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  1. This does not constitute evidence that we should be supplementing with glycine, but I'm filing it under "an additional small reason to think that the glycine I take for sleep might not be so bad": University of Tsukuba. "Scientists reverse aging in human cell lines and give theory of aging a new lease of life." ScienceDaily. www.sciencedaily.com/releases/2015/05/150526085138.htm (accessed May 27, 2015). (http://www.sciencedaily.com/releases/2015/05/150526085138.htm) But mostly, it's just a really cool finding! Brian P.S. Full text of research report: http://www.nature.com/srep/2015/150522/srep10434/full/srep10434.html
  2. All, Over on the thread Common Chronic Viral Infections Linked to Cognitive Decline we've seen how cytomegalovirus (CMV) is associated with immunosenescence, atherosclerotic plaques, and cognitive decline. It appear the body's immune system gets worn out (i.e. immune system stem cells get depleted) by trying in vain to eliminate chronic CMV infection. This heighted immune response results in systemic inflammation, increased plaque formation in arteries and reduced blood flow to the brain, triggering cognitive decline. Overall bad news. The news is made even worse by the fact that between 50 and 80% of people are infected with cytomegalovirus by age 40! And in the elderly, the typical infection rate can be upwards of 95%... But the real kicker, and the reason for this new thread devoted to CMV, is this study [1], ominously titled Cytomegalovirus infection accelerates epigenetic aging, which was covered this week in a blog post by Reason over at FightAging! In the study, they looked at the CMV status of two sets of people - some their 20s and some in their 90+ and correlated CMV status with "epigenetic age" as measured by "clock like" changes in DNA methylation that appear to happen as people age. This epigenetic age metric has been shown in several studies to correlated with both physical and mental fitness [2], and with mortality rate [3]. For example Marioni et al. [3] observed that 69–79 year old individuals had a 16% increased mortality during a 4–10 year follow-up if the epigenetic age was 5 years higher than the calendar age. What they found first was that 57% of the 20-somethings tested positive for CMV, and 95% of the nonagenarians tested positive - once again showing CMV infection is extremely common in the general population. Further, they found that in the younger cohort, being CMV-positive as associated with a 2.5 year increase in epigenetic age, and in the older folks, testing positive for CMV was associated with a 7 year increase in epigenetic age. But it gets worse. This 2011 study [4] found that in 14,000+ people age ≥25 from the NHANES III cohort, being CMV-positive was associated with an 20% increase in all-cause mortality over a ~16 year follow-up period. People who were both CMV-positive and had elevated C-reactive protein (> 3.0 mg/L) had it even worse - they were at a 30% higher risk of mortality relative to the (already mortality-challenged) CMV-positive folks with low CRP. Here is the graph of the data for all-cause mortality as a function of CMV status and CRP level ("high" CRP means ≥ 3.0 mg/L): Notice how simply being CMV-positive (even with low CRP) was dramatically worse for all-cause mortality risk than if you have a CRP of > 3.0 mg/L, but are free from CMV infection. How sucky is that? We try so hard to make sure our level of systemic inflammation (as measured by C-reative protein) is low. But it turns out having high CRP isn't nearly as bad for longevity as simply having a chronic CMV infection, which almost everyone has. In short, having what has long been thought to be a (relatively) harmless chronic infection with CMV appears associated with dramatic speeding up of the aging process and an increase in mortality risk. More bad news - once you've got CMV, you've got it for life. There are antiviral drugs to fight CMV given to people who have compromised immune systems and solid organ recipients, but they don't cure it and have nasty side effects like immune system suppression and kidney damage to boot. LEF offers tests for chronic CMV infection or acute CMV infection for $59 and $99 respectively (member pricing), but for those who've recently donated blood, you should be able to call your blood bank like I did to find out your CMV status for free. What can someone do to avoid contracting CMV if they are lucky enough not to have it already? It's passed via bodily fluids, so the best way to avoid contracting it is through practicing good hygiene, including: Wash your hands often. Use soap and water for 15 to 20 seconds, especially if you have contact with young children or their diapers, drool or other oral secretions. This is especially important if the children attend child care. Avoid contact with tears and saliva when you kiss. Instead of kissing on the lips, for instance, kiss on the forehead. This is especially important if you're pregnant. Avoid sharing food or drinking out of the same glass as others. Sharing glasses and kitchen utensils can spread the CMV virus. Be careful with disposable items. When disposing of diapers, tissues and other items that have been contaminated with bodily fluids, be careful not to touch your hands to your face until after thoroughly washing your hands. Clean toys and countertops. Clean any surfaces that come into contact with children's urine or saliva. Practice safe sex. Wear a condom during sexual contact to prevent spreading the CMV virus through semen and vaginal fluids. Given the serious apparent downsides of CMV infection, protecting my current CMV-negative status seems to me the most compelling reason to diligently adhering to this admittedly rather burdensome set of hygiene practices. --Dean ------- [1] Exp Gerontol. 2015 Dec;72:227-9. doi: 10.1016/j.exger.2015.10.008. Epub 2015 Oct 17. Cytomegalovirus infection accelerates epigenetic aging. Kananen L(1), Nevalainen T(2), Jylhävä J(3), Marttila S(4), Hervonen A(5), Jylhä M(6), Hurme M(7). Full text: http://sci-hub.cc/10.1016/j.exger.2015.10.008 Epigenetic mechanisms such as DNA methylation (DNAm) have a central role in the regulation of gene expression and thereby in cellular differentiation and tissue homeostasis. It has recently been shown that aging is associated with profound changes in DNAm. Several of these methylation changes take place in a clock-like fashion, i.e. correlating with the calendar age of an individual. Thus, the epigenetic clock based on these kind of DNAm changes could provide a new biomarker for human aging process, i.e. being able to separate the calendar and biological age. Information about the correlation of the time indicated by this clock to the various aspects of immunosenescence is still missing. As chronic cytomegalovirus (CMV) infection is probably one of the major driving forces of immunosenescence, we now have analyzed the correlation of CMV seropositivity with the epigenetic age in the Vitality 90+cohort 1920 (122 nonagenarians and 21 young controls, CMV seropositivity rates 95% and 57%, respectively). The data showed that CMV seropositivity was associated with a higher epigenetic age in both of these age groups (median 26.5 vs. 24.0 (p < 0.02,Mann–Whitney U-test) in the young controls and 76.0 vs. 70.0 (p < 0.01) in the nonagenarians). Thus, these data provide a new aspect to the CMV associated pathological processes. DOI: 10.1016/j.exger.2015.10.008 PMID: 26485162 ------ [2] Marioni, R.E., Shah, S., McRae, A.F., Ritchie, S.J., Muniz-Terrera, G., Harris, S.E., et al., 2015b. The epigenetic clock is correlated with physical and cognitive fitness in the Lothian birth cohort 1936. Int. J. Epidemiol. (doi:dyu277 [pii]) ------- [3] Marioni, R.E., Shah, S., McRae, A.F., Chen, B.H., Colicino, E., Harris, S.E., et al., 2015a. DNA methylation age of blood predicts all-cause mortality in later life. Genome Biol. 16 (1), 25 (doi:s13059-015-0584-6 [pii]). ------- [4] PLoS One. 2011 Feb 17;6(2):e16103. doi: 10.1371/journal.pone.0016103. Seropositivity to cytomegalovirus, inflammation, all-cause and cardiovascular disease-related mortality in the United States. Simanek AM(1), Dowd JB, Pawelec G, Melzer D, Dutta A, Aiello AE. Free full text: http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21379581/ BACKGROUND: Studies have suggested that CMV infection may influence cardiovascular disease (CVD) risk and mortality. However, there have been no large-scale examinations of these relationships among demographically diverse populations. The inflammatory marker C-reactive protein (CRP) is also linked with CVD outcomes and mortality and may play an important role in the pathway between CMV and mortality. We utilized a U.S. nationally representative study to examine whether CMV infection is associated with all-cause and CVD-related mortality. We also assessed whether CRP level mediated or modified these relationships. METHODOLOGY/PRINCIPAL FINDINGS: Data come from subjects ≥ 25 years of age who were tested for CMV and CRP level and were eligible for mortality follow-up on December 31(st), 2006 (N = 14153) in the National Health and Nutrition Examination Survey (NHANES) III (1988-1994). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all-cause and CVD-related mortality by CMV serostatus. After adjusting for multiple confounders, CMV seropositivity remained statistically significantly associated with all-cause mortality (HR 1.19, 95% CI: 1.01, 1.41). The association between CMV and CVD-related mortality did not achieve statistical significance after confounder adjustment. CRP did not mediate these associations. However, CMV seropositive individuals with high CRP levels showed a 30.1% higher risk for all-cause mortality and 29.5% higher risk for CVD-related mortality compared to CMV seropositive individuals with low CRP levels. CONCLUSIONS/SIGNIFICANCE: CMV was associated with a significant increased risk for all-cause mortality and CMV seropositive subjects who also had high CRP levels were at substantially higher risk for both for all-cause and CVD-related mortality than subjects with low CRP levels. Future work should target the mechanisms by which CMV infection and low-level inflammation interact to yield significant impact on mortality. DOI: 10.1371/journal.pone.0016103 PMCID: PMC3040745 PMID: 21379581
  3. Dean Pomerleau

    FOXO and Cider Vinegar

    All, Paul McGlothin and I have been having a discussion about the merits or risks of cider vinegar for longevity. Unfortunately the discussion is behind the CR Way paywall :( , so I won't post Paul's side of the discussion directly, but paraphrase him instead. Paul fears that the acetic acid in vinegar (cider or otherwise) gets converted into acetyl groups, which as discussed in this post, tend to unsilence genes by unwrapping them from histones in the nucleus so they can be transcribed into proteins. In particular, Paul is concerned that vinegar might reverse the effects of the Sirtuins, which are histone deacetylases, meaning they wrap genes tighter around histones, effectively silencing them. But when I questioned him about evidence for this specific effect of vinegar / acetic acid, he acknowledged that it's just a mechanistic hunch on his part. His hunch seems somewhat naive to me. Clearly some genes should be silenced and some expressed for effective aging, so its not clear a priori whether having more acetyl groups floating around would be good or bad from an aging perspective. In fact, the one piece of hard evidence I came across [1], seems to support the opposite of Paul's argument, i.e. it suggests vinegar / acetic acid may actually be an anti-aging agent, at least in C. Elegans. It found that acetic acid upregulated the expression of DAF-16 in C. Elegans, leading to a 25% increase in lifespan. It doesn't appear to be having this effect by directly unwrapping DAF-16 for increased expression, but by somehow interfering with another gene, DAF-2, which normally suppresses the expression of DAF-16. But whatever the mechanism, it suggests vinegar might not be so bad after all. Of course this is only a single study in worms, so there is no guarantee it is applicable to humans. But encouragingly, the human version of the DAF-16 gene upregulated by vinegar is the FOXO3 gene, the overexpression of which is well-known to be longevity-promoting in humans (e.g. [2]). BTW, 23andMe has a SNP for determining one's FOXO3 variant, rs2802292. From [2], the odds ratio for reaching 100 years of age for rs2802292(G;G) vs (T;T) carriers was 2.75 (p = 0.00009; adjusted p = 0.00135). One's odds of living to 100 with one copy of 'G' for rs2802292 (i.e. G:T), appears to be about 1.5-2 times greater than people with T:T. I'm G:T for rs2802292, so I've got that goin' for me :) Does anyone have and thoughts on vinegar, and whether you include it in your diet? --Dean ---------------- [1] Bioorganic & Medical Chemistry. 2009 Nov 15;17(22):7831-40. doi: 10.1016/j.bmc.2009.09.002. Epub 2009 Sep 6. The lifespan-promoting effect of acetic acid and Reishi polysaccharide. ChuangMH(1), Chiou SH, Huang CH, Yang WB, Wong CH. Author information: (1)Genomics Research Center, Academia Sinica, Taipei 115, Taiwan. Using Caenorhabditis elegans as a model organism, various natural substances and commercial health-food supplements were screened to evaluate their effects on longevity. Among the substances tested, acetic acid and Reishi polysaccharide fraction 3 (RF3) were shown to increase the expression of the lifespan and longevity-related transcription factor DAF-16 in C. elegans. We have shown that RF3 activates DAF-16 expression via TIR-1 receptor and MAPK pathway whereas acetic acid inhibits the trans-membrane receptor DAF-2 of the insulin/IGF-1 pathway to indirectly activate DAF-16 expression. In addition, a mixture of acetic acid and RF3 possesses a combined effect 30-40% greater than either substance used alone. A proteomic analysis of C. elegans using 2-DE and LC-MS/MS was then carried out, and 15 differentially expressed proteins involved in the lifespan-promoting activity were identified. PMID: 19837596 ------------- [2] Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):13987-92. doi: 10.1073/pnas.0801030105. Epub 2008 Sep 2. FOXO3A genotype is strongly associated with human longevity. Willcox BJ(1), Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD. Author information: (1)Pacific Health Research Institute, 846 South Hotel Street, Honolulu, HI 96813, USA. bjwillcox@phrihawaii.org Human longevity is a complex phenotype with a significant familial component, yet little is known about its genetic antecedents. Increasing evidence from animal models suggests that the insulin/IGF-1 signaling (IIS) pathway is an important, evolutionarily conserved biological pathway that influences aging and longevity. However, to date human data have been scarce. Studies have been hampered by small sample sizes, lack of precise phenotyping, and population stratification, among other challenges. Therefore, to more precisely assess potential genetic contributions to human longevity from genes linked to IIS signaling, we chose a large, homogeneous, long-lived population of men well-characterized for aging phenotypes, and we performed a nested-case control study of 5 candidate longevity genes. Genetic variation within the FOXO3A gene was strongly associated with human longevity. The OR for homozygous minor vs. homozygous major alleles between the cases and controls was 2.75 (P = 0.00009; adjusted P = 0.00135). Long-lived men also presented several additional phenotypes linked to healthy aging, including lower prevalence of cancer and cardiovascular disease, better self-reported health, and high physical and cognitive function, despite significantly older ages than controls. Several of these aging phenotypes were associated with FOXO3A genotype. Long-lived men also exhibited several biological markers indicative of greater insulin sensitivity and this was associated with homozygosity for the FOXO3A GG genotype. Further exploration of the FOXO3A gene, human longevity and other aging phenotypes is warranted in other populations. PMCID: PMC2544566 PMID: 18765803
  4. Dean Pomerleau

    CR May Make Your Kids Chill Out

    I thought this new study [1] that James Cain posted in his great weekly CR research update (thanks James!) was well worth promoting to its own post/thread. And without a little digging & careful reading, it wasn't clear to me what it was saying. So here is my interpretation. These researchers subjected adult male rats to 25% CR prior to breeding them. They then raised the male offspring of these CR'ed rats to adulthood, and subjected them to a battery of tests to measure their anxiety-related behavior. What they found across a variety of metrics was that the male offspring of CR'ed rats were less anxious than the male offspring of rats fed ad lib. One test where the offspring of CR'ed rats weren't less anxious / cautious was the alarm they exhibited when exposed to signs of a predator (cat urine). So in a sense, the offspring of CR'ed rodents were more mellow, but no less sensitive to real danger. Overall, it seemed like a good result to me, and one that I wouldn't have necessarily expected. My intuition would say that hardship of CR in dad might make his kids more neurotic, rather than less. The authors suggest the influence of CR in one generation on the psychological tendencies of offspring in the following generation is potentially mediated epigenetically. To me it seems hard to imagine how it would happen otherwise, since I don't believe the male parent rats were involved in the rearing of their offspring in this study (i.e. it was a one-night-stand with mom after which the dads were out of the kids' life). So this study did not address the influence of practicing CR in the presence of children on the children's psychological health, attitude towards food, etc. I think that would be at least as interesting a topic to investigate. --Dean ------------- [1] Psychoneuroendocrinology. 2015 Oct 30;64:1-11. doi: 10.1016/j.psyneuen.2015.10.020. [Epub ahead of print] Paternal calorie restriction prior to conception alters anxiety-like behavior of the adult rat progeny. Govic A(1), Penman J(2), Tammer AH(3), Paolini AG(4). The maternal environment influences a broad range of phenotypic outcomes for offspring, with anxiety-like behavior being particularly susceptible to maternal environmental perturbations. Much less is known regarding paternal environmental influences. To investigate this, adult male rats were exposed to 25% calorie restriction (CR) or glucocorticoid elevation (CORT; 200μg/ml of corticosterone in drinking water) for ∼6 weeks prior to breeding. Elevated plus maze (EPM), open field (OF), predator odor (cat urine), and acoustic startle/pre-pulse inhibition (AS/PPI) were characterised in the adult male offspring. Plasma concentrations of corticotrophin-releasing hormone (CRF), adrenocorticotropin hormone (ACTH), and serum lepin were characterised in both sires and offspring. Maternal care received by litters was additionally observed. Expectedly, CR and CORT treatment attenuated weight gain, whilst only CR induced anxiolytic behavior in the EPM. The adult offspring sired by CR males also demonstrated a reduction in weight gain, food intake and serum leptin levels when compared to controls. Moreover, CR offspring demonstrated an anxiolytic-like profile in the EPM and OF, enhanced habituation to the AS pulse, reduced PPI, but no alteration to predator odor induced defensiveness compared to control. CORT offspring failed to demonstrate any behavioral differences from controls, however, exhibited a trend towards reduced ACTH and leptin concentration. Collectively, the results indicate that a reduction in calories in males prior to conception can affect the behavior of adult offspring. The phenotypic transmission of CR experiences from fathers to the progeny could potentially be mediated epigenetically. The role of glucocorticoid elevation and maternal care are also discussed. Copyright © 2015 Elsevier Ltd. All rights reserved. PMID: 26571216
  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
  6. Dean Pomerleau

    Epigenetics and "Intelligent Design"

    [Note: I really hate to put this post on the "Chit-Chat" forum, since it is science heavy. It would fit much better on a (longed-for) "Non-CR Health and Longevity" forum. But its too far from CR to justify posting it to "CR Science", so here goes...] I'm reading philosopher Thomas Nagel's most recent book, Mind and Cosmos in which he argues that the "neo-Darwinian conception of nature is almost certainly false" - in fact, that is the subtitle of the book. Key to his argument is that it doesn't appear that the cornerstone of neo-Darwinism, namely random mutation to genes that turn out to be fitness enhancing, could ever come up with the vast variety of large scale variations in body morphology and physiological systems we see in the world, many of which are argued to be "irreducibly complex" (i.e. all-or-nothing from an evolutionary fitness perspective). The architecture of the eye, and the molecular motor that powers flagellum in bacteria are examples of these complex biological structures that would seem (to some) impossible to evolve through simple random mutation. Nagel, and others (and not just intelligent design (ID) folks, some of whom think God orchestrates evolution) see the need for some more directed form of evolution to explain the diversity and complexity of life on our planet. Nagel seems to think mind / consciousness, and not God in the traditional conception of the term, might fit the bill. But to me that seems rather extreme, and goes against "reductive materialism / naturalism" that has been so successful at explaining how the world works over the last few hundred years. One wonders if a less drastic solution that tweaks the mechanism of neo-Darwinian evolution, might be invoked to save the day for materialism / naturalism. As discussed elsewhere (see this post for details), I've recently been studying epigenetics, where gene expression can be modulated by methylation (among other mechanisms). In methylation, a methyl groups can attach to a particular DNA base pair, causing the gene to "wrap up" around a histone, preventing it from being transcribed into RNA, thereby suppressing expression of the protein that the gene codes for. This methylation can be driven by environmental factors, is quite localized, specific, and repeatable, and can occur not only in somatic cells, but also in germ-line cells (eggs and sperm), and thereby get passed down to several subsequent generations. While the epigenetic changes can be adaptive both for the organism in which they first occur, as well as their progeny, they aren't permanent changes to the base-pair sequence of genes, so they aren't heritable variations over thousands or millions of years, like we see across species in the world. So they are "Lamarkian" to a point, but not in the true sense of the world - giraffe necks could get longer for a generation or two after (hypothetical) epigenetic changes occurred as a result of a giraffe stretching to reach the high leaves on a tree, but eventually the epigenetic changes would "wear off" and subsequent generations would go back to having short necks. But what if epigenetic changes via methylation not only silences genes, but also made those silenced genes more prone to mutation? The methylation would not only be a signal that "this gene isn't worth expressing in the current environment", it would also be signaling "this gene is not very useful in is current form in the current environment, so target it for mutation". With an elevated mutation rate specific to maladaptive genes lasting several generations, new variations should more readily arise in subsequent generations, accelerating experimentation with parts of the genome where changes would be mostly likely to be beneficial in a rapidly changing environment. This sort of elevated mutation rate in parts of genes that have been methylated (silenced) is exactly what this study [1] found. To quote the abstract: Our results ... provid[e] the first supporting evidence of mutation rate variation at human methylated CpG sites using the genome-wide sing-base resolution methylation data. It's not clear that this targeting of random mutations to specific maladaptive genes could result in the type of big changes Nagel and others point to when criticizing neo-Darwinian evolution. But it seems like a way to facilitate a sort of "semi-Intelligent Design", without an explicit designer, by focusing "random tinkering" with the genome in places where genetic changes could do the most good in the current environment. Anyway, while not (directly) related to CR, I thought it was interesting nonetheless. Comments appreciated. --Dean ---------- [1] Full text: http://www.biomedcentral.com/1471-2164/13/S8/S7 BMC Genomics. 2012;13 Suppl 8:S7. doi: 10.1186/1471-2164-13-S8-S7. Epub 2012 Dec 17.Investigating the relationship of DNA methylation with mutation rate and allele frequency in the human genome. Xia J1, Han L, Zhao Z. Author information AbstractBACKGROUND:DNA methylation, which mainly occurs at CpG dinucleotides, is a dynamic epigenetic regulation mechanism in most eukaryotic genomes. It is already known that methylated CpG dinucleotides can lead to a high rate of C to T mutation at these sites. However, less is known about whether and how the methylation level causes a different mutation rate, especially at the single-base resolution. RESULTS:In this study, we used genome-wide single-base resolution methylation data to perform a comprehensive analysis of the mutation rate of methylated cytosines from human embryonic stem cell. Through the analysis of the density of single nucleotide polymorphisms, we first confirmed that the mutation rate in methylated CpG sites is greater than that in unmethylated CpG sites. Then, we showed that among methylated CpG sites, the mutation rate is markedly increased in low-intermediately (20-40% methylation level) to intermediately methylated CpG sites (40-60% methylation level) of the human genome. This mutation pattern was observed regardless of DNA strand direction and the sequence coverage over the site on which the methylation level was calculated. Moreover, this highly non-random mutation pattern was found more apparent in intergenic and intronic regions than in promoter regions and CpG islands. Our investigation suggested this pattern appears primarily in autosomes rather than sex chromosomes. Further analysis based on human-chimpanzee divergence confirmed these observations. Finally, we observed a significant correlation between the methylation level and cytosine allele frequency. CONCLUSIONS:Our results showed a high mutation rate in low-intermediately to intermediately methylated CpG sites at different scales, from the categorized genomic region, whole chromosome, to the whole genome level, thereby providing the first supporting evidence of mutation rate variation at human methylated CpG sites using the genome-wide sing-base resolution methylation data. PMID: 23281708