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  1. All, Keeping one's immune system healthy is important for everyone, but this is especially true for CR practitioners. Anecdotally we appear to have a very competent immune system, and this has been shown to be true clinically in early stage anorexics. But at the same time we have fewer metabolic reserves to fight off infections if/when we do get sick. With that background, Dr. Greger has an amusing and informative video out today on the impact of various social behaviors on immune system function. It turns out that laughing (or crying) as a result of watching funny (or sad) videos boosts immune system response for at least 24 hours. But you actually have to laugh or cry to get the effect; just watching the video doesn't cut it. What's more, kissing and sex also work to improve allergic responses in people with allergies. I've found that CR has had a tempering influence on both my positive and negative affective states (to put it rather clinically), so I don't find these insights to be too personally relevant, but they are interesting nonetheless. I've included the transcript and references (with links) below, for people who hate watching videos. --Dean Transcript: Laughter as Medicine The study I explored about how listening to Mozart can reduce allergic reactions reminded me of a similar study on humor. Took a bunch of people with dust mite allergies; half watched Charlie Chaplin; half watched the weather channel. Then, they injected them with dust mite poop, and the allergic response was significantly reduced after viewing the humorous video for a matter of hours, suggesting that the induction of laughter may play some role in alleviating allergic diseases. But, might it suppress our immune system too much? No. Say we have people watch a comedian for an hour, and their natural killer cell activity goes up, compared to watching nothing. And, their white blood count goes up, the number of immune cells in their bloodstream, the level of immune-boosting interferon goes up and stays up the next day, and the same with antibody production; pumping out more antibodies because yesterday you saw some video. So, humor seems to offer the best of both worlds at preventing the over reactive allergic response while boosting immune protection. But, you actually have to laugh. The more you laugh, the better your natural killer cell activity gets, but exposure to a humorous video alone did not significantly affect immune function. Those that didn’t laugh—maybe because it was a Bill Cosby video, did not benefit, reinforcing that it is not the funny video that improved immune function, but our laughter in response. Because of the role natural killer cells play in viral illness and various types of cancer, the ability to significantly increase their activity in a brief period of time using a noninvasive method could be clinically important the next time you have a cold or cancer. Laughter, like music or healthy food, offers potential benefits without any risk, or almost any risk. You’ve heard of side-splitting laughter? 67-year old woman attending laughter therapy sessions and evidently, rapture led to rupture. Thankfully, you can’t actually laugh your head off, but you can laugh until you wet yourself, called "giggle incontinence" in the medical literature—it's actually quite common in women, and no laughing matter. So, the next time you’re in the theater, should you choose the comedy over the tear-jerker? Not necessarily. If you take people with latex allergy and have them watch a weather video versus a heart-warming drama, viewing the weather information video did not cause emotion with tears, and it failed to modulate allergic responses. The tear-jerker, however, successfully reduced the allergic response, but only in those whose tears were actually jerked. So, to improve allergies laughing works, crying works. I laughed, I cried; it was better than Cats— especially if you have a cat allergy. Anything else you can do? Kissing! There’s actually a whole science of kissing, which sounds a pleasant enough college major, until you realize it’s about all the diseases you can get. But, if you take people with seasonal pollen allergies, or dust mite allergies, and have them kiss someone in a room for 30 minutes, they have a significant reduction in their allergic reactions, for both the pollen and the dust mites, whereas, if you just have them hug for a half-hour instead - no benefit. Bottomline, kissing significantly reduced allergic responses in patients with both allergic rhinitis (runny nose, itchy eyes) or allergic dermatitis. Collectively, these findings indicate that the direct action of love may be beneficial, though evidently cuddling wasn’t quite direct enough. With all the side-effects of antihistamine drugs, you’d think it would be easy to get people to sign up for the study, but this was done in Japan where, evidently, they do not kiss habitually. The follow-up study, which found similar benefit for an action of love that was even more direct, was also performed by researchers for whom English may not be their primary language, as evidenced by their speculation about females having more, “organisms.” Video Sources H Kimata. Listening to mozart reduces allergic skin wheal responses and in vitro allergen-specific IgE production in atopic dermatitis patients with latex allergy. Behav Med. 2003 Spring;29(1):15-9. H Kimata. Effect of humor on allergen-induced wheal reactions. JAMA. 2001 Feb 14;285(6):738. L S Berk, S A Tan, W F Fry, B J Napier, J W Lee, R W Hubbard, J E Lewis, W C Eby. Neuroendocrine and stress hormone changes during mirthful laughter. Am J Med Sci. 1989 Dec;298(6):390-6. L S Berk, D L Felten, S A Tan, B B Bittman, J Westengard. Modulation of neuroimmune parameters during the eustress of humor-associated mirthful laughter. Altern Ther Health Med. 2001 Mar;7(2):62-72, 74-6. M P Bennett, J M Zeller, L Rosenberg, J McCann. The effect of mirthful laughter on stress and natural killer cell activity. Altern Ther Health Med. 2003 Mar-Apr;9(2):38-45. H Sharma, N S Shekhawat, S Bhandari, Breda Memon, M A Memon. Rectus sheath haematoma: a rare presentation of non‐contact strenuous exercises. Br J Sports Med. 2007 Oct; 41(10): 688–690. M P Rogers, R F Gittes, D M Dawson, P Reich. Giggle incontinence. JAMA. 1982 Mar 12;247(10):1446-8. H Kimata. Emotion with tears decreases allergic responses to latex in atopic eczema patients with latex allergy. J Psychosom Res. 2006 Jul;61(1):67-9. H Kimata. Kissing reduces allergic skin wheal responses and plasma neurotrophin levels. Physiol Behav. 2003 Nov;80(2-3):395-8. L Z G Touyz. Kissing and hpv: honest popular visions, the human papilloma virus, and cancers. Curr Oncol. 2014 Jun; 21(3): e515–e517. J S Alpert. Philematology: the science of kissing. A message for the marital month of june. Am J Med. 2013 Jun;126(6):466.
  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, CR appears to reduce our susceptibility to upper respiratory tract infections (e.g. colds and flu) - we've known this for quite some time based on personal anecdotes, backed up by our recent poll on the topic, and confirmed a study of anorexics by Luigi Fontana discussed in this post. But the immunity story for CR practitioners may not be quite so cut and dried. As discussed in this post, CR may make it harder for us to fight off infections once we do get sick. Plus, you've got to die of something (at least for the foreseeable future :-) ), and flu/pneumonia are the 3rd leading killer of centenarians. So it was heartening to see today's video by Dr. Greger (embedded below) which reports on the strong evidence that eating lots of fruits and vegetables, which virtually all of us do, helps to boost the immune system. Perhaps the most interesting sound-bite from the video comes from this study [1], which found that obesity, low physical activity, and low fruit/vegetable consumption were all associated with higher rates of hospitalizations for acute upper respiratory infections. But low fruits/veggies intake edged out the other two as the most predictive lifestyle factor for increased URI risk. So eat your fruits and veggies! --Dean ----------- [1] Influenza Other Respir Viruses. 2013 Sep;7(5):718-28. doi: 10.1111/irv.12019. Epub 2012 Nov 8. Relationship between community prevalence of obesity and associated behavioral factors and community rates of influenza-related hospitalizations in the United States. Charland KM(1), Buckeridge DL, Hoen AG, Berry JG, Elixhauser A, Melton F, Brownstein JS. Author information: (1)Children's Hospital Informatics Program, Children's Hospital Boston, Boston, MA, USA. katia.charland@mcgill.ca BACKGROUND: Findings from studies examining the association between obesity and acute respiratory infection are inconsistent. Few studies have assessed the relationship between obesity-related behavioral factors, such as diet and exercise, and risk of acute respiratory infection. OBJECTIVE: To determine whether community prevalence of obesity, low fruit/vegetable consumption, and physical inactivity are associated with influenza-related hospitalization rates. METHODS: Using data from 274 US counties, from 2002 to 2008, we regressed county influenza-related hospitalization rates on county prevalence of obesity (BMI ≥ 30), low fruit/vegetable consumption (<5 servings/day), and physical inactivity (<30 minutes/month recreational exercise), while adjusting for community-level confounders such as insurance coverage and the number of primary care physicians per 100,000 population. RESULTS: A 5% increase in obesity prevalence was associated with a 12% increase in influenza-related hospitalization rates [adjusted rate ratio (ARR) 1.12, 95% confidence interval (CI) 1.07, 1.17]. Similarly, a 5% increase in the prevalence of low fruit/vegetable consumption and physical inactivity was associated with an increase of 12% (ARR 1.12, 95% CI 1.08, 1.17) and 11% (ARR 1.11, 95% CI 1.07, 1.16), respectively. When all three variables were included in the same model, a 5% increase in prevalence of obesity, low fruit/vegetable consumption, and physical inactivity was associated with 6%, 8%, and 7% increases in influenza-related hospitalization rates, respectively. CONCLUSIONS: Communities with a greater prevalence of obesity were more likely to have high influenza-related hospitalization rates. Similarly, less physically active populations, with lower fruit/vegetable consumption, tended to have higher influenza-related hospitalization rates, even after accounting for obesity. © 2012 John Wiley & Sons Ltd. PMID: 23136926 Dr. Greger references on fruits/veggies & immunity B Watzi, A Bub, K Briviba, G Rechkemmer. Supplementation of a low-carotenoid diet with tomato or carrot juice modulates immune functions in healthy men. Ann Nutr Metab. 2003;47(6):255-61. L Li, M M Werler. Fruit and vegetable intake and risk of upper respiratory tract infection in pregnant women. Public Health Nutr. 2010 Feb;13(2):276-82. NA. The blood film in meningococcal disease. Med J Aust. 1983 May 28;1(11):502. H M Averill, J E Averill. The effect of daily apple consumption on dental caries experience, oral hygiene status and upper respiratory infections. N Y State Dent J. 1968 Aug-Sep;34(7):403-9. K M Charland, D L Buckeridge, A G Hoen, J G Berry, A Elixhauser, F Melton, J S Brownstein. Relationship between community prevalence of obesity and associated behavioral factors and community rates of influenza-related hospitalizations in the United States. Influenza Other Respir Viruses. 2013 Sep;7(5):718-28. B Watzi, A Bub, B R Brandstetter, G Rechkemmer. Modulation of human T-lymphocyte functions by the consumption of carotenoid-rich vegetables. Br J Nutr. 1999 Nov;82(5):383-9. N Acs, F Banhidy, E Horvath-Puho, A E Czeizel. Population-based case-control study of the common cold during pregnancy and congenital abnormalities. Eur J Epidemiol. 2006;21(1):65-75. K Kurppa, P C Holmberg, E Kuosma, T Aro, L Saxen. Anencephaly and maternal common cold. Teratology. 1991 Jul;44(1):51-5. J Zhang, W W Cai. Association of the common cold in the first trimester of pregnancy with birth defects. Pediatrics. 1993 Oct;92(4):559-63. M Veldhoen, V Bruchlacher-Waldert. Dietary influences on intestinal immunity. Nat Rev Immunol. 2012 Oct;12(10):696-708. A Gibson, J D Edgar, C E Neville, S E Gilchrist, M C McKinley, C C Patterson, I S Young, J V Woodside. Effect of fruit and vegetable consumption on immune function in older people: a randomized controlled trial. Am J Clin Nutr. 2012 Dec;96(6):1429-36.
  4. Dean Pomerleau

    CR and Cold / Flu Survey Results

    Hey Everybody, The CR Cold & Flu survey has been active for about a week, and we got 14 responses, with no more coming in lately, so I figured I'd summarize the results. I've screen captured the entire results as an image below so you can see the details, but here are the highlights: We got half of our respondents from the CR Forums, and half from the Facebook CRS group. We got a pretty good split of genders (9 male / 5 female) A pretty wide distribution of ages and time practicing CR, with quite a few veterans. A good number of low-BMI, apparently serious CR practitioners, so it was a pretty good sample. 80% of people reported getting a single cold / flu or less per year on average. This seems a lot lower than the general population. Nearly 80% say they get fewer colds / flu now than they did before starting CR. 54% say they get colds / flu less frequently than others in their household. 85% said they have low or low-normal white blood cell counts. 57% percent never get the flu shot. Overall, I think this confirms our hypothesis - that CR folks have a less inflammable body (reflected in low WBC count), but if anything possess a more competent immune system, as reflected in contracting fewer colds and flu than before they started CR, than others in their household, and than is average in the general population. --Dean
  5. In his weekly post of new CR Science studies, James Cain (thanks James!) posted [1], another in the series of papers about results from the CALERIE study of six months of CR in modestly overweight humans. In this analysis they divided 24 people into three groups of 8 people each and followed them for six months: control diet (control group) 25% Calorie Restriction (CR group) 12.5% CR + enough exercise to equal a 25% calorie deficit (CREX group). Both intervention groups lost about the same amount of bodyweight (~11%). They took subcutaneous fat cell biopsies from the three groups at baseline and at six months, and subjected them to gene expression analysis. Here are the major highlights from the full text: Despite comparable transcriptional and clinical response in energy metabolism, we showed that CR vastly outweighed CREX in the total number of differentially regulated genes (88 vs 39) and pathways (28 vs 6). This suggests that calorie restriction is probably eliciting molecular changes beyond adaptations to energy deficit per se. <snip> CR induced a ... 2.1-fold (p < .05) increase in the mRNA expression of ... CGI-85 [a regulator of epigenetic histone modification - DP], ...whereas CREX and Control were without effect. <snip> [W]e observed a distinct effect of CR on downregulating the chemokine signaling-related pathways. [From this description of the chemokine signalling pathways: "chemokines are a critical component of basal leukocyte trafficking essential for immune system architecture and development, and immune surveillance." - DP] <snip> Together, our data suggest that CR regulates the overall transcriptional function, and this does not appear to be a primary response to energy deficit per se but rather a distinct effect of calorie restriction. Genomic effects may also be the key regulator of the aging process. Pioneering work from the laboratories of Weindruch and Spindler showed that most differential gene expression induced by aging in rodents was at least partly or completely reversed by calorie restriction (42,43). The Spindler group further showed that shifting mice from long-term calorie restricted to control diet reversed 90% of the transcriptional changes induced by calorie restriction and returned the animals to an aging rate similar to the controls (44), implicating a causal relationship between calorie restriction, gene expression, and aging. <snip> Available literature to date largely agrees that calorie restriction and exercise training overlap in a wide range of health benefits from weight loss to protection against some age-related diseases (55). Extension of maximal life span, however, remains as a unique feature of calorie restriction that so far cannot be replicated by any form of exercise training (56,57). <snip> Finally, given the enormous challenge (and an almost impossible task) of maintaining drastic lifestyle changes such as life-long calorie restriction, identifying specific molecular targets will be critical for the development of calorie restriction mimetics (59). Its pretty annoying that authors feel obligated to dismiss the possibility of people practicing long-term CR as being "almost impossible". Luigi Fontana wasn't an author on this one (thankfully), and perhaps if he had been the paper wouldn't have ended on such a low note. But despite this disempowering and dismissive ending, it was one of the most interesting papers I've seen coming out of the CALERIE study, suggesting that CR in humans (whether induced by straight calorie reduction or CR + exercise) does have some pretty fundamental effects on gene expression in fat cells. In addition, it found that CR-alone has a more profound and widespread impact on gene expression than more modest CR "topped off" with extra exercise (the CREX group), at least in the relatively short term (6 months) in this (relatively overweight) cohort. In particular, they found that CR (but not CR+EX) downregulates certain aspects of chemokine pathways related to immune system function (good or bad, who knows, but our immune systems seem pretty competent...), and changes the expression of genes involved in epigenetic regulation (master genes regulating expression of other genes) - which is increasingly thought to be important in the aging process. These results complement and extend similar findings in skeletal muscle cells from this same cohort [2] and some of us long-term CR practitioners [3]. Interestingly, from [2], it seems that CR-alone and CR+Exercise had much more similar effects on muscle cell gene expression as compared to this study of gene expression in fat cells, where the effects of CR-alone differed markedly from CR+exercise. --Dean ------------ [1] J Gerontol A Biol Sci Med Sci. 2015 Oct 20. pii: glv194. [Epub ahead of print] Six-month Calorie Restriction in Overweight Individuals Elicits Transcriptomic Response in Subcutaneous Adipose Tissue That is Distinct From Effects of Energy Deficit. Lam YY1, Ghosh S2, Civitarese AE3, Ravussin E4. Abstract Calorie restriction confers health benefits distinct from energy deficit by exercise. We characterized the adipose-transcriptome to investigate the molecular basis of the differential phenotypic responses. Abdominal subcutaneous fat was collected from 24 overweight participants randomized in three groups (N = 8/group): weight maintenance (control), 25% energy deficit by calorie restriction alone (CR), and 25% energy deficit by calorie restriction with structured exercise (CREX). Within each group, gene expression was compared between 6 months and baseline with cutoffs at nominal p ≤ .01 and absolute fold-change ≥ 1.5. Gene-set enrichment analysis (false discovery rate < 5%) was used to identify significantly regulated biological pathways. CR and CREX elicited similar overall clinical response to energy deficit and a comparable reduction in gene transcription specific to oxidative phosphorylation and proteasome function. CR vastly outweighed CREX in the number of differentially regulated genes (88 vs 39) and pathways (28 vs 6). CR specifically downregulated the chemokine signaling-related pathways. Among the CR-regulated genes, 27 functioned as transcription/translation regulators (eg, mRNA processing or transcription/translation initiation), whereas CREX regulated only one gene in this category. Our data suggest that CR has a broader effect on the transcriptome compared with CREX which may mediate its specific impact on delaying primary aging. PMID: 26486851 ----------- [2] PLoS Med. 2007 Mar;4(3):e76. Calorie restriction increases muscle mitochondrial biogenesis in healthy humans. Civitarese AE(1), Carling S, Heilbronn LK, Hulver MH, Ukropcova B, Deutsch WA, Smith SR, Ravussin E; CALERIE Pennington Team. BACKGROUND: Caloric restriction without malnutrition extends life span in a range of organisms including insects and mammals and lowers free radical production by the mitochondria. However, the mechanism responsible for this adaptation are poorly understood. METHODS AND FINDINGS: The current study was undertaken to examine muscle mitochondrial bioenergetics in response to caloric restriction alone or in combination with exercise in 36 young (36.8 +/- 1.0 y), overweight (body mass index, 27.8 +/- 0.7 kg/m(2)) individuals randomized into one of three groups for a 6-mo intervention: Control, 100% of energy requirements; CR, 25% caloric restriction; and CREX, caloric restriction with exercise (CREX), 12.5% CR + 12.5% increased energy expenditure (EE). In the controls, 24-h EE was unchanged, but in CR and CREX it was significantly reduced from baseline even after adjustment for the loss of metabolic mass (CR, -135 +/- 42 kcal/d, p = 0.002 and CREX, -117 +/- 52 kcal/d, p = 0.008). Participants in the CR and CREX groups had increased expression of genes encoding proteins involved in mitochondrial function such as PPARGC1A, TFAM, eNOS, SIRT1, and PARL (all, p < 0.05). In parallel, mitochondrial DNA content increased by 35% +/- 5% in the CR group (p = 0.005) and 21% +/- 4% in the CREX group (p < 0.004), with no change in the control group (2% +/- 2%). However, the activity of key mitochondrial enzymes of the TCA (tricarboxylic acid) cycle (citrate synthase), beta-oxidation (beta-hydroxyacyl-CoA dehydrogenase), and electron transport chain (cytochrome C oxidase II) was unchanged. DNA damage was reduced from baseline in the CR (-0.56 +/- 0.11 arbitrary units, p = 0.003) and CREX (-0.45 +/- 0.12 arbitrary units, p = 0.011), but not in the controls. In primary cultures of human myotubes, a nitric oxide donor (mimicking eNOS signaling) induced mitochondrial biogenesis but failed to induce SIRT1 protein expression, suggesting that additional factors may regulate SIRT1 content during CR. CONCLUSIONS: The observed increase in muscle mitochondrial DNA in association with a decrease in whole body oxygen consumption and DNA damage suggests that caloric restriction improves mitochondrial function in young non-obese adults. PMID: 17341128 -------------- [3] Aging Cell. 2013 Aug;12(4):645-51. doi: 10.1111/acel.12088. Epub 2013 Jun 5. Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Mercken EM(1), Crosby SD, Lamming DW, JeBailey L, Krzysik-Walker S, Villareal DT, Capri M, Franceschi C, Zhang Y, Becker K, Sabatini DM, de Cabo R, Fontana L. Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here, we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR induces dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans, CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated with longevity: IGF-1/insulin signaling, mitochondrial biogenesis, and inflammation. Furthermore, our data identify promising pathways for therapeutic targets to combat age-related diseases and promote health in humans. PMID: 23601134