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  1. All, Despite low levels of white blood cells, anorexics have been found to be less susceptible to certain viral infections, at least until very advanced stages of the disease [2,3]. Anecdotally, the same has been reported in CR practitioners. While anorexia is far from a perfect model of CR as properly practiced (i.e with less extreme restriction and with adequate nutrition), a lot can be learned from people who severely restrict calories even without adequate nutrition. Thanks to Al Pater for pointing to a new study by our friend Luigi Fontana and his team which investigated the effects of anorexia on the immune system and other blood parameters. The researchers tested the blood of 15 young (15-24) anorexics (avg BMI 15.9) and compared them with age-matched controls. The anorexics had lower IGF-1 and leptin hormone levels, which is also a typical response in CR practitioners. They also had fewer peripheral blood mononuclear cells (PBMCs), which basically comprise several types of the white blood cells responsible for the bodies immune response, including lymphocytes (including natural killer cells), monocytes, and others. This too is commonly observed among CR practitioners. PBMCs from the anorexics that were cultured for two days produced fewer markers of inflammation than controls. The anorexics cells also generated more endogenous antioxidants, and were therefore 24% more stress resistant when exposed to a pro-oxidant (H2O2) than those of controls. They concluded: [O]ur data suggest that excessive CR in AN patients is associated with a reduction in several key immune cell populations, impaired metabolic activity, but preserved immune function. Moreover, our findings suggest that chronic severe CR in young AN patients results in an enhanced anti-oxidant and anti-inflammatory status, which may protect cells from biochemical stress. This study suggests that what may appear like a compromised immune system in CR practitioners (based on numbers like our low WBC count) may actually be a sign of a more efficient and perhaps more robust and effective immune system. It would be nice if someone would do a study in which they directly expose CR practitioners or anorexics (or their immune cells) to an explicit viral challenge to directly test whether our immune systems are more effective at fighting off infections. --Dean -------------- [1] Metabolism. 2015 Mar;64(3):396-405. doi: 10.1016/j.metabol.2014.10.025. Epub 2014 Oct 29. Immune-metabolic profiling of anorexic patients reveals an anti-oxidant and anti-inflammatory phenotype. Omodei D(1), Pucino V(2), Labruna G(3), Procaccini C(4), Galgani M(4), Perna F(5), Pirozzi D(6), De Caprio C(7), Marone G(2), Fontana L(8), Contaldo F(7), Pasanisi F(7), Matarese G(9), Sacchetti L(10). CONTEXT: Anorexia nervosa (AN) is an excessive form of calorie restriction (CR) associated with pathological weight loss and alterations of the immune system. However, AN patients seem to be protected from common viral infections. OBJECTIVES: To investigate the metabolic and molecular adaptations induced by sustained extreme CR in the peripheral blood mononuclear cells (PBMCs) of patients with restrictive alimentary AN. DESIGN: Inflammatory cytokines and adipokines were measured in 15 young (age range, 15-24 years) AN female patients and 20 age-matched healthy controls. Isolated PBMCs were immunophenotyped by flow cytometry, and glycolysis and mitochondrial respiration were determined by measuring the extracellular acidification and oxygen consumption rate. Stress resistance to H2O2 and the antioxidant transcriptional profile of PBMCs and human fibroblasts incubated with sera from AN patients were also determined. RESULTS: Compared with controls, AN patients (BMI, 15.9±0.4 kg/m(2)) had significantly fewer leucocytes, lymphocytes and NK cells, lower serum concentrations of leptin, IGF-1 and sTNFR1, and higher levels of adiponectin, sCD40L and sICAM-1 (p<0.05). IL-1β, TNFα, and IL-6 produced by PBMC cultured with autologous serum for 48 h were significantly lower in AN patients than in controls (p<0.01). Moreover, glycolysis and mitochondrial respiration were lower, and the antioxidant transcriptional profile was higher in the PBMCs of AN patients. Fibroblasts cultured in serum from AN patients showed a 24% increase in resistance to H2O2 damage. CONCLUSIONS: Extreme CR in AN patients is associated with a reduction in several immune cell populations, but with higher antioxidant potential, stress resistance and an anti-inflammatory status. Copyright © 2015 Elsevier Inc. All rights reserved. PMID: 25500208 ------------------ [2] Eur J Clin Nutr. 2002 Aug;56 Suppl 3:S34-7. The adaptive response of the immune system to the particular malnutrition of eating disorders. Nova E(1), Samartín S, Gómez S, Morandé G, Marcos A. Author information: (1)Instituto de Nutrición y Bromatología (CSIC), Edificio Instituto del Frío, Madrid, Spain. Despite the seriously undernourished state of patients with anorexia nervosa (AN) and bulimia nervosa (BN), controversial findings have been published regarding some aspects of the immune system that are otherwise impaired in more typical types of malnutrition, such as protein-energy malnutrition. In general, adaptation processes seem to occur enabling immune function to be preserved during long periods of the illness. However, cell-mediated immunity is usually altered in AN and BN as reflected by lymphocyte subset counts and the response to delayed hypersensitivity tests. Regarding the helper/cytotoxic T cell ratio (CD4:CD8), an immunological marker of the nutritional status, the results of our studies on AN and BN patients showed that the duration of the eating disorder and the time when appropriate treatment is achieved are likely contributors to the alteration of this ratio. Despite these findings, it has been repeatedly pointed out that anorexic patients seem to be free of common viral infections at least until the most advanced stages of debilitation. Some hypotheses that could explain the lack of infection symptoms are reviewed. Cytokines and the altered acute phase response to infection, as well as cortisol and leptin, are considered to be potential factors involved in the adaptation processes occurring in these syndromes. Further progress in the knowledge of the psychoneuroendocrine-immune interactions established in AN and BN will be relevant to the understanding of the aetiology and maintenance mechanisms of these pathologies. PMID: 12142959 ----------------------- [3] Eur J Clin Nutr. 2000 Mar;54 Suppl 1:S61-4. Eating disorders: a situation of malnutrition with peculiar changes in the immune system. Marcos A(1). Author information: (1)Instituto de Nutrición, Facultad de Farmacia, Ciudad Universitaria, Madrid, Spain. amarcos@eucmax.sim.ucm.es Eating disorders, such as anorexia nervosa and bulimia nervosa, are significant public health concerns for a great deal of the population, and thus are even considered to be epidemics. These syndromes have a common aim: the pursuit of a desirable and extremely low weight, which is obviously very far from the ideal body weight. Therefore, these patients show abnormal food behavior, leading to a situation of malnutrition. Nutrients play an important role in the development and functionality of the immune system. Thus, the assessment of immunological parameters acquires great interest as a useful tool to evaluate the nutritional status of these patients. In addition, it is very well known that a depleted immune system as a consequence of malnutrition is linked to an increased susceptibility to infections. However, an extensive literature has pointed out that anorexic patients, even though severely malnourished, are relatively free from infectious diseases. As the immune system is altered by distorted food behaviors, such as in case of eating disorders, the awareness of the characteristics of other systems involved in these pathologies, and therefore altered, would be very helpful for the understanding of the mechanisms triggered in these syndromes. In fact, the interactions among the immune system and the remaining systems in eating disorders are beginning to be studied. Finally, the main goal is to limit the evolution of these illnesses through an early diagnosis and appropriate therapy to subsequently get a constant and definitive cure for the patients. PMID: 10805041
  2. Hello! I am a woman of reproductive age and am interested in the idea of CR. I am looking for information on how this affects the hormonal profile and function, and whether it causes amenorrhea, and if so, whether this is by default a bad thing. Most of the information on amenorrhea I can find tends to refer to anorexic or overly athletic individuals and classifies this as a non-desirable or pathological occurrence. However, I have read before that having fewer periods and lower levels of female hormones can have a protective effect against cancers. If I go on a CR diet, will I be at risk of losing my periods, and is this dangerous to my health if so? What is the experience of other CR women, and have their been tests or studies on this particular topic? Any help pointing me in the direction of resources on this topic would be greatly appreciated. Thank you!
  3. All, Recall the cautionary tale of a CR veteran, Warren Taylor, that I posted a while back. Here is another profile from a friend and former CR practitioner who I happened to communicate with off-forum, and who agreed to share his story anonymously so that others might learn from his CR experiences. Note - some people may say "he wasn't really practicing CR, he had an eating disorder. And he only did it for a year - so it wasn't long-term CR." But in his mind at the time, he was practicing CR, and so his experience should be of interest to anyone else who believes themselves to be practicing CR. First I asked him to share some CR-related biographical information. Here is our Q&A: 1. How old were you when you started CR? I was about 20 years old, in my junior-senior year of college. 2. Had you had eating problems before then, or other health problems that motivated you to start CR? No. In my senior year of high school, I became very depressed and isolated. I would "wait" to eat my school lunch until after school ended, when I was then starving and scarfed it down. But I did not do this with any conscious intention of being CR (I was unaware of CR), anorexic, or bulimic. I just thought it was a fun game to play. In hindsight, I think it shows that certain people are drawn to CR and dieting naturally as a kind of masochistic reward or social signaling mechanism. After I spent a month in a mental health hospital to recover from the eating disorder (recovery can be much easier for men than women), I later discovered that I have many symptoms associated with Asperger's Syndrome. I have never been diagnosed, the DSM criteria keep changing (it's a spectrum disorder), and psychiatrists use about 5 different diagnostic forms, which vary in their strictness by orders of magnitude. I'm clearly on the very high functioning end of the spectrum, but I nevertheless realized that I have many symptoms associated with AS (including low body weight, obsessive thinking, eating disordered behavior, depression, etc.). Reading about AS and proactively taking steps to counteract it was a real turning point for me. (The eating disorder clinic never suggested AS, which I find shocking in retrospect.) I should add this to the checklist of warning signs: do you have symptoms associated with AS? Eating disorders are relatively rare among men, but they are much less rare among men with AS (and most people who have AS are men). 3. How long did you practice CR? I practiced it for about the year of my eating disorder. I don't remember exact starting and stopping dates. I was basically incredibly depressed and disordered my junior year of college, went to the hospital that summer, and was pretty much recovered by the middle of my senior year in college. 4. What BMI were you when you started and how low did you get while practicing CR?' I don't remember my BMI. But I got to 104.5 pounds on the scale at 6 feet tall. You could see my heart beating through my chest (very very slowly). 5. How long did it take to extricate yourself from your troubles resulting from CR? After I told my mother and father, I basically stopped vomiting, which led to stopping restricting calories. The first few times I binged and wanted to vomit, it was hard to resist, resulting in some emotional breakdowns and some tearful calls to my parents. But after that, I stopped. BTW in the eating disorder clinic, I was surrounded by about a dozen girls and no guys. One of the girls had a heart attack and died. Another girl left the clinic, relapsed with extreme alcohol poisoning and ended up back in the emergency room and clinic. Two of the girls became my friends (at the same college) and later confessed that they lied the entire time in the clinic and never stopped purging. Ever. They were out patients and they purged before they came into the clinic, purged during the clinic, and purged after. They were shocked that I actually stopped without lying. My conclusion is that stopping an eating disorder, and vomiting, is much harder for the average female patient than male, mostly because of the intense social pressure for women to look skinny, which does not really apply to men. 6. How long have you been free of those troubles, and what is your BMI now? I have not really thought about CR, calories, or eating disorders for over a decade, after I graduated in 2004, went to law school and now practice as a lawyer. The only reason I am even thinking about these things now is because Dean's birthday reminder popped up on Google Calendar and I wanted to send him a card. I don't know my BMI now, and I never calculate it, but I weigh about 155 pounds, which is about 50 pounds more than at the depth of my disorder. Obviously, I am still quite slender for my height, but this seems to be my natural set point because I eat whatever I want, whenever I want, without really thinking about my weight or calories. If anything, I try to gain weight, which is surprisingly hard for me to do past my current weight. 7. Someone with a speciality in eating disorders has contacted me privately about promoting CR to anorexic young women as a way to at least get them healthier by focusing on their health and nutrition. I can see the logic of their idea, but I am extremely reluctant to endorse such a strategy knowing how easy it is to hide destructive behavior by couching one's lifestyle as CR. What are your thoughts? I agree that this is a horrible idea. People with eating disorders typically need love, reassurance, and a rich network of friend and family support, rather than something risky and extreme like CR. In many cases, eating disorders develop from severe emotional, psychological, and social problems, and dealing with those problems can address the symptom of the ED. But eating disorders are also highly deadly and in many cases resistant to treatment. I am not an expert and I do not know what the solution is to resistant EDs, but I'm sure that CR is not it. The anonymous former CR practitioner then said the following: Here are some general thoughts about CR and eating disorders. These are all based on my own understanding, as an outsider who has not really thought about CR for over a decade. Note: I have not kept up to date on human and animal trials involving CR, but all of the ones that I've read about previously generally reported mixed results at best. 1. The longevity benefits of CR are controversial. For example, some experts like Aubrey de Grey have argued forcefully that CR may only provide diminishing returns for species as big as humans. CR may nevertheless provide "squaring the curve" benefits, rather than longevity benefits. It is difficult to know how powerful these benefits would be without RCTs. Statistical, lower body weight is associated with several bad life outcomes, but it is difficult to distinguish causation from correlation. It is plausible, however, that CR can result in irritability, decreased ability to move or exercise (because these require calories), lower sexual performance and attractiveness, and lower resistance and resilience to some stresses (CR is essentially a type of stress, which would be added on to the other stresses of life). Considering how important social life, sexual life, movement and exercise, and resilience to stress are to human happiness and flourishing, it is plausible that one or more of these drawbacks (if realized) could significantly or entirely undercut the alleged benefits of CR. That would also help explain statistical studies showing that lower body weight is sometimes associated with increased mortality, rather than decreased. 2. In one interpretation, the idea of CR is based on a type of hormesis: an optimal middle-ground of stress triggers repair mechanisms that create a net benefit. But it is difficult to determine what the "Goldilocks" point of hormesis is, instead of applying too little or too much stress. Remember also that other things (e.g., exercise) arguably work through a hormesis effect, and there can eventually be a necessary trade-off between one form of hormesis and another. It's not clear what the optimum level of CR is, or the optimum level of exercise, but a rigorous program of CR probably prevents you from exercising as much as you might otherwise. 3. CR tries to work by systematically and perpetually keeping your body below the "set point" at which it would normally try to stay. In other words, feelings of hunger, irritation, or distraction are virtually impossible to eliminate on most any CR program that is sufficiently rigorous. It is hard to overstate how difficult it is to overcome your body's set point. To see one example: studies repeatedly show that dieting (which is similar to CR) does not work for most people, most of the time, and often results in greater weight gain in the long run. Another way to think of this is that you maintain your own weight (mine is about 155 pounds), pretty much the same, throughout the entire year, putting aside minor fluctuations. Yet most people do this without any conscious thought, calorie counting, etc. People do not think "oh, I've eaten precisely 1895 calories today, but I need to eat 1923 to maintain my set point, so I need to eat X number of raisins." Instead, the body's own incredibly complex and powerful system of metabolism and appetite regulation does this automatically, through automatic regulation of hormones like leptin and ghrelin. All of this shows that trying to fight your body's automatic self-regulating appetite system is incredibly, incredibly hard. 4. Because there are strong, good faith arguments that CR provides some benefits, CR can serve as an excellent cover and rationalization to disguise an eating disorder. When I became heavily involved with CR, I was (A) depressed and (B) very isolated. I started restricting calories using the excuse of CR. I'm a fairly smart person (Merit Scholar, patent attorney), and I so I was able to defend my rationalization strongly. Note that, as far as I can tell, pretty much the only difference between CR and dieting is that CR requires you to ensure that you obtain enough micronutrients, which could be solved by something as simple as taking vitamins and/or eating lots of spinach and other vegetables. Thus, as long as you keep obtaining those micronutrients (i.e., taking your Flintstones vitamins, eating your spinach), as well as a baseline of the essential macronutrient, protein, you have pretty wide discretion in restricting calories and losing weight. It is far from clear what level of calories/weight in humans brings you the benefits of CR, what is the optimal level of calories/weight for CR, and/or when calories/weight becomes so low that you lose the benefits and incur net-costs, becoming disordered. Remember, it is far from proven that CR provides net benefits in longevity for humans, or even any net benefits, after you factor in all of the potential costs and risks! With so much discretion, the CR practitioner has a lot of room to go in restricting calories, losing weight, and entering disordered territory. 5. Of course, there were definitely clues that my behavior had become disordered. Here are some that I would list that others can check for: Are you lonely? Are you depressed? Do you have an active and healthy emotional and social life? Do you have a rich network of friends and family who love and support you? Do you have any other disordered behaviors (drugs, alcohol, cutting)? If any of 1-4 are not true, I would correct that before trying something as risky and potentially dangerous as CR. Are you self-inducing vomiting, ever, to maintain CR goals? I rationalized the first time I threw up, saying "well, even if vomiting once has costs, they have to be small in comparison to all of the huge benefits that Roy Walford and other experts announce for CR." Then I vomited twice. Every time I just blamed myself for lacking enough self-discipline and promised to do better in the future. I would say "even if I have thrown up too much now to obtain a net benefit from CR, I will in the future when I do it right without throwing up." Soon I was full blown bulimic. Is any part of your CR behavior secretive? My calorie restriction was fully open to the public, defended by my overly intellectual mind, but my bulimia was secretive. How is your heart health? Mine showed mitral valve relapse, which was likely exacerbated by poor CR, bulimia, and over exercise. Another doctor has told me that nearly all naturally skinny, and healthy, people have a mild heart murmur. According to my last check up, mine is gone now. However, this was a big red flag at the eating disorder clinic. The last part I would reemphasize is that CR is incredibly difficult to do. To see this, ask yourself how active the CR forum/list is, and on the list, how many people practice CR (1) rigorously, (2) for an extended period of time of many years, (3) without cheating or compromising their health, (4) long enough and well enough to be confident that they are seeing CR benefits to justify the risks? Back when I was involved, there seemed to only be about a handful of people on the list who did this, and I am guessing that the list was pretty representative of the entire world. Even if you multiplied that number by 5, 10, 100, or 1000, it still results in a tiny, tiny, tiny fraction of the world's population who successfully practice CR in a meaningful way. I would suggest that this tiny tiny number is very telling: it tells you how incredibly difficult it is to actually do CR right. Human biomechanics and automated appetite regulation are incredibly powerful and complex things - they were not meant be messed with lightly. In view of the above, I'm highly skeptical that CR is right for the vast majority of people on earth, excluding possibly extremely smart and disciplined (nearly superhuman) individuals like Michael Rae and Dean (and even in their case, I am not 100% convinced, and perhaps they aren't either given the uncertainties involved, but I'm also far from fully informed on their progress and latest science, nor do I have much interest in picking a fight or winning an argument). For the vast majority of mere mortals, I suspect that you can obtain most or all of the benefits you are looking for by maintaining a vigorously healthy life in terms of diet, exercise, social flourishing, and retirement planning (which can potentially let you take advantage of cutting edge technologies near the end of life). You can read a lot more about this research in fantastic books like Aging Well and The Longevity Project, which teach numerous proven techniques for aging gracefully and living marginally longer without any reference to incredibly difficult, risky, unusual, and extreme behaviors like CR. For example, you could simply buy a treadmill desk and work hard to build a solid network of friends and family. What I am absolutely sure of, however, is that CR is not for me. Nevertheless, I still consider Michael Rae, Dean, and others to be geniuses and role models whom I treasure as friends. Later, he sent me the following additional thoughts: I want to follow up on some things in my earlier email: Yes, I recognize that people can exercise and do CR at the same time. For example, a person doing (A) CR at 1500 calories with no exercise could also also do (B) CR at 2500 calories and 1000 calories of exercise, still resulting in a calorie deficit. I don't think there is any conclusive evidence about whether (A) and (B) both create net benefits in humans or which one is superior. I don't want to put too much emphasis on my off-the-cuff remarks about exercise. My point is simply that CR theoretically works through a kind of hormesis, there are other options for hormesis out there (exercise, temperature stress, etc.), and these different types potentially conflict. People on rigorous CR typically don't have the strength and energy to do extended vigorous exercise, which plausibly prevents them from obtaining benefits that are unique to extended, vigorous exercise. Even if I'm wrong about this, you can just ignore this point and focus on the rest of what I say. Yes, I recognize that CR is typically described in terms of calories, not weight, but I referenced weight several times. It is a natural consequence of significantly lowering calories that you tend to lower weight. Weight is a good (excellent?) proxy for calories, and so I don't pay much attention to this distinction. The other point I wanted to bring up was the replication crisis in social science and (relevant here) medical and nutrition science. Researchers like Stanford's Ioannidis have done groundbreaking work exposing the huge problems and errors in wide swaths of medical science. This is true for allegedly proven results that make newspaper headlines all over the world (salt is bad for you!). It will be even more true for research, like CR research, that is already couched in terms of numerous uncertainties. This is not to say that CR is definitely proven to be bad or unhelpful in humans. But it is to say that if you, like me, are looking for a reason to avoid CR and the associated risks of eating disorders, the simple fact that the science underlying CR, and much medical science, is surprisingly weak, is an excellent reason to cite as justification. You will sometimes hear people say "yes, this is not a rigorous double blind RCT that has been replicated several times, but those are too difficult or expensive or unethical to do in humans, and this is the best evidence we have, so we have to use this evidence as our primary guidepost." No you don't. If you have bad evidence, then you know very little, don't pretend otherwise. A lack of good evidence doesn't elevate bad evidence to some superior position, which lets you steer your life more correctly. It's just bad evidence, noise, deal with it, and don't pretend that it's something that it's not. You can read about Ioannidis here, where he concludes: "Science is a noble endeavor, but it’s also a low-yield endeavor," he says. "I’m not sure that more than a very small percentage of medical research is ever likely to lead to major improvements in clinical outcomes and quality of life. We should be very comfortable with that fact." --------------------- End of transcript I think we should all be extremely grateful for the courage, time and energy this friend was willing to commit in order to share his experiences with us. At the very least we should all think carefully about our own practice of CR and other lifestyle choices, to see if we might be ignoring warning signs of potential problems with either our physical or psychological health. In addition, we should be willing to entertain the possibility, if only briefly, that our CR practice may be a form of eating disorder or a mask for concealing one. As this story about a former vegan's struggle with orthorexia shows, its not just CR practitioners who struggle with the blurry line between healthy and disordered eating. Presuming one is physically healthy, to me it boils down to how much CR is interfering with (vs. facilitating) one's enjoyment of life and one's personal relationships with family & friends in the here and now. Sometimes I wonder if I'm striking the best balance. If CR didn't make me feel so darn good (energetic and happy / content for no reason), I'd seriously question if it were worth it. --Dean