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I'm curious if any of you have supplement regimens for "Methylation" support. I've been prophylactically taking 1mg of methyl-b12 and 800mcg of methyl-folate for a few years after learning of my +/+ C677T polymorphism (among others.) More recently, I've tacked on B1, B2, and B6 (P5P.) I've been thinking about readdressing this stack and pulling back on everything but the b12 & b9, then maybe experimenting with trimethylglycine. I did come across this article: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4262445/ Would TMG be more likely to ferment to TMAO or promote cardiovascular disease, or might this be a health-promoting cardio-protective supplement? Have you experimented with dialing in an ideal b-vitamin complex to address things like C677T?
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 , 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. ). BTW, 23andMe has a SNP for determining one's FOXO3 variant, rs2802292. From , 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 ----------------  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 -------------  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. email@example.com 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
[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  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 ----------  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