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  1. CRON is well known to greatly reduce inflammation. For years, I've been measuring CRP and TNF_alpha, which are supposed to be measurements of inflammation. All but once, I've gotten CRP <5, meaning immeasurably low. All but the last two measurements (in 2016 and 2017) were vanishingly small for TNF_alpha as well -- but the last two measurements were surprisingly high. So a major contradiction between CRP (vanishingly small) and TNF_alpha (high) on these last two measurements. Weird. I asked my CR friendly nephrologist. He didn't know; suggested that I check with some of the CRONNies -- I guess he thinks it possible that it might be one of the weird looking numbers that happen with CR. So I'm following his advice. Anybody -- who is knowledgeable in the mechanisms of these proteins -- have any ideas? -- Saul
  2. Charles Raison, M.D. is a professor at the School of Human Ecology at the University of Wisconsin-Madison and Founding Director of the Center for Compassion Studies in the College of Social and Behavioral Sciences at the University of Arizona. Dr. Raison’s research focuses on inflammation and the development of depression in response to illness and stress. He also examines the physical and behavioral effects of compassion training on the brain, inflammatory processes, and behavior as well as the effect of heat stress as a potentially therapeutic intervention major depressive disorder.
  3. 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
  4. All, Over on the loneliness thread we've discussed how loneliness (or perhaps even simply living alone) can increase mortality (PMID 21834390). And as Zeta pointed out in this post about this article, loneliness can aggravate chronic viral infections, which in turn are associated with more rapid cognitive decline, as discussed in this post about PMID 26710257. So besides practicing CR, which at least in some of us seems to promote psychological resilience and a sense of "calm abiding", what can we do to avoid the apparent negative effects (esp. inflammation) resulting from loneliness, and stress/anxiety in general? This new study [1] (popular press article) from CMU1 researchers, and some of the papers it cites (see below) suggest a solution, namely mindfulness meditation, a practice I find quite helpful, as discussed here. Study [1] was a randomized control trial comparing the effects of 3-days of mindfulness training vs. relaxation training in 35 stressed and unemployed job seekers. Using FMRI brain imaging, they found that mindfulness training (vs. relaxation training) positively influenced activity in both the default mode network (the network of areas in the brain that becomes active when we aren't engaged in deliberate thought - e.g. when ruminating) and in the left dorsolateral prefrontal cortex, a brain area involved in executive function. But most importantly for this topic, they found that four months after the intervention, those in the mindfulness meditation group had reduced levels of an important marker of inflammation, interleukin-6, relative to the relaxation training group. This effect was independent of whether during the intervening 4 months the subjects found a job or not, which half of the subjects in each group in fact did. Some of the interesting commentary on the research expressed by the authors in the popular press article : The researchers concluded that the changes in functional brain connectivity resulting from the mindfulness program seemed to help the brain manage stress (a known inflammation trigger), and therefore is responsible for the reduced levels of inflammation. Why does it seem to be more beneficial than mere relaxation for managing stress? [Lead researcher] Creswell suggests that mindfulness may have a more lasting impact. "Mindfulness meditation teaches participants how to be more open and attentive to their experiences, even difficult ones," Creswell said. "By contrast, relaxation approaches are good in the moment for making the body feel relaxed, but ... [they're] harder to translate when you are dealing with difficult stressors in your daily life." In the full text of the paper, the authors point to a number of other recent studies [2-5] that have found mindfulness meditation reduces both stress and inflammatory markers in the elderly, people experiencing job stress, as well as cancer patients and caregivers. Study [2] by this same group of researchers is particularly germane for this topic, since it investigated the effects of mindfulness meditation on feelings of loneliness and inflammation in elderly subjects. People who did 8 weeks of once-per-week mindfulness classes reported reduced loneliness and exhibited a decrease in pro-inflammatory gene expression relative to a control group from the waiting list for the mindfulness training. I resonated with this quote from the introduction of [2]: “Usually we regard loneliness as an enemy. Heartache is not something we choose to invite in. It's restless and pregnant and hot with the desire to escape and find something or someone to keep us company. When we can rest in the middle [through meditation practice], we begin to have a nonthreatening relationship with loneliness, a relaxing and cooling loneliness that completely turns our usual fearful patterns upside down” -- Pema Chodron (2000), Buddhist nun and teacher These were small studies and not without some shortcomings - e.g. the mindfulness training classes themselves might have reduced loneliness in [2]. But they are nonetheless suggestive evidence that practicing mindfulness meditation can help one deal with the negative effects of loneliness and stress in general. --Dean ----------- 1CMU is my alma mater and is located in Pittsburgh. Those Pittsburgh scientists are really churning out interesting research! -------------- [1] Biological Psychiatry, http://dx.doi.org/10.1016/j.biopsych.2016.01.008 Alterations in resting state functional connectivity link mindfulness meditation with reduced interleukin-6: a randomized controlled trial, J. David Creswell PhD, Adrienne A. Taren MD, Emily K. Lindsay MA, Carol M. Greco PhD, Peter J. Gianaros PhD, April Fairgrieve BS, Anna L. Marsland PhD, Kirk Warren Brown PhD, Baldwin M. Way PhD, Rhonda K. Rosen LCSW, Jennifer L. Ferris MA Full text: http://dx.doi.org.sci-hub.io/10.1016/j.biopsych.2016.01.008 Abstract Background Mindfulness meditation training interventions have been shown to improve markers of health, but the underlying neurobiological mechanisms are not known. Building on initial cross-sectional research showing that mindfulness meditation may increase default mode network (DMN) resting state functional connectivity (rsFC) with regions important in top-down executive control (dorsolateral prefrontal cortex, dlPFC), here we test whether mindfulness meditation training increases DMN-dlPFC rsFC, and whether these rsFC alterations prospectively explain improvements in interleukin-6 (IL-6) in a randomized controlled trial. Method Stressed job-seeking unemployed community adults (N=35) were randomized to either a 3-day intensive residential mindfulness meditation or relaxation training program. Participants completed a five-minute resting state scan before and after the intervention program. Participants also provided blood samples at pre-intervention and at 4-month follow-up, which were assayed for circulating IL-6, a biomarker of systemic inflammation. Results We tested for alterations in DMN rsFC using a posterior cingulate cortex (PCC) seed-based analysis, and found that mindfulness meditation training, and not relaxation training, increased PCC rsFC with left dlPFC (p<.05, corrected). These pre-post training alterations in PCC-dlPFC rsFC statistically mediated mindfulness meditation training improvements in IL-6 at 4-month follow-up. Specifically, these alterations in rsFC statistically explained 30% of the overall mindfulness meditation training effects on IL-6 at follow-up. Conclusions These findings provide the first evidence that mindfulness meditation training functionally couples the DMN with a region known to be important in top-down executive control at rest (left dlPFC), which in turn is associated with improvements in a marker of inflammatory disease risk. Trial Registration The RCT is registered on clinicaltrials.gov (#NCT01628809) Key words: mindfulness meditation, functional connectivity, IL-6, unemployment, fMRI, stress ---------------- [2] Brain Behav Immun. 2012 Oct;26(7):1095-101. doi: 10.1016/j.bbi.2012.07.006. Epub 2012 Jul 20. Mindfulness-Based Stress Reduction training reduces loneliness and pro-inflammatory gene expression in older adults: a small randomized controlled trial. Creswell JD1, Irwin MR, Burklund LJ, Lieberman MD, Arevalo JM, Ma J, Breen EC, Cole SW. Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635809/ Abstract Lonely older adults have increased expression of pro-inflammatory genes as well as increased risk for morbidity and mortality. Previous behavioral treatments have attempted to reduce loneliness and its concomitant health risks, but have had limited success. The present study tested whether the 8-week Mindfulness-Based Stress Reduction (MBSR) program (compared to a Wait-List control group) reduces loneliness and downregulates loneliness-related pro-inflammatory gene expression in older adults (N = 40). Consistent with study predictions, mixed effect linear models indicated that the MBSR program reduced loneliness, compared to small increases in loneliness in the control group (treatment condition × time interaction: F(1,35) = 7.86, p = .008). Moreover, at baseline, there was an association between reported loneliness and upregulated pro-inflammatory NF-κB-related gene expression in circulating leukocytes, and MBSR downregulated this NF-κB-associated gene expression profile at post-treatment. Finally, there was a trend for MBSR to reduce C Reactive Protein (treatment condition × time interaction: (F(1,33) = 3.39, p = .075). This work provides an initial indication that MBSR may be a novel treatment approach for reducing loneliness and related pro-inflammatory gene expression in older adults. PMID: 22820409 ---------- [3] Malarkey WB, Jarjoura D, Klatt M (2013): Workplace based mindfulness practice and inflammation: A randomized trial. Brain Behav Immun. 27: 145–154. --------- [4] Rosenkranz MA, Davidson RJ, MacCoon DG, Sheridan JF, Kalin NH, Lutz A (2013): A comparison of mindfulness-based stress reduction and an active control in modulation of neurogenic inflammation. Brain Behav Immun. 27C: 174–184. -------------- [5] Lengacher CA, Kip KE, Barta MK, Post-White J, Jacobsen P, Groer M, et al. (2012): A Pilot Study Evaluating the Effect of Mindfulness-Based Stress Reduction on Psychological Status, Physical Status, Salivary Cortisol, and Interleukin-6 Among Advanced-Stage Cancer Patients and Their Caregivers. J Holist Nurs. 30: 170–185.
  5. All, The benefits of yoga has been discussed on various threads lately, so I figured it was time to consolidate the discussions into a single master thread, particularly since there is a new study I wanted to post (see below). First we saw in this thread that yoga beats both walking and a mediterranean diet for CVD risk reduction. Then we saw in this post by Cloud that 12 weeks of yoga reduces inflammatory markers in recovering cancer patients. Now, a new study [1] (popular press story) found that 12 weeks of yoga beat out the "gold standard" memory training technique in people with mild cognitive impairment. The yoga group had lower depression scores, and improved verbal and visuospatial memory compared with memory training. While the study was small, its effects were pretty impressive, and were accompanied by changes in brain region connectivity as measured by FMRI brain scans. With all this evidence of benefit, it seems like a good idea to start practicing yoga, and consider having the next CR Conference at a yoga center like Saul suggests - maybe Sthira and Saul can teach the rest of us! --Dean ---------- [1] J Alzheimers Dis. 2016 Apr 5;52(2):673-84. doi: 10.3233/JAD-150653. Changes in Neural Connectivity and Memory Following a Yoga Intervention for Older Adults: A Pilot Study. Eyre HA(1,)(2), Acevedo B(1), Yang H(1), Siddarth P(1), Van Dyk K(1), Ercoli L(1), Leaver AM(3), Cyr NS(1), Narr K(3), Baune BT(2), Khalsa DS(4), Lavretsky H(1). Author information: (1)Semel Institute for Neuroscience and Human Behavior, UCLA, Los Angeles, CA, USA. (2)Discipline of Psychiatry, University of Adelaide, Adelaide, South Australia, Australia. (3)Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, UCLA, Los Angeles, CA, USA. (4)Alzheimer's Research and Prevention Foundation, Tucson, AZ, USA. BACKGROUND: No study has explored the effect of yoga on cognitive decline and resting-state functional connectivity. OBJECTIVES: This study explored the relationship between performance on memory tests and resting-state functional connectivity before and after a yoga intervention versus active control for subjects with mild cognitive impairment (MCI). METHODS: Participants ( ≥ 55 y) with MCI were randomized to receive a yoga intervention or active "gold-standard" control (i.e., memory enhancement training (MET)) for 12 weeks. Resting-state functional magnetic resonance imaging was used to map correlations between brain networks and memory performance changes over time. Default mode networks (DMN), language and superior parietal networks were chosen as networks of interest to analyze the association with changes in verbal and visuospatial memory performance. RESULTS: Fourteen yoga and 11 MET participants completed the study. The yoga group demonstrated a statistically significant improvement in depression and visuospatial memory. We observed improved verbal memory performance correlated with increased connectivity between the DMN and frontal medial cortex, pregenual anterior cingulate cortex, right middle frontal cortex, posterior cingulate cortex, and left lateral occipital cortex. Improved verbal memory performance positively correlated with increased connectivity between the language processing network and the left inferior frontal gyrus. Improved visuospatial memory performance correlated inversely with connectivity between the superior parietal network and the medial parietal cortex. CONCLUSION: Yoga may be as effective as MET in improving functional connectivity in relation to verbal memory performance. These findings should be confirmed in larger prospective studies. PMID: 27060939
  6. All, There seems to be growing evidence that systemic inflammation is involved in many diseases of aging, including cardiovascular disease, diabetes and cognitive impairment / Alzheimer's disease. This new study [1] speaks to the latter. It found the rate of cognitive decline in people suffering from mild cognitive impairment or early-stage Alzheimer's disease was 6x higher in those people who also suffered from periodontal disease, likely as a result of the systemic inflammatory effects of the subjects' infected gums. So take care of those teeth and gums! --Dean ---------- [1] PLoS One. 2016 Mar 10;11(3):e0151081. doi: 10.1371/journal.pone.0151081. eCollection 2016. Periodontitis and Cognitive Decline in Alzheimer's Disease. Ide M(1), Harris M(2), Stevens A(3), Sussams R(2,)(3), Hopkins V(3), Culliford D(4), Fuller J(5), Ibbett P(5), Raybould R(6), Thomas R(6), Puenter U(5), Teeling J(5), Perry VH(5), Holmes C(2,)(3). Author information: (1)Dental Institute, Kings College London, Guy's Hospital, London, United Kingdom. (2)University of Southampton, Faculty of Medicine, Clinical Experimental Science, Southampton, United Kingdom. (3)Memory Assessment and Research Centre, Moorgreen Hospital, Southampton, United Kingdom. (4)University of Southampton, Faculty of Health Sciences, NIHR CLAHRC Wessex Methodological Hub, Southampton, United Kingdom. (5)University of Southampton, Faculty of Natural and Environmental Science, Centre for Biological Sciences, Southampton, United Kingdom. (6)Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom. Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786266/ Periodontitis is common in the elderly and may become more common in Alzheimer's disease because of a reduced ability to take care of oral hygiene as the disease progresses. Elevated antibodies to periodontal bacteria are associated with an increased systemic pro-inflammatory state. Elsewhere raised serum pro-inflammatory cytokines have been associated with an increased rate of cognitive decline in Alzheimer's disease. We hypothesized that periodontitis would be associated with increased dementia severity and a more rapid cognitive decline in Alzheimer's disease. We aimed to determine if periodontitis in Alzheimer's disease is associated with both increased dementia severity and cognitive decline, and an increased systemic pro inflammatory state. In a six month observational cohort study 60 community dwelling participants with mild to moderate Alzheimer's Disease were cognitively assessed and a blood sample taken for systemic inflammatory markers. Dental health was assessed by a dental hygienist, blind to cognitive outcomes. All assessments were repeated at six months. The presence of periodontitis at baseline was not related to baseline cognitive state but was associated with a six fold increase in the rate of cognitive decline as assessed by the ADAS-cog over a six month follow up period. Periodontitis at baseline was associated with a relative increase in the pro-inflammatory state over the six month follow up period. Our data showed that periodontitis is associated with an increase in cognitive decline in Alzheimer's Disease, independent to baseline cognitive state, which may be mediated through effects on systemic inflammation. PMCID: PMC4786266 PMID: 26963387
  7. AlPater

    Vegetables, CR

    I did not remember seeing this paper previously but it certainly interested me for comparing effects of healthy eating with CR: "comparing the changes induced by high vegetable intake with changes induced by energy restriction, it has been shown that part of vegetables’ health benefits are mediated by changes in energy metabolism, inflammatory processes and oxidative stress." Nutrigenomics approach elucidates health-promoting effects of high vegetable intake in lean and obese men. Pasman WJ, van Erk MJ, Klöpping WA, Pellis L, Wopereis S, Bijlsma S, Hendriks HF, Kardinaal AF. Genes Nutr. 2013 Sep;8(5):507-21. doi: 10.1007/s12263-013-0343-9. Epub 2013 Apr 18. PMID: 23595524 Free PMC Article http://genesandnutrition.biomedcentral.com/articles/10.1007/s12263-013-0343-9 Abstract We aimed to explore whether vegetable consumption according to guidelines has beneficial health effects determined with classical biomarkers and nutrigenomics technologies. Fifteen lean (age 36 ± 7 years; BMI 23.4 ± 1.7 kg m(-2)) and 17 obese (age 40 ± 6 years; BMI 30.3 ± 2.4 kg m(-2)) men consumed 50- or 200-g vegetables for 4 weeks in a randomized, crossover trial. Afterward, all subjects underwent 4 weeks of energy restriction (60 % of normal energy intake). Despite the limited weight loss of 1.7 ± 2.4 kg for the lean and 2.1 ± 1.9 kg for the obese due to energy restriction, beneficial health effects were found, including lower total cholesterol, LDL cholesterol and HbA1c concentrations. The high vegetable intake resulted in increased levels of plasma amino acid metabolites, decreased levels of 9-HODE and prostaglandin D3 and decreased levels of ASAT and ALP compared to low vegetable intake. Adipose tissue gene expression changes in response to vegetable intake were identified, and sets of selected genes were submitted to network analysis. The network of inflammation genes illustrated a central role for NFkB in (adipose tissue) modulation of inflammation by increased vegetable intake, in lean as well as obese subjects. In obese subjects, high vegetable intake also resulted in changes related to energy metabolism, adhesion and inflammation. By inclusion of sensitive omics technologies and comparing the changes induced by high vegetable intake with changes induced by energy restriction, it has been shown that part of vegetables' health benefits are mediated by changes in energy metabolism, inflammatory processes and oxidative stress.
  8. All, Dr. Greger had another fascinating video out today on the link between inflammation and depression, and why an anti-inflammatory diet might be effective for treating depression. Apparently, it has long been known that systemic inflammation and depression are pretty highly correlated. And apparently, based on several studies cited in the video, you can induce depression in people by increasing the inflammation level in their bodies. Researchers have made an argument for why evolution might have set it up this way. Throughout our evolutionary history, systemic inflammation has been almost exclusively associated with infections of some sort, many of which are contagious. When we develop an infection, and our body responds with an inflammatory response, it would have been 'good' for our kin (and therefore our genes, which they share), if we felt crappy, and all we wanted to do is curl up in a corner and avoid contact with other people - in order not to infect them. So, the evolutionary theorists say, we developed a mechanism by which systemic inflammation triggers a depressed mood. Fast forward to today. We've pretty much defeated pathogenic infections, but still feel like curling up and dying when we get an infection - not much we can do about that. But in addition, despite few pathogenic infections, the bodies of most people are still inflamed continuously these days, largely as a result of the crappy diet most people eat. So the same depressive response to inflammation that used to provide a survival advantage, now simply makes us depressed, as a result of the food we're eating. Not surprisingly, Dr. Greger goes on to advocate an anti-inflammatory diet centered around whole plant foods. He says meats in general, and even fatty fish, are proinflammatory for a variety of reasons, including endotoxins. He says that may be why the early hopes for fish and fish oil as a treatment for depression haven't seemed to pan out in larger studies. I thought the most interesting graphs in the whole video are shown below, taken from [1]. In this study, researchers injected into human subjects an endotoxin derived from E. Coli, and then measured both their blood markers of inflammation and their mood over the next few hours. As their bodies mounted an inflammatory response to the endotoxin (as indicated by the IL-6 and TNF-a markers of inflammation), subjects reported a depressed mood. As the inflammation subsided, so did the depressed mood. The correlation between the inflammation and the depressed mood was high, and wasn't observed in the subjects injected with a placebo. I thought it was a really thought provoking video, and a reasonable explanation for the mystery of why depression might have evolved and persisted in our highly social species. Maybe the fact that CR practitioners generally eat a highly anti-inflammatory diet, and have low levels of inflammation as measured by blood tests like C-reactive protein (CRP), may explain why, after the initial weight loss period when toxins may be released from the fat we're losing, triggering inflammation and therefore depressed mood, CR practitioners generally report being in very good moods - quite in contrast to the expectation most people have that CR would make you permanently irritable. Finally, I don't want to oversimplify true clinical depression - which is an incredibly complex and debilitating condition. The kind of "depression" Dr. Greger is talking about in this video and that may be associated with chronic inflammation might be better characterized as "depressed mood", as opposed to true clinical depression. For more info on some of the complexities of clinical depression, including its genetic component, check out this short video on the science of depression. --Dean ------------ [1] Brain Behav Immun. 2010 May;24(4):558-63. doi: 10.1016/j.bbi.2009.12.009. Epub 2010 Jan 4. Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Eisenberger NI(1), Inagaki TK, Mashal NM, Irwin MR. Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856755/ Although research has established links between feelings of social isolation and inflammation, the direction of these effects is unclear. Based on the role that proinflammatory cytokines play in initiating "sickness behavior," which includes symptoms such as social withdrawal, it is possible that inflammatory processes heighten feelings of 'social disconnection.' Here, we examined whether exposure to an inflammatory challenge increased self-reported feelings of social disconnection. In addition, because both inflammatory processes and feelings of social disconnection contribute to depressive symptoms, we also explored whether increases in feelings of social disconnection played a role in the link between inflammation and depressed mood. Participants were randomly assigned to either receive endotoxin, an inflammatory challenge, or placebo. Proinflammatory cytokines (IL-6, TNF-alpha) were collected at baseline and then hourly for 6h. Participants completed self-reports of sickness symptoms ("fatigue"), social disconnection ("I feel disconnected from others"), and depressed mood ("unhappy") hourly. Results revealed that endotoxin led to significant increases (from baseline) in IL-6 and TNF-alpha levels as well as feelings of social disconnection and depressed mood. Moreover, controlling for increases in social disconnection eliminated the relationship between exposure to inflammatory challenge and depressed mood. This study demonstrates that inflammation can have social psychological consequences, which may play a role in cytokine-related depressive symptoms. Copyright 2009 Elsevier Inc. All rights reserved. PMCID: PMC2856755 PMID: 20043983
  9. Here is another study posted by Al Pater that particularly interested me, both because it focused on inflammation (now understood to be an important contributor to all of the major chronic diseases of aging) and because it focused on CR vs. exercise vs. both. It compared the effects of one-year of a calorie restricted diet, aerobic exercise (without calorie restriction) or both exercise and calorie restriction on biomarkers of inflammation in overweight/obese postmenopausal women. The results can be summarized as follows: The diet-only group and the diet+exercise group lost close to the same amount of weight (8.5% vs 10.5%, respectively). The exercise-only group lost much less on average (2.5%), although there were some women in the exercise-only group who lost > 5% (see below). "There were no significant differences between the diet and diet+exercise groups or between the exercise[-only] and control groups, in any inflammatory biomarker." Virtually everyone* in the study who lost >5% of body weight saw a significant reduction in hr-CRP, an important marker of inflammation, independent of whether they lost weight via diet-alone, exercise-alone, or diet+exercise. So by my reading, it looks like its either the weight/fat loss or possibly the energy deficit, rather than simply eating fewer calories, that determines the benefits, at least when it comes to biomarkers of inflammation in this population. In particular, the women who lost nearly 10% of their bodyweight saw a dramatic (and equivalent) improvement in biomarkers of inflammation whether they achieved this weight loss via a large calorie deficit, or via a more modest calorie deficit "topped off" with exercise. --Dean * Except for two outliers with very high hr-CRP who were excluded ------------------------ [1] Effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in overweight/obese postmenopausal women: a randomized controlled trial. Imayama I, Ulrich CM, Alfano CM, Wang C, Xiao L, Wener MH, Campbell KL, Duggan C, Foster-Schubert KE, Kong A, Mason CE, Wang CY, Blackburn GL, Bain CE, Thompson HJ, McTiernan A. Cancer Res. 2012 May 1;72(9):2314-26. doi: 10.1158/0008-5472.CAN-11-3092. PMID:22549948 Free PMC Article http://cancerres.aacrjournals.org/content/72/9/2314.long http://cancerres.aacrjournals.org/content/72/9/2314.full.pdf+html Abtract Obese and sedentary persons have increased risk for cancer; inflammation is a hypothesized mechanism. We examined the effects of a caloric restriction weight loss diet and exercise on inflammatory biomarkers in 439 women. Overweight and obese postmenopausal women were randomized to 1-year: caloric restriction diet (goal of 10% weight loss, N = 118), aerobic exercise (225 min/wk of moderate-to-vigorous activity, N = 117), combined diet + exercise (N = 117), or control (N = 87). Baseline and 1-year high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA), interleukin-6 (IL-6), leukocyte, and neutrophil levels were measured by investigators blind to group. Inflammatory biomarker changes were compared using generalized estimating equations. Models were adjusted for baseline body mass index (BMI), race/ethnicity, and age. Four hundred and thirty-eight (N = 1 in diet + exercise group was excluded) were analyzed. Relative to controls, hs-CRP decreased by geometric mean (95% confidence interval, P value): 0.92 mg/L (0.53-1.31, P < 0.001) in the diet and 0.87 mg/L (0.51-1.23, P < 0.0001) in the diet + exercise groups. IL-6 decreased by 0.34 pg/mL (0.13-0.55, P = 0.001) in the diet and 0.32 pg/mL (0.15-0.49, P < 0.001) in the diet + exercise groups. Neutrophil counts decreased by 0.31 × 10(9)/L (0.09-0.54, P = 0.006) in the diet and 0.30 × 10(9)/L (0.09-0.50, P = 0.005) in the diet + exercise groups. Diet and diet + exercise participants with 5% or more weight loss reduced inflammatory biomarkers (hs-CRP, SAA, and IL-6) compared with controls. The diet and diet + exercise groups reduced hs-CRP in all subgroups of baseline BMI, waist circumference, CRP level, and fasting glucose. Our findings indicate that a caloric restriction weight loss diet with or without exercise reduces biomarkers of inflammation in postmenopausal women, with potential clinical significance for cancer risk reduction.