NEW STUDY DISPROVES ALL MAINSTREAM THEORIES OF AGING-AND REVEALS THE NEW & CORRECT: PROGRAMMED LOSS OF CELLULAR DIFFERENTIATION THEORY OF AGING

NEW STUDY DISPROVES ALL MAINSTREAM THEORIES OF AGING

MUTATION ACCUMULATION THEORY

FREE RADICAL THEORY

ANTAGONISTIC PLEIOTROPY

MITOCHONDRIAL AGING THEORY

 DISPOSABLE SOMA THEORY

DNA DAMAGE THEORY

 AND REVEALS THE NEW & CORRECT:

PROGRAMMED LOSS

OF

CELLULAR DIFFERENTIATION

THEORY OF AGING

 

Keep checking back as this post is often updsated! Updates usually added at the end.

JEFF T. BOWLES

1/23/2021

Before we get started let me just whet your appetite about what is contained in the rest of this article. The results of the most important study on aging EVER, that will be the most important study of aging for all time- have just been released! Steve Horvath’s :

Universal DNA methylation age across mammalian tissues

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.

The new study also reveals the true cause of aging at the cellular level- the programmed loss of cellular differentiation.

Recently, a preprint of a journal article that is expected to be published in Nature, was released that completely breaks open the cause of aging in mammals of almost all species. The paper shows that this aging is highly conserved by evolution and ends the debate about whether aging is caused by accidental DNA damage  or is programmed. The answer?- aging evolved, is highly conserved, and  is programmed- no doubt about it!

The paper was lead-authored by  Steve Horvath and co-authored with a long list of collaborators. It is currently titled>> Universal DNA methylation age across mammalian tissues.

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.

Here is the link  to the preprint>>    https://www.biorxiv.org/content/10.1101/2021.01.18.426733v1.full

In the last sentence of his abstract Horvath bravely states-

“Collectively, these new observations support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species – a notion that was long-debated without the benefit of this new and compelling evidence.”

NOT ONLY IS THIS THE MOST IMPORTANT STUDY CONCERNING AGING EVER- IT ALSO PROVES

THAT

THE MAINSTREAM SCIENCE’S VERSION OF THEORY OF EVOLUTION IS WRONG!

All those evolution professors  are going to have to go back to the drawing board because in their view of evolution it is impossible for aging to have evolved  and be selected for because it is bad for the spread of your selfish genes! Virtrually all evolutionary biologists believe that aging being selected for by  evolution is impossible!

Actually, I propose in another article with a link at the end of this one, that the selfish gene theory of evolution is mostly correct  but it is only half the story. There is a missing half  of the theory of evolution that has yet to be revealed. I take a stab at it, and succeed,  in the article linked to at the end. Okay  back to aging…

Here is a summary of what Horvath et al  found:

Horvath and this team looked at the DNA of a large number of mammals  and determined what were the genes that experienced  major changes of DNA methylation (both increases and decreases) at older ages.  Increased methylation at the beginning of a gene would basically shut it down, removal of methylation from the beginning of a gene would allow that gene to be expressed at older ages

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.

They found a highly conserved aging program driven by DNA methylation changes that for the most part  shut down genes that produced transcription factors  by adding methyl groups to the promoter area of the genes. They found 36 genes that were affected  /shut down  by DNA methylation and almost all of them were transcription factors that are involved in the differentiation of cells during development  that have homeobox domains. They found very few genes that experienced loss of methylation which was a surprise to me based on my predictions in my 1998 paper . I expected it to be the other way around because the entire genome loses a lot of methylation during aging. So, these instances of hypermethylation must be very  special to buck the overall trend in the global DNA demethylation with age, apparently most DNA methylation is uninvolved with direct aging control.

Overall, they found 3,617  cases of hypermethylated  cytosines in the DNA associated with aging and only  12 hypomethylated cytosines!  This blew my mind.

Well, those 12 hypomethylated  sites must be next to some very interesting genes! They analyzed these hypomethylated genes and found the #1 gene that was most hypomethylated in liver and #2  across all tissue types was the LARP1 gene.  This gene being more expressed at older ages  must be doing something very naughty!  Let us take a look at the LARP 1 gene’ function as described by Wikipedia>>>>

Well, what do you know?? LARP1 has a unique region that binds to RNA transcripts! My guess is that this is the protein that is involved in truncating the Lamin A protein in normally aging cells, and likely it is truncating the WRN protein in normally aging cells (truncated WRN protein being found in normally aging and senescent cells has yet to be shown true-but I predict someday this will be found to be occurring).

LARP1

From Wikipedia, the free encyclopedia

La-related protein 1 (LARP1) is a 150 kDa protein that in humans is encoded by the LARP1 gene.[5][6][7] LARP1 is a novel target of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, a circuitry often hyperactivated in cancer which regulates cell growth and proliferation primarily through the regulation of protein synthesis.[8]

Function

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 epithelialmesenchymal 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]

LARP1 binds to and regulates the translation of terminal oligopyrimidine motif (TOP mRNAs) and can directly interact with the 5′ cap of mRNAs.[17][18] It has also been shown to interact with the 3′ end and coding regions (CDS) of other genes.[17] LARP1 protein colocalizes with stress granules and P-bodies,[19] which function in RNA storage and degradation. It has been suggested that LARP1 functions in P-bodies to attenuate the abundance of conserved RasMAPK mRNAs. The cluster of LARP1 homologs may function to control the expression of key developmental regulators.[19]

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.

It turns out I predicted most of this  long ago in 1998.

In 1998, I published a paper titled “The Evolution of Aging: A New Approach to an Old Problem of Biology”

in Medical Hypotheses Sep 1998.

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.

Many good predictions came out of the paper which proved to be true such as:

-Aging is driven by the loss of DNA methylation of cytosines (actually driven by cytosine’s gain or loss of methylation  (CH3’s))  also known as epigenetics. The next paper confirming this prediction did not come out until 2012 >  Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock. Cell 2012 Jan 20;148(1-2):46-57.  (written by some guy at Stanford- who did not mention my 1998 paper )

-Alzheimer’s and dementia would be found to be driven by the increase in Luteinizing Hormone that occurs  after age 50 in both men and women. Confirmed in 2005 at the NIH>> Evidence for the role of gonadotropin hormones in the development of Alzheimer disease. Cell Mol Life Sci. 2005 Feb;62(3):293-8.

-Luteinizing Hormone and Follicle Stimulating Hormone would be found to play a central role in aging . Confirmed >> Data mining of human plasma proteins generates a multitude of highly predictive aging clocks that reflect different aspects of aging. October 2020  Aging Cell 19(1):e13256 ( the #1 and #2  proteins that increase the most in the aging cell are related to LH(#1) and FSH (#2).)

-The Hierarchy of programmed aging control was predicted to be

Hormone Changes>> Loss of Methylation >>> Expression of genes that cause aging.

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

Hormone Changes >>>>  Gain of Methylation >>>  Suppression of genes required for cellular differentiation.

-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.

-The first 2 sentences in the abstract of my paper claimed that aging evolved and aging and development were intimately linked. This new study proves it to be 100% true.

The evolution of aging: a new approach to an old problem of biology”

Bowles, JT Medical Hypotheses Sep 98

Abstract

“Most gerontologists believe aging did not evolve, is accidental, and is unrelated to development.

The opposite viewpoint is most likely correct.”

The problems with the paper were caused by my trying to put all the aging puzzle pieces together without enough information. For example, I imagined that the protein that is defective in Werner’s Syndrome (truncated) was generating excessive free radicals during the DNA unwinding process that catalyzed the demethylation of cytosines in the DNA. I thought this allowed pro-aging genes to be expressed, filling the body with destructive proteins. I received endless  ridicule and derision from mainstream aging theorists who believed that the evolution of pro-aging genes was impossible. The new study shows that there are pro-aging genes, just not as many as I had imagined. It turns out that  a lot of the programmed aging is caused by the suppression of genes that make transcription factors involved in maintaining cellular differentiation during and after development.

In reality what was happening was that the WRN helicase consists of 6 identical subunits which come together to form a helicase. The job of a helicase is to unwind and rewind the DNA.The single subunit also has another job as a transcription factor that binds to and silences some genes in stem cells to allow them to retain their differentiation and remain stem cells. But this was not known when I wrote the paper, so I gave it my best guess.

See>> A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging  Science. 2015 Jun 5; 348(6239): 1160–1163.

Abstract

Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of  and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.

“Finally, we asked whether heterochromatin disorganization could be a common hallmark for physiological human stem cell aging. For this purpose, we compared the levels of heterochromatin marks in primary dental pulp MSCs derived from six young (7–26 year old) and six old (58–72 year old) individuals (fig. S10I, and Table S4) (20). A marked downregulation of WRN protein associated with a decrease in H3K9me3, HP1α, SUV39H1, and LAP2β levels in MSCs derived from old individuals (Fig. 4E). Therefore, specific heterochromatin changes may underlie both pathological as well as physiological mesenchymal stem cell aging.

In summary, we have found that WRN protein, besides its role in DNA repair, functions to safeguard heterochromatin stability (fig. S11). Our results unveil that the progressive heterochromatin disorganization observed in WRN deficient MSCs underlies cellular aging, but more extensive studies are needed to examine its role during physiological aging.”Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.

Werner’s Syndrome is a rapid aging disease that kicks in around puberty and leads to  thoroughly aged people by the age of 45 or so>>

Werner’s Syndrome is caused by the WRN protein being improperly truncated so that it is too short  to do its job properly of preserving the differentiation status  of human stem cells.

Werner’s Syndrome is very much the same as normal aging. These patients have all the classic signs of aging , but they also have some extra-rare forms of disease which is what has led scientists to try and claim that this was not real aging. WS patients are afflicted with quite a few rare cancers  as well as the normal aging processes.

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.

(To my knowledge, truncated WRN protein being found in normally aging and senescent cells has yet to be discovered-but I predict someday this will be forthcoming).

The truncated differentiation/helicase protein found in Werner’s Syndrome is similar in concept to the disease called progeria which attacks  young children from the time they are born and turns them into very old  decrepit individuals by the age of 12 or so where they usually die of heart disease or atheroscelrosis. Progeria  is also caused by a truncated protein , the Lamin A protein which is a protein that is found in the nuclear envelope inside the cell. I proposed that progeria recapitulates many of the aging symptoms seen at a higher rate in normally aging males.

The truncated Lamin A protein causes the envelope that surrounds the DNA in the nucleus to be misshapen>>

Normal Nucleus         Progeria Nucleus

What is not that well known is that the progeria Lamin A protein has a 2nd function of binding to the DNA to act as a transcription factor that silences various genes  so that various cells maintain their differentiation with the proper gene expression profile (for example so that a skin cell remains a skin cell by keeping a certain set of genes silenced).

Well, it turns out that this truncated Lamin A protein is not unique to progeria kids but is also seen in normal aging at older ages in normal adults! It is found in senescent cells in normal humans- there are a number of  studies on this  for example>>>

PLoS One. 2007; 2(12): e1269.

Published online 2007 Dec 5.

The Mutant Form of Lamin A that Causes Hutchinson-Gilford Progeria Is a Biomarker of Cellular Aging in Human Skin

Abstract Hutchinson-Gilford progeria syndrome is a rare disorder characterized by accelerated aging and early death, frequently from stroke or coronary artery disease. 90% of HGPS cases carry the LMNA G608G (GGC>GGT) mutation within exon 11 of LMNA, activating a splice donor site that results in production of a dominant negative form of lamin A protein, denoted progerin. Screening 150 skin biopsies from unaffected individuals (newborn to 97 years) showed that a similar splicing event occurs in vivo at a low level in the skin at all ages. While progerin mRNA remains low, the protein accumulates in the skin with age in a subset of dermal fibroblasts and in a few terminally differentiated keratinocytes. Progerin-positive fibroblasts localize near the basement membrane and in the papillary dermis of young adult skin; however, their numbers increase, and their distribution reaches the deep reticular dermis in elderly skin. Our findings demonstrate that progerin expression is a biomarker of normal cellular aging and may potentially be linked to terminal differentiation and senescence in elderly individuals. “

So, in both cases of Werner’s Syndrome  and progeria we find a truncated protein that is used for differentiating cells is defective and unable to properly do its job of maintaining the differentiated state of the cell.

So, what could have been predicted from these facts?

That aging is caused by nothing more than cells losing their differentiation or becoming de- differentiated as I state in the title of this article. In reality, this should have been predicted long ago after studying Werner’s Syndrome and progeria. This prediction could have easily been made in 2014  and probably earlier after studies came out showing that Lamin A protein was involved in maintaining cellular differentiation in stem cells.)

See> Gerontology. 2014;60(3):197-203. Epigenetic involvement in Hutchinson-Gilford progeria syndrome: a mini-review

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 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!

I theorized  in my 1998 paper,  that more primitive organisms , early in evolution, probbaly reproduced in this manner- a quote-

“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.”

And it turns out that there are still animals on earth that can reproduce this way..take the immortal jellyfish for example:

From National Geographic Magazine-

How the Jellyfish Becomes “Immortal”

“Turritopsis typically reproduces the old-fashioned way, by the meeting of free-floating sperm and eggs. And most of the time they die the old-fashioned way too. But when starvation, physical damage, or other crises arise, “instead of sure death, [Turritopsis] transforms all of its existing cells into a younger state,” said study author Maria Pia Miglietta, a researcher at Pennsylvania State University.The jellyfish turns itself into a bloblike cyst, which then develops into a polyp colony, essentially the first stage in jellyfish life.The jellyfish’s cells are often completely transformed in the process. Muscle cells can become nerve cells or even sperm or eggs.Through asexual reproduction, the resulting polyp colony can spawn hundreds of genetically identical jellyfish—near perfect copies of the original adult.”

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!

If this concept is correct then we can expect that with the addition of a number of healthy transcription factors back to an older cell that it could be made younger, and this has indeed been proven to be the case. All that was needed were the four transcription factors known as Yamanaka factors to reverse aging in the cell dramatically. The first experiment with Yamanaka factors  took an adult cell and reprogrammed it all the way back to an embryonic state. They later  just subjected an adult cell to transient expression of the Yamanaka factors and were able to make the cell significantly younger, but not return all the way to embryo status.

See> Cell. 2016 Dec 15; 167(7): 1719–1733.e12.In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming

Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process through reprogramming has not been directly demonstrated in vivo. Here, we report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging.

“Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process through reprogramming has not been directly demonstrated in vivo. Here, we report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging.”

Okay, so here is another a little prediction that could be made:

If aging is caused by the loss of differentiation in your cells, then one would expect to see genes that produce transcription factors  shut down. Also, thinking back to Werner’s Syndrome and progeria  we would also expect to see some sort of pro-aging related protein unleashed that leads to truncated differentiation proteins like Lamin A  and WRN.

What kind of gene product would we be looking for that truncates differentiation proteins? The easiest way to truncate proteins would not be at the protein level, but rather at the mRNA level. The way proteins are produced is that the genes in our DNA  are read and copied to a very similar molecule called mRNA which is almost identical to  DNA with the exception of using the base pair Uracil in place of Thymine in the GCAT  alphabet of your DNA. The only difference  between Uracil and Thymine is a single methyl group (CH3) which is found attached to the 5’ carbon in thymine but only an H is attached to the 5’ carbon in uracil.

Prediction: There should exist some sort of protein that truncates mRNA transcripts at inappropriate places that increase with age to cause impairment of various differentiation proteins  like WRN and Lamin A. This would be a lot  easier that cutting the proteins after they have already been made. In fact, I did make this prediction to a pair of researchers  who were able to rejuvenate old mice by removing half their blood plasma and replacing it with saline and albumin. I suggested they look for an aging-promoting RNA-ase  that ran around truncating mRNA transcripts in inappropriate places-I never heard back from them.

Well as mentioned before, LARP1  seems to fit the description of this hypothetical protein! It has a very unique sequence that is specific for binding to RNA transcripts. It is found at high levels in cancers. Werner’s Syndrome victims suffer from normal cancers at a high rate as well- is LARP1  cleaving the WRN protein which leads to cancer?

So, the bottom-line conclusions we can draw from this amazing new study are these:

  1. Because the large set of genes shut down by methylation during the aging process (as well as the upregulated LARP1 gene( a true aging gene) ) are primarily the same across all mammalian species it very, very, strongly suggests that aging evolved and is highly conserved. This is in complete contradiction to modern mainstream evolutionary theory which proclaims that aging could never have evolved because it is bad for  the individual and reduces the spread of the individual’s genes. For most modern aging theorists, they think an evolved aging program is something akin to a perpetual motion machine, completely impossible. In fact, this was once the quote by Aubrey De Gray in his sophomoric paper about how programmed aging was impossible.

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 that’s about it for now…The last thing to  figure out is how to reactivate the 36 genes that are shut down by methylation, what gene when activated is causing the methylation of these 36 genes and how to shut it down,  and how to suppress that LARP1 gene to allow us to return back to a more differentiated version of ourselves.

Please Notice  I did not cross out the hormonal/neuroendocrine theory of aging…that one is still valid  and will be found to be the upstream controller of the programmed loss of cellular differentiation primarily through the large/dramatic  post age 50 increases in LH, FSH, and hCG with the simultaneous dramatic decline in night time melatonin peaks, dhea, pregnenolone, and progesterone.

Interestingly, melatonin has been found to do all sorts of amazing things, like reversing recent onset menopause (probably due to melatonin’s ability to suppress LH and FSH), preventing the progression of Alzheimer’s, increasing dramatically during caloric restriction, acting as birth control in women at 75 mg per night, and even extending the lives of mice by 20%. I can easily imagine that melatonin somehow has a central role in maintiaing  the methylated status  of the circadian rythym and Alzheimer’s genes that become hypomethylated during aging (Horvath found these  in the small group of genes that get activated with aging along with LARP1). A quick Pub Med search of the terms  “melatonin AND DNA AND methylation” gives you 96 studies , most of which show that melatonin is intricately involved with DNA methylation, and the decline of melatonin with age might be the reason for the global hypomethylated status of DNA in the elderly. Studies with titles such as>> Melatonin and sirtuins: A “not-so unexpected” relationship., or Neuroendocrine aging precedes perimenopause and is regulated by DNA methylation  Melatonin-induced demethylation of antioxidant genes increases antioxidant capacity through RORalpha in cumulus cells of prepubertal lambs, Melatonin-Mediated Development of Ovine Cumulus Cells, Perhaps by Regulation of DNA Methylation,Melatonin restores the pluripotency of long-term-cultured embryonic stem cells through melatonin receptor-dependent m6A RNA regulation (of Yamanaka factors) are not uncommon.

Likewise, a few studies have recently shown that DHEA also afffects  DNA methylation and DNA methyltransferase activity>> Epigenetic Age Reversal by Cell-Extrinsic and Cell-Intrinsic Means.A DNA Methylation Signature of Addiction in T Cells and Its Reversal With DHEA Intervention.Ethnic differences in DNA methyltransferases expression in patients with systemic lupus erythematosus.

There are numerous studies showing that progesterone, testosteone, and estrogens have draamtic effects on DNA methylation.

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 also did not cross out the telomere theory of aging. However, this theory becomes just a subset of the loss of cellular differentiation theory of aging in that telomeres when they are long, fold back over on the coding DNA and suppress various genes, probably aging genes. As the telomere shortens, these genes are then expressed. This is called the telomere position effect.

Also, Horvath noted that some other genes that were hypermethylated and thus shut down were a group of genes involved with the circadian rythym. 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 Alzheimers disease that also lose methylation and are more highly expressed.

So of course this study raises the important question-What is the purpose of the evoluton of programmed aging and how could it evolve?

A brief article about how evolution can select FOR aging>>

A Unifying Theory of The Evolution of Sex and Aging Via Predator Selection

Or a more in depth book on the topic>>>>

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 nucleus? 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.
Image result for fsh lh aging levels

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?

Image result for babiues that look the same

Image result for very old peopleImage result for very old peopleImage result for very old people
Image result for baby to adult pictures

 

Update 3- It appears this aging system is kind of a case of antagonistic pleiotropy (AP). How? It is a new kind of AP where something that was good for your distant ancestors (dissolution of the organism into millions of billions  of single cell clones that can each grow into a new adult) from an evolutionary perspective, evolves into something that is bad for the more modern descendents of the ancestral species. The ancient, dramatically prolific  system of reproduction has evolved into something that now kills an individual at a programmed time.

Please email me or leave a message here if you find any typos or have anything I should add.. thanks! Jeffbo@aol.com

 

 

8 thoughts on “NEW STUDY DISPROVES ALL MAINSTREAM THEORIES OF AGING-AND REVEALS THE NEW & CORRECT: PROGRAMMED LOSS OF CELLULAR DIFFERENTIATION THEORY OF AGING”

  1. interesting article and brilliant analysis!!…quite paradoxical to other schools ( even lifeextensionists)….my questionists is do u have hint on “how to reactivate the 36 genes that are shut down by methylation and how to suppress that LARP1 gene to allow us to return back to a more differentiated version of ourselves”. I’m just curious to what youthink, since your high intuitions predicted this close since 1998 without sophisticated data..

  2. How could we possible know that it is hormone changes driving aging, and not aging driving hormone changes? I do not say rebalancing hormones to a more youthful state could not be beneficial, but it seems a stretch to say they are the cause of aging. To do that we’d need to see what the signal is that causes them to go awry. It could just be a feedback mechanism that gradually fails.

    1. Good question- and valid question..but after 35+ years of research on the question..I have found that it is the hornones that drive the aging process
      It is a bit slow to see in humans..so instead why dont you take a look at the atlantic salmon..who rapidly age and die in 3 days after spawning

      check out their hormone changes you will see LH shooting up 10,000 percent

      also check out the Pacific Salmon who also show the rapid aging and death after spawening and only live 3 years..
      you cut out their sex hormone producing glands and they live 7 years.

      1. I understand what you are saying, but I’d still like to know WHY hormone levels change so much. In the various Salmon cases you could either argue that the massive hormone boost is required to make the arduous journey back up rivers. Or perhaps it is intentionally to kill the salmon and make way for their young. It is plausible that a similar, albeit slower signal could be occurring in humans. But what is driving it? How does the body know when to turn on the kill switch?

        Regarding LH and FSH, is there a recommended range that older folks should aim for?

        1. HI there..good points/questions. One way I look at it is rather than ask if aging is programmed..Ask if menopause appears programmed. You would agree that that is true right? Well menopause just so happens to be the evolutionary equivalent of death . Once you cannot reproduce from either menopause death or aging, evolution does not care about you and you can have no more effect on the gene pool.How is menopause triggered? By a huge drop in melatonin levels. Melatonin suppresses LH and FSH. LH and FSH are very important hormones that control women’s reproductive cycle ona monthly basis. At menopause these hormoens do not go down. they shoot sky high..! And the same thing happens in men. If a women is just eentereing menopause, melatonin can reverse the process. For how long I don’t know that would make a great study. But what I can say is taking high doses of melatonin at night (75 mg + for women and maybe 120 mg + for men -due to weight differences) will help keep LH and FSH suppressed.

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