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Part 4 Hormesis - Calorie Restriction

Contributor Bio

Alex Tarnava is the CEO of Drink HRW, and the primary inventor of the open-cup hydrogen tablets. Alex runs the clinical outreach program for our company, working with over a dozen universities coordinating research. Alex has also published research of his own. You can find it on his ResearchGate. Additionally, he has been interviewed for many prominent publications, such as Entrepreneur and Forbes, and on many popular Podcasts. You can find all of his interviews and articles on his media page.

Part 4 Hormesis - Calorie Restriction

Hormesis (which means exposure to stress to create a benefit) is proving to be an extremely valuable tool in our health arsenal. From cold exposure to psychedelic micro-dosing and much more in between, the field has lots of potential. Part 4 in our 7 part series addresses, in my opinion, the most difficult form of hormesis to follow. Despite its difficulty, many do. Are they doing it for nothing?

Read the first part of our Hormesis series for a full introduction to Hormesis.

Calorie Restriction

It is hard to say when exactly calorie restriction and the link between diet and longevity came onto our (humanities) radar. Advice regarding limiting obesity and gluttony has been documented since the Ancient Greeks. However, a systematic analysis of over-controlled populations did not occur until observations on energy efficiency were documented following the First World War.1

Since then, numerous disproven theories on diet have come and gone as fads, however, we have amassed significant evidence to support the strengths and weakness’ of caloric restriction as well as various long-term dietary protocols and their potential to maximize the human lifespan.

Calorie restriction wasn’t studied with the intent to evaluate potential health benefits until a study in mice in 1935.2 After that, research moved slowly with supplemental findings in humans that had been carried out with other intents contributing to the hypotheses that dietary intervention alone could dramatically impact markers of health, such as cholesterol, blood pressure, and resting heart rate, for better or worse.3 Caloric restriction is generally considered to work via hormesis.4

Caloric restriction and its implications for human longevity have been subject to a seeming paradox based on popular and published positions as well as observations. Caloric restriction has been shown to positively impact biomarkers of aging, such as fasting blood glucose, cholesterol, oxidative stress, adiposity as well as age-related diseases, such as diabetes, cancer, brain atrophy and heart disease in humans5 and other primates.6

In studies on macaque monkeys, the results have been inconsistent, with one of three studies on the subject reporting no significance in life extension despite being seemingly healthier at an advanced age,7 with the other two showing significant benefits and life extension.8 One study on the primate mouse lemur also showed an extension in lifespan and benefit in health markers.9

A 2017 review of macaque monkey studies suggests that the monkeys in the “non-significant” trial did, in fact, live longer when compared to typical life expectancy and that issues with controls between the studies could explain conclusions.10

That said, a 2018 review concluded that the trials showing a statistically significant increase in lifespan were more attributable to poor diet and overfeeding, arguing that calorie restriction would have shown no benefit compared to a healthy weight control group.11

For humans, arguments exist that the benefits do in fact exist, but quality of life and adherence are significant concerns.12 On the other side, the benefits of calorie restriction may not translate significantly to humans at all, with pharmaceutical intervention being a more viable candidate.13 Other positions remain relatively and rightfully neutral, concluding that we simply do not have enough human data on non-obese healthy participants and increased study on the subject is long overdue.14 As for experts on aging itself, Aubrey De Grey, a noted biogerontologist leading the charge to undo the damages caused by aging, believes that caloric restriction may only increase human lifespan by 2-3 years and concedes that may justify its use for some people.15

Valter Longo, another notable biogerontologist who has studied caloric restriction in yeast, hypothesized about fasting and short-term restriction incurring the benefits of a lifetime of caloric restriction. He has recently started publicly promoting his own “Longevity Diet” and “Fasting-Mimicking Diet” on both podcasts and speaking circuits as well as in his own recently published book, and has suggested that caloric restriction in old age, as adherents are beginning to suffer muscle and strength loss, may partially reverse the benefits incurred earlier in life.

He proposes that dietary restrictions should change, increasing animal protein intake and caloric intake later in life to preserve strength and muscle function. This is in contrast to studies on mice16 and humans,17 showing that even advanced age caloric restriction can extend lifespan or incur health benefits.

That said, another study concluded that the benefits of later life caloric restriction came from the actual weight loss,18 and as such, participants who had adhered to a restricted diet throughout life would not incur the benefits as they would not have weight to lose. Therefore, the data does not necessarily contradict Prof. Longo’s position.

Further adding confusion, while it is often reported that caloric restriction significantly extends lifespans of both yeast and rodents as a matter of consensus,192021 a 2014 review and meta-analysis of 40 publications on life extension in yeast concluded that calorie restriction alone did not significantly extend lifespan and that outcomes are condition-specific.22

Furthermore, a review and meta-analysis on rodents concluded that rats respond significantly better to caloric restriction than mice and that the research has been biased by the use of laboratory-bred, gene-altered species, as wild mice have not shown an extension of lifespan with dietary restriction.23

The evidence on caloric restriction seems strongly based on preliminary assessments, but numerous variables and unknowns as well as contradictory data, and a dearth of evidence in humans leave the prognosis of dramatic extension of lifespan bleak, and the thought of subjecting oneself to a lifetime of stress less than appealing, at least in my opinion.

Combined with the evidence that fasting could match the benefits when done even intermittently twice a year, and rodent evidence that markers improve in just two weeks of caloric restriction,24 and another showing that benefits last for weeks after ad libitum feeding begins,25 I cannot fathom subjecting myself to a lifetime of caloric restriction. I personally found fasting to be a relatively simple endeavor.

Valter Longo’s Longevity Diet

Prof. Longo released a book in 2018 on his proposed “Longevity Diet” and intermittent use of a “Fasting Mimicking Diet” as a proposed alternative for caloric restriction and extended 3-5 day (or longer) water fasts. While I wouldn’t consider Prof. Longo’s longevity diet to be hormetic, his popularity and the extent in which he is tied to coverage on fasting and caloric restriction necessitates coverage of his positions.

Prof. Longo spends almost 100 pages in his book (although a more standard use of spacing, indexing, and font size could have easily reduced this to ~30 pages) weaving a story in the attempt to reframe what in essence is a pescatarian diet with specific restrictions, particularly on eggs and dairy from cows (although he does recommend hard cheese from sheep and mentions yogurt from goat’s milk, etc.).

He brings up centenarians and the diets found in the various “blue zones”, areas in the world with statistically very high rates of individuals living to and past 100, emphasizing more on their diet and lifestyle than genetics.

I forced myself to think long and hard about Prof. Longo’s positions. After watching several of his podcast interviews totaling hours of time listening to his positions and beliefs and reading his book, I was quite aware of a halo effect I had. Prof. Longo is quite transparent with his biases, criticizing pharmacology and the pharmacological approach to disease management, using statins as evidence. Criticism of statins is widespread, however, the ineffectiveness of statins for improving mortality is not evidence other drugs do not and cannot work.

Prof. Longo contradicts himself by using his own family, and the anecdotal prevalence of obesity and heart disease in his relatives from Chicago compared to his relatives in Italy, as evidence that diet is more important than genes.

He then goes to claim the explanation of Emma Morano’s incredible longevity, the second-longest living European recorded and longest-living Italian, an “example of good genetics, as her diet was poor.” Emma consumed 3 eggs a day, which does not fit into Prof. Longo’s position. Prof. Longo states, however, that his friend Salvatore Caruso, who does not make the list of the 100 longest lived Italians, was a perfect example of longevity from adhering to an ideal diet and not genetics.

Prof. Longo is also quite noticeably proud of being Italian and excited about areas where he had spent a childhood being among those of the longest-lived. His dietary recommendations tend to be skewed to the Italian side, drawing stronger conclusions on an Italian town of 2,000 inhabitants, rather than for instance the more logical skew, statistically speaking towards those in Okinawa, Japan, and the 1.4 million inhabitants.

Sitting back and carefully considering Prof. Longo’s position, I tend to agree with much of what he says, despite my “bullshit detector” going off while listening to him quite frequently. I have long been of the position that a modified pescatarian diet was likely the best choice for health.

I have even discussed adopting a modified version of this lifestyle with my spouse, who has recently gone vegetarian. The benefits of the diet extend into sustainability as well, with Lord Martin Rees, a renowned British cosmologist, and astrophysicist, suggesting at a talk I watched live years ago that the planet could sustain 35 billion people if everyone simply lived in high rise condos, ceased to own pets, and ate a pescatarian diet. Contributing to his position that fish protein intake should be limited to a few times a week and in small quantities, this study on caloric restriction showed that IGF-1 does not increase in humans even under caloric restriction unless protein is also reduced.26

When stripping away his biases and storytelling, I believe the longevity diet is prudent advice based on the best evidence we have. That said, other considerations need to be considered, such as the pursuit of athletics for enjoyment. Competing in sports typically isn’t done for health and longevity, but passion and enjoyment. I cannot imagine a lifestyle in which I didn’t exercise more than what is deemed “moderate and healthful.” I still exercise above this level, while waiting for surgery, just greatly modified to avoid my injuries.

I’ve attempted to eat diets closely related to Prof. Longo’s longevity diet in the past and simply could not function while exercising to even an above moderate level. Upping my vegetables and nuts caused digestive distress, and increasing my whole grains from pasta, brown and wild rice, and whole-grain breads caused gains in adipose tissue and not muscle fibers.

Training above a light 30-45 minutes a day, I found I cannot function without the inclusion of eggs and daily meat protein intake. I may be an exception and cannot prove I am not, or could not eventually get the protocol to work under some modified increase of both nuts and whole grains, that said I am not convinced that the suggested dietary interventions and restrictions are the answer for everyone, always. They may simply be a good guideline for most people, most of the time.

VL’s Fasting-Mimicking Diet

Prof. Longo developed the fasting-mimicking diet (FMD) as he believed acceptance and observation of a sustained three day or faster to be unlikely and difficult for most individuals, and that potential health hazards would exist for a portion of the population. Based on quick math, his five-day FMD protocol is very close to the total caloric deficit of a three day fast, based on the standard 2,000 calorie diet. Based on 2,000 calories, a three day fast puts a stress on your body to account for 6,000 calories, first by exhausting glycogen stores before moving to fat burning or ketosis.

During the FMD, Prof. Longo recommends a 1,100 calorie day one, split evenly between carbohydrates from vegetables, a small number of proteins from nuts, which also contribute to fats alongside a bit of olive oil, before moving to the same 50/50 split days two to five, but on 800 calories. Over the five days, an expected 10,000 calories becomes a deficit of 5,700 calories (300 less than a three-day water fast), with the elimination of animal proteins and a decrease in total proteins (likely) contributing to a similar decrease in IGF-1 as would be expected in a three day fast. The FMD also comes with a very low glycemic load and low total sugar and carbohydrate intake, which I would hypothesize would lead to ketosis. To experiment on this, I subjected myself to the FMD and this is my experience:

I will note that mathematically Prof. Longo’s FMD is a larger stress to me than a three day fast. I am a larger than average man with significantly more muscle mass than standard. Since my injuries, I have also put on considerable fat mass, but have dropped 16 pounds in four months, or roughly a pound a week, while not just maintaining but increasing muscle mass, on a ~3,000 calorie a day diet. A three day fast put me on a ~9,000~ calorie deficit, whereas Prof. Longo’s FMD will put me at a deficit of ~9,700 calories.

Day 1 

To make sure I was closely matching my experience from the three-day water fast, I started the FMD with a high protein and fat/low carb meal right after a soccer game. Since before the soccer game my spouse had run a marathon, I also tracked about 8 km of movement parking and jogging to see her at various spots (7x, 8x if counting a drive-by). I tried to be active during day one, doing a short work out, working up a heavy sweat moving around totes and bins at my R&D facility and then going for a 2 km walk in the evening.

I had diligently mapped out my daily meals of almonds, green vegetables, and two tablespoons of olive oil. I choose to err “low” in calories in every measurement, maybe totaling ~780/day, coupled with needing more calories than the average person. Day one was almost as challenging as day one on a water fast. I was irritable and constantly hungry. I had serious issues falling asleep and ended up “sleeping” for 10 hours, or rather spending 10 hours in bed.

Day 2 

I woke up on day two of my FMD with a splitting headache. My blood-glucose was not altered from my typical readings, at about 5.1 mmo/L or 92 mg/dl. I didn’t bother to check for ketones as I was certain I was not yet in ketosis. As a result of my blood glucose being much higher, I opted to take AGEless Defense during the FMD as several of the ingredients are known to be “caloric restriction mimetics.” I tried to have my “breakfast” and the food only further agitated me. My headache became worse and my food cravings higher. My mouth was watering constantly throughout day two and I bit almost everyone’s proverbial head off that I spoke with. I was cranky, aggressive, stupid, and managed very little productive work.

I had an indoor soccer game at 7:30 pm that I did not want to show up to. Since it was my last game for my men’s team before shoulder surgery, which would have me sidelined for months, I went despite feeling awful. I wasn’t very optimistic about my ability to play and warned my teammates. My first shift went quite poorly. I was low on energy, tired quickly, and wasn’t recovering. I contemplated telling my team I couldn’t play another shift. We were short on subs as some of our players were late to show, so I went back on for another shift thinking I would just coast. I was playing mid and figured I needed to be more defense-focused due to limited energy.

A chance break with one of my teammates, and the forward being caught back had me sprint the end of the field for support. I one-timed his rebound missing just high, then headed my own rebound in. I tell this, not to brag about my low-level rec soccer accomplishments, but because interestingly instead of being “gassed” from a full sprint at the end of a normal shift I felt charged. My skin was buzzing.

I played the rest of the game at mid (I am usually a forward), running up and down the field much easier than I typically manage. I ended up getting another goal, a one-timer on a full sprint, which surprised me as lately my coordination in a full run has been clumsy and reflexes slow, or at least much slower than my own self-perception. This was my first two-goal game of the season and I was playing mid, not forward. It was also the first game in quite a long time where I was coming off the field when I was out of breath and not because my muscles were exhausted.

After the game, I went upstairs with some others and talked as they had wings and beer. This was by far the closest I came to giving up. The smell of the wings had me in a frenzy. My mouth was watering. I tried to break my stare on the wings and had myself looking at an empty spot of the table. A lid from a blue cheese dip container was in the corner of my eye and soon I was fixed, staring at it.

I’m not sure how much time went by staring at the blue cheese lid, battling myself on not picking it up and licking the sauce. I was in my own world, fighting a battle. I’ve never been addicted to a drug, but this is the closest thing I could relate to. My breathing was altered and I couldn’t hear what others around me were saying. The “owner” of the blue cheese lid finished his wings and piled all the trash on his plate, freeing me from my gaze.

I was upstairs with others for almost an hour and a half, but on the drive home I could recall all of 10 minutes of conversation. I had just been “gone,” and when I was part of the conversation I was unpleasant. At one point I needed to use the restroom, finding the one upstairs in the pub was closed for maintenance so needed to go downstairs. I stared at the stairs and almost gave up and went back to my seat. A single flight seemed daunting. I knew I wouldn’t make it home, so pushed through and went down, again feeling a rush of energy after using the restroom and washing my face with cold water. I jogged back to the stairs and went to run up them. I made it halfway and felt dizzy, clinging to the railing. A friend and teammate started walking down as I was about to sit down on the stairs and I changed my mind, struggled up, and went and told everyone I was going home.

I made it home and could barely manage to drink some water, brush my teeth, and crawl into bed. My head was spinning, I couldn’t even shower. I passed out early and slept solidly for 9 hours.

Day 3 

I woke up after 9 hours of sleep and could barely roll over in bed. I was weak and dizzy. Half an hour went by and finally, I was able to pop up with ample energy. When I finally managed to get up, I felt “good,” or at least relative to how I had felt half an hour before. I measured my ketones right away, and sure enough trace levels were detectable. I measured my blood glucose at 4.6 mmol/L or 84 mg/dl. I was quite behind on some e-mails and spent the first hour catching up and another hour writing.

I didn’t “want” food but wanted to adhere to the protocol properly so had my breakfast. Almost immediately my brain function became impaired; I became agitated and all I could think of was food. About an hour went by and I accomplished maybe 5 minutes of total productivity. Another hour went by and I slowly started to feel OK again. I was able to start writing and responding to e-mails and started remembering tasks that had vacated my consciousness an hour before. My muscles, that said, were devastated. It was an arduous task to take the garbage out.

To keep my body working and mimic my behavior from the three-day water fast, I decided to try a round on my Thai bag. While walking out the garbage was a daunting task that proved to be laborious, once my heart rate elevated I was able to get through a few rounds on the bag with no problem. I felt fine, my reflexes and speed were as normal. I tried to pick up some weights to do some bicep curls and deadlifts, and that was a mistake.

Within a few reps, my muscles were tasked on the curls and my elbows hurt. I went to try some light deadlifts and by rep two my back was pinched, although minor. The work out did increase my energy levels and I was able to plow through more work, more tasks, and get more writing done.

One thing I noticed is that hydrogen water seems to have less of an impact during the FMD for the biggest side effect: headaches. During the water fast, the biggest downside was the lethargy. Using a hydrogen tablet would charge me up for a time and I would be good to go. During the FMD, while I experienced a burst in energy after drinking the high dose hydrogen water, my headache wasn’t going away.

The worst of the water fast was the waves in energy and how I would only get work done in a couple of hour spurts a day after drinking hydrogen water. I was getting much more done on the FMD, but the biggest side effects had no solution.

Interestingly, “dinner” on day three led to an increase in energy and satiation for a couple hours, with a yo-yo to the worst I felt so far. Perhaps a combination of burning ketones with a small burst of calories allowed my body the energy it needed for a moment. My stomach, or ability to eat, shrank dramatically. The small bowl of vegetables and almonds filled me up. I needed roughly 30 minutes to finish the bowl completely. This is anecdotally an even more aggressive temporary reduction in appetite than I experienced in my first meal following the actual complete three-day water fast.

The burst of energy ran out suddenly and I stopped writing mid-sentence with a spinning and throbbing headache. I ended up going to bed hours before I typically do and fell asleep. If only I could stay asleep… I shot up awake around when I usually fall asleep, my body tingling a high. I went to the bathroom and checked my ketones. Sure enough, they were somewhere between 1.5-4 mmol/L.

I spent the next two hours, however, salivating, thinking about food, and what I would eat when this was over. If I had any food in the house other than for my FMD, I may have actually cracked.

Day 4 

I woke up on day four feeling weak and exhausted. I checked my ketones and they hadn’t moved from the night before, my blood glucose being 4.5 mmol/L or ~82 mg/dl. I wasn’t capable of having a hot then ice shower, even starting it off close to hot, my body didn’t take it well. I settled on a lukewarm shower.

I had shockingly lost 9 lbs waking up the start of day four when during the water fast I was only down 7 lbs by the end. While I was not tracking water intake, it was well above usual, plus the vegetables I was consuming are high in water content.

Day four struggled on, feeling like day two of the water fast. My energy was up and down, with periods when I felt OK, and periods I had to sit or lie down. I was able to get periods of work done while at other times my brain would shut off and I couldn’t formulate sentences.

After “dinner” on day four, it felt as if I had turned a corner. I was able to do a few hours of solid work and then managed through 3x five-minute sets on the Thai bag at a reasonable pace. My body was no longer “tingling” when I experienced energy rushes nor crashing moments later. Towards bedtime, I was exhausted, my head hurt again, and I had fairly intense cravings; although not as bad as days two and three.

Day 5 

I woke up day five feeling like a train had run me over. My muscles were sore from the 15 minutes on the bag, my head was spinning, and I lacked energy. It took me 45 minutes to get out of bed. My blood glucose and ketones were identical to day four and I had lost another pound. I slowly got going and ate my entire daily allotment of almonds. I had a busy morning and needed to get through it.

I was doing R&D scale up tries at my facility, dragging containers around, lifting buckets, barrels, and bags weighing ~50-100 lbs, and felt fine. I worked up a huge sweat and the more I worked, the better I felt. I put in a solid four hours of fairly strenuous manual work before heading home to take care of e-mails and writing, etc.

By the time I got home, I was getting hungry. I drank 1.5 L of water and that took care of my hunger pangs for a while. The last bit of my fast finished up the easiest. Right before finishing, I tested my ketones and blood again. My ketones were well above 8 mmol/L, significantly darker in the urine test but not yet at the next measurement of 16 mmol. My blood-glucose was 3.8 mmol/L or 68 mg/dl. It was hard to draw my blood, I failed twice. My hands were shaking, and I couldn’t get the drop in the sensor.

Research on FMD

There is some early research on the FMD published. For instance, a randomized trial of 100 participants found benefits in the FMD in reducing body weight, body fat, and blood pressure.27 Several studies in rodents have found benefits in the FMD for improving the microbiota and function of the gastrointestinal system,282930 which may contribute to observations of diabetic reversal in mice.31

Elsewhere, the FMD has been studied for its role assisting chemotherapy treatment, specifically targeting cancerous cells,3233 and in assisting in various autoimmune diseases.3435 As per Prof. Longo, numerous teams around the world are currently utilizing the FMD in studying numerous conditions and I (and others) are anxiously awaiting further results and data from human trials.

Hormesis - Calorie Restriction Conclusion

Personally, I do not believe a lifetime caloric restriction is a viable option for life extension, based not only on the difficulty of the task but the potential downsides of caloric restriction for the elderly. As for the fasting-mimicking diet, it was an interesting experience and has interesting data.

From a personal standpoint, I found a three-day water fast to be much easier mentally. That said, I got substantially more work done during the FMD, I was just extremely grouchy and miserable. This may be a matter of personal preference and if the results are the same (and my markers were very similar), the FMD gives a viable option for those who may have a significantly harder time with a water fast than I did.

Perhaps the minimal nutrient intake and repeated shocks to the system confer added benefits in the FMD over a water fast, an argument I have heard from a few. As of now, I am unsure of the data points either direction and until it does, I would suggest both options be viewed as equal and chosen based on personal experience and the likelihood of adherence.