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It appears that our human development/ aging program of increasing differentiation then decreasing differentiation probably evolved from this ancient form of a reproduction system. Instead of a human dissolving into 30 trillion identical clonal spores to reproduce (which one would expect to happen if the selfish gene theory of evolution was the only way evolution worked), we instead lose our cellular differentiation in a way that harms and eventually kills. We might go so far to say that we age by getting younger from a differentiation point of view!-talk about an unexpected conclusion! Biallelic mutations in ATM result in the neurodegenerative syndrome Ataxia-Telangiectasia, while ATM haploinsufficiency increases the risk of cancer and other diseases. Previous studies revealed low reprogramming efficiency from A-T and carrier fibroblasts, a barrier to iPS cell-based modeling and regeneration. Here, we tested the feasibility of employing circulating erythroid cells, a compartment no or minimally affected in A-T, for the generation of A-T and carrier iPS cells. Our results indicate that episomal expression of Yamanaka factors plus BCL-xL in erythroid cells results in highly efficient iPS cell production in feeder-free, xeno-free conditions. Moreover, A-T iPS cells generated with this protocol maintain long-term replicative potential, stable karyotypes, re-elongated telomeres and capability to differentiate along the neural lineage in vitro and to form teratomas in vivo. Finally, we find that haploinsufficiency for ATM does not limit reprogramming from human erythroid cells or in vivo teratoma formation in the mouse. Update #16- in progress Overall, they found 3,617 cases of hypermethylated cytosines in the DNA associated with aging and only 12 hypomethylated cytosines! This blew my mind.
Introduction: Liver cancer is a major cause of mortality and is characterized by the transformation of cells into an uncontrolled mass of tumor cells with many genetic and epigenetic changes, which lead to the development of tumors. A small subpopulation of cell population known as Cancer Stem Cells (CSCs) is responsible for cancer stemness and chemoresistance. Yamanaka factors [octamer-binding transcription factor 4 (OCT4), SRY (sex-determining region Y)-box 2 (SOX2), kruppel like factor 4 (KLF4), and Myelocytomatosis (MYC); OSKM] are responsible for cancer cell stemness, chemoresistance, and recurrence. A major manner in which genetic signaling occurs is through alteration of the methylation status of 5mC in 5mC demethylation is catalyzed by free radicals and methylation by antioxidants.”Update #14- A new Horvath article has just been published in Nature..it turns out as expected transient expression of Yamanaka factors can reverse the aging process!! Incomplete cellular reprogramming of colorectal cancer cells elicits an epithelial/mesenchymal hybrid phenotype Results: We show that an optimal zone of innate immune activation, as defined by maximal yield of induced pluripotent stem cells, is determined by the degree of activation of nuclear factor κ-light-chain-enhancer of activated B cells; NO generation; S-nitrosylation of nuclear proteins; and DNA accessibility as reflected by histone markings and increased mononucleosome generation in a micrococcal nuclease assay. Genetic or pharmacological inhibition of inducible NO synthase reduces DNA accessibility and suppresses induced pluripotent stem cell generation. (free radicals catalyze demethylation) The effect of NO on DNA accessibility is mediated in part by S-nitrosylation of nuclear proteins, including MTA3 (Metastasis Associated 1 Family Member 3), a subunit of NuRD (Nucleosome Remodeling Deacetylase) complex. S-Nitrosylation of MTA3 is associated with decreased NuRD activity. Overexpression of mutant MTA3, in which the 2 cysteine residues are replaced by alanine residues, impairs the generation of induced pluripotent stem cells. Several studies have demonstrated that LARP1 deficiency selectively affects the recruitment of TOP mRNAs to polysomes In some cancer cells, LARP1 deficiency reduces proliferation and activates apoptotic cell death. [13] Even though a decrease abundance of proteins encoded by TOP mRNAs has been reported in LARP1 silenced cells, some researchers believe that this can be explained simply by the reduced number of TOP mRNA transcripts in LARP1-deficient cells. Also, Horvath noted that some other aging genes that were hypomethylated and thus activated were a group of genes involved with the circadian rhythm. This suggests to me a connection to melatonin and other hormones that vary throughout the day. He noted another set of genes involved with causing Alzheimer’s disease that also lose methylation and are more highly expressed. (This might explain why melatonin seems so effective at stopping the progression of Alzheimer’s).
Let us consider the case of female offspring of stressed mothers being more promiscuous than the female offspring of non-stressed mothers. This also jibes well with the BIG PICTURE as promiscuous females who have offspring from multiple males rather than bonding with a single one will add more diversity to the gene pool than if she just mated with a single male for life. As we will see later diversity in the gene pool is the defense to evolving predation that evolution seeks with all these mysterious adaptations. How is having homosexual offspring a defense to predation? Having homosexual offspring is a form of birth control for mothers who are considered by evolution to be unfit in the presence of predation. The stress from predator encounters if extreme enough can kill the mothers and their unborn babies. If the stress is less extreme it can lead to homosexual offspring that need to be nursed for a relatively significant period of time. Nursing prevents the mother from becoming fertile for mating. So, in a sense having homosexual offspring is just nature’s form of birth control for mothers perceived as temporarily “unfit” due to stress.The Dramatic Hyaluronic Acid Decline (After Age 40) that Causes Wrinkles, Hair Graying/Thinning, Arthritis, Chronic Pain/Diminished Eyesight/Joint Replacement So my examination of the 200+ journal articles in Pub Med that contain the term “Yamanaka factors ” yields some very interesting results… It turns out that it appears that the general rule is that adding antioxidants to the Yamanaka factors greatly increases their differentiation into specific cell lines (presumably through increasing general cytosine methylation and shutting down of various genes.). It also appears to be generally true that adding free radicals to the mix greatly increases the loss of differentiation of the cells and allows them to become pluripotent (blank) stem cells (presumably by increasing loss of cytosine methylation) . I think it is the most important study concerning aging and always will be. And I have been studying aging for 35+ years and have seen almost everything! Horvath’s travels through the methylation of the DNA of so many animals is certainly as important as and probably more so than Darwin’s 5 years on the HMS Beagle. Research Gate Link to Published Journal Articles>>>JT Bowles on ResearchGate
The truncated Lamin A protein causes the envelope that surrounds the DNA in the nucleus to be misshapen>> Silencing of the transcription factors Oct4, Sox2, Klf4, c-Myc or Nanog has different effect on teratoma growth Similarly, given that the LH and FSH subunits are found to be the #1 and #2 proteins that increase inside a cell during aging, it is not too far a leap to suggest that these proteins might have a central role in the methylation of the 36 genes that become hypermethylated with aging. LH and FSH not only increase dramatically during aging after the age of female menopause (in both men and women-up to 1,000%+!), they also have a primary role in initiating pre-pubertal/pubertal development in children as well when they increase.
About Jeff T. Bowles
Oncogenic transcription factors are known to mediate the conversion of somatic cells to tumour or induced pluripotent stem cells (iPSCs).
Richard Dawkins, as courageous as he is, at least gives an explanation a try in a 2015 YouTube video. I share the link with you below. If you want a good laugh give it a watch. I am not laughing at Dawkins himself just at him trying to perform the impossible task of explaining homosexuality from the selfish gene point of view. Prevailing evolutionary theory cannot explain the conundrum of homosexuality. Current theory requires defining homosexuality as an evolutionary accident as homosexual offspring would not be expected to reproduce. Is evolution so sloppy that the sexual preferences of 10% to 20% of the human population (78) is simply a random mistake of nature? And why does it also occur throughout the animal kingdom from sheep (79) on down to rats (80)? If one accepts group selection as a reality, the purpose of homosexuality has a simple explanation. This paper was the result of almost 10 years of non-stop 7 day a week, feverish research at the Northwestern Medical School library where I read everything I could find about aging. At the end of 10 years, I was like the first paleontologist who had uncovered the complete skeleton of a dinosaur but the bones were strewn about. I had identified almost all the relevant factors related to aging. It was time to put the bones together to see what the dinosaur looked like. Just like that first paleontologist’s attempt, my assembled dinosaur (aging theory) was mostly correct, but there were some bones placed in the wrong position.See Update #23 with a link to a new Horvath study in press where he determined that this technique of transient expression of Yamanaka Factors that was applied to old rats reversed the aging in their cells by 54% to 75% depending on the tissue type, and had a major rejuvenating effect on them! Induced pluripotent stem cells (iPSCs) hold great promise for cell therapy. However, their low efficiency of lineage-specific differentiation and tumorigenesis severely hinder clinical translation. We hypothesized that reprogramming of somatic cells into lineage-specific progenitor cells might allow for large-scale expansion, avoiding the tumorigenesis inherent with iPSCs They looked at the DNA methylation changes with age in 59 different tissue types from 128 mammalian species to see what they all had in common.
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