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  1. mccoy

    Exrteme proliferation & growth

    Riccardo Piana (better known as Rich Piana) was a former bodybuilder and social media star, very well known for his youtube videos often portraying his supermassive supertatooed body. He deceased recently in August 2017. In this video, 2 years ago, he warns kids about the use of growth factors and the damage he suffered. It is very interesting to listen from a self-experimenter the dranatic deleterious effects of the use of GH, IGF-1 and insulin on organs. Proliferation and growth of muscle tissue and all internal organs, even guts. Everything we already know from teh sceintific literature stands absolutely true in the real world. https://www.youtube.com/watch?v=ssORS0QMJe0
  2. 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
  3. All, It's been argued by respected aging researchers like Luigi Fontana that CR is likely to extend human lifespan through its effects on the somatotropic axis [2] - the signalling pathway involving growth hormone, insulin and IGF-1. In fact, Luigi argues that the monkeys in the NIA CR longevity trial may not have benefited because they may not have been restricted enough to show the biomarkers of CR-induced extended longevity, which especially includes low IGF-1, as has been observed in CRed rodents, and like he has observed in long-term human CR practitioners from the CR Society. This new review article [1] begs to differ. It uses two lines of reasoning to argue that modulation of the IGF-1 pathway via CR, genetic manipulation or drugs, won't extend human lifespan. The first argument is an evolutionary one that has been made before (e.g. by Aubrey) - that humans use different strategies unavailable to rodents and other lower organisms for dealing with food shortage - i.e. migration, and so humans wouldn't have had the evolutionary pressure to maintain the genetic machinery to hunker down and boost longevity when faced with famine. The second line of argument looks at data from a variety of non-rodent animal and human studies of the association between the IGF-1 pathway and longevity. He suggests the fact that CR didn't work in the NIA monkeys suggests it won't work in humans, although as mentioned above it's unclear how restricted the NIA CR monkeys were, or whether the CR monkeys' IGF-1 pathway was downregulated (somewhere on these forums Michael points to evidence that it was...). The author also points to data from dwarf humans with congenitally low IGF-1 who he says don't live longer. He looks at studies of gene polymorphisms involving expression of IGF-1 and says people with genetically-low IGF-1 levels don't live longer. He says studies of IGF-1 levels of centenarians and their offspring have been equivocal at best. He criticizes data showing shorter people live longer, and even questions the longevity of traditional Okinawans. He's a real skeptic, concluding: The main conclusion of this article is that modulation of the somatotropic axis does not explain longevity variations of ad libitum-fed animals but is a tool to face food shortage, leading to increased longevity in some species only. One can hope that a better knowledge of this axis could help to fight various pathologies, such as obesity not linked to an excessive food intake. However, one should give up the idea that it could help to modulate the ageing process and increase longevity of people not suffering from metabolic disorders. This post by Brett Black argues that low IGF-1 is likely to be detrimental, while the two that follow it in that thread (by me and Michael), suggest the opposite - that lower IGF-1 is indeed associated with improved longevity in humans, contra what the current paper [1] suggests. It seems hard to say who's right on this, given the evidence available to us about the effect of IGF-1 on human longevity, and (unfortunately) the evidence likely to be available to us during our lifetimes... --Dean ---------- [1] Biogerontology. 2016 Apr;17(2):421-9. doi: 10.1007/s10522-015-9632-6. Epub 2015 Dec 28. The somatotropic axis may not modulate ageing and longevity in humans. Le Bourg É(1). Full text: http://sci-hub.io/10.1007/s10522-015-9632-6 Studies in nematodes and mice have shown that the somatotropic axis can modulate their longevity and it has been argued that it could also modulate human longevity. Thus, like nematodes and mice, human beings should live longer when facing starvation and genetic variation of the somatotropic axis should be linked to longevity. This article argues that, because the life-history strategies of humans are very different from those of mice, these hypotheses are not warranted. PMID: 26712318 -------- [2] Aging (Albany NY). 2013 Jul;5(7):507-14. Will calorie restriction work in humans? Cava E(1), Fontana L. Author information: (1)Division of Geriatrics and Nutritional Science and Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO 63130, USA. Calorie Restriction (CR) without malnutrition slows aging and increases average and maximal lifespan in simple model organisms and rodents. In rhesus monkeys long-term CR reduces the incidence of type 2 diabetes, cardiovascular disease and cancer, and protects against age-associated sarcopenia and neurodegeneration. However, so far CR significantly increased average lifespan only in the Wisconsin, but not in the NIA monkey study. Differences in diet composition and study design between the 2 on-going trials may explain the discrepancies in survival and disease. Nevertheless, many of the metabolic and hormonal adaptations that are typical of the long-lived CR rodents did not occur in either the NIA or WNPRC CR monkeys. Whether or not CR will extend lifespan in humans is not yet known, but accumulating data indicate that moderate CR with adequate nutrition has a powerful protective effect against obesity, type 2 diabetes, inflammation, hypertension, cardiovascular disease and reduces metabolic risk factors associated with cancer. Moreover, CR in human beings improves markers of cardiovascular aging, and rejuvenates the skeletal muscle transcriptional profile. More studies are needed to understand the interactions between CR, diet composition, exercise, and other environmental and psychological factors on metabolic and molecular pathways that regulate health and longevity. PMCID: PMC3765579 PMID: 23924667
  4. On the thread about cranberries, Rodney got us talking about prunes, and how they may be good for maintaining bone health via increased IGF-1, which is a double-edged sword. This is pretty well-known among knowledgeable CR practitioners, but I thought it worth highlighting, particularly since I came across this interesting discussion & video on the potential tradeoff between "performance" and longevity with respect to IGF-1. It discusses (and gives citations) for many of the benefits of IGF-1, including muscle repair/preservation as well as long-term cognitive health. Interestingly, it doesn't mention helping maintain bone health as another benefit of the anabolic effects of IGF-1. But on the downside, it talks about increased cancer risk and the widely-observed reduced longevity (in humans and animals) associated with higher levels of IGF-1. Here is the summary paragraph: There you have it. It’s a trade-off when it comes to growth hormone and IGF-1. More of it enhances muscle and neuronal growth while simultaneously preventing atrophy. Less of it will increase the expression of stress resistance genes and extend your lifespan. Which do you prefer, having better muscle and cognitive performance or living longer? Overall, it seems like a good primer for anyone who wants to learn about the pros and cons of the reduced IGF-1 often associated with practicing CR. --Dean
  5. There is a really interesting new meta-analysis [1] in this week's issue of The Lancet on the association between height and health/longevity. Here is a popular press article on the study, with the title Big And Tall: Nutritious Meals May Make Us Taller But They Could Also Increase Our Cancer Risk. The researchers looked at 121 epidemiological studies of over a million people that assessed the association of height with health and lifespan. The heart of the paper are these two graphs: showing how in both men and women, being taller reduces risk of coronary heart disease, but increases risk of cancer. Here is a graphical representation of the over/undernutrition-based mechanisms the authors postulate to explain the observations: The link to cancer via higher insulin in people who eat a lot (and hence grow taller) is familiar. What was a bit surprising was their suggestion that increased levels of grow factors like IGF-1 in taller people may actually improve insulin sensitivity and hence reduce diabetes and cardiovascular disease. --Dean ------------- [1] The Lancet Diabetes & Endocrinology Available online 28 January 2016 DOI: http://dx.doi.org/10.1016/S2213-8587(15)00474-X| Divergent associations of height with cardiometabolic disease and cancer: epidemiology, pathophysiology, and global implications Norbert Stefan, MD, Hans-Ulrich Häring, MD, Frank B Hu, MD, Dr Matthias B Schulze, DrPHcorrespondenceemail Full text: http://dx.doi.org.sci-hub.io/10.1016/S2213-8587(15)00474-X Summary Among chronic non-communicable diseases, cardiometabolic diseases and cancer are the most important causes of morbidity and mortality worldwide. Although high BMI and waist circumference, as estimates of total and abdominal fat mass, are now accepted as predictors of the increasing incidence of these diseases, adult height, which also predicts mortality, has been neglected. Interestingly, increasing evidence suggests that height is associated with lower cardiometabolic risk, but higher cancer risk, associations supported by mendelian randomisation studies. Understanding the complex epidemiology, biology, and pathophysiology related to height, and its association with cardiometabolic diseases and cancer, is becoming even more important because average adult height has increased substantially in many countries during recent generations. Among the mechanisms driving the increase in height and linking height with cardiometabolic diseases and cancer are insulin and insulin-like growth factor signalling pathways. These pathways are thought to be activated by overnutrition, especially increased intake of milk, dairy products, and other animal proteins during different stages of child development. Limiting overnutrition during pregnancy, early childhood, and puberty would avoid not only obesity, but also accelerated growth in children—and thus might reduce risk of cancer in adulthood.
  6. I stumbled across an new paper [1] which contrasts the impact of calorie restriction vs. protein restriction (PR) in C57BL/6 mice. Interestingly, and contrary to some other studies I've seen (e.g. see Dr. Greger's video on CR vs. PR), it didn't find that PR induced the same kind of changes to hormone levels (e.g. < IGF-1) or improvements in glucose regulation as CR. The protein restricted mice were restricted to get the same percent of calories from protein from their diet as the CR mice, but their absolute level of protein intake (i.e. grams of protein) was nonetheless a lot higher than the CR mice, because the PR mice were eating an ad lib number of calories (and as a result didn't lose weight). Plus, the percent of protein wasn't all that low (the PR groups were 16%, 14% and 12% protein vs. 20% protein for control diet). Plus the protein in the chow fed to all the rats was all casein, which is high in the two amino acids thought to be inversely related to the CR-effect - methionine and cysteine. Not only that, but the mice chow used in the study had additional cystine, which is in very closely related to cysteine (in fact metabolically interchangeable to some extent). So it seems to me this wasn't a very good test of the hypothesis that restricting specific amino acids (methionine and cysteine) has similar effects on health markers (and lifespan) as CR. But I thought it was an interesting study nonetheless. It would seem to bolster the hypothesis (as outlined in Dr. Greger's video) that it is restriction in protein high in these two amino acids (i.e. animal products), and not protein restriction in general, that could mimic CR. Go vegan :) . --Dean ----------------------------------------------- [1] The effects of graded levels of calorie restriction: II. Impact of short term calorie and protein restriction on circulating hormone levels, glucose homeostasis and oxidative stress in male C57BL/6 mice Sharon E. Mitchell1, Camille Delville1, Penelope Konstantopedos1, Jane Hurst2, Davina Derous1, Cara Green1, Luonan Chen3, Jackie J.D. Han4, Yingchun Wang5, Daniel E.L. Promislow6, David Lusseau1, Alex Douglas1, John R. Speakman1,5 Keywords: calorie restriction, protein restriction, glucose homeostasis, oxidative stress, adipokines Received: April 01, 2015 Accepted: May 20, 2015 Published: June 01, 2015 Link: http://www.researchgate.net/profile/David_Lusseau/publication/277688862_The_effects_of_graded_levels_of_calorie_restriction_II._Impact_of_short_term_calorie_and_protein_restriction_on_circulating_hormone_levels_glucose_homeostasis_and_oxidative_stress_in_male_C57BL6_mice/links/5572be2c08ae75215868be71.pdf ABSTRACT Limiting food intake attenuates many of the deleterious effects of aging, impacting upon healthspan and leading to an increased lifespan. Whether it is the overall restriction of calories (calorie restriction: CR) or the incidental reduction in macronutrients such as protein (protein restriction: PR) that mediate these effects is unclear. The impact of 3 month CR or PR, (10 to 40%), on C57BL/6 mice was compared to controls fed ad libitum. Reductions in circulating leptin, tumor necrosis factor-α and insulin-like growth factor-1 (IGF-1) were relative to the level of CR and individually associated with morphological changes but remained unchanged following PR. Glucose tolerance and insulin sensitivity were improved following CR but not affected by PR. There was no indication that CR had an effect on oxidative damage, however CR lowered antioxidant activity. No biomarkers of oxidative stress were altered by PR. CR significantly reduced levels of major urinary proteins suggesting lowered investment in reproduction. Results here support the idea that reduced adipokine levels, improved insulin/IGF-1 signaling and reduced reproductive investment play important roles in the beneficial effects of CR while, in the short-term, attenuation of oxidative damage is not applicable. None of the positive effects were replicated with PR.