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 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. 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. Studies have shown that human females, male transsexuals, and homosexuals share similarities in certain brain structures which differ with heterosexual males (83, 84). Also, it is believed that testosterone derived DHT is required during fetal brain development to create a “male brain” (85). Likewise, we might assume that estradiol exposure creates a “female brain” by feminizing some brain structures. If a stress-induced maternal cortisol surge suppresses the embryo’s testosterone or estradiol, then homosexual offspring, of either sex could result . Interestingly, some researchers found that in a large group of homosexuals interviewed in Germany, many more were born during the war years of 1941 to 1947 than before or after this stressful period with the birth peak occurring in 1944-1945 ( 86). Silencing of the transcription factors Oct4, Sox2, Klf4, c-Myc or Nanog has different effect on teratoma growth

See> Calorie restriction, post-reproductive life span, and programmed aging: a plea for rigor. Grey AD, Ann N Y Acad Sci. 2007 Nov;1119:296-305. So the bottom line here is we see that semelparous species no longer have to be put in a special category and hidden away and ignored as not related to normal aging. Rather they now provide a somewhat typical case of programmed aging being driven by the post reproductive dramatic increases in FSH and LH seen also in humans and most other animals from fish to mammals to birds, etc. The salmon are only unusual in the speed at which they age and the height to which their LH and FSH levels can reach. 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. Recent note-which we will later find this to be not group but an even higher-level form of selection called species selection which I have refined and coined the name “Predator Selection”). Update 1. The recent study where 50% of the blood plasma of mice was replaced with saline and albumin which led to a dramatic rejuvenation of the mice earlier was suggested herein to possibly be caused by a reduction of the LARP1 protein. However, what if LARP1 protein does not circulate in the blood but is only found inside the cell? What else could be being removed from the blood that stops the aging process and allows rejuvenation to happen? How about a 50% reduction in the circulating gonadotropins LH, FSH, and hCG ? These are the pro-aging hormones that increase with age by hundreds of percent and even up to 1,000% in women and men after age 50.And one more little thing predicted in my 98 paper , that aging EVOLVED and is PROGRAMMED and is controlled by the same things that control development. Once evolutionary biologists realize that there is something more going on to drive evolution than the selfish gene, once they realize there are evolutionary forces that also limit the spread of an individual’s genes for the good of the species which I describe in my article “Sex & Aging , How Evolution Selects For Them Almost Everywhere All the Time” many enduring mysteries of evolution can be easily explained. For example, here is a large portion of the chapter on homosexuality in my book “What Darwin Could Not See- The Missing Half of the Theory”:

I had designated Werner’s syndrome as the dominant aging system that coopted and controlled all the other aging systems-you will see why when you study the table- but basically because WS shows all the symptoms of normal human aging while other rapid aging diseases just show a segment.. Efficient generation of integration-free ips cells from human adult peripheral blood using BCL-XL together with Yamanaka factors See> Cell. 2016 Dec 15; 167(7): 1719–1733.e12.In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming Sell R. Wells J. Wypij D. The prevalence of homosexual behavior and attraction in the United States, the United Kingdom, and France: results of national population-based samples. Archives of Sexual Behavior 24(3). 1995. 235-248. Epigenetic reprogramming of primary pancreatic cancer cells counteracts their in vivo tumourigenicity

Based on Evidence, Case Studies, & Evolutionary Logic

At this point in evolution, reproduction likely occurred through parthenogenesis and possibly the complete dissociation of the multi-celled organism into a myriad of single cell, clonal spores; in an unrestricted environment, this would provide a great reproductive advantage.” High dose Vitamin D3 therapy over the last year-CURED ALL MY CHRONIC CONDITIONS-SOME THAT I’D HAD FOR 20+ YEARS! This update discussion has been deleted I am still working on it but I provide an interesting abstract to consider

Take a skin cell for example, as it loses the factors that are suppressing genes that are not involved with being a skin cell, the cell starts adopting a more and more unusual (undifferentiated) phenotype. If your body expects famine-like conditions caused by winter to be likely- it will conserve your critical resources for the future. This leads to what I call the Incomplete Repair Syndrome which in turn causes most of the diseases humans face other than spontaneous gene mutations that cause syndromes and diseases caused exclusively by aging. High D3 can be used to prevent or treat a huge number of diseases MS, asthma, 17 kinds of cancer, lupus, arthritis, heart disease, obesity, depression, Parkinsons+many more… LARP1 is the largest of a 7-member family of LARP proteins (others are: LARP1B, LARP3 (aka genuine La or SSB), LARP4A, LARP4B, LARP6 and LARP7). [9] All LARP proteins, including human LARPs, contain 2 conserved regions. The first conserved region shares homology with La proteins (called the La motif, see SSB) whereas the second conserved region (called the LA- motif) is restricted to LARP proteins. LARP1 and 1B also contain a conserved “DM15 region” within their C-terminus. [10] This region is unique and has been shown to be required for RNA-binding.Mouse Larp1 is expressed in dorsal root ganglia and spinal cord, as well as in developing organs characterized by epithelial– mesenchymal interactions . [6] Human LARP1 is present at low levels in normal, non-embryonic cells but is highly expressed in epithelial cancers (such as ovarian, colorectal, prostate, non-small cell lung, hepatocellular and cervical cancers). [11] [12] [13] [14] Some studies have shown that high levels of LARP1 protein correlate with worse prognosis in cancer patients. [15] [16] Certainly, this must be harder for selfish gene promoters to explain than sex. At least with sex, the reproducer gets to pass on half of his or her genes. Here the selfish gene-ist has to explain how it evolved that someone passes on NO GENES WHATSOEVER! Given the very tough problem to solve here, the topic of homosexuality is just ignored for the most part, by evolutionary biologists. It turns out, I believe, given the connection between development and aging we now understand thanks to Horvath, that the normal Werner’s syndrome protein apparently is also the coordinator and master regulator of all other development genes and transcription factors. The WRN protein does not do all the work itself, it has apparently coopted downstream transcription/differentiation factors and tells them when to be turned on and turned off. WRN is the master regulator of development.Human mesenchymal cells can become pluripotent by the addition of Yamanaka factors OCT3/4, SOX2, c-MYC, KLF4. We have recently reported that centenarians overexpress BCL-xL, which has been shown to improve pluripotency; thus, we aimed to determine the expression of pluripotency-related genes in centenarians. We recruited 22 young, 32 octogenarian, and 47 centenarian individuals and determined the mRNA expression of Yamanaka factors and other stemness-related cell surface marker genes (VIM, BMP4, NCAM, BMPR2) in peripheral blood mononuclear cells by reverse transcription polymerase chain reaction. We found that centenarians overexpress OCT3/4, SOX2, c-MYC, VIM, BMP4, NCAM, and BMPR2, when compared with octogenarians (p < .05). We further tested the functional role of BCL-xL in centenarians’ ability to express pluripotency-related genes: lymphocytes from octogenarians transduced with BCL-xL overexpressed SOX2, c-MYC, and KLF4. We conclude that centenarians overexpress Yamanaka Factors and other stemness-related cell surface marker genes, which may contribute to their successful aging. I believe that the excess of rare cancers and other oddities associated with WS are caused not by the single truncated protein which causes all the features of normal aging, but rather by the improper functioning for the DNA helicase made by the 6 identical but defective WRN helicase subunits. Because proper functioning of DNA helicases are required for proper DNA maintenance and repair, it is not surprising that defective helicases would be associated with various odd forms of cancer. The study proves conclusively that aging is selected for by evolution and is programmed. A result that contradicts all major mainstream theories of aging that have been proposed since the early 1900’s. It turns out August Weisman got the right answer in 1882 but with the wrong reasoning. 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. If the process were to continue long enough the skin cell would be unrecognizable eventually. In some ways you could say the skin cell is returning to its undifferentiated, earlier (younger) state, but in an unhealthy way that ends up killing the bearer of these undifferentiated cells throughout the body. Counterintuitively, detrimental aging appears to actually be caused by cells becoming younger in a way, less differentitated, more like an embryonic stem cell!

Update 2. It is interesting to note how babies often look so much alike due to their not being fully “differentiated”. They are much more unique and differentiated as children and adults. But then think of the elderly; don’t they seem to be very similar looking? Is this an example of a gain then a loss of cellular differentiation manifesting itself in physical appearance? Swaab D. Gooren L. Hofman M. Gender and sexual orientation in relation to hypothalamic structures. Hormone Research. 38 Suppl 2:51-61, 1992.Recent advances in the direct conversion of fibroblasts to cardiomyocytes suggest this process as a novel promising approach for cardiac cell-based therapies. Here, by screening the effects of 10 candidate small molecules along with transient overexpression of Yamanaka factors, we show ascorbic acid (AA), also known as vitamin C, enhances reprogramming of mouse fibroblasts into beating cardiomyocytes. Immunostaining and gene expression analyses for pluripotency and cardiac lineage markers confirmed beating patches were derived from non-cardiac lineage cells without passing through a pluripotent intermediate. Further analysis revealed that AA also increased the size of the beating areas and the number of cardiac progenitors. Immunostaining for cardiac markers, as well as electrophysiological analysis confirmed the functionality of directly converted cardiomyocytes. These results illustrate the importance of AA in direct conversion of fibroblasts to cardiomyocytes and may open new insights into future biomedical applications for induced cardiomyocytes. This study proves this to be true, but to a lesser extent than I expected. What I did not expect was another hierarchy revealed by this study A better molecular understanding of gastrointestinal cancers arising either from the stomach, the pancreas, the intestine, or the liver has led to the identification of a variety of potential new molecular therapeutic targets. However, in most cases surgery remains the only curative option. The intratumoral cellular heterogeneity of cancer stem cells, bulk tumor cells, and stromal cells further limits straightforward targeting approaches. Accumulating evidence reveals an intimate link between embryonic development, stem cells, and cancer formation. In line, a growing number of oncofetal proteins are found to play common roles within these processes. Cancer stem cells share features with true stem cells by having the capacity to self-renew in a de-differentiated state, to generate heterogeneous types of differentiated progeny, and to give rise to the bulk tumor. Further, various studies identified genes in cancer stem cells, which were previously shown to regulate the pluripotency circuitry, particularly the so-called “Yamanaka-Factors” (OCT4, KLF4, SOX2, and c-MYC). However, the true stemness potential of cancer stem cells and the role and expression pattern of such pluripotency genes in various tumor cell types remain to be explored. Here, we summarize recent findings and discuss the potential mechanisms involved, and link them to clinical significance with a particular focus on gastrointestinal cancers. Update #12 Turns out lamin A is missing in undifferentiated embryonic stem cells and is defective in the rapid aging disease of progeria : I theorized in my 1998 paper, that more primitive organisms , early in evolution, probably reproduced in this manner- a quote-