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  1. 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
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