food around us we scarcely unplug from the charging outlet. In this case, the batteries are primarily the adipose tissue and triglycerides (fat) stored within, which are eagerly stockpiled (or sometimes also synthesized!) by your body to be burned for energy in case food becomes scarce. This was all very clever and dandy when our hunter gatherer ancestors downed a mammoth once in a while during an ice age, but not so much today with weaponized truffle double chocolate fudge cheesecakes masquerading on dessert menus.
Body’s batteries. To be precise, the body has roughly 4 batteries available to it, each varying in its total capacity and the latency/throughput with which it can be mobilized. The biochemical implementation details of each storage medium vary but, remarkably, in every case your body discharges the batteries for a single, unique purpose: to synthesize adenosine triphosphate, or ATP from ADP (alright technically/aside some also goes to the “redox power” of NADH/NADPH). The synthesis itself is relatively straightforward, taking one molecule of adenosine diphosphate (ADP), and literally snapping on a 3rd phosphate group to its end. Doing this is kind of like a molecular equivalent of squeezing and loading a spring:
This is completely not obvious and remarkable - a single molecule (ATP) functions as a universal $1 bill that energetically “pays for” much of the work done by your protein machinery. Even better, this system turns out to have an ancient origin and is common to all life on Earth. Need to (active) transport some molecule across the cell membrane? ATP binding to the transmembrane protein provides the needed “umph”. Need to temporarily untie the DNA against its hydrogen bonds? ATP binds to the protein complex to power the unzipping. Need to move myosin down an actin filament to contract a muscle? ATP to the rescue! Need to shuttle proteins around the cell’s cytoskeleton? ATP powers the tiny molecular motor (kinesin). Need to attach an amino acid to tRNA to prepare it for protein synthesis in the ribosome? ATP required. You get the idea.
Now, the body only maintains a very small amount ATP molecules “in supply” at any time. The ATP is quickly hydrolyzed, chopping off the third phosphate group, releasing energy for work, and leaving behind ADP. As mentioned, we have roughly 4 batteries that can all be “discharged” into re-generating ATP from ADP:
- super short term battery. This would be the Phosphocreatine system that buffers phosphate groups attached to creatine so ADP can be very quickly and locally recycled to ATP, barely worth mentioning for our purposes since its capacity is so minute. A large number of athletes take Creatine supplements to increase this buffer.
- short term battery. Glycogen, a branching polysaccharide of glucose found in your liver and skeletal muscle. The liver can store about 120 grams and the skeletal muscle about 400 grams. About 4 grams of glucose also circulates in your blood. Your body derives approximately ~4 kcal/g from full oxidation of glucose (adding up glycolysis and oxidative phosphorylation), so if you do the math your glycogen battery stores about 2,000 kcal. This also happens to be roughly the base metabolic rate of an average adult, i.e. the energy just to “keep the lights on” for 24 hours. Now, glycogen is not an amazing energy storage medium - not only is it not very energy dense in grams/kcal, but it is also a sponge that binds too much water with it (~3g of water per 1g of glycogen), which finally brings us to:
- long term battery. Adipose tissue (fat) is by far your primary super high density super high capacity battery pack. For example, as of June 2019, ~40lb of my 200lb weight was fat. Since fat is significantly more energy dense than carbohydrates (9 kcal/g instead of just 4 kcal/g), my fat was storing 40lb = 18kg = 18,000g x 9kcal/g = 162,000 kcal. This is a staggering amount of energy. If energy was the sole constraint, my body could run on this alone for 162,000/2,000 = 81 days. Since 1 stick of dynamite is about 1MJ of energy (239 kcal), we’re talking 678 sticks of dynamite. Or since a 100KWh Tesla battery pack stores 360MJ, if it came with a hand-crank I could in principle charge it almost twice! Hah.
- lean body mass :(. When sufficiently fasted and forced to, your body’s biochemistry will resort to burning lean body mass (primarily muscle) for fuel to power your body. This is your body’s “last resort” battery.
All four of these batteries are charged/discharged at all times to different amounts. If you just ate a cookie, your cookie will promptly be chopped down to glucose, which will circulate in your bloodstream. If there is too much glucose around (in the case of cookies there would be), your anabolic pathways will promptly store it as glycogen in the liver and skeletal muscle, or (more rarely, if in vast abundance) convert it to fat. On the catabolic side, if you start jogging you’ll primarily use (1) for the first ~3 seconds, (2) for the next 8-10 seconds anaerobically, and then (2, 3) will ramp up aerobically (a higher latency, higher throughput pathway) once your body kicks into a higher gear by increasing the heart rate, breathing rate, and oxygen transport. (4) comes into play mostly if you starve yourself or deprive your body of carbohydrates in your diet.
Since I am a computer scientist it is hard to avoid a comparison of this “energy hierarchy” to the memory hierarchy of a typical computer system. Moving energy around (stored chemically in high energy C-H / C-C bonds of molecules) is expensive just like moving bits around a chip. (1) is your L1/L2 cache - it is local, immediate, but tiny. Anaerobic (2) via glycolysis in the cytosol is your RAM, and aerobic respiration (3) is your disk: high latency (the fatty acids are shuttled over all the way from adipose tissue through the bloodstream!) but high throughput and massive storage.
The source of weight loss. So where does your body weight go exactly when you “lose it”? It’s a simple question but it stumps most people, including my younger self. Your body weight is ultimately just the sum of the individual weights of the atoms that make you up - carbon, hydrogen, nitrogen, oxygen, etc. arranged into a zoo of complex, organic molecules. One day you could weigh 180lb and the next 178lb. Where did the 2lb of atoms go? It turns out that most of your day-to-day fluctuations are attributable to water retention, which can vary a lot with your levels of sodium, your current glycogen levels, various hormone/vitamin/mineral levels, etc. The contents of your stomach/intestine and stool/urine also add to this. But where does the fat, specifically, go when you “lose” it, or “burn” it? Those carbon/hydrogen atoms that make it up don’t just evaporate out of existence. (If our body could evaporate them we’d expect E=mc^2 of energy, which would be cool). Anyway, it turns out that you breathe out most of your weight. Your breath looks transparent but you inhale a bunch of oxygen and you exhale a bunch of carbon dioxide. The carbon in that carbon dioxide you just breathed out may have just seconds ago been part of a triglyceride molecule in your fat. It’s highly amusing to think that every single time you breathe out (in a fasted state) you are literally breathing out your fat carbon by carbon. There is a good TED talk and even a whole paper with the full biochemistry/stoichiometry involved.
Combustion. Let’s now turn to the chemical process underlying weight loss. You know how you can take wood and light it on fire to “burn” it? This chemical reaction is combustion; You’re taking a bunch of organic matter with a lot of C-C and C-H bonds and, with a spark, providing the activation energy necessary for the surrounding voraciously electronegative oxygen to react with it, stripping away all of the carbons into carbon dioxide (CO2) and all of the hydrogens into water (H2O). This reaction releases a lot of heat in the process, thus sustaining the reaction until all energy-rich C-C and C-H bonds are depleted. These bonds are referred to as “energy-rich” because energetically carbon reeeallly wants to be carbon dioxide (CO2) and hydrogen reeeeally wants to be water (H2O), but this reaction is gated by an activation energy barrier, allowing large amounts of C-C/C-H rich macromolecules to exist in stable forms, in ambient conditions, and in the presence of oxygen.
Cellular respiration: “slow motion” combustion. Remarkably, your body does the exact same thing as far as inputs (organic compounds), outputs (CO2 and H2O) and stoichiometry are concerned, but the burning is not explosive but slow and controlled, with plenty of molecular intermediates that torture biology students. This biochemical miracle begins with fats/carbohydrates/proteins (molecules rich in C-C and C-H bonds) and goes through stepwise, complete, slow-motion combustion via glycolysis / beta oxidation, citric acid cycle, oxidative phosphorylation, and finally the electron transport chain and the whoa-are-you-serious molecular motor - the ATP synthase, imo the most incredible macromolecule not DNA. Okay potentially a tie with the Ribosome. Even better, this is an exceedingly efficient process that traps almost 40% of the energy in the form of ATP (the rest is lost as heat). This is much more efficient than your typical internal combustion motor at around 25%. I am also skipping a lot of incredible detail that doesn’t fit into a paragraph, including how food is chopped up piece by piece all the way to tiny acetate molecules, how their electrons are stripped and loaded up on molecular shuttles (NAD+ -> NADH), how they then quantum tunnel their way down the electron transport chain (literally a flow of electricity down a protein complex “wire”, from food to oxygen), how this pumps protons across the inner mitochondrial membrane (an electrochemical equaivalent of pumping water uphill in a hydro plant), how this process is brilliant, flexible, ancient, highly conserved in all of life and very closely related to photosynthesis, and finally how the protons are allowed to flow back through little holes in the ATP synthase, spinning it like a water wheel on a river, and powering its head to take an ADP and a phosphate and snap them together to ATP.
Photosynthesis: “inverse combustion”. If H2O and CO2 are oh so energetically favored, it’s worth keeping in mind where all of this C-C, C-H rich fuel came from in the first place. Of course, it comes from plants - the OG nanomolecular factories. In the process of photosynthesis, plants strip hydrogen atoms away from oxygen in molecules of water with light, and via further processing snatch carbon dioxide (CO2) lego blocks from the atmosphere to build all kinds of organics. Amusingly, unlike fixing hydrogen from H2O and carbon from CO2, plants are unable to fix the plethora of nitrogen from the atmosphere (the triple bond in N2 is very strong) and rely on bacteria to synthesize more chemically active forms (Ammonia, NH3), which is why chemical fertilizers are so important for plant growth and why the Haber-Bosch process basically averted the Malthusian catastrophe. Anyway, the point is that plants build all kinds of insanely complex organic molecules from these basic lego blocks (carbon dioxide, water) and all of it is fundamentally powered by light via the miracle of photosynthesis. The sunlight’s energy is trapped in the C-C / C-H bonds of the manufactured organics, which we eat and oxidize back to CO2 / H2O (capturing ~40% of in the form of a 3rd phosphate group on ATP), and finally convert to blog posts like this one, and a bunch of heat. Also, going in I didn’t quite appreciate just how much we know about all of the reactions involved, that we we can track individual atoms around all of them, and that any student can easily calculate answers to questions such as “How many ATP molecules are generated during the complete oxidation of one molecule of palmitic acid?” (it’s 106, now you know).
We’ve now established in some detail that fat is your body’s primary battery pack and we’d like to breathe it out. Let’s turn to the details of the accounting.
Energy input. Humans turn out to have a very simple and surprisingly narrow energy metabolism. We don’t partake in the miracle of photosynthesis like plants/cyanobacteria do. We don’t oxidize inorganic compounds like hydrogen sulfide or nitrite or something like some of our bacteria/archaea cousins. Similar to everything else alive, we do not fuse or fission atomic nuclei (that would be awesome). No, the only way we input any and all energy into the system is through the breakdown of food. “Food” is actually a fairly narrow subset of organic molecules that we can digest and metabolize for energy. It includes classes of molecules that come in 3 major groups (“macros”): proteins, fats, carbohydrates and a few other special case molecules like alcohol. There are plenty of molecules we can’t metabolize for energy and don’t count as food, such as cellulose (fiber; actually also a carbohydrate, a major component of plants, although some of it is digestible by some animals like cattle; also your microbiome loooves it), or hydrocarbons (which can only be “metabolized” by our internal combustion engines). In any case, this makes for exceedingly simple accounting: the energy input to your body is upper bounded by the number of food calories that you eat. The food industry attempts to guesstimate these by adding up the macros in each food, and you can find these estimates on the nutrition labels. In particular, naive calorimetry would over-estimate food calories because as mentioned not everything combustible is digestible.
Energy output. You might think that most of your energy output would come from movement, but in fact 1) your body is exceedingly efficient when it comes to movement, and 2) it is energetically unintuitively expensive to just exist. To keep you alive your body has to maintain homeostasis, manage thermo-regulation, respiration, heartbeat, brain/nerve function, blood circulation, protein synthesis, active transport, etc etc. Collectively, this portion of energy expenditure is called the Base Metabolic Rate (BMR) and you burn this “for free” even if you slept the entire day. As an example, my BMR is somewhere around 1800kcal/day (a common estimate due to Mifflin St. Jeor for men is 10 x weight (kg) + 6.25 x height (cm) - 5 x age (y) + 5). Anyone who’s been at the gym and ran on a treadmill will know just how much of a free win this is. I start panting and sweating uncomfortably just after a small few hundred kcal of running. So yes, movement burns calories, but the 30min elliptical session you do in the gym is a drop in the bucket compared to your base metabolic rate. Of course if you’re doing the elliptical for cardio-vascular health - great! But if you’re doing it thinking that this is necessary or a major contributor to losing weight, you’d be wrong.
Energy deficit. In summary, the amount of energy you expend (BMR + movement) subtract the amount you take in (via food alone) is your energy deficit. This means you will discharge your battery more than you charge it, and breathe out more fat than you synthesize/store, decreasing the size of your battery pack, and recording less on the scale because all those carbon atoms that made up your triglyceride chains in the morning are now diffused around the atmosphere.
So… a few textbooks later we see that to lose weight one should eat less and move more.
Experiment section. So how big of a deficit should one introduce? I did not want the deficit to be so large that it would stress me out, make me hangry and impact my work. In addition, with greater deficit your body will increasingly begin to sacrifice lean body mass (paper). To keep things simple, I aimed to lose about 1lb/week, which is consistent with a few recommendations I found in a few papers. Since 1lb = 454g, 1g of fat is estimated at approx. 9 kcal, and adipose tissue is ~87% lipids, some (very rough) napkin math suggests that 3500 kcal = 1lb of fat. The precise details of this are much more complicated, but this would suggest a target deficit of about 500 kcal/day. I found that it was hard to reach this deficit with calorie restriction alone, and psychologically it was much easier to eat near the break even point and create most of the deficit with cardio. It also helped a lot to adopt a 16:8 intermittent fasting schedule (i.e. “skip breakfast”, eat only from e.g. 12-8pm) which helps control appetite and dramatically reduces snacking. I started the experiment in June 2019 at about 195lb (day 120 on the chart below), and 1 year later I am at 165lb, giving an overall empirical rate of 0.58lb/week:
Other stuff. I should mention that despite the focus of this post the experiment was of course much broader for me than weight loss alone, as I tried to improve many other variables I started to understand were linked to longevity and general well-being. I went on a relatively low carbohydrate mostly Pescetarian diet, I stopped eating nearly all forms of sugar (except for berries) and processed foods, I stopped drinking calories in any form (soda, orange juice, alcohol, milk), I started regular cardio a few times a week (first running then cycling), I started regular resistance training, etc. I am not militant about any of these and have cheated a number of times on all of it because I think sticking to it 90% of the time produces 90% of the benefit. As a result I’ve improved a number of biomarkers (e.g. resting heart rate, resting blood glucose, strength, endurance, nutritional deficiencies, etc). I wish I could say I feel significantly better or sharper, but honestly I feel about the same. But the numbers tell me I’m supposed to be on a better path and I think I am content with that 🤷.
Explicit modeling. Now, getting back to weight, clearly the overall rate of 0.58lb/week is not our expected 1lb/week. To validate the energy deficit math I spent 100 days around late 2019 very carefully tracking my daily energy input and output. For the input I recorded my total calorie intake - I kept logs in my notes app of everything I ate. When nutrition labels were not available, I did my best to estimate the intake. Luckily, I have a strange obsession with guesstimating calories in any food, I’ve done so for years for fun, and have gotten quite good at it. Isn’t it a ton of fun to always guess calories in some food before checking the answer on the nutrition label and seeing if you fall within 10% correct? No? Alright. For energy output I recorded the number my Apple Watch reports in the “Activity App”. TLDR simply subtracting expenditure from intake gives the approximate deficit for that day, which we can use to calculate the expected weight loss, and finally compare to the actual weight loss. As an example, an excerpt of the raw data and the simple calculation looks something like:
2019-09-23: Morning weight 180.5. Ate 1700, expended 2710 (Δkcal 1010, Δw 0.29). Tomorrow should weight 180.2 2019-09-24: Morning weight 179.8. Ate 1790, expended 2629 (Δkcal 839, Δw 0.24). Tomorrow should weight 179.6 2019-09-25: Morning weight 180.6. Ate 1670, expended 2973 (Δkcal 1303, Δw 0.37). Tomorrow should weight 180.2 2019-09-26: Morning weight 179.7. Ate 2140, expended 2529 (Δkcal 389, Δw 0.11). Tomorrow should weight 179.6 2019-09-27: Morning weight nan. Ate 2200, expended 2730 (Δkcal 530, Δw 0.15). Tomorrow should weight nan 2019-09-28: Morning weight nan. Ate 2400, expended 2800 (Δkcal 400, Δw 0.11). Tomorrow should weight 2019-09-29: Morning weight 181.0. Ate 1840, expended 2498 (Δkcal 658, Δw 0.19). Tomorrow should weight 180.8 2019-09-30: Morning weight 181.8. Ate 1910, expended 2883 (Δkcal 973, Δw 0.28). Tomorrow should weight 181.5 2019-10-01: Morning weight 179.4. Ate 2000, expended 2637 (Δkcal 637, Δw 0.18). Tomorrow should weight 179.2 2019-10-02: Morning weight 179.5. Ate 1920, expended 2552 (Δkcal 632, Δw 0.18). Tomorrow should weight 179.3
Where we have a few nan if I missed a weight measurement in the morning. Plotting this we get the following:
Clearly, my actual weight loss (red) turned out to be slower than expected one based on our simple deficit math (blue). So this is where things get interesting. A number of possibilities come to mind. I could be consistently underestimating calories eaten. My Apple Watch could be overestimating my calorie expenditure. The naive conversion math of 1lb of fat = 3500 kcal could be off. I think one of the other significant culprits is that when I eat protein I am naively recording its caloric value under intake, implicitly assuming that my body burns it for energy. However, since I was simultaneously resistance training and building some muscle, my body could redirect 1g of protein into muscle and instead mobilize only ~0.5g of fat to cover the same energy need (since fat is 9kcal/g and protein only 4kcal/g). The outcome is that depending on my muscle gain my weight loss would look slower, as we observe. Most likely, some combination of all of the above is going on.
Water factor. Another fun thing I noticed is that my observed weight can fluctuate and rise a lot, even while my expected weight calculation expects a loss. I found that this discrepancy grows with the amount of carbohydrates in my diet (dessert, bread/pasta, potatoes, etc.). Eating these likely increases glycogen levels, which as I already mentioned briefly, acts as a sponge and soaks up water. I noticed that my weight can rise multiple pounds, but when I revert back to my typical low-carbohydrate pasketerianish diet these “fake” pounds evaporate in a matter of a few days. The final outcome are wild swings in my body weight depending mostly on how much candy I’ve succumbed to, or if I squeezed in some pizza at a party.
Body composition. Since simultaneous muscle building skews the simple deficit math, to get a better fit we’d have to understand the details of my body composition. The weight scale I use (Withings Body+) claims to estimate and separate fat weight and lean body weight by the use of bioelectrical impedance analysis, which uses the fact that more muscle is more water is less electrical resistance. This is the most common approach accessible to a regular consumer. I didn’t know how much I could trust this measurement so I also ordered three DEXA scans (a gold standard for body composition measurements used in the literature based on low dosage X-rays) separated 1.5 months apart. I used BodySpec, who charge $45 per scan, each taking about 7 minutes at one of their physical locations. The amount of radiation is tiny - about 0.4 uSv, which is the dose you’d get by eating 4 bananas (they contain radioactive potassium-40). I was not able to get a scan recently due to COVID-19. Here is my body composition data visualized from both sources during late 2019:
red = fat, blue = lean body mass. (also note two y-axes are superimposed)
BIA vs DEXA. Unfortunately, we can see that the BIA measurement provided by my scale disagrees with DEXA results by a lot. That said, I am also forced to interpret the DEXA scan with skepticism specifically for the lean body mass amount, which is affected by hydration level, with water showing up mostly as lean body mass. In particular, during my third measurement I was fasted and in ketosis. Hence my glycogen levels were low and I was less hydrated, which I believe showed up as a dramatic loss of muscle. That said, focusing on fat, both approaches show me losing body fat at roughly the same rate, though they are off by an absolute offset.
BIA. An additional way to see that BIA is making stuff up is that it shows me losing lean body mass over time. I find this relatively unlikely because during the entire course of this experiment I exercised regularly and was able to monotonically increase my strength in terms of weight and reps for most exercises (e.g. bench press, pull ups, etc.). So that makes no sense either ¯\(ツ)/¯
Summary So there you have it. DEXA scans are severely affected by hydration (which is hard to control) and BIA is making stuff up entirely, so we don’t get to fully resolve the mystery of the slower-than-expected weight loss. But overall, maintaining an average deficit of 500kcal per day did lead to about 60% of the expected weight loss over the course of a year. More importantly, we studied the process by which our Sun’s free energy powers blog posts via a transformation of nuclear binding energy to electromagnetic radiation to heat. The photons power the fixing of carbon in CO2 and hydrogen in H2O into C-C/C-H rich organic molecules in plants, which we digest and break back down via a “slow” stepwise combustion in our cell’s cytosols and mitochondria, which “charges” some (ATP) molecular springs, which provide the “umph” that fires the neurons and moves the fingers. Also, any excess energy is stockpiled by the body as fat, so we need to intake less of it or “waste” some of it away on movement to discharge our primary battery and breathe out our weight. It’s been super fun to self-study these topics (which I skipped in high school), and I hope this post was an interesting intro to some of it. Okay great. I’ll now go eat some cookies, because yolo.
(later edits)
- discussion on hacker news
- my original post used to be about twice as long due to a section of nutrition. Since the topic of what to each came up so often alongside how much to each I am including a quick TLDR on my final diet here, without the 5-page detail. In rough order of importance: Eat from 12-8pm only. Do not drink any calories (no soda, no alcohol, no juices, avoid milk). Avoid sugar like the plague, including carbohydrate-heavy foods that immediately break down to sugar (bread, rice, pasta, potatoes), including to a lesser extent natural sugar (apples, bananas, pears, etc - we’ve “weaponized” these fruits in the last few hundred years via strong artificial selection into actual candy bars), berries are ~okay. Avoid processed food (follow Michael Pollan’s heuristic of only shopping on the outer walls of a grocery store, staying clear of its center). For meat stick mostly to fish and prefer chicken to beef/pork. For me the avoidance of beef/pork is 1) ethical - they are intelligent large animals, 2) environmental - they have a large environmental footprint (cows generate a lot of methane, a highly potent greenhouse gas) and their keeping leads to a lot of deforestation, 3) health related - a few papers point to some cause for concern in consumption of red meat, and 4) global health - a large fraction of the worst offender infectious diseases are zootopic and jumped to humans from close proximity to livestock.