84 replies to this topic

[Lazarus Long]

Since the beginning of this organization there has been a quiet but serious debate to reconcile certain seemingly contradictory aspects of aging theory between genetic based evolutionary models, cellular decay (immune failure, telomere shortening/oxidation and mtDNA mutation) models and systemic models that imply the presence of some type of staging mechanism that for better or worse might be called a clock model.

Recently as I suggested all the way back in the BKlein.com period a study of Progeria has produced some very important genetic results that have highlighted the Lamin A gene. Now a group in Hong Kong has shed new light on aging based on those findings earlier this year. This study is in Nature Medicine July issue and I hope we can get it for discussion soon.

Here is a news article concerning their findings but it appears Lamin A is a type of master regulatory gene that may trigger large scale systemic changes due to mutation over time. Conversely this gene may express complex regulatory enzymes that if better understood may not only lead to treatment and prevention for cancer as the researchers hope but also I suggest the ability to reverse or at least prevent normal aging if the body's metabolic systems can be augmented with the necessary enzyme regulation from artificial sources in time to prevent irreversible cellular damage.

There may be a cumulative interaction at work that in fact is regulated in a physiologically global manner by a few key genes like Lamin A and clearly these findings suggest a need to delve further in this direction.

Please take this opportunity to reflect on how much we have learned in a relatively short time and how we might offer a new model for aging that not only treats it as a disease but goes further to establish a systemic model to demonstrate the interactivity of the different subsystems and both immediate genetic and evolutionary biological models for why these systems have evolved.

It might be helpful for this discussion if we can get the original study and its findings for discussion and add to that the references cited in that study.

Also no approach I am suggesting precludes the ability to integrate such a broader understanding of methodologies for tissue repair, general disease prevention (immunology) and repair/replacement methodologies through gene insertion, mtDNA engineering, or SCNT but in fact may offer a significantly better comprehension for targeting general research efforts and integrating them with the body's *natural* physiology.

Any thoughts on this specific approach and how we could perhaps work it toward developing a grant proposal thesis perhaps?

Scientists shed new light on aging process
By Tan Ee Lyn
Thu Jun 30, 9:24 AM ET

HONG KONG (Reuters) - Scientists in Hong Kong have shed new light on why cell repair is less efficient in older people after a breakthrough discovery on premature aging, a rare genetic disease that affects one in four million babies.

Premature aging, or Hutchison-Gilford Progeria Syndrome (progeria), is obvious in the appearance of a child before it is a year old. Although their mental faculties are normal, they stop growing, lose body fat and suffer from wrinkled skin and hair loss.

Like old people, they suffer stiff joints and a buildup of plaque in arteries which can lead to heart disease and stroke. Most die of cardiovascular diseases before they are 20.

In 2003, a team of scientists in the United States found that progeria was caused by mutation in a protein called Lamin A, which lines the nucleus in human cells.

A team at the University of Hong Kong, led by Zhou Zhongjun, took the research a step further in 2004 and found that mutated Lamin A actually disrupted the repair process in cells, thus resulting in accelerated aging.

The study was published in the July issue of the Nature Medicine journal.

Zhou said the team came by their findings after comparing skin cells taken from two progeria sufferers, normal humans, progeria mice and normal mice.

While damaged DNA was quickly repaired in the healthy human and mice cell samples, the samples taken from the progeria humans and mice had difficulty repairing damaged DNA.

"Mutation in this protein (Lamin A) can cause defects in repair and thus lead to progeria," Zhou, a research assistant professor with the biochemistry department at the University of Hong Kong, said in an interview.

"DNA damage is not effectively repaired in cells with defective Lamin A but very efficiently repaired in normal cells."

The study highlights the importance of Lamin A to the repair process, and any mutation to Lamin A that disrupts repair will bring about aging, Zhou said.

Having established the link between Lamin A and repair, Zhou is using major findings from other research he did in 2002 to work on his next project, a product which he hopes could kill cancer cells.

Zhou, Professor Karl Tryggvason in Sweden's Karolinska Institute and a Spanish research group found in 2002 that the enzyme Zmpste 24 was responsible in converting prelamin A to functional Lamin A.

Zhou's laboratory is now developing inhibitors to Zmpste 24, which he hopes to apply to tumors. These inhibitors should theoretically disrupt Lamin A production, thwart the repair function in cancer cells, and bring on their premature aging and death.

"We're now trying to develop inhibitors to Zmpste 24 and apply it to tumor cells," he said.

[knowitall]

This work on Lamin doesn't necessarily tell us anything about aging. All it says is that when you create an unstable genome you can get phenotypes that look like accelerated aging. Lamin A likely plays no role in the aging process of a normal person and is only important in the context of Progeria.

[Lazarus Long]

That is simply not true given the arguments of the recent findings *knowitall*. [lol]

The point of Lamin A is that it very well may describe a controlling master gene with respect to a number of systems simultaneously that in turn as they fail contribute to a destructive synergy and ultimate catastrophic failure commonly called death.

The reason I am asking to approach this from a more global perspective is precisely because the accepted Aging theories appear to be too *partisan* and perhaps that is because each possesses a competing *piece of the truth* combined with a *shared fallacy* that there may be a singular approach to the underlying theory.

I think it is fallacious to ignore Progeria in this context and treat the genetic analysis as aberrant or too specific when conversely what we see with mutation in Lamin A failure is a broad system onset of aging from to include oxidative cellular breakdown and sclerosis etc.

This is why I prefer a systemic understanding and I suggest the results we are seeing support that approach. In respect to Lamin A that doesn't mean that Lamin A is a singular aspect either but that it might offer a direct ability to influence aging on a more global scale.

[Mark Hamalainen]

If mutation of Lamin A causes accelerated aging of the host cell, that means that there was already a baseline rate of aging going on since Lamin A was mutated. Repair of Lamin A could only restore the baseline rate. I don't imagine the proportion of cells with mutated Lamin A would be very high even in a very old person, so the mutated cells would have to either induce aging in a large number of other cells or have a selective growth advantage (unlikely since they are aging rapidly) in order to have a significant effect on organismal aging. Since those situations are unlikely, I don't think there's much reason to suspect this line of investigation will help us slow, and certainly not reverse, aging.

In other words, aging occurs with or without Lamin A mutation. Rejuvenating cellular information by cell and tissue therapy is still the best route to fix this.

[Lazarus Long]

Except if you read the article above what they are saying Lamin A controls is the genetic repair process.

While damaged DNA was quickly repaired in the healthy human and mice cell samples, the samples taken from the progeria humans and mice had difficulty repairing damaged DNA.

"Mutation in this protein (Lamin A) can cause defects in repair and thus lead to progeria," Zhou, a research assistant professor with the biochemistry department at the University of Hong Kong, said in an interview.

So it appears they are offering a system interpretation that is not in accord with the accepted doctrine being offered by others.

The argument of the article (and I have not read the original studies) suggests that this is not a single cell specific problem when considered as a genetic defect but a systemic problem for ALL the cells in the body simultaneously. Additionally, the failure is precisely in the repair process for dealing with mutations caused during normal cell replication, hence the controller (or template) master gene argument and why the disease manifests itself from the beginning to initiate systemic wide aging.

It is not a mimicry of aging or a single system but a broad level of age related physiological failures being simultaneously experienced. IOW's this mutation is to cellular repair what say AIDS is to the immune system, as an analogy.

I suggest that means that a bit of review is in order before applying a more understanding. I obviously could be wrong and I am only making a suggestion and asking for help getting the source info but I think we are overlooking the possibility of what happens if we can repair the body's natural ability to repair itself.

Also how as this gene fails over time we begin seeing the onset of cumulative failures that contribute to the general decay called aging.

[Mark Hamalainen]

So it appears they are offering a system interpretation that is not in accord with the accepted doctrine being offered by others

I must be missing something, I don't see what is particularly new.

Additionally, the failure is precisely in the repair process for dealing with mutations caused during normal cell replication, hence the controller (or template) master gene argument and why the disease manifests itself from the beginning to initiate systemic wide aging

The failure/mutation can't occur as a result of itself. My point was that aging is occuring before the failure of that gene.

The argument of the article (and I have not read the original studies) suggests that this is not a single cell specific problem when considered as a genetic defect but a systemic problem for ALL the cells in the body simultaneously

Honestly I don't know much about Progeria, but if its an inherited mutation then all copies of the gene will be mutated. How would this situation ever arise in a person born with the healthy gene? By the time a significant number of copies of that gene are mutated, a lot of other damage will have occured and the person will have died of something else.

Its certainly a gene worth investigating, I just don't see how it is revolutionary or even very new in any way.

[olaf.larsson]

Here is the text:

http://www.ncbi.nlm....0864&query_hl=7



Liu B, Wang J, Chan KM, Tjia WM, Deng W, Guan X, Huang JD, Li KM, Chau PY, Chen DJ, Pei D, Pendas AM, Cadinanos J, Lopez-Otin C, Tse HF, Hutchison C, Chen J, Cao Y, Cheah KS, Tryggvason K, Zhou Z.
"Genomic instability in laminopathy-based premature aging."
Nat Med. 2005 Jun 26;

[Lazarus Long]

In what amounts to another confirmation of a mutation theory of aging as opposed to the oxidative stress or a programed theory of aging, here is a study releasing findings about the mouse genome that concludes that aging is a composite failure of multiple systems due to accumulated genetic defects (principally in the mtDNA).

What I also found interesting about the article published in Live Science is that it makes reference to Kurzweil and multiple cites to articles about Aubrey and the MMP. I suggest the authors of the study at my old alma mater (UW) deserve an outreach as well as the author of the article.

BTW, thank you for including the link Wolfram though I still only have access to the abstract. I haven't had much opportunity to check back here for a while and was pleasantly surprised to be able to read it.


http://news.yahoo.co...couldhelphumans

Aging Cause Found in Mice, Could Help Humans

Bjorn Carey, LiveScience Staff Writer, LiveScience.com
Thu Jul 14, 3:08 PM ET

The buildup of mutated DNA triggers aging in mice, according to a new study that could help advance research into human aging.

As a lifetime of small mutations in the genetic code build up, cells begin to die. These deaths lead to such things as graying hair and weight changes, hearing and vision impairment, loss of muscle and weakened bones.

"We think that the key to what is happening in aging is that as (genetic) mutations or DNA damage accumulates, critical cells die," said Tomas Prolla of the University of Wisconsin-Madison. "These experiments favor a major role for programmed cell death in aging."

This study, expected help scientists understand how humans grow old and die, is detailed in the July 15 issue of the journal Science.

The DNA mutations accumulate specifically in each cell's mitochondria – the energy plant for a cell. When these mitochondria shut off, so do the cells, leading to the signs of aging.

Prolla and his group used mice that were genetically altered to lack the protein necessary to repair mitochondrial DNA. These mice accumulated mutations at a higher rate than seen in unaltered mice.

"It's like a broken spellchecker," Prolla said. "By introducing a malfunction in the (genetic) proofreading domain, these mutations accumulate much more rapidly."

These findings lend support to the theory that cell death is the cause of aging. The other theory, called oxidative stress, says that the aging process is the result of a lifetime of oxygen reacting with free radicals -- cell-damaging molecules that are produced naturally throughout the body.

Prolla's team found no evidence indicating oxidative stress is the cause of aging. In fact, they discovered less oxidative stress than normal in tissues like the liver, suggesting that the damage to mitochondria was so severe that the mice's metabolism was lagging and producing fewer free radicals.

This research suggests that someday anti-aging drugs could be developed that would prevent mutations from occurring in mitochondrial DNA – either for the whole body, or just for specialized areas, like the ears or hair follicles.

Of course, mice would again be important for the beginning stages of this type of research.

"The idea would be to reduce the level of cell death and improve function," Prolla said. "If that pans out, then we can begin to think about pharmaceutical interventions to retard aging by preserving mitochondrial function."

Hang in There: The 25-Year Wait for Immortality

Infusion of Young Blood Revives Old Muscles

Ray Kurzweil Aims to Live Forever

Anti-Aging Prize Tops $1 Million

[Mind]

The scientist in the article foresees anti-cancer therapy, perhaps also the Lamin A gene may lead to drugs that enhance genone stability. While this wouldn't stop aging, it could certainly increase your chances of living to the maximum possible age (without other revolutionary breakthroughs).

[apocalypse]

If I'm not mistaken the lamin-A protein's part of the nuclear envelope, destabilization of nuclear structure should compromise repair function, which is what we're seeing.

I would guess that it may be possible that some mutations compromise its function but not to the degree seen in progeria, thus some individuals may experience slightly but less noticeably reduced lifespans.

[cessationoftime]

Here is my view on the theories of aging. I hit on why i think mitochondrial damage is not what we should focus on, and why DNA damage seems more likely. I believe it is a drop in protein production that leads to aging and cell death. And that there are two stages to aging, DNA damage followed by telomere loss.

PLEASE rip it to shreds, but please reference your shredder.

I put it together yesterday so its still quite rough...


---Chris

[1966]

I do not know what "cell lines" are, but immortality is possible at the level of cell lines.
However, as far as I know, there are no immortal muticellular organisms.
As genetics and biochemistry is similar among all multicellular organisms including plants, I think immortality might one day be possible either for all multicellular organisms or for none.
Yeast is not a multicellular organism, so I do not beleive that ageing of the yeast will shine much light on the ageing in multicellular organisms. However, I believe that ageing in worms, flies, mice or maize is basically similar to ageing in humans.
I do not believe that accumulation of mtDNA mutations explains ageing, because it can not explain rejuvenation by gametogenesis, fertilization and embryogenesis and survival of life from generation to generation. It might be that some kinds of cell signalling connected with mitochondria might be connected with ageing

[1966]

Is hydra an immortal multicellular organism or not?
I do not understand why people connect cell division with rejuvenation, and stopping of cell division with ageing. Cell division is just a mechanistic process and is not the same as rejuvenation. Human egg cells are not more aged because they do not divide from birth, than they would be if they divided in the meantime.
I do not understand why people connect ageing with accumulation of DNA mutations. All "ageing influence" of accumulated mutations disappears in gametogenesis, fertilization and embryogenesis and survival of life from generation to generation.
Besides, cancer cells are genetically unstable, which probably means that they accumulate DNA mutations more easily than, for instance, normal fibroblasts. However, normal fibroblasts age, and cancer cells form IMmortal cell lines.

[caston]

Here is my view on the theories of aging.  I hit on why i think mitochondrial damage is not what we should focus on, and why DNA damage seems more likely.  I believe it is a drop in protein production that leads to aging and cell death.  And that there are two stages to aging, DNA damage followed by telomere loss.

PLEASE rip it to shreds, but please reference your shredder.

I put it together yesterday so its still quite rough...


---Chris

Is cessationoftime.com still running?

[Avatar of Horus]

To post #1,#2:
Recent evidence suggests that it plays some role in the normal aging process too:

Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging
Circulation. 2010 May 25;121(20):2200-10. doi: 10.1161/CIRCULATIONAHA.109.902056. Epub 2010 May 10.
Ragnauth CD, Warren DT, Liu Y, McNair R, Tajsic T, Figg N, Shroff R, Skepper J, Shanahan CM.
Division of Cardiovascular Medicine, Kings College London, James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK.
http://www.ncbi.nlm....pubmed/20458013

Abstract
BACKGROUND:
Hutchinson-Gilford progeria syndrome is a rare inherited disorder of premature aging caused by mutations in LMNA or Zmpste24 that disrupt nuclear lamin A processing, leading to the accumulation of prelamin A. Patients develop severe premature arteriosclerosis characterized by vascular smooth muscle cell (VSMC) calcification and attrition.
METHODS AND RESULTS:
To determine whether defective lamin A processing is associated with vascular aging in the normal population, we examined the profile of lamin A expression in normal and aged VSMCs. In vitro, aged VSMCs rapidly accumulated prelamin A coincidently with nuclear morphology defects, and these defects were reversible by treatment with farnesylation inhibitors and statins. In human arteries, prelamin A accumulation was not observed in young healthy vessels but was prevalent in medial VSMCs from aged individuals and in atherosclerotic lesions, where it often colocalized with senescent and degenerate VSMCs. Prelamin A accumulation correlated with downregulation of the lamin A processing enzyme Zmpste24/FACE1, and FACE1 mRNA and protein levels were reduced in response to oxidative stress. Small interfering RNA knockdown of FACE1 reiterated the prelamin A-induced nuclear morphology defects characteristic of aged VSMCs, and overexpression of prelamin A accelerated VSMC senescence. We show that prelamin A acts to disrupt mitosis and induce DNA damage in VSMCs, leading to mitotic failure, genomic instability, and premature senescence.
CONCLUSIONS:
This study shows that prelamin A is a novel biomarker of VSMC aging and disease that acts to accelerate senescence. It therefore represents a novel target to ameliorate the effects of age-induced vascular dysfunction.

[adamh]

Perhaps prelamin A not only disrupts the cellular repair mechanism in the cell in which it resides but also seeps out of the cell and causes disruption in nearby cells with normal function? It seems like this would be easy to test, simply inject it into animals without signs of the disease and see what happens. We know that some protiens called prions can self replicate despite not having any dna or rna. Perhaps the prelamin A disrupts the normal dna in healthy cells and causes it to produce more prelamin A?

 

Just a hypothesis, I don't have enough data to call it a theory.

[Avatar of Horus]

some more infos about the similarities:
from the study's text:
http://circ.ahajourn...21/20/2200.long

... in HGPS patients, the most catastrophic defect is VSMC dysfunction. Affected individuals develop severe premature arteriosclerosis and die of myocardial infarction or stroke usually within the second decade of life.4,11,12 Large arteries and small arterioles show characteristic VSMC changes including calcification, lipid accumulation, fibrosis, and VSMC attrition.16,17 These VSMC defects are highly reminiscent of those occurring in common, age-associated vascular pathologies, including atherosclerosis and related arteriosclerotic processes such as medial calcification.18,19 Thus, an important question is whether the dysfunctional pathways in HGPS are relevant to normal aging.

To date, the role of nuclear lamina defects in normal aging processes is unclear. One study showed that the alternate splicing of LMNA to produce progerin is consistently utilized in a low percentage of cells in both young and old individuals but with no age-associated rise in expression.9 Accumulation of progerin in a very small fraction of skin fibroblasts in aged individuals has also been demonstrated.20 However, despite the prevalent vascular phenotype of HGPS, analyses of lamin A processing in human VSMCs have not been performed. Therefore, we sought to determine the contribution, if any, of lamin A dysfunction in human VSMC aging. We demonstrate that prelamin A accumulation is a novel and specific hallmark of VSMC aging and disease and may be a therapeutic target to ameliorate the effects of age-related vascular dysfunction.
...

Additionally, the failure is precisely in the repair process for dealing with mutations caused during normal cell replication, hence the controller (or template) master gene argument and why the disease manifests itself from the beginning to initiate systemic wide aging

The failure/mutation can't occur as a result of itself. My point was that aging is occuring before the failure of that gene.

The argument of the article (and I have not read the original studies) suggests that this is not a single cell specific problem when considered as a genetic defect but a systemic problem for ALL the cells in the body simultaneously

Honestly I don't know much about Progeria, but if its an inherited mutation then all copies of the gene will be mutated. How would this situation ever arise in a person born with the healthy gene? By the time a significant number of copies of that gene are mutated, a lot of other damage will have occured and the person will have died of something else.

The study suggests:

FACE1 Is Downregulated by Oxidative Stress
A crucial event in the accumulation of prelamin A was the downregulation of FACE1. Its sensitivity to oxidative stress, as well as the correlation of its loss with oxidative DNA damage, suggests that it may be a key factor in age-related vascular decline. Oxidative damage is detectable in >90% of cells in atherosclerotic plaques.38 Therefore, it could be envisaged that a vicious cycle of stress-induced FACE1 downregulation and prelamin A accumulation, leading to a potentiation of DNA damage, mitotic catastrophe, premature senescence, and aberrant differentiation, could be occurring in the vessel wall to accelerate VSMC aging and induce age-associated pathologies. FACE1 is clearly a novel candidate for genetic study because decreased levels may be associated with increased cardiovascular risk. ...

 
BTW here is an article about another important effect of oxidative stress:
Vascular Smooth Muscle Cells Undergo Telomere-Based Senescence in Human Atherosclerosis - Effects of Telomerase and Oxidative Stress
http://circres.ahajo...t/99/2/156.full

So what seems to be occuring is that an elevated level of oxidative stress can induce multiple effects in the VSMCs, including the downregulation of FACE1/ZMPSTE24, and accumulation of prelamin A, telomere shortening and DNA damage and response. And since oxidative stress can be widespread, so can these changes be.
 

Perhaps prelamin A not only disrupts the cellular repair mechanism in the cell in which it resides but also seeps out of the cell and causes disruption in nearby cells with normal function? It seems like this would be easy to test, simply inject it into animals without signs of the disease and see what happens. We know that some protiens called prions can self replicate despite not having any dna or rna. Perhaps the prelamin A disrupts the normal dna in healthy cells and causes it to produce more prelamin A?

Just a hypothesis, I don't have enough data to call it a theory.

 
As to the other possible systemic effects, speculatively mentioned/questioned also in post#4:

If mutation of Lamin A causes accelerated aging of the host cell, that means that there was already a baseline rate of aging going on since Lamin A was mutated. Repair of Lamin A could only restore the baseline rate. I don't imagine the proportion of cells with mutated Lamin A would be very high even in a very old person, so the mutated cells would have to either induce aging in a large number of other cells or have a selective growth advantage (unlikely since they are aging rapidly) in order to have a significant effect on organismal aging. Since those situations are unlikely, I don't think there's much reason to suspect this line of investigation will help us slow, and certainly not reverse, aging.

In other words, aging occurs with or without Lamin A mutation. Rejuvenating cellular information by cell and tissue therapy is still the best route to fix this.

 
another such systemic thing was reported too, by Liu et al. 2013:

Prelamin A accelerates vascular calcification via activation of the DNA damage response and senescence-associated secretory phenotype in vascular smooth muscle cells
http://circres.ahajo...112/10/e99.long

Abstract
RATIONALE:
Vascular calcification is prevalent in the aging population, yet little is known of the mechanisms driving age-associated vascular smooth muscle cell (VSMC) phenotypic change.
OBJECTIVE:
To investigate the role of nuclear lamina disruption, a specific hallmark of VSMC aging, in driving VSMC osteogenic differentiation.
METHODS AND RESULTS:
Prelamin A, the unprocessed form of the nuclear lamina protein lamin A, accumulated in calcifying human VSMCs in vitro and in vivo, and its overexpression promoted VSMC osteogenic differentiation and mineralization. During VSMC aging in vitro, prelamin A accumulation occurred concomitantly with increased p16 expression and osteogenic differentiation and was associated with increased levels of DNA damage. Microarray analysis showed that DNA damage repair pathways were significantly impaired in VSMCs expressing prelamin A and that chemical inhibition and siRNA depletion of the DNA damage response kinases ataxia-telangiectasia mutated/ataxia-telangiectasia- and Rad3-related effectively blocked VSMC osteogenic differentiation and mineralization. In coculture experiments, prelamin A-expressing VSMCs induced alkaline phosphatase activity in mesenchymal progenitor cells, and this was abrogated by inhibition of ataxia-telangiectasia-mutated signaling, suggesting that DNA damage induces the secretion of pro-osteogenic factors by VSMCs. Cytokine array analysis identified several ataxia-telangiectasia mutated-dependent senescence-associated secretory phenotype factors/cytokines released by prelamin A-positive VSMCs, including the calcification regulators bone morphogenetic protein 2, osteoprotegerin, and interleukin 6.
CONCLUSIONS:
Prelamin A promotes VSMC calcification and aging by inducing persistent DNA damage signaling, which acts upstream of VSMC osteogenic differentiation and the senescence-associated secretory phenotype. Agents that target the DNA damage response and prelamin A toxicity may be potential therapies for the treatment of vascular calcification.
KEYWORDS:
DNA damage, aging, calcification, lamin A/C, osteogenesis, senescence, vascular smooth muscle cells

[addx]

Is hydra an immortal multicellular organism or not?
I do not understand why people connect cell division with rejuvenation, and stopping of cell division with ageing. Cell division is just a mechanistic process and is not the same as rejuvenation. Human egg cells are not more aged because they do not divide from birth, than they would be if they divided in the meantime.
I do not understand why people connect ageing with accumulation of DNA mutations. All "ageing influence" of accumulated mutations disappears in gametogenesis, fertilization and embryogenesis and survival of life from generation to generation.
Besides, cancer cells are genetically unstable, which probably means that they accumulate DNA mutations more easily than, for instance, normal fibroblasts. However, normal fibroblasts age, and cancer cells form IMmortal cell lines.

Cell division is also a possible cleansing for one of the daughter cells if it keeps only "good stuff" and lets the other cell keep "accumulated bad stuff". AFAIK amoeba can hold onto immortality using that technique. One daughter cell can die off and the other is rejuvenated.

Aside from that fundamental fact it is in fact the stopping of stem cell division that provides most of ageing effects IMO. Worn out cells can be and are replaced in the body in continuity but the source - stem cells - wear out as well and lose ability to provide new differentiated cells. So, restoring proper division/differentiation ability of stem cells is in fact restoring of the bodies rejuvenation mechanism or at least a part of it.

As explained in my poll thread in this forum, ageing is evolutionary purposeful, hydra can resist it, but without it, evolution for the species advances very slowly and into a "plant-like"(behaviour wise) direction(hydra, corals, jelly fish). I do believe the ceasing of stem cell immortality is purposeful for this reason rather than accidental as it seems the first life forms could retain it, it shouldn't have accidentally been lost, it just didn't lead to anything - evolutionary wise, it created a dead end. Ageing gives the body as a "disposable reproduction vehicle"(created as "behaviour" of the zygote and resulting cascading cell collective that is the body) a limited time to exist so this forces evolution of behaviour to *compete* for resources and reproduction(animal-lively-like) rather than *wait* for them and focus on survival/resistance/longevity(plant-like). If time is limited vehicles that perform better *per same life time* will spread more genes. If lime time is limited in an ingenious way(by stopping repairs rather than sudden death) natural selection of bodies/vehicles also remains meaningful although sudden death works to an extent as well but in species with large reproducing populations(insects, fish) which can spare the death toll of it. Stopping repairs is meaningful because it pushes for evolution of *behavior* rather than *form*. Behavior that spares the form after repairs cease prolongs life time of the form and thus reproduction time and so spreads more genes and thus is selected for. This pushes evolution of the nervous system rather than evolution of form as in tough shells, armour, expensive tough big clumsy stupid bodies. Time proves this is a wise choice. Pushing the nervous system results in the ability to increasingly adapt behaviour without DNA reconfiguration and finally results in ability to transfer behaviour without genetic transfer in mammals. The transfer and evolution of knowledge is again forced by ageing, young are full of zest for competition, knowledge and bettering it in relation to their parents and each other and are more unaware of danger, some progress and spread new better survival/thriving knowledge, some fail, those that survive spread genes are full of experience/fears which cause them to teach rather than do it further. This forces evolution of knowledge rather than strong form that would enforce wrong knowledge. Knowledge(of control) is a prize achievement of evolution as it allows evolution of behaviour(and spread of it) in a much more rapid way, without reconfiguring DNA. I do actually think nothing more needs to be said to explain the essence of ageing.

Edited by addx, 19 April 2014 - 12:42 PM.

[Avatar of Horus]

Another similarity:
a discovery about the aging related loss of two lamin A binding proteins: RBBP4 and RBBP7:
a summary:
http://home.ccr.canc...s/misteli_2.asp

Molecular Clues to Physiological and Premature Ageing Revealed
Reviewed by Donna Kerrigan
There are many theories about the molecular basis of ageing. One of the most popular ones postulates that organisms age by accumulating damage to their tissues, cells, and molecules. On the cellular level, ageing is associated with progressive changes in chromatin (a combination of DNA and proteins that makes up chromosomes). These changes include loss of chromatin structure, loss and/or modification of essential proteins, and accumulation of DNA damage.

Many chromatin defects that gradually appear in physiological ageing are also observed in children affected with the premature ageing disease Hutchison-Gilford Progeria Syndrome (HGPS). Thus, studying cells derived from HGPS patients helps scientists understand the molecular basis of normal ageing. Using HGPS cells as a model, Gianluca Pegoraro, Ph.D., a postdoctoral fellow working with Tom Misteli, Ph.D., in the Cell Biology of Genomes Group in the CCR Laboratory of Receptor Biology and Gene Expression, and collaborators identified several key molecular players that affect ageing-related chromatin changes. The results of their study were published in a recent issue of Nature Cell Biology.

The disease-causing factor in HGPS is a genetic mutation that leads to the production of a shortened form of the protein lamin A, also known as progerin. Lamin A is an architectural protein which supports the membrane that surrounds the cell nucleus. Cells with a mutated lamin A protein have a disorganized nuclear membrane, accumulation of chromatin defects, and impaired repair of damaged DNA. Dr. Pegoraro and his coauthors found that the levels of two key nuclear proteins, RBBP4 and RBBP7 were lower in cells from HGPS patients than in those from healthy volunteers. This loss of RBBP4 and RBBP7 protein was dependent on the presence of progerin and reduction of the cellular levels of RBBP4 and RBBP7 contributed to changes in chromatin structure and increased DNA damage, which are typically observed in HGPS and normal ageing.

RBBP4 and RBBP7 proteins are components of various protein machineries important for establishing chromatin structure and repairing DNA damage, including the nucleosome remodeling and deacetylase NURD complex. Testing confirmed that several subunits of NURD are absent from HGPS cells as well as from cells of normally aged individuals. These findings suggest that loss of NURD is a feature of both premature and normal ageing. Further research is needed to determine how loss of NURD components occurs.

Based on the results of this study, Dr. Pegoraro and colleagues propose a molecular model of ageing. The first step in the initiation of ageing-associated chromatin defects is loss of chromatin proteins such as RBBP4 and RBBP7 proteins, which leads to changes in chromatin structure. These alterations then result in higher levels of unrepaired DAN lesions. The study suggests that maintenance of chromatin and the genome is a critical determinant of aging.

Summary Posted: 12/2009

Image

Loss of RBBP4 protein occurs in accelerated and physiological ageing. Immunofluorescence staining of skin cells from a (top) young, (middle) premature ageing /Hutchison-Gilford Progeria Syndrome patient and (bottom) a normally aged individual. RBBP4 is lost in aged cells. Arrowheads point to cell nuclei.

the study's link:
Ageing-related chromatin defects through loss of the NURD complex
Pegoraro et al. 2009, Nat Cell Biol.
http://www.ncbi.nlm....pubmed/19734887

Also worth noting: a more recent study about RBBP4 (=RbAp48) :
Molecular mechanism for age-related memory loss: the histone-binding protein RbAp48
Pavlopoulos et al. 2013, Sci Transl Med.
http://www.ncbi.nlm....pubmed/23986399

The finding was covered by other sources, for example:

Histone-Binding Protein Slows 'Normal Aging'?
Alzforum, 30 Aug 2013, Steve Haggerty
http://www.alzforum....ws-normal-aging
Cognitive impairment due to Alzheimers disease, and memory loss that occurs simply as we grow older, seem to stem from deficiencies in different areas of the hippocampus. Now, research published in the August 28 Science Translational Medicine identifies a molecule responsible for slowing normal aging in particular. It is the histone-binding protein RbAp48. Brain levels of this protein appear to drop with age, and researchers at Columbia University Medical Center, New York, showed they could boost cognition in old mice, or induce deficits in young mice, by dialing expression of RbAp48 up or down in the brain, respectively. The findings could pave the way for developing better diagnostics and interventions for age-related memory decline, said Scott Small, who co-led the study with Columbia colleague Eric Kandel.
...
The transcriptional regulator RbAp48, a gene in the latter group, showed the most robust age-related loss in expression. RbAp48 promotes expression of other genes by interacting with c-AMP response element binding protein (CREB) proteins to encourage histone acetylation, which is critical to maintain cognitive function. ...

and:
Increased Expression of RbAp48 Restores Memory Capacity in Old Mice
https://www.fightagi...in-old-mice.php
its topic in the BioscienceNews section of the forum:
http://www.longecity...ty-in-old-mice/

Edited by Avatar of Horus, 31 May 2014 - 01:04 PM.

[Avatar of Horus]

I was continuing the examination of this subject in the form of secondary (literature) research, and I think I may have found something, that may be relevant to the aging process.
If a unified theory is sought to be created, processes as wide as possible, i.e. in multiple tissues and organs, should be identified, and this is something like that.
The mechanism is present in the aging of every species and cells/tissues/organs I examined so far (see the list below). I don't know exactly its significance yet, it may be fundamental or a dead end. Anyway I share the findings with the community, with the reference studies in a number of consecutive posts - more or less in the sequence I have found them -, thus anyone interested can decide for oneself.

This mechanism controls and/or pertains to the following aging-processes/organs/tissues: brain, neurogenesis, cognition, heart, vascular aging, atherosclerosis, muscles, bone marrow, blood, immune system, bone, pancreas, thymus, liver, skin, wrinkles, hair, balding, hair graying, stem cell aging, epigenetics, telomerase depletion, lysosomes, lipofuscin, amyloidosis, mitochondria, advanced glycation end-products, cross-links, cancer.

the main proteins involved:
Brahma - BRM
Brahma related gene 1 - BRG1
main function: chromatin remodelling,
protein complex: SWI/SNF

Enhancer of Zeste Homolog 2 - EZH2
main function: histone lysine metyltransferase (KMT), gene silencing
protein complex: the Polycomb Repressive Complex 2, PRC2
and the PRC1 protein BMI1

Some general info from the Medical Subject Headings - MeSH database:
http://www.ncbi.nlm.nih.gov/mesh

Polycomb-Group Proteins
A family of proteins that play a role in CHROMATIN REMODELING. They are best known for silencing HOX GENES and the regulation of EPIGENETIC PROCESSES.
http://www.ncbi.nlm....v/mesh/68063146

Polycomb Repressive Complex 2
A multisubunit polycomb protein complex that catalyzes the METHYLATION of chromosomal HISTONE H3. It works in conjunction with POLYCOMB REPRESSIVE COMPLEX 1 to effect EPIGENETIC REPRESSION.
http://www.ncbi.nlm....v/mesh/68063151

Polycomb Repressive Complex 1
A multisubunit polycomb protein complex with affinity for CHROMATIN that contains methylated HISTONE H3. It contains an E3 ubiquitin ligase activity that is specific for HISTONE H2A and works in conjunction with POLYCOMB REPRESSIVE COMPLEX 2 to effect EPIGENETIC REPRESSION.
http://www.ncbi.nlm....v/mesh/68063150

one of the features of KMTs is the SET domain: Su(var)3-9, Enhancer of zeste, Trithorax domain,
named after the Drosophila fruit fly genes:
Su(var)3-9    http://www.sdbonline...mb/suvr39-1.htm
E(z)    http://www.sdbonline...mb/enhzeste.htm
Trx    http://www.sdbonline...mb/trithrx1.htm

the pathway of the Bone Morphogenetic Proteins, BMPs,
and other growth factors, like the platelet derived growth factor, PDGF pathway

and the
E2F/Rb pathway,
with the E2F transcription factors, like E2F1, and the Retinoblastoma protein

and others proteins and pathways, like e.g. the:
Myc, Nanog, Wnt, mTOR.

The point is the dysregulation (up or down) of members of these in the aging process;
moderate dysregulation results in aging and the extreme level in cancer.

 

 

The starting point is the second prelamin A study a couple of posts above, this:

Prelamin A accelerates vascular calcification via activation of the DNA damage response and senescence-associated secretory phenotype in vascular smooth muscle cells
Liu et al. 2013, http://www.ncbi.nlm....pubmed/23564641

 

with the observation about the possible role of BMPs in blood vessel aging/atherosclerosis:

in the form of the senescence-associated secretory phenotype (SASP), with the age-related increases:

BMP2 4.5, IL1B 4.12, BMP6 4.03, IL1A 3.11, BMP4 2.51.

and another independent one, that the BMP receptor, BMPR2, is upregulated in the aged hematopoietic stem cells:
Cell intrinsic alterations underlie hematopoietic stem cell aging
Rossi DJ, Bryder D, Zahn JM, Ahlenius H, Sonu R, Wagers AJ, Weissman IL.
Proc Natl Acad Sci U S A. 2005 Jun 28;102(26):9194-9. Epub 2005 Jun 20.
http://www.ncbi.nlm....pubmed/15967997

this led me to two studies, first that this SASP is present in the bone marrow too:

Hematopoietic stem cells regulate mesenchymal stromal cell induction into osteoblasts thereby participating in the formation of the stem cell niche
Jung et al. 2008, http://www.ncbi.nlm....pubmed/18499897

"Stressed and nonstressed HSCs were cocultured with bone marrow stromal cells to map mesenchymal fate. The data suggest that HSCs are able to guide mesenchymal differentiation toward the osteoblastic lineage under basal conditions. HSCs isolated from animals subjected to an acute stress were significantly better at inducing osteoblastic differentiation in vitro and in vivo than those from control animals. Importantly, HSC-derived bone morphogenic protein 2 (BMP-2) and BMP-6 were responsible for these activities. Furthermore, significant differences in the ability of HSCs to generate a BMP response following stress were noted in aged and in osteoporotic animals. Together these data suggest a coupling between HSC functions and bone turnover as in aging and in osteoporosis."

Figure:

 

and that this pathway may modulate the neurogenesis process:

Bone morphogenetic protein 2 inhibits neurite outgrowth of motor neuron-like NSC-34 cells and up-regulates its type II receptor
Benavente et al. 2012, http://www.ncbi.nlm....pubmed/22612292

"BMP-2 inhibits the differentiation of NSC-34 cells, an effect that correlates with activation of a Smad-dependent pathway, induction of the inhibitory Id1 transcription factor, and down-regulation of the neurogenic factor Mash1. BMP-2 also activates effectors of Smad-independent pathways. Remarkably, BMP-2 treatment significantly increases the expression of BMPRII."

Here the point is the Mash1=Ascl1 protein, but more on this later.

 

I've made some more searches in PubMed regarding this and found this recent study:

Age-Associated Increase in BMP Signaling inhibits Hippocampal Neurogenesis
Yousef H1, Morgenthaler A, Schlesinger C, Bugaj L, Conboy IM, Schaffer DV.
Stem Cells. 2014 Dec 23. doi: 10.1002/stem.1943. [Epub ahead of print]
http://www.ncbi.nlm....pubmed/25538007
 

Abstract
Hippocampal neurogenesis, the product of resident neural stem cell proliferation and differentiation, persists into adulthood but decreases with organismal aging, which may contribute to the age-related decline in cognitive function. The mechanisms that underlie this decrease in neurogenesis are not well understood, although evidence in general indicates that extrinsic changes in an aged stem cell niche can contribute to functional decline in old stem cells. Bone morphogenetic protein (BMP) family members are intercellular signaling proteins that regulate stem and progenitor cell quiescence, proliferation, and differentiation in various tissues and are likewise critical regulators of neurogenesis in young adults. Here, we establish that BMP signaling increases significantly in old murine hippocampi and inhibits neural progenitor cell proliferation. Furthermore, direct in vivo attenuation of BMP signaling via genetic and transgenic perturbations in aged mice led to elevated neural stem cell proliferation, and subsequent neurogenesis, in old hippocampi. Such advances in our understanding of mechanisms underlying decreased hippocampal neurogenesis with age may offer targets for the treatment of age-related cognitive decline.

 

Also here can be mentioned another study - which seems to support that the above may have some relevance to the aging - about the Activin/TGFB/BMP antagonist follistatin:

A mesenchymal stromal cell gene signature for donor age
Alves et al. 2012, http://www.ncbi.nlm....pubmed/22927939

Abstract
Human aging is associated with loss of function and regenerative capacity. Human bone marrow derived mesenchymal stromal cells (hMSCs) are involved in tissue regeneration, evidenced by their capacity to differentiate into several lineages and therefore are considered the golden standard for cell-based regeneration therapy. Tissue maintenance and regeneration is dependent on stem cells and declines with age and aging is thought to influence therapeutic efficacy, therefore, more insight in the process of aging of hMSCs is of high interest. We, therefore, hypothesized that hMSCs might reflect signs of aging. In order to find markers for donor age, early passage hMSCs were isolated from bone marrow of 61 donors, with ages varying from 17-84, and clinical parameters, in vitro characteristics and microarray analysis were assessed. Although clinical parameters and in vitro performance did not yield reliable markers for aging since large donor variations were present, genome-wide microarray analysis resulted in a considerable list of genes correlating with human age. By comparing the transcriptional profile of aging in human with the one from rat, we discovered follistatin as a common marker for aging in both species. The gene signature presented here could be a useful tool for drug testing to rejuvenate hMSCs or for the selection of more potent, hMSCs for cell-based therapy.

 

To be continued...

 

Edited by Avatar of Horus, 28 April 2015 - 03:50 AM.

[Avatar of Horus]

continuation:
Considering that the leading cause of death is the cardiovascular disease, this may be rather important, but any relevant biological find first needs to be translated into biomedical intervention for therapeutic purposes. Some preliminary informations and thoughts on this for consideration:
A study:

Inhibition of bone morphogenetic protein signaling reduces vascular calcification and atherosclerosis
Derwall et al.  Arterioscler Thromb Vasc Biol. 2012 Mar
http://www.ncbi.nlm....pubmed/22223731
Abstract
OBJECTIVE:
The expression of bone morphogenetic proteins (BMPs) is enhanced in human atherosclerotic and calcific vascular lesions. Although genetic gain- and loss-of-function experiments in mice have supported a causal role of BMP signaling in atherosclerosis and vascular calcification, it remains uncertain whether BMP signaling might be targeted pharmacologically to ameliorate both of these processes.
METHODS AND RESULTS:
We tested the impact of pharmacological BMP inhibition on atherosclerosis and calcification in LDL receptor-deficient (LDLR-/-) mice. LDLR-/- mice fed a high-fat diet developed abundant vascular calcification within 20 weeks. Prolonged treatment of LDLR-/- mice with the small molecule BMP inhibitor LDN-193189 was well-tolerated and potently inhibited development of atheroma, as well as associated vascular inflammation, osteogenic activity, and calcification. Administration of recombinant BMP antagonist ALK3-Fc replicated the antiatherosclerotic and anti-inflammatory effects of LDN-193189. Treatment of human aortic endothelial cells with LDN-193189 or ALK3-Fc abrogated the production of reactive oxygen species induced by oxidized LDL, a known early event in atherogenesis. Unexpectedly, treatment of mice with LDN-193189 lowered LDL serum cholesterol by 35% and markedly decreased hepatosteatosis without inhibiting HMG-CoA reductase activity. Treatment with BMP2 increased, whereas LDN-193189 or ALK3-Fc inhibited apolipoprotein B100 secretion in HepG2 cells, suggesting that BMP signaling contributes to the regulation of cholesterol biosynthesis.
CONCLUSION:
These results definitively implicate BMP signaling in atherosclerosis and calcification, while uncovering a previously unidentified role for BMP signaling in LDL cholesterol metabolism. BMP inhibition may be helpful in the treatment of atherosclerosis and associated vascular calcification.

left of its Figure 6:

Bone morphogenetic protein (BMP) inhibition lowers hepatic cholesterol biosynthesis
(a) Serum HDL and LDL levels were measured in HFD-fed LDLR−/− mice treated with vehicle (n=8) or LDN-193189 (n=7, 2.5 mg/kg IP, daily) for 20 weeks...    (b) LDN-193189 did not inhibit HMG-CoA reductase in vitro. HMG-CoA reductase enzyme activity was measured in vitro in the absence (Control) or presence of LDN-193189 (LDN, 50 nmol/L and 100 nmol/L) or pravastatin. Pravastatin, but not LDN-193189, inhibited HMG-CoA reductase activity.    (c:) HepG2 cells were incubated for 24 hours with or without BMP2 (100 ng/mL) in the presence or absence of an HMG-CoA reductase inhibitor, atorvastatin (ATS, 1 μmol/L), or LDN-193189 (LDN, 100 nmol/L). Apolipoprotein B100 (ApoB 100) levels in the culture medium were measured. (d) Hepatic tissue sections from HFD-fed LDLR−/− mice treated with either vehicle (n=20, left) or LDN-193189 (n=20, 2.5 mg/kg IP, daily; right) for 20 weeks were stained with H+E and photographed. Liver sections from 3 mice (representative of 6) from each group are shown. LDN-193189 protects HFD-fed mice from hepatic steatosis.

 
another one with focus on Matrix Gla protein:

Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification
Yao Y et al.    Circ Res. 2010 Aug 20
http://www.ncbi.nlm....pubmed/20576934
Abstract
RATIONALE:
The bone morphogenetic proteins (BMPs), a family of morphogens, have been implicated as mediators of calcification and inflammation in the vascular wall.
OBJECTIVE:
To investigate the effect of altered expression of matrix Gla protein (MGP), an inhibitor of BMP, on vascular disease.
METHODS AND RESULTS:
We used MGP transgenic or MGP-deficient mice bred to apolipoprotein E mice, a model of atherosclerosis. MGP overexpression reduced vascular BMP activity, atherosclerotic lesion size, intimal and medial calcification, and inflammation. It also reduced expression of the activin-like kinase receptor 1 and the vascular endothelial growth factor, part of a BMP-activated pathway that regulates angiogenesis and may enhance lesion formation and calcification. Conversely, MGP deficiency increased BMP activity, which may explain the diffuse calcification of vascular medial cells in MGP deficient aortas and the increase in expression of activin-like kinase receptor 1 and vascular endothelial growth factor. Unexpectedly, atherosclerotic lesion formation was decreased in MGP-deficient mice, which may be explained by a dramatic reduction in expression of endothelial adhesion molecules limiting monocyte infiltration of the artery wall.
CONCLUSIONS:
Our results indicate that BMP signaling is a key regulator of vascular disease, requiring careful control to maintain normal vascular homeostasis.

and:

Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis
Saeed et al., Arterioscler Thromb Vasc Biol. 2012.
http://www.ncbi.nlm....pubmed/22095982
Abstract
OBJECTIVE:
We recently reported that lowering of macrophage free intracellular iron increases expression of cholesterol efflux transporters ABCA1 and ABCG1 by reducing generation of reactive oxygen species. In this study, we explored whether reducing macrophage intracellular iron levels via pharmacological suppression of hepcidin can increase macrophage-specific expression of cholesterol efflux transporters and reduce atherosclerosis.
METHODS AND RESULTS:
To suppress hepcidin, increase expression of the iron exporter ferroportin, and reduce macrophage intracellular iron, we used a small molecule inhibitor of bone morphogenetic protein (BMP) signaling, LDN 193189 (LDN). LDN (10 mg/kg IP b.i.d.) was administered to mice, and its effects on atherosclerosis, intracellular iron, oxidative stress, lipid efflux, and foam cell formation were measured in plaques and peritoneal macrophages. Long-term LDN administration to apolipoprotein E-/- mice increased ABCA1 immunoreactivity within intraplaque macrophages by 3.7-fold (n=8; P=0.03), reduced Oil Red O-positive lipid area by 50% (n=8; P=0.02), and decreased total plaque area by 43% (n=8; P=0.001). LDN suppressed liver hepcidin transcription and increased macrophage ferroportin, lowering intracellular iron and hydrogen peroxide production. LDN treatment increased macrophage ABCA1 and ABCG1 expression, significantly raised cholesterol efflux to ApoA-1, and decreased foam cell formation. All preceding LDN-induced effects on cholesterol efflux were reversed by exogenous hepcidin administration, suggesting modulation of intracellular iron levels within macrophages as the mechanism by which LDN triggers these effects.
CONCLUSIONS:
These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.

 
What I have in mind is a possibility to design a molecule based on gene and protein segments and/or protein interactions that intervenes in these processes, the neuro- and vasculature-related aging, but more on this later, where it also has implications.

 
Another aspect which may worth consideration is a financial one - aside from the prospect to be a general anti-aging, life-extending drug - this avenue, the cardiovascular/atherosclerotic, seems worthy in its own right to be pursued, since the main cholesterol drugs currently are the so-called statins are blockbuster drugs, the top of them is atorvastatin, which:

 

Lipitor becomes world's top-selling drug
By Associated Press December 28, 2011
http://www.crainsnew..._CARE/111229902
"Over 14.5 years, the cholesterol-lowering medicine has made over $125 billion in sales, and has provided up to a quarter of Pfizer Inc.'s annual revenue for years.

Lipitor has become the best-selling drug in the history of pharmaceuticals, and is expected to stay in the top 20, by revenue, through 2015.
Lipitor, the best-selling drug in the history of pharmaceuticals, is the blockbuster ... By the time Lipitor went on sale in early 1997, it was the fifth drug in a class called statins that lower LDL, or bad cholesterol. The class already included three blockbusters, drugs with sales of $1 billion a year or more. ..."

another one is simvastatin:
Merck Loses Protection for Patent on Zocor
By ALEX BERENSON    Published: June 23, 2006
http://www.nytimes.c...s/23statin.html

"... Pfizer, whose rival cholesterol drug, Lipitor, is the world's most popular medicine, with global sales last year of $12 billion. ... Zocor ... generated sales last year for Merck of $3.1 billion in the United States and $4.4 billion worldwide."

Another one:
Crestor
October 9, 2012
http://www.fiercepha...reports/crestor
"Last year, AstraZeneca put up $6.62 billion in Crestor sales; this year's total is estimated at $6.65 billion."

etc.

This means that even if a future drug would have only a one hundreth financial success rate of this, it would still mean a lucrative revenue of hundreds of millions $ per year.

Big Pharma, too, knows this, and:
Big Pharma betting billions in high-stakes hunt for the next Lipitor
August 29, 2012 | By John Carroll
http://www.fiercebio...itor/2012-08-29

To be continued ...

[Avatar of Horus]

Continuing:
In the post before the last I mentioned the neurogenic transcription factor Mash1 / Ascl1, this clue has led to this study:

An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma
Rheinbay et al. 2013
http://www.ncbi.nlm....pubmed/23707066
Abstract
Glioblastoma (GBM) is thought to be driven by a subpopulation of cancer stem cells (CSCs) that self-renew and recapitulate tumor heterogeneity yet remain poorly understood. Here, we present a comparative analysis of chromatin state in GBM CSCs that reveals widespread activation of genes normally held in check by Polycomb repressors. These activated targets include a large set of developmental transcription factors (TFs) whose coordinated activation is unique to the CSCs. We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1. We show that ASCL1 is essential for the maintenance and in vivo tumorigenicity of GBM CSCs. Genome-wide binding profiles for ASCL1 and the Wnt effector LEF-1 provide mechanistic insight and suggest widespread interactions between the TF module and the signaling pathway. Our findings demonstrate regulatory connections among ASCL1, Wnt signaling, and collaborating TFs that are essential for the maintenance and tumorigenicity of GBM CSCs.

 
This study revealed the role the WNT pathway and also of the Polycomb repressors: PRC2, mainly the Enhancer of Zeste homolog 2 protein, EZH2.

On the pharmacological side: based on this it may be possible to extend the drug development to anti-cancer too, but more on this later, too.

EZH2 is a KMT, with the main function of the trimethylation of histone H3 lysine 27, H3K27me3:
also a connection to HGPS:
Epigenetic regulation of cell adhesion and communication by enhancer of zeste homolog 2 in human endothelial cells
Dreger et al. Hypertension. 2012 Nov
http://www.ncbi.nlm....pubmed/22966008
from the study:

The histone methyltransferase enhancer of zeste homolog 2 (Ezh2) mediates trimethylation of lysine 27 in histone 3, which acts as a repressive epigenetic mark.
...
studies on the Hutchinson-Gilford progeria syndrome suggest that accelerated atherosclerosis - a hallmark of this childhood disease - is caused, at least in part, by a loss of epigenetic control, including a deficit of repressive epigenetic marks such as H3K27me3.13

this reference 13 is:

Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging
Shumaker et al. 2006
http://www.ncbi.nlm....pubmed/16738054
Abstract
The premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS) is caused by a mutant lamin A (LADelta50). Nuclei in cells expressing LADelta50 are abnormally shaped and display a loss of heterochromatin. To determine the mechanisms responsible for the loss of heterochromatin, epigenetic marks regulating either facultative or constitutive heterochromatin were examined. In cells from a female HGPS patient, histone H3 trimethylated on lysine 27 (H3K27me3), a mark for facultative heterochromatin, is lost on the inactive X chromosome (Xi). The methyltransferase responsible for this mark, EZH2, is also down-regulated. These alterations are detectable before the changes in nuclear shape that are considered to be the pathological hallmarks of HGPS cells. ... The epigenetic changes described most likely represent molecular mechanisms responsible for the rapid progression of premature aging in HGPS patients.

 
Also another connection with this PRC2 is in the second previous post, where I described a study from an independent angle, with the focus on two proteins: the retinoblastoma binding proteins RBBP4 and RBBP7. And these are connected to this PRC2, cf. with the categories info in the MeSH link of PRC2 above.
 
More to follow on the Ezh2 and H3K27me3 later.

 

 
About DKK1, the Dickkopf-1 protein:

Dickkopf makes fountain of youth in the brain run dry
Helmholtz Association, 7-Feb-2013
http://www.eurekaler...g-dmf020713.php

DKFZ researchers find the cause of age-related cognitive decline
Cognitive decline in old age is linked to decreasing production of new neurons. Scientists from the German Cancer Research Center have discovered in mice that significantly more neurons are generated in the brains of older animals if a signaling molecule called Dickkopf-1 is turned off. In tests for spatial orientation and memory, mice in advanced adult age whose Dickkopf gene had been silenced reached an equal mental performance as young animals. ...

 

Loss of Dickkopf-1 restores neurogenesis in old age and counteracts cognitive decline
Seib et al. 2013

http://www.ncbi.nlm....pubmed/23395445
Abstract
Memory impairment has been associated with age-related decline in adult hippocampal neurogenesis. Although Notch, bone morphogenetic protein, and Wnt signaling pathways are known to regulate multiple aspects of adult neural stem cell function, the molecular basis of declining neurogenesis in the aging hippocampus remains unknown. Here, we show that expression of the Wnt antagonist Dickkopf-1 (Dkk1) increases with age and that its loss enhances neurogenesis in the hippocampus. Neural progenitors with inducible loss of Dkk1 increase their Wnt activity, which leads to enhanced self-renewal and increased generation of immature neurons. This Wnt-expanded progeny subsequently matures into glutamatergic granule neurons with increased dendritic complexity. As a result, mice deficient in Dkk1 exhibit enhanced spatial working memory and memory consolidation and also show improvements in affective behavior. Taken together, our findings show that upregulating Wnt signaling by reducing Dkk1 expression can counteract age-related decrease in neurogenesis and its associated cognitive decline.

also:
Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain
Caricasole et al. J Neurosci. 2004 Jun 30;24(26):6021-7.
http://www.ncbi.nlm....pubmed/15229249

Two relevant studies on the neuronal differentiation process of neurogenesis:

Jmjd3 activates Mash1 gene in RA-induced neuronal differentiation of P19 cells
Dai et al. 2010
http://www.ncbi.nlm....pubmed/20506217

Abstract
Covalent modifications of histone tails have fundamental roles in chromatin structure and function. Tri-methyl modification on lysine 27 of histone H3 (H3K27me3) usually correlates with gene repression that plays important roles in cell lineage commitment and development. Mash1 is a basic helix-loop-helix regulatory protein that plays a critical role in neurogenesis, where it expresses as an early marker. In this study, we have shown a decreased H3K27me3 accompanying with an increased demethylase of H3K27me3 (Jmjd3) at the promoter of Mash1 can elicit a dramatically efficient expression of Mash1 in RA-treated P19 cells. Over-expression of Jmjd3 in P19 cells also significantly enhances the RA-induced expression and promoter activity of Mash1. By contrast, the mRNA expression and promoter activity of Mash1 are significantly reduced, when Jmjd3 siRNA or dominant negative mutant of Jmjd3 is introduced into the P19 cells. Chromatin immunoprecipitation assays show that Jmjd3 is efficiently recruited to a proximal upstream region of Mash1 promoter that is overlapped with the specific binding site of Hes1 in RA-induced cells. Moreover, the association between Jmjd3 and Hes1 is shown in a co-Immunoprecipitation assay. It is thus likely that Jmjd3 is recruited to the Mash1 promoter via Hes1. Our results suggest that the demethylase activity of Jmjd3 and its mediator Hes1 for Mash1 promoter binding are both required for Jmjd3 enhanced efficient expression of Mash1 gene in the early stage of RA-induced neuronal differentiation of P19 cells.

Histone marks and chromatin remodelers on the regulation of neurogenin1 gene in RA induced neuronal differentiation of P19 cells
Wu et al. 2009
http://www.ncbi.nlm....pubmed/19308998
Abstract
Neurogenin1 is an important bHLH protein that plays crucial role in neurogenesis. We first show that the expression of ngn1 increases drastically in RA induced neuronal differentiation. During which, a three successive stages of the epigenetic changes surrounding the ngn1 gene are found correlated with a repression to activation of the gene in P19 cells. Recruiting of a repressive histone code H3K27me3 on the ngn1 gene is the dominant change in first repression stage, which is followed by the binding of the active codes of H3K9ac, H3K14ac, and the H3K4me3 in the second and third stages of RA treatment. Additionally, BRM but not BRG1 is specifically recruited to ngn1 gene at the third stage and is positively involved in the RA induced ngn1 expression. We propose that histone modifiers and chromatin remodelers are pivotal in the activation of the ngn1 gene in RA induced differentiation of P19 cells.

 
Here note the protein Brahma, BRM and the RA, retinoic acid (more on these too later).
 

 

Now going further, to the aging of: hair.
Comparing with the data I presented above and in the 2nd previous post, a similar process is occuring here:

The thinning top: why old people have less hair
Reddy and Garza 2014
http://www.ncbi.nlm....pubmed/25029319

Abstract
Changes in the hair cycle underlie age-related alopecia, but the causative mechanisms have remained unclear. Chen et al. point to an imbalance between stem cell-activating and -inhibitory signals as the key determinant of age-related regenerative decline. Further, they identify a secreted protein, follistatin, that may be able to shift the balance toward renewal.

 

Regenerative hair waves in aging mice and extra-follicular modulators follistatin, dkk1, and sfrp4
Chen et al. 2014, J Invest Dermatol.
http://www.ncbi.nlm....pubmed/24618599

Abstract
Hair cycling is modulated by factors both intrinsic and extrinsic to hair follicles. Cycling defects lead to conditions such as aging-associated alopecia. Recently, we demonstrated that mouse skin exhibits regenerative hair waves, reflecting a coordinated regenerative behavior in follicle populations. Here, we use this model to explore the regenerative behavior of aging mouse skin. Old mice (>18 months) tracked over several months show that with progressing age, hair waves slow down, wave propagation becomes restricted, and hair cycle domains fragment into smaller domains. Transplanting aged donor mouse skin to a young host can restore donor cycling within a 3 mm range of the interface, suggesting that changes are due to extracellular factors. Therefore, hair stem cells in aged skin can be reactivated. Molecular studies show that extra-follicular modulators Bmp2, Dkk1, and Sfrp4 increase in early anagen. Further, we identify follistatin as an extra-follicular modulator, which is highly expressed in late telogen and early anagen. Indeed, follistatin induces hair wave propagation and its level decreases in aging mice. We present an excitable medium model to simulate the cycling behavior in aging mice and illustrate how the interorgan macroenvironment can regulate the aging process by integrating both "activator" and "inhibitor" signals.

 

To be continued...

 

 
A note: I have made a search at Longecity and found that the possible role of DKK1 in neurogenesis and hair loss was pointed out already, though from a totally different approach, in the forum and is the subject of this topic:
L-Threonate for neurogenesis, alzheimer's, hair loss, osteoarthritis
http://www.longecity...osteoarthritis/

 

[Avatar of Horus]

continuing with the hair and skin:
the aging of the skin is obvious and apparent.
 
An overview:
Epidermal homeostasis: a balancing act of stem cells in the skin
Blanpain and Fuchs,    2009
http://www.ncbi.nlm....pubmed/19209183

Some of the control mechanisms:

Polycomb repression under the skin
Pirrotta 2009
http://www.ncbi.nlm....pubmed/19303840

Ezh2 orchestrates gene expression for the stepwise differentiation of tissue-specific stem cells
Ezhkova et al. 2009
http://www.ncbi.nlm....pubmed/19303854

Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3
Sen et al. 2008
http://www.ncbi.nlm....pubmed/18628393
 
 
the role of BMP pathway:
Bone morphogenetic protein (BMP) signaling controls hair pigmentation by means of cross-talk with the melanocortin receptor-1 pathway
Sharov et al. 2005
http://www.ncbi.nlm....pubmed/15618398
 

Inhibition of Bmp signaling affects growth and differentiation in the anagen hair follicle
Kulessa et al. 2000
http://www.ncbi.nlm....pubmed/11118201

Abstract
Growth and differentiation of postnatal hair follicles are controlled by reciprocal interactions between the dermal papilla and the surrounding epidermal hair precursors. The molecular nature of these interactions is largely unknown, but they are likely to involve several families of signaling molecules, including Fgfs, Wnts and Bmps. To analyze the function of Bmp signaling in postnatal hair development, we have generated transgenic mice expressing the Bmp inhibitor, Noggin, under the control of the proximal Msx2 promoter, which drives expression in proliferating hair matrix cells and differentiating hair precursor cells. Differentiation of the hair shaft but not the inner root sheath is severely impaired in Msx2-Noggin transgenic mice. In addition to hair keratins, the expression of several transcription factors implicated in hair development, including Foxn1 and Hoxc13, is severely reduced in the transgenic hair follicles. Proliferating cells, which are normally restricted to the hair matrix surrounding the dermal papilla, are found in the precortex and hair shaft region. These results identify Bmps as key regulators of the genetic program controlling hair shaft differentiation in postnatal hair follicles.

Here note the gene FOXN1, which has a role in the aging of the immune system, namely in the thymus (more on this later).
It was formally called the "nude gene", cf. the so-called "nude mice": http://en.wikipedia....wiki/Nude_mouse.

Two more reviews:

BMP signaling in the control of skin development and hair follicle growth
Botchkarev and Sharov, 2004
http://www.ncbi.nlm....pubmed/15617562

Abstract
Bone morphogenetic proteins (BMPs), their antagonists, and BMP receptors are involved in controlling a large number of biological functions including cell proliferation, differentiation, cell fate decision, and apoptosis in many different types of cells and tissues during embryonic development and postnatal life. BMPs exert their biological effects via using BMP-Smad and BMP-MAPK intracellular pathways. The magnitude and specificity of BMP signaling are regulated by a large number of modulators operating on several levels (extracellular, cytoplasmic, nuclear). In developing and postnatal skin, BMPs, their receptors, and BMP antagonists show stringent spatio-temporal expressions patterns to achieve proper regulation of cell proliferation and differentiation in the epidermis and in the hair follicle. Genetic studies assert an essential role for BMP signaling in the control of cell differentiation and apoptosis in developing epidermis, as well as in the regulation of key steps of hair follicle development (initiation, cell fate decision, cell lineage differentiation). In postnatal hair follicles, BMP signaling plays an important role in controlling the initiation of the growth phase and is also involved in the regulation of apoptosis-driven hair follicle involution. However, additional efforts are required to fully understand the mechanisms and targets involved in the realization of BMP effects on distinct cell population in the skin and hair follicle. Progress in this area of research will hopefully lead to the development of new therapeutic approaches for using BMPs and BMP antagonists in the treatment of skin and hair growth disorders.

Bone morphogenetic proteins and their antagonists in skin and hair follicle biology
Botchkarev, 2003
http://www.ncbi.nlm....pubmed/12535196

Abstract
Bone morphogenetic proteins (BMP) are members of the transforming growth factor-beta superfamily regulating a large variety of biologic responses in many different cells and tissues during embryonic development and postnatal life. BMP exert their biologic effects via binding to two types of serine/threonine kinase BMP receptors, activation of which leads to phosphorylation and translocation into the nucleus of intracellular signaling molecules, including Smad1, Smad5, and Smad8 ("canonical" BMP signaling pathway). BMP effects are also mediated by activation of the mitogen-activated protein (MAP) kinase pathway ("noncanonical" BMP Signaling pathway). BMP activity is regulated by diffusible BMP antagonists that prevent BMP interactions with BMP receptors thus modulating BMP effects in tissues. During skin development, BMPs its receptors and antagonists show stringent spatiotemporal expressions patterns to achieve proper regulation of cell proliferation and differentiation in the epidermis and in the hair follicle. In normal postnatal skin, BMP are involved in the control of epidermal homeostasis, hair follicle growth, and melanogenesis. Furthermore, BMP are implicated in a variety of pathobiologic processes in skin, including wound healing, psoriasis, and carcinogenesis. Therefore, BMPs represent new important players in the molecular network regulating homeostasis in normal and diseased skin. Pharmacologic modulation of BMP signaling may be used as a new approach for managing skin and hair disorders.

it also controls wound healing BTW:

Bone morphogenetic protein signaling suppresses wound-induced skin repair by inhibiting keratinocyte proliferation and migration
Lewis et al. 2014
http://www.ncbi.nlm....pubmed/24126843

...  this study demonstrates that BMPs inhibit keratinocyte proliferation, cytoskeletal organization, and migration in regenerating skin epithelium during wound healing, and raises a possibility for using BMP antagonists for the management of chronic wounds."

To the pharma/drug development I have been speaking about before and also the 2 reviews above:

Anti-wrinkle effect of bone morphogenetic protein receptor 1a-extracellular domain (BMPR1a-ECD)
Yoon et al. 2013 Sep.
http://www.ncbi.nlm....pubmed/24064062

Abstract
Bone morphogenetic proteins (BMPs) have diverse and important roles in the proliferation and differentiation of adult stem cells in our tissues. Especially, BMPs are well known to be the main inducers of bone formation, by facilitating both proliferation and differentiation of bone stem cells. Interestingly, in skin stem cells, BMPs repress their proliferation but are indispensable for the proper differentiation into several lineages of skin cells. Here, we tested whether BMP antagonists have an effect on the prevention of wrinkle formation. For this study we used an in vivo wrinkle-induced mouse model. As a positive control, retinoic acid, one of the top anti-wrinkle effectors, showed a 44% improvement compared to the non-treated control. Surprisingly, bone morphogenetic protein receptor 1a extracellular domain (BMPR1a-ECD) exhibited an anti-wrinkle effect which was 6-fold greater than that of retinoic acid. Our results indicate that BMP antagonists will be good targets for skin or hair diseases.

About retinoic acid, from the MeSH:

Tretinoin
An important regulator of GENE EXPRESSION during growth and development, and in NEOPLASMS. Tretinoin, also known as retinoic acid and derived from maternal VITAMIN A, is essential for normal GROWTH; and EMBRYONIC DEVELOPMENT. An excess of tretinoin can be teratogenic. It is used in the treatment of PSORIASIS; ACNE VULGARIS; and several other SKIN DISEASES. It has also been approved for use in promyelocytic leukemia (LEUKEMIA, PROMYELOCYTIC, ACUTE).
http://www.ncbi.nlm....v/mesh/68014212

Some words about the so-called "anti-aging creams":
from: http://en.wikipedia....nti-aging_cream
"One study found that the best performing creams reduced wrinkles by less than 10% ...[2]"
this reference [2] is the:
Wrinkle cream buying guide
Last updated: April 2012
http://www.consumerr...uying-guide.htm

Based on these, some estimates:
So their effect is genereally less than 10%, and that, with some allowance, is about 10 years, and if some method would be 6 times more effective than this that'd give 60%, i.e. people could look as good in their 90s as in their 30s, and this, in itself, could revolutionize the field of the anti-aging industry, not to speak of its financial potential.

to be continued, with the other cells, tissues and organs.

[Avatar of Horus]

concluding the skin part:

Age-associated changes in human epidermal cell renewal
Grove and Kligman, 1983
http://www.ncbi.nlm..../pubmed/6827031

Abstract
Epidermal cell renewal was assessed nonintrusively in normal human volunteers by monitoring the disappearance of a fluorescent marker dye, dansyl chloride, from the skin surface. In young adults, stratum corneum transit time was approximately 20 days, whereas in older adults this was lengthened by more than 10 days. Because the number of horny cell layers does not change with age, these data indicate that the increased stratum corneum transit time was a reflection of diminished epidermal cell proliferation. Additional analysis indicated that the decline in epidermal cell renewal may not occur at a constant rate throughout the adult lifespan but, instead, remains relatively constant in the younger years and then begins to drop dramatically after age 50. This suggests that a linear-spline model rather than a simple linear model may be more appropriate for analyzing these results.

I.e. it seems there is an aging-related decrease in cell and protein turnover, and one of the consequences of this is considered to be the increase in the so-called collagen cross-links, cf.:

Restrictive dermopathy: a disorder of fibroblasts
Paige et al. 1992
http://www.ncbi.nlm..../pubmed/1476923
Abstract
Restrictive dermopathy is a rare, lethal genodermatosis, characterized by a thin, tightly adherent skin which causes a dysmorphic facies, arthrogryposis and respiratory insufficiency. The recorded cases to date show a remarkable phenotypic similarity. Thinning of the dermis and the arrangement of collagen in parallel bundles appear to be constant findings. We have found many dead and degenerating fibroblasts in the dermis on ultrastructural examination, and have demonstrated their poor growth in vitro. Studies of collagen from a skin sample showed a marked increase in mature cross-links, indicating a decrease in skin collagen turnover. These findings suggest a primary disorder of fibroblasts, and may explain the apparent arrest in growth and differentiation of the skin which appears to be important in the pathogenesis of this rare condition.

BTW this disease has some implications to the topic of this topic, cf.:
from http://en.wikipedia....tive_dermopathy

Mechanism
Restrictive dermopathy (RD) is caused either by the loss of the gene ZMPSTE24, which encodes a protein responsible for the cleavage of farnesylated prelamin A (progerin) into mature non-farnesylated lamin, or by a mutation in the LMNA gene. This results in the accumulation of farnesyl-prelamin A at the nuclear membrane.[2] Mechanistically, restrictive dermopathy is somewhat similar to Hutchinson-Gilford progeria syndrome (HGPS), a disease where the last step in lamin processing is hindered by a mutation that causes the loss of the ZMPSTE24 cleavage site in the lamin A gene.

ref 2 =
Prelamin A farnesylation and progeroid syndromes
Young et al. 2006
http://www.ncbi.nlm....pubmed/17090536

Which has some similarities to the "normal" aging of the skin, cf.:

Looking older: fibroblast collapse and therapeutic implications
Fisher, Varani, Voorhees, 2008
http://www.ncbi.nlm....pubmed/18490597

Abstract
Skin appearance is a primary indicator of age. During the last decade, substantial progress has been made toward understanding underlying mechanisms of human skin aging. This understanding provides the basis for current use and new development of antiaging treatments. Our objective is to review present state-of-the-art knowledge pertaining to mechanisms involved in skin aging, with specific focus on the dermal collagen matrix. A major feature of aged skin is fragmentation of the dermal collagen matrix. Fragmentation results from actions of specific enzymes (matrix metalloproteinases) and impairs the structural integrity of the dermis. Fibroblasts that produce and organize the collagen matrix cannot attach to fragmented collagen. Loss of attachment prevents fibroblasts from receiving mechanical information from their support, and they collapse. Stretch is critical for normal balanced production of collagen and collagen-degrading enzymes. In aged skin, collapsed fibroblasts produce low levels of collagen and high levels of collagen-degrading enzymes. This imbalance advances the aging process in a self-perpetuating, never-ending deleterious cycle. Clinically proven antiaging treatments such as topical retinoic acid, carbon dioxide laser resurfacing, and intradermal injection of cross-linked hyaluronic acid stimulate production of new, undamaged collagen. Attachment of fibroblasts to this new collagen allows stretch, which in turn balances collagen production and degradation and thereby slows the aging process. Collagen fragmentation is responsible for loss of structural integrity and impairment of fibroblast function in aged human skin. Treatments that stimulate production of new, nonfragmented collagen should provide substantial improvement to the appearance and health of aged skin.

 
I presented infos about the role of the H3K27 demethylase JMJD3 in the control of neuronal and epidermal cells' proliferation and differentiation, in cooperation with other proteins, like Brahma (SMARCA2) in neuronal, and the following in epidermal cells:
from the previously mentioned: "Epidermal homeostasis: a balancing act of stem cells in the skin - Blanpain and Fuchs, 2009" paper :
"MYC might regulate the transition from quiescent SCs to transit-amplifying (TA) cells by inducing global histone modifications that are typically associated with an activate chromatin state.22"
ref. 22 =

Epidermal stem cells are defined by global histone modifications that are altered by Myc-induced differentiation
Frye et al. 2007.
http://www.ncbi.nlm....pubmed/17712411

 
about the role of these proteins: Brahma, BRM and c-Myc in another organ:

Aging and liver regeneration
Timchenko, 2009
http://www.ncbi.nlm....pubmed/19359195

Abstract
The loss of regenerative capacity is the most dramatic age-associated alteration in the liver. Although this phenomenon was reported over 50 years ago, the molecular basis for the loss of regenerative capacity of aged livers has not been fully elucidated. Aging causes alterations of several signal-transduction pathways and changes in the expression of CCAAT/enhancer-binding protein (C/EBP) and chromatin-remodeling proteins. Consequently, aging livers accumulate a multi-protein C/EBPalpha-Brm-HDAC1 complex that occupies and silences E2F-dependent promoters, reducing the regenerative capacity of livers in older mice. Recent studies have provided evidence for the crucial role of epigenetic silencing in the age-dependent inhibition of liver proliferation. This review focuses on mechanisms of age-dependent inhibition of liver proliferation and approaches for correcting liver regeneration in the elderly.

Aging reduces proliferative capacities of liver by switching pathways of C/EBPalpha growth arrest
Iakova, Awad, Timchenko, 2003
http://www.ncbi.nlm....pubmed/12757710

"In this paper, we present evidence that aging switches the C/EBPα pathway of growth arrest in liver from cdk inhibition to repression of E2F transcription. Aging increases levels of a chromatin remodeling protein Brm, which in turn interacts with C/EBPα and initiates the formation of a high MW complex: C/EBPα-Rb-E2F4. This age-specific C/EBPα-Rb-E2F4 complex binds to promoters regulated by E2F and represses expression of these genes in quiescent and regenerating livers of old animals. We present evidence that the C/EBPα-Rb-E2F4 complex blocks the activation of the c-myc promoter in old livers after PH and in tissue culture models. Our data provide a molecular basis for the reduced proliferative response in old livers; the switch of the C/EBPα growth arrest pathway from inhibition of cdks to repression of E2F transcription leads to a failure of the old livers to eliminate the growth inhibitory activity of C/EBPα."

 

Here note the E2F/Rb, more on these later.
 
to be continued...

[Avatar of Horus]

continuing with the Polycomb group, PRC2 protein:
EZH2
I had written already about its role in aging of brain and blood vessels, but according to several other studies this seems to be a "little" wider phenomenon, which I will present here (I divided this text into three posts):

 

Epigenetic repression of cardiac progenitor gene expression by Ezh2 is required for postnatal cardiac homeostasis
Delgado-Olguín et al. 2012
http://www.ncbi.nlm....pubmed/22267199
Abstract
Adult-onset diseases can be associated with in utero events, but mechanisms for this remain unknown(1,2). The Polycomb histone methyltransferase Ezh2 stabilizes transcription by depositing repressive marks during development that persist into adulthood(3-9), but its function in postnatal organ homeostasis is unknown. We show that Ezh2 stabilizes cardiac gene expression and prevents cardiac pathology by repressing the homeodomain transcription factor gene Six1, which functions in cardiac progenitor cells but is stably silenced upon cardiac differentiation. Deletion of Ezh2 in cardiac progenitors caused postnatal myocardial pathology and destabilized cardiac gene expression with activation of Six1-dependent skeletal muscle genes. Six1 induced cardiomyocyte hypertrophy and skeletal muscle gene expression. Furthermore, genetically reducing Six1 levels rescued the pathology of Ezh2-deficient hearts. Thus, Ezh2-mediated repression of Six1 in differentiating cardiac progenitors is essential for stable gene expression and homeostasis in the postnatal heart. Our results suggest that epigenetic dysregulation in embryonic progenitor cells is a predisposing factor for adult disease and dysregulated stress responses.

 

Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging
Beerman et al. 2013
http://www.ncbi.nlm....pubmed/23415915
Abstract
The functional potential of hematopoietic stem cells (HSCs) declines during aging, and in doing so, significantly contributes to hematopoietic pathophysiology in the elderly. To explore the relationship between age-associated HSC decline and the epigenome, we examined global DNA methylation of HSCs during ontogeny in combination with functional analysis. Although the DNA methylome is generally stable during aging, site-specific alterations of DNA methylation occur at genomic regions associated with hematopoietic lineage potential and selectively target genes expressed in downstream progenitor and effector cells. We found that age-associated HSC decline, replicative limits, and DNA methylation are largely dependent on the proliferative history of HSCs, yet appear to be telomere-length independent. Physiological aging and experimentally enforced proliferation of HSCs both led to DNA hypermethylation of genes regulated by Polycomb Repressive Complex 2. Our results provide evidence that epigenomic alterations of the DNA methylation landscape contribute to the functional decline of HSCs during aging.

from the study's text:
"PRC2 core components were significantly age downregulated in HSCs, with Ezh2 showing the greatest fold difference (3.7-fold) and Suz12 and Eed showing more modest downregulation (both 1.4-fold)"
 

Epigenetic control of hematopoietic stem cell aging: the case of Ezh2
De Haan and Gerrits 2007.
http://www.ncbi.nlm....pubmed/17332078
Abstract
Hematopoietic stem cells have potent, but not unlimited, selfrenewal potential. The mechanisms that restrict selfrenewal are likely to play a role during aging. Recent data suggest that the regulation of histone modifications by Polycomb group genes may be of crucial relevance to balance selfrenewal and aging. We provide evidence for the involvement of one of these Polycomb group genes, Ezh2, in aging of the hematopoietic stem cell system.

The authors call Ezh2 a general cell senescence preventing gene.
The above study is based on this one:

The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion
Kamminga et al. 2006
http://www.ncbi.nlm....pubmed/16293602
Abstract
The molecular mechanism responsible for a decline of stem cell functioning after replicative stress remains unknown. We used mouse embryonic fibroblasts (MEFs) and hematopoietic stem cells (HSCs) to identify genes involved in the process of cellular aging. In proliferating and senescent MEFs one of the most differentially expressed transcripts was Enhancer of zeste homolog 2 (Ezh2), a Polycomb group protein (PcG) involved in histone methylation and deacetylation. Retroviral overexpression of Ezh2 in MEFs resulted in bypassing of the senescence program. More importantly, whereas normal HSCs were rapidly exhausted after serial transplantations, overexpression of Ezh2 completely conserved long-term repopulating potential. Animals that were reconstituted with 3 times serially transplanted control bone marrow cells all died due to hematopoietic failure. In contrast, similarly transplanted Ezh2-overexpressing stem cells restored stem cell quality to normal levels. In a "genetic genomics" screen, we identified novel putative Ezh2 target or partner stem cell genes that are associated with chromatin modification. Our data suggest that stabilization of the chromatin structure preserves HSC potential after replicative stress.

 

An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state
Wahlestedt et al. 2013
http://www.ncbi.nlm....pubmed/23476050
Abstract
Aging of hematopoietic stem cells (HSCs) leads to several functional changes, including alterations affecting self-renewal and differentiation. Although it is well established that many of the age-induced changes are intrinsic to HSCs, less is known regarding the stability of this state. Here, we entertained the hypothesis that HSC aging is driven by the acquisition of permanent genetic mutations. To examine this issue at a functional level in vivo, we applied induced pluripotent stem (iPS) cell reprogramming of aged hematopoietic progenitors and allowed the resulting aged-derived iPS cells to reform hematopoiesis via blastocyst complementation. Next, we functionally characterized iPS-derived HSCs in primary chimeras and after the transplantation of re-differentiated HSCs into new hosts, the gold standard to assess HSC function. Our data demonstrate remarkably similar functional properties of iPS-derived and endogenous blastocyst-derived HSCs, despite the extensive chronological and proliferative age of the former. Our results, therefore, favor a model in which an underlying, but reversible, epigenetic component is a hallmark of HSC aging.

from the study's text about the mechanism:
"... We interpret our data to show that the epigenetic reset coinciding with iPS induction has immediate functional benefits for subsequent differentiation. This should be the result of normalized regulation of certain defined loci dysregulated with age, and thus a careful evaluation of the epigenetic properties of aged HSPCs might provide both candidate genes and more general regulators. For instance, the key epigenetic regulator Ezh2 is down-regulated in aged HSCs... the broad and potent roles of Ezh2 might well underlie other epigenetic alterations governing the HSC aging process. ..."
 
Nanog reverses the effects of organismal aging on mesenchymal stem cell proliferation and myogenic differentiation potential
Han J et al. 2012.
http://www.ncbi.nlm....pubmed/22949105

about the underlying mechanism,
from the study's text:
"... EZH2, which was shown to restore proliferation of aged β-cells and hematopoietic stem cells, was significantly upregulated by Nanog in aBM-MSC."

about Nanog regulation:

Inhibition of platelet-derived growth factor receptor signaling regulates Oct4 and Nanog expression, cell shape, and mesenchymal stem cell potency
Ball et al. 2012.
http://www.ncbi.nlm....pubmed/22213560
Abstract
Defining the signaling mechanisms that regulate the fate of adult stem cells is an essential step toward their use in regenerative medicine. ... Thus, inhibiting these specific receptor tyrosine kinases, which play essential roles in tissue formation, offers a novel approach to unlock the therapeutic capacity of MSCs. ...

 

PDGF signalling controls age-dependent proliferation in pancreatic β-cells
Chen et al. 2011
http://www.ncbi.nlm....pubmed/21993628
Abstract
Determining the signalling pathways that direct tissue expansion is a principal goal of regenerative biology. Vigorous pancreatic β-cell replication in juvenile mice and humans declines with age, and elucidating the basis for this decay may reveal strategies for inducing β-cell expansion, a long-sought goal for diabetes therapy. Here we show that platelet-derived growth factor receptor (Pdgfr) signalling controls age-dependent β-cell proliferation in mouse and human pancreatic islets. With age, declining β-cell Pdgfr levels were accompanied by reductions in β-cell enhancer of zeste homologue 2 (Ezh2) levels and β-cell replication. Conditional inactivation of the Pdgfra gene in β-cells accelerated these changes, preventing mouse neonatal β-cell expansion and adult β-cell regeneration. Targeted human PDGFR-α activation in mouse β-cells stimulated Erk1/2 phosphorylation, leading to Ezh2-dependent expansion of adult β-cells. Adult human islets lack PDGF signalling competence, but exposure of juvenile human islets to PDGF-AA stimulated β-cell proliferation. The discovery of a conserved pathway controlling age-dependent β-cell proliferation indicates new strategies for β-cell expansion.

also of note, from the study's text:
"β-cell PDGFR controls Ezh2 via Erk and Rb/E2f"
 
Combined modulation of polycomb and trithorax genes rejuvenates β cell replication
Zhou et al. 2013
http://www.ncbi.nlm....pubmed/24216481
 
If these above really are somewhat relevant to aging, the manipulation of the members of these protein complexes and pathways may or should result in life extension.
I checked whether it has been examined, and yes, some of it was. And resulted in about 30-76 % life span elongation in the worm C. elegans and fruit fly Drosophila species.

The H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent manner
Maures et al. 2011
http://www.ncbi.nlm....pubmed/21834846

Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway
Jin et al. 2011
http://www.ncbi.nlm....pubmed/21803287

here note in insulin/IGF1.

Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance
Siebold et al. 2009
http://www.ncbi.nlm....pubmed/20018689

here note the ODC1 gene, the ornithine decarboxylase 1.

also a relevant review:

Histone methylation makes its mark on longevity
Han and Brunet 2012
http://www.ncbi.nlm....pubmed/22177962
Abstract
How long organisms live is not entirely written in their genes. Recent findings reveal that epigenetic factors that regulate histone methylation, a type of chromatin modification, can affect lifespan. The reversible nature of chromatin modifications suggests that therapeutic targeting of chromatin regulators could be used to extend lifespan and healthspan. This review describes the epigenetic regulation of lifespan in diverse model organisms, focusing on the role and mode of action of chromatin regulators that affect two epigenetic marks, trimethylated lysine 4 of histone H3 (H3K4me3) and trimethylated lysine 27 of histone H3 (H3K27me3), in longevity.

 
I don't know about any specific data on this in higher species, but some independent lines of research in mouse suggest that it could have similar - or less or more - life extension effect in those species too. I will present these in the next post.
 
to be continued ...

[Avatar of Horus]

...

If these above really are somewhat relevant to aging, the manipulation of the members of these protein complexes and pathways may or should result in life extension.
I checked whether it has been examined, and yes, some of it was. And resulted in about 30-76 % life span elongation in the worm C. elegans and fruit fly Drosophila species.

The H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent manner
Maures et al. 2011
http://www.ncbi.nlm....pubmed/21834846

Histone demethylase UTX-1 regulates C. elegans life span by targeting the insulin/IGF-1 signaling pathway
Jin et al. 2011
http://www.ncbi.nlm....pubmed/21803287

here note in insulin/IGF1.

Polycomb Repressive Complex 2 and Trithorax modulate Drosophila longevity and stress resistance
Siebold et al. 2009
http://www.ncbi.nlm....pubmed/20018689

here note the ODC1 gene, the ornithine decarboxylase 1.

...
I don't know about any specific data on this in higher species, but some independent lines of research in mouse suggest that it could have similar - or less or more - life extension effect in those species too. I will present these in the next post.

 

Regarding this, two things can be mentioned:

 

the first is the relatively known rapamycin, with reported effects on HSC rejuvenation and lifespan extension:

mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells
Chen et al. 2009
http://www.ncbi.nlm....pubmed/19934433
Abstract
Age-related declines in hematopoietic stem cell (HSC) function may contribute to anemia, poor response to vaccination, and tumorigenesis. Here, we show that mammalian target of rapamycin (mTOR) activity is increased in HSCs from old mice compared to those from young mice. mTOR activation through conditional deletion of Tsc1 in the HSCs of young mice mimicked the phenotype of HSCs from aged mice in various ways. These included increased abundance of the messenger RNA encoding the CDK inhibitors p16(Ink4a), p19(Arf), and p21(Cip1); a relative decrease in lymphopoiesis; and impaired capacity to reconstitute the hematopoietic system. In old mice, rapamycin increased life span, restored the self-renewal and hematopoiesis of HSCs, and enabled effective vaccination against a lethal challenge with influenza virus. Together, our data implicate mTOR signaling in HSC aging and show the potential of mTOR inhibitors for restoring hematopoiesis in the elderly.

 
This later study examined some effects of rapamycin in HSCs:

Rapamycin enhances long-term hematopoietic reconstitution of ex vivo expanded mouse hematopoietic stem cells by inhibiting senescence
Luo Y et al. 2014
http://www.ncbi.nlm....pubmed/24092377

The increase in long-term hematopoiesis of expanded HSCs is likely attributable in part to rapamycin-mediated up-regulation of Bmi1 ...

 
This is the PRC1 protein BMI1, so it seems that the mTOR related lifespan extension may be also partially connected to the Polycomb. More on BMI1 later.
 
For comparison:

Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway
Kapahi et al. 2004
http://www.ncbi.nlm....pubmed/15186745
Abstract
In many species, reducing nutrient intake without causing malnutrition extends lifespan. Like DR (dietary restriction), modulation of genes in the insulin-signaling pathway, known to alter nutrient sensing, has been shown to extend lifespan in various species. In Drosophila, the target of rapamycin (TOR) and the insulin pathways have emerged as major regulators of growth and size. Hence we examined the role of TOR pathway genes in regulating lifespan by using Drosophila. We show that inhibition of TOR signaling pathway by alteration of the expression of genes in this nutrient-sensing pathway, which is conserved from yeast to human, extends lifespan in a manner that may overlap with known effects of dietary restriction on longevity. In Drosophila, TSC1 and TSC2 (tuberous sclerosis complex genes 1 and 2) act together to inhibit TOR (target of rapamycin), which mediates a signaling pathway that couples amino acid availability to S6 kinase, translation initiation, and growth. We find that overexpression of dTsc1, dTsc2, or dominant-negative forms of dTOR or dS6K all cause lifespan extension. Modulation of expression in the fat is sufficient for the lifespan-extension effects. The lifespan extensions are dependent on nutritional condition, suggesting a possible link between the TOR pathway and dietary restriction.

 
Various genes of the TOR pathway have been investigated in the study about their effect on Drosophila lifespan, and the results were: 12-37% life extension. Compare with the above Polycomb 47-76%!
Futhermore, dietary restriction works also in mice.
 
The second is similar but the connection here is the insulin/IGF signaling, and related to the - btw Mprize record holder - so-called dwarf mice phenomenon, specifically the Ames type, its description:

Primordial follicle activation in the ovary of Ames dwarf mice
Schneider et al. 2014
http://www.ncbi.nlm....pubmed/25543533

The Ames dwarf mice (df/df) carry a mutation at the Prop1 (Prophet of Pit1) locus that impairs the development of the anterior pituitary gland [1], resulting in deficiency of growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin [2]. As the result of the GH deficiency these mice are characterized by severely low circulating insulin-like growth factor I (IGF-I) and reduced adult body size [3]. Importantly, regardless of these hormonal deficiencies, df/df mice live 35-75% longer than their normal littermates [4].

 
In the following paper the researchers investigated the possibly underlying life extension mechanism:
"Furthermore, increased longevity due to decreased GH or IGF-1 signaling led us to investigate the post-transcriptional regulation of genes involved in this desired phenotype-the delayed onset of aging-while bypassing undesirable effects associated with these hormonal deficiencies (e.g., reduced size, impaired reproductive capacity, etc.).",
and mentioned the role of ornithine decarboxylase, ODC1:

MicroRNA regulation in Ames dwarf mouse liver may contribute to delayed aging
Bates et al. 2009
http://www.ncbi.nlm....pubmed/19878148
Abstract
The Ames dwarf mouse is well known for its remarkable propensity to delay the onset of aging. Although significant advances have been made demonstrating that this aging phenotype results primarily from an endocrine imbalance, the post-transcriptional regulation of gene expression and its impact on longevity remains to be explored. Towards this end, we present the first comprehensive study by microRNA (miRNA) microarray screening to identify dwarf-specific lead miRNAs, and investigate their roles as pivotal molecular regulators directing the long-lived phenotype. Mapping the signature miRNAs to the inversely expressed putative target genes, followed by in situ immunohistochemical staining and in vitro correlation assays, reveals that dwarf mice post-transcriptionally regulate key proteins of intermediate metabolism, most importantly the biosynthetic pathway involving ornithine decarboxylase and spermidine synthase. Functional assays using 3'-untranslated region reporter constructs in co-transfection experiments confirm that miRNA-27a indeed suppresses the expression of both of these proteins, marking them as probable targets of this miRNA in vivo. Moreover, the putative repressed action of this miRNA on ornithine decarboxylase is identified in dwarf mouse liver as early as 2 months of age. Taken together, our results show that among the altered aspects of intermediate metabolism detected in the dwarf mouse liver--glutathione metabolism, the urea cycle and polyamine biosynthesis--miRNA-27a is a key post-transcriptional control. Furthermore, compared to its normal siblings, the dwarf mouse exhibits a head start in regulating these pathways to control their normality, which may ultimately contribute to its extended health-span and longevity.

 
to be continued ...

[Avatar of Horus]

continuing, with EZH2 and its main target the histone 3 lysine 27, H3K27me3:
 
First another paper about the HGPS connection:

Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome
McCord et al. 2013
http://www.ncbi.nlm....pubmed/23152449
Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease that is frequently caused by a de novo point mutation at position 1824 in LMNA. This mutation activates a cryptic splice donor site in exon 11, and leads to an in-frame deletion within the prelamin A mRNA and the production of a dominant-negative lamin A protein, known as progerin. Here we show that primary HGPS skin fibroblasts experience genome-wide correlated alterations in patterns of H3K27me3 deposition, DNA-lamin A/C associations, and, at late passages, genome-wide loss of spatial compartmentalization of active and inactive chromatin domains. We further demonstrate that the H3K27me3 changes associate with gene expression alterations in HGPS cells. Our results support a model that the accumulation of progerin in the nuclear lamina leads to altered H3K27me3 marks in heterochromatin, possibly through the down-regulation of EZH2, and disrupts heterochromatin-lamina interactions. These changes may result in transcriptional misregulation and eventually trigger the global loss of spatial chromatin compartmentalization in late passage HGPS fibroblasts.

 
This dysregulation is connected also to the age related increase in cancer incidents, e.g. two papers:

Polycomb-mediated methylation on Lys27 of histone H3 pre-marks genes for de novo methylation in cancer
Schlesinger et al. 2007
http://www.ncbi.nlm....pubmed/17200670
Abstract
Many genes associated with CpG islands undergo de novo methylation in cancer. Studies have suggested that the pattern of this modification may be partially determined by an instructive mechanism that recognizes specifically marked regions of the genome. Using chromatin immunoprecipitation analysis, here we show that genes methylated in cancer cells are specifically packaged with nucleosomes containing histone H3 trimethylated on Lys27. This chromatin mark is established on these unmethylated CpG island genes early in development and then maintained in differentiated cell types by the presence of an EZH2-containing Polycomb complex. In cancer cells, as opposed to normal cells, the presence of this complex brings about the recruitment of DNA methyl transferases, leading to de novo methylation. These results suggest that tumor-specific targeting of de novo methylation is pre-programmed by an established epigenetic system that normally has a role in marking embryonic genes for repression.
 
Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer
Teschendorff et al. 2010
http://www.ncbi.nlm....pubmed/20219944
Abstract
Polycomb group proteins (PCGs) are involved in repression of genes that are required for stem cell differentiation. Recently, it was shown that promoters of PCG target genes (PCGTs) are 12-fold more likely to be methylated in cancer than non-PCGTs. Age is the most important demographic risk factor for cancer, and we hypothesized that its carcinogenic potential may be referred by irreversibly stabilizing stem cell features. To test this, we analyzed the methylation status of over 27,000 CpGs mapping to promoters of approximately 14,000 genes in whole blood samples from 261 postmenopausal women. We demonstrate that stem cell PCGTs are far more likely to become methylated with age than non-targets (odds ratio = 5.3 [3.8-7.4], P < 10(-10)), independently of sex, tissue type, disease state, and methylation platform. We identified a specific subset of 69 PCGT CpGs that undergo hypermethylation with age and validated this methylation signature in seven independent data sets encompassing over 900 samples, including normal and cancer solid tissues and a population of bone marrow mesenchymal stem/stromal cells (P < 10(-5)). We find that the age-PCGT methylation signature is present in preneoplastic conditions and may drive gene expression changes associated with carcinogenesis. These findings shed substantial novel insights into the epigenetic effects of aging and support the view that age may predispose to malignant transformation by irreversibly stabilizing stem cell features.

 
and in "normal" aging:

Genome-wide age-related changes in DNA methylation and gene expression in human PBMCs
Steegenga et al. 2014
http://www.ncbi.nlm....pubmed/24789080

... Aging-related differential methylation of genes involved in developmental processes has also been observed in previous studies. Bork et al. (2010) found enrichment in the differential methylation of a specific subset of developmental genes, the HOX genes, in mesenchymal stromal cells in response to aging. Furthermore, aging-related hypermethylation of polycomb target genes have been reported by Maegawa et al. (2010) in the intestine, by Teschendorff et al. (2010) in different cell types and by Beerman colleagues in hematopoietic stem cells (Beerman et al. 2013). ...

 

It seems to be "the unifying epigenomic principle of aging":

Polycomb Repressive Complex 2 epigenomic signature defines age-associated hypermethylation and gene expression changes
Dozmorov, Epigenetics. 2015 Apr 16.
http://www.ncbi.nlm....pubmed/25880792
Abstract
Although age-associated gene expression and methylation changes have been reported throughout the literature, the unifying epigenomic principles of aging remain poorly understood. Recent explosion in availability and resolution of functional/regulatory genome annotation data (epigenomic data), such as that provided by the ENCODE and Roadmap Epigenomics projects, provides an opportunity for the identification of epigenomic mechanisms potentially altered by age-associated differentially methylated regions (aDMRs) and to find regulatory signatures in the promoters of age-associated genes (aGENs). In this study we found that aDMRs and aGENs identified in multiple independent studies share a common Polycomb Repressive Complex 2 signature marked by EZH2, SUZ12, CTCF binding sites, repressive H3K27me3, and activating H3K4me1 histone modification marks, and a "poised promoter" chromatin state. This signature is depleted in RNAP II-associated transcription factor binding sites, activating H3K79me2, H3K36me3, H3K27ac marks, and an "active promoter" chromatin state. The PRC2 signature was shown to be generally stable across cell types. When considering the directionality of methylation changes, we found the PRC2 signature to be associated with aDMRs hypermethylated with age, while hypomethylated aDMRs were associated with enhancers. In contrast, aGENs were associated with the PRC2 signature independently of the directionality of gene expression changes. In this study we demonstrate that the PRC2 signature is the common epigenomic context of genomic regions associated with hypermethylation and gene expression changes in aging.
 
KEYWORDS:
Aging; ENCODE; ENCODE -Encyclopedia of DNA elements; Epigenetics; Epigenomics; GenomeRunner; Methylation; PRC2; PRC2 -Polycomb repressive complex 2; Polycomb; TFBS -transcription factor binding site; aDMR -age-associated differentially methylated region; aGEN -promoter of an age-associated gene

 
 
There were some news about a recent finding, named as human "biological clock":
http://en.wikipedia....l_clock_(aging)

 

UCLA scientist uncovers biological clock able to measure age of most human tissues
Elaine Schmidt ,    October 21, 2013
http://newsroom.ucla...ological-248950
 
Everyone grows older, but scientists don't really understand why. Now a UCLA study has uncovered a biological clock embedded in our genomes that may shed light on why our bodies age and how we can slow the process.
Published in the Oct. 21 edition of the journal Genome Biology, the findings could offer valuable insights to benefit cancer and stem cell research.
 
While earlier biological clocks have been linked to saliva, hormones and telomeres, the new research is the first to result in the development of an age-predictive tool that uses a previously unknown time-keeping mechanism in the body to accurately gauge the age of diverse human organs, tissues and cell types. ...

 

Biomarkers and ageing: The clock-watcher
Biomathematician Steve Horvath has discovered a strikingly accurate way to measure human ageing through epigenetic signatures.
W. Wayt Gibbs    08 April 2014
http://www.nature.co...watcher-1.15014
 
As a teenager in Germany, Steve Horvath, his identical twin Markus and their friend Jörg Zimmermann formed 'the Gilgamesh project', which involved regular meetings where the three discussed mathematics, physics and philosophy. The inspiration for the name, Horvath says, was the ancient Sumerian epic in which a king of Uruk searches for a plant that can restore youth. Fittingly, talk at the meetings often turned to ideas for how science might extend lifespan.
...
Horvath's clock emerges from epigenetics, the study of chemical and structural modifications made to the genome that do not alter the DNA sequence but that are passed along as cells divide and can influence how genes are expressed. As cells age, the pattern of epigenetic alterations shifts, and some of the changes seem to mark time. To determine a person's age, Horvath explores data for hundreds of far-flung positions on DNA from a sample of cells and notes how often those positions are methylated - that is, have a methyl group attached.
 
... his findings ... published last year1, the clock's median error was 3.6 years ... for a broad selection of tissues. That accuracy improves to 2.7 years for saliva alone, 1.9 years for certain types of white blood cell and 1.5 years for the brain cortex. The clock shows stem cells removed from embryos to be extremely young and the brains of centenarians to be about 100.
 
“Such tight correlations suggest there is something seemingly immutable going on in cells,” says Elizabeth Blackburn of the University of California, San Francisco, who won a Nobel prize for her research on telomeres - caps on the ends of chromosomes that shorten with age. It could be a clue to undiscovered biology, she suggests. ...
 
In the months since Horvath's paper appeared, other researchers have replicated and extended the results. The study has stirred up excitement about potential applications, but also debate about the underlying biology at work.
 
“It's something new,” says Peter Visscher, chair of quantitative genetics at the University of Queensland in Australia. “If he's right that there is something like an inherently epigenetic clock at work in ageing, that is very interesting. It must be important.”
 
Horvath ... “Everyone who develops biomarkers knows what to expect: a very strong biomarker gives you a correlation of, say, 0.6 or 0.7.” For example, the correlation between age and the length of telomeres is less than 0.5. For Horvath's clock algorithm, that figure is 0.96. He confesses that he had trouble believing it himself until other researchers independently confirmed the tight association.
...
An age-old question
Medical researchers might be able to use the epigenetic clock to better diagnose and classify illnesses even without really understanding how the biology works. But Horvath hopes that the science won't stop there.
 
“The big question is whether the clock measures a biochemical process that serves a purpose,” he says. His best guess is that the clock corresponds to the function of an epigenomic housekeeping system, which helps to stabilize the genome by maintaining methylation patterns. The more active this mechanism, he proposes, the faster the epigenetic clock ticks.
 
Because methylation is usually reversible, Wei says, it might be possible to grab the minute hand of the epigenetic clock and retard its incessant progress - an idea that makes Horvath's solemn adolescent vow sound almost attainable. “The greatest hope is that this clock measures the output of a process that really does relate to ageing - even causes ageing,” Horvath says. ...

 
The referred study:

DNA methylation age of human tissues and cell types
Horvath, 2013
http://www.ncbi.nlm....pubmed/24138928

 
and it is based on an earlier one, which showed that it "is associated with Polycomb group target occupancy counts", this:

Aging effects on DNA methylation modules in human brain and blood tissue
Horvath et al. 2012
http://www.ncbi.nlm....pubmed/23034122

 
An interview with the discoverer:

Novel epigenetic clock predicts tissue age
Posted by Biome on 21st October 2013
http://biome.biomedc...cts-tissue-age/

When it comes to measuring cellular age, telomere length is often the first method that comes to mind. However an increasing body of work suggests that telling time using an epigenetic clock may be even more accurate - specifically through the detection of DNA methylation. Previous studies have shown how age-related changes in DNA methylation vary with tissue type. In a Genome Biology study published today, Steve Horvath from the University of California, Los Angeles, USA reveals his novel ‘age calculator’ that is able to accurately predict DNA methylation age across multiple tissue types. In his evaluation of this age predictor, Horvath takes advantage of large volumes of publicly available DNA methylation data sets. He explains more about how this study came about, as well as discussing the potential impact this could have on diagnosing and characterizing disease, specifically in the context of cancer where Horvath noticed a particularly intriguing result.
 
What was the motivation behind this study, and how did your previous research lead up to it?
 
In order to study what causes aging and what can be done against it, we need a way to measure age. In other words, there is a need for accurate aging clocks.
...
Last year, Roel Ophoff and I published an article in Genome Biology that showed that many age related changes in brain tissue can also be found in blood tissue. These results, which echo those from many other groups, provide a first glimpse of the epigenetic clock.
...
... is merely symptomatic of disease or do you think it might represent a therapeutic target?
 
I think this is clearly the most pressing question. The epigenetic clock is the new elephant in the room of aging research. It will probably stimulate a lively scientific discussion and carefully designed follow up studies. It would be wonderful news for anybody who wants to live a long and healthy life if DNA methylation age turns out to be closely related to a process that causes aging. If so, it would become a valuable surrogate marker for evaluating rejuvenating interventions.
...
We understand that you are continuing the study of DNA methylation age and disease. What directions are you taking this research in?
 
Many of the most exciting questions will require teams of researchers. We should try to develop a similar epigenetic clock for mice. ...

 
Two comments: one to this question: so is it merely a consequence or causative?
and: Is it present in other species, like for instance in mouse?

 

The answer seems to be yes to both:
 
I've presented data in the 2nd previous post which suggest that it is a causal, contributive factor, like this one:

Proliferation-dependent alterations of the DNA methylation landscape underlie hematopoietic stem cell aging
Beerman et al. 2013
http://www.ncbi.nlm....pubmed/23415915

"... Physiological aging and experimentally enforced proliferation of HSCs both led to DNA hypermethylation of genes regulated by Polycomb Repressive Complex 2. Our results provide evidence that epigenomic alterations of the DNA methylation landscape contribute to the functional decline of HSCs during aging."

 
Regarding mouse, data suggest that something similar is present here too:

DNA methylation analysis of murine hematopoietic side population cells during aging
Taiwo et al. 2013
http://www.ncbi.nlm....pubmed/23949429
 
"... Interestingly, the polycomb repressive complex -2 (PCRC2) target genes ... were hypermethylated with age. ... We report that DNA methylation patterns are well preserved during hematopoietic stem cell aging, confirm that PCRC2 targets are increasingly methylated with age ..."
 
Widespread and tissue specific age-related DNA methylation changes in mice
Maegawa et al. 2010
http://www.ncbi.nlm....pubmed/20107151
 
"... There was partial conservation between age-related hypermethylation in human and mouse intestines, and Polycomb targets in embryonic stem cells were enriched among the hypermethylated genes. Our findings demonstrate a surprisingly high rate of hyper- and hypomethylation as a function of age in normal mouse small intestine tissues and a strong tissue-specificity to the process. We conclude that epigenetic deregulation is a common feature of aging in mammals."

 
And it seems here too: as it is not only a measure of age, but also:

'Biological Clock' Found In DNA Could Predict How Long You're Going To Live
Researchers have discovered a biological clock that could help predict how long a person will live.
By Rebekah Marcarelli    Feb 02, 2015
http://www.hngn.com/...ing-to-live.htm

the paper of the research:

DNA methylation age of blood predicts all-cause mortality in later life
Marioni et al. 2015
http://www.ncbi.nlm....pubmed/25633388

 
Moreover, if this study, quoted before, is recalled:

Histone methylation makes its mark on longevity
Han and Brunet 2012
http://www.ncbi.nlm....pubmed/22177962
Abstract
How long organisms live is not entirely written in their genes. Recent findings reveal that epigenetic factors that regulate histone methylation, a type of chromatin modification, can affect lifespan. The reversible nature of chromatin modifications suggests that therapeutic targeting of chromatin regulators could be used to extend lifespan and healthspan. This review describes the epigenetic regulation of lifespan in diverse model organisms, focusing on the role and mode of action of chromatin regulators that affect two epigenetic marks, trimethylated lysine 4 of histone H3 (H3K4me3) and trimethylated lysine 27 of histone H3 (H3K27me3), in longevity.

 
and its other connected SET and Trithorax members are put into the picture, there seems to be an effect on the lifespans of the offsprings too, up to three generations:

Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans
Greer et al. 2010
http://www.ncbi.nlm....pubmed/20555324

Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans
Greer et al. 2011
http://www.ncbi.nlm....pubmed/22012258

 
to be continued, with the E2F/Rb, and muscle and thymus ...

[Avatar of Horus]

...
to be continued, with the E2F/Rb, and muscle and thymus ...

 

muscle

 

Chromatin modifications as determinants of muscle stem cell quiescence and chronological aging
Liu et al. 2013
http://www.ncbi.nlm....pubmed/23810552

... Using a ChIP-seq approach to obtain global epigenetic profiles of quiescent SCs (QSCs), we show that QSCs possess a permissive chromatin state in which few genes are epigenetically repressed by Polycomb group (PcG)-mediated histone 3 lysine 27 trimethylation (H3K27me3), and a large number of genes encoding regulators that specify nonmyogenic lineages are demarcated by bivalent domains at their transcription start sites (TSSs). By comparing epigenetic profiles of QSCs from young and old mice, we also provide direct evidence that, with age, epigenetic changes accumulate and may lead to a functional decline in quiescent stem cells. These findings highlight the importance of chromatin mapping in understanding unique features of stem cell identity and stem cell aging.

 

NIH scientists identify gene that could hold the key to muscle repair
16-Apr-2011 NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases
http://www.eurekaler...a-nsi041611.php
 
Gene that could hold the key to muscle repair identified
April 26, 2011 Source: NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases
http://www.scienceda...10418093848.htm
 
... Key to the development of skeletal muscle of the embryo and fetus, satellite cells continue to actively increase muscle mass through infancy. After that, they decrease in number and become quiescent, or inactive, until they are activated by injury or degeneration to proliferate. The process, which enables the body to repair damaged muscle, works quite well -- to a point, says Vittorio Sartorelli, M.D., senior investigator in the NIAMS Laboratory of Muscle Stem Cells and Gene Regulation and lead author of the study.

For example, when a young person experiences muscle loss after a period of inactivity, muscle rebuilds as soon as activity is resumed. However, in the elderly, muscles lose that capacity. Similarly, in patients with DMD, the initial phases of muscle degeneration are effectively counteracted by the ability of satellite cells to regenerate.

"That is why people can survive until they are 20 years old without much of a problem, but, at a certain point, satellite cells stop proliferating," said Dr. Sartorelli. "That is the point at which the patient will start developing weakness and problems that will ultimately lead to death."

Suspecting a genetic switch that might turn off satellite cell proliferation in these circumstances, the scientists looked to a gene called Ezh2, known to keep the activity of other genes in check. When they genetically inactivated Ezh2 in satellite cells of laboratory mice, the mice failed to repair muscle damage caused by traumatic injury -- satellite cells could not proliferate.
Ezh2 expression is known to decline during aging, and the new research in mice suggests that therapies to activate Ezh2 and promote satellite cell proliferation might eventually play a role in treating degenerative muscle diseases.
... Likewise, in the elderly, tweaking the gene in satellite cells would not increase their lifespan, but could increase their quality of life by helping to prevent falls and enabling them to move and walk better and go about their daily activities.
Dr. Sartorelli cautions that while the identification of Ezh2's role is a crucial step, any therapies are still many years away.

 

Polycomb EZH2 controls self-renewal and safeguards the transcriptional identity of skeletal muscle stem cells
Juan et al. 2011
http://www.ncbi.nlm....pubmed/21498568
Abstract
Satellite cells (SCs) sustain muscle growth and empower adult skeletal muscle with vigorous regenerative abilities. Here, we report that EZH2, the enzymatic subunit of the Polycomb-repressive complex 2 (PRC2), is expressed in both Pax7+/Myf5⁻ stem cells and Pax7+/Myf5+ committed myogenic precursors and is required for homeostasis of the adult SC pool. Mice with conditional ablation of Ezh2 in SCs have fewer muscle postnatal Pax7+ cells and reduced muscle mass and fail to appropriately regenerate. These defects are associated with impaired SC proliferation and derepression of genes expressed in nonmuscle cell lineages. Thus, EZH2 controls self-renewal and proliferation, and maintains an appropriate transcriptional program in SCs.

 
 
E2F/Rb

 

As I have found that the E2F/Rb pathway's dysregulation plays a role in the normal aging of the liver and the pancreas (studies presented above), I've checked this in the case of HGPS and other laminopathies:
 

Alterations in mitosis and cell cycle progression caused by a mutant lamin A known to accelerate human aging
Dechat et al. 2007
http://www.ncbi.nlm....pubmed/17360326
Abstract
Mutations in the gene encoding nuclear lamin A (LA) cause the premature aging disease Hutchinson-Gilford Progeria Syndrome. The most common of these mutations results in the expression of a mutant LA, with a 50-aa deletion within its C terminus. In this study, we demonstrate that this deletion leads to a stable farnesylation and carboxymethylation of the mutant LA (LADelta50/progerin). These modifications cause an abnormal association of LADelta50/progerin with membranes during mitosis, which delays the onset and progression of cytokinesis. Furthermore, we demonstrate that the targeting of nuclear envelope/lamina components into daughter cell nuclei in early G(1) is impaired in cells expressing LADelta50/progerin. The mutant LA also appears to be responsible for defects in the retinoblastoma protein-mediated transition into S-phase, most likely by inhibiting the hyperphosphorylation of retinoblastoma protein by cyclin D1/cdk4. These results provide insights into the mechanisms responsible for premature aging and also shed light on the role of lamins in the normal process of human aging.

 

Defective skeletal muscle growth in lamin A/C-deficient mice is rescued by loss of Lap2α
Cohen et al. 2013
http://www.ncbi.nlm....pubmed/23535822
http://hmg.oxfordjou...22/14/2852.long

 

Figure 3 c

C Regulated transcription factor pathways in Lmna−/− H-2K MBs. The X-axis represents activation state: downregulated indicating ‘repressed’ and upregulated indicating ‘activated’ transcription factor pathways. Triple asterisks indicate significantly regulated transcription factor pathways for E2F1, MyoD1, Rb and Smad3 (P < 0.005).

 
Here also note the BMP/TGFB/myostatin/follistatin target - which is connected to the Rb pathway through CDK4 BTW- SMAD3, covered here:

Putting Old Stem Cells Back to Work: Another Drug Target Emerges From Parabiosis Research
http://www.longecity...iosis-research/

 
and details available here:

Compound found to perk up old muscles and ageing brains
http://www.longecity...-ageing-brains/

 
And then the comparison to the normal aging:
 
The preceding post from the BioscienceNews / fightaging section of the forum:
Silencing p16 to Reverse Senescence in Old Muscle Stem Cells
http://www.longecity...cle-stem-cells/

Do we know how to decrease expression of P16 ? and eventually P53 ?

 
Regarding P16:
I am currently working on a study about things connected to these, including this study, which I intended to post in detailed form shortly in the topic of Bioscience - Aging theories:
Creating a unified theory of aging
http://www.longecity...heory-of-aging/
 
But as a starting point the Polycomb group proteins (PcG) can be mentioned:
the study too mentions the Bmi1 protein as a regulator/repressor of p16ink4a.
Bmi1 is a member of the Polycomb repressive complex (PRC1), which can cooperate with the members of the PRC2 especially EZH2, in this repressive function:
The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells
Bracken et al. Genes Dev. 2007 Mar 1;21(5):525-30.
http://www.ncbi.nlm....pubmed/17344414
Abstract
The p16INK4A and p14ARF proteins, encoded by the INK4A-ARF locus, are key regulators of cellular senescence, yet the mechanisms triggering their up-regulation are not well understood. Here, we show that the ability of the oncogene BMI1 to repress the INK4A-ARF locus requires its direct association and is dependent on the continued presence of the EZH2-containing Polycomb-Repressive Complex 2 (PRC2) complex. Significantly, EZH2 is down-regulated in stressed and senescing populations of cells, coinciding with decreased levels of associated H3K27me3, displacement of BMI1, and activation of transcription. These results provide a model for how the INK4A-ARF locus is activated and how Polycombs contribute to cancer.
...

 
a comment article:

Ageing: Genetic rejuvenation of old muscle
Li M, Izpisua Belmonte JC.    Nature. 2014 Feb 20
http://www.nature.co...ature13058.html
 
In advanced age, the stem cells responsible for muscle regeneration switch from reversible quiescence to irreversible senescence. Targeting a driver of senescence revives muscle stem cells and restores regeneration. See Article p.316

and the:

Editor's summary
One of the properties crucial to the function of adult mammalian stem cells is the capacity to remain in a quiescent state for prolonged periods - and to respond when the need to regenerate arises. Loss of skeletal muscle mass and function are common features of advanced ageing in humans, associated with a loss of regenerative capacity of the skeletal muscle stem cells, known as satellite cells. Pura Muñoz-Cánoves and colleagues show that ageing satellite cells undergo an irreversible transition from quiescence to a pre-senescence state associated with increased expression of p16INK4a, a tumour-suppressor protein that has been identified as a marker for senescence. Repression of p16INK4a during adult life is shown to maintain satellite cells in a reversible quiescence state that allows muscle regeneration; p16INK4a is dysregulated in human geriatric satellite cells and the potential for muscle regeneration is lost.

on the study:

Geriatric muscle stem cells switch reversible quiescence into senescence
Sousa-Victor P, Gutarra S, García-Prat L, Rodriguez-Ubreva J, Ortet L, Ruiz-Bonilla V, Jardí M, Ballestar E, González S, Serrano AL, Perdiguero E, Muñoz-Cánoves P
Nature. 2014 Feb 20
http://www.ncbi.nlm....pubmed/24522534
Abstract
Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with ageing. Here we report that geriatric satellite cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and that this irreversibly affects their intrinsic regenerative and self-renewal capacities. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16(INK4a) (also called Cdkn2a). On injury, these cells fail to activate and expand, undergoing accelerated entry into a full senescence state (geroconversion), even in a youthful environment. p16(INK4a) silencing in geriatric satellite cells restores quiescence and muscle regenerative functions. Our results demonstrate that maintenance of quiescence in adult life depends on the active repression of senescence pathways. As p16(INK4a) is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.

 
Some details highlighted in the paper:

Figure 2: Satellite cell reversible quiescence is impaired at geriatric age and in progeria
http://www.nature.co...re13013_F2.html
 
Figure 5: p16INK4a-driven Rb/E2F axis regulates geroconversion
http://www.nature.co...re13013_F5.html
 
Figure 6: p16INK4a/Rb/E2F senescence pathway in human geriatric satellite cells
http://www.nature.co...re13013_F6.html

 
another overview article from the same team:

Geroconversion of aged muscle stem cells under regenerative pressure
Sousa-Victor P1, Perdiguero E, Muñoz-Cánoves P.
Cell Cycle. 2014
http://www.ncbi.nlm....pubmed/25485497
Abstract
Regeneration of skeletal muscle relies on a population of quiescent stem cells (satellite cells) and is impaired in very old (geriatric) individuals undergoing sarcopenia. Stem cell function is essential for organismal homeostasis, providing a renewable source of cells to repair damaged tissues. In adult organisms, age-dependent loss-of-function of tissue-specific stem cells is causally related with a decline in regenerative potential. Although environmental manipulations have shown good promise in the reversal of these conditions, recently we demonstrated that muscle stem cell aging is, in fact, a progressive process that results in persistent and irreversible changes in stem cell intrinsic properties. Global gene expression analyses uncovered an induction of p16(INK4a) in satellite cells of physiologically aged geriatric and progeric mice that inhibits satellite cell-dependent muscle regeneration. Aged satellite cells lose the repression of the INK4a locus, which switches stem cell reversible quiescence into a pre-senescent state; upon regenerative or proliferative pressure, these cells undergo accelerated senescence (geroconversion), through Rb-mediated repression of E2F target genes. p16(INK4a) silencing rejuvenated satellite cells, restoring regeneration in geriatric and progeric muscles. Thus, p16(INK4a)/Rb-driven stem cell senescence is causally implicated in the intrinsic defective regeneration of sarcopenic muscle. Here we discuss on how cellular senescence may be a common mechanism of stem cell aging at the organism level and show that induction of p16(INK4a) in young muscle stem cells through deletion of the Polycomb complex protein Bmi1 recapitulates the geriatric phenotype.

 
and a blog coverage:

Forever young muscle
danielbeltran on March 10, 2014 at 3:48 am
http://blogs.biomedc...r-young-muscle/
 
Based on the gene expression profile of muSCs isolated from geriatric and progeric (SAMP8 KO) mice Muñoz-Cánoves’ group defined a sarcopenia-associated satellite cell signature in which p16INK4a (the master regulator of cellular senescence) was significantly upregulated. INK4a locus is known to be repressed by the polycomb repression complex (PRC1), of which Bim1 is an essential member. The fact that Bim1 deficient mice show premature aging and Bim1-KO muSCs show high p16INK4a expression levels indicates that PRC1 malfunction underlies p16INK4a de-repression in muSCs. The retinoblastoma (Rb) protein most likely acts downstream of p16INK4a leading to senescence. In fact high p16INK4a expression levels correlated with reduced phosphorylated Rb protein in geriatric muSCs.
 
The role of p16INK4 in muSC senescence is highlighted by the fact that its silencing restored geriatric and Bmi1-null satellite cell proliferation and self-renewal capacity when transplanted into mice. The authors also revealed the involvement of p16INK4a in human skeletal muscle since its expression in human geriatric muSCs prevented their myogenic functions whilst inducing senescence. In addition, genetic interference of human p16INK4a restored geriatric muSCs proliferation by reducing senescence.

 
 
thymus

I've already mentioned FOXN1 at the skin part.
 
Here is a topic from BioscienceNews / fightaging section of the forum:

A Programmed Aging Point of View on Objectives in Treating Age-Related Degeneration
http://www.longecity...d-degeneration/

 
about the online blog article of:

Open Letter on Research Priorities in Aging
http://joshmitteldor...ities-in-aging/
 
... {3) Multiple treatments have been documented over the years to increase thymus size in humans and in animals.  These include growth hormone, zinc, melatonin, and thymic peptides.  A recent breakthrough from Univ of Edinburgh suggests a particularly effective treatment.

 

about the study:

Thymus Regeneration Demonstrated via Increased FOXN1
http://www.longecity...ncreased-foxn1/

 

Regeneration of the aged thymus by a single transcription factor
Bredenkamp et al. 2014
http://www.ncbi.nlm....pubmed/24715454
Abstract
Thymic involution is central to the decline in immune system function that occurs with age. By regenerating the thymus, it may therefore be possible to improve the ability of the aged immune system to respond to novel antigens. Recently, diminished expression of the thymic epithelial cell (TEC)-specific transcription factor Forkhead box N1 (FOXN1) has been implicated as a component of the mechanism regulating age-related involution. The effects of upregulating FOXN1 function in the aged thymus are, however, unknown. Here, we show that forced, TEC-specific upregulation of FOXN1 in the fully involuted thymus of aged mice results in robust thymus regeneration characterized by increased thymopoiesis and increased naive T cell output. We demonstrate that the regenerated organ closely resembles the juvenile thymus in terms of architecture and gene expression profile, and further show that this FOXN1-mediated regeneration stems from an enlarged TEC compartment, rebuilt from progenitor TECs. Collectively, our data establish that upregulation of a single transcription factor can substantially reverse age-related thymic involution, identifying FOXN1 as a specific target for improving thymus function and, thus, immune competence in patients. More widely, they demonstrate that organ regeneration in an aged mammal can be directed by manipulation of a single transcription factor, providing a provocative paradigm that may be of broad impact for regenerative biology.

 
Next I've searched about the upstream signaling that may be responsible for this, and it seems the same pathway's dysregulation occurs here too:

Global transcriptional profiling reveals distinct functions of thymic stromal subsets and age-related changes during thymic involution
Ki et al. 2014
http://www.ncbi.nlm....pubmed/25284794
Abstract
Age-associated thymic involution results in diminished T cell output and function in aged individuals. However, molecular mediators contributing to the decline in thymic function during early thymic involution remain largely unknown. Here, we present transcriptional profiling of purified thymic stromal subsets from mice 1, 3, and 6 months of age spanning early thymic involution. The data implicate unanticipated biological functions for a subset of thymic epithelial cells. The predominant transcriptional signature of early thymic involution is decreased expression of cell-cycle-associated genes and E2F3 transcriptional targets in thymic epithelial subsets. Also, expression of proinflammatory genes increases with age in thymic dendritic cells. Many genes previously implicated in late involution are already deregulated by 3-6 months of age. ...

 

Inactivation of the RB family prevents thymus involution and promotes thymic function by direct control of Foxn1 expression
Garfin et al. 2013
http://www.ncbi.nlm....pubmed/23669396
Abstract
Thymic involution during aging is a major cause of decreased production of T cells and reduced immunity. Here we show that inactivation of Rb family genes in young mice prevents thymic involution and results in an enlarged thymus competent for increased production of naive T cells. This phenotype originates from the expansion of functional thymic epithelial cells (TECs). In RB family mutant TECs, increased activity of E2F transcription factors drives increased expression of Foxn1, a central regulator of the thymic epithelium. Increased Foxn1 expression is required for the thymic expansion observed in Rb family mutant mice. Thus, the RB family promotes thymic involution and controls T cell production via a bone marrow-independent mechanism, identifying a novel pathway to target to increase thymic function in patients.

 
 
to be continued with the brain, BMI1, lipofuscin, lysosomes, mitochondria ...

[Avatar of Horus]

...
to be continued with the brain, BMI1, lipofuscin, lysosomes, mitochondria ...

 
After I've identified the roles Polycomb proteins BMI1 and EZH2 and Trithorax proteins in the aging of the muscle, cf.:

Epigenetic regulation of satellite cell activation during muscle regeneration
Dilworth and Blais, 2011
http://www.ncbi.nlm....pubmed/21542881
Abstract
Satellite cells are a population of adult muscle stem cells that play a key role in mediating muscle regeneration. Activation of these quiescent stem cells in response to muscle injury involves modulating expression of multiple developmentally regulated genes, including mediators of the muscle-specific transcription program: Pax7, Myf5, MyoD and myogenin. Here we present evidence suggesting an essential role for the antagonistic Polycomb group and Trithorax group proteins in the epigenetic marking of muscle-specific genes to ensure proper temporal and spatial expression during muscle regeneration. The importance of Polycomb group and Trithorax group proteins in establishing chromatin structure at muscle-specific genes suggests that therapeutic modulation of their activity in satellite cells could represent a viable approach for repairing damaged muscle in muscular dystrophy.
 
Bmi1 is expressed in postnatal myogenic satellite cells, controls their maintenance and plays an essential role in repeated muscle regeneration
Robson et al. 2011
http://www.ncbi.nlm....pubmed/22096526

 

and found that the

...

Geroconversion of aged muscle stem cells under regenerative pressure
Sousa-Victor P1, Perdiguero E, Muñoz-Cánoves P.
Cell Cycle. 2014
http://www.ncbi.nlm....pubmed/25485497
Abstract
.. deletion of the Polycomb complex protein Bmi1 recapitulates the geriatric phenotype.

 

 

I tried to find out whether is something similar happening elsewhere, has it any role in the aging of other organs, for instance in the
brain.

Bmi1 is down-regulated in the aging brain and displays antioxidant and protective activities in neurons
Abdouh et al. 2012
http://www.ncbi.nlm....pubmed/22384090
http://journals.plos...al.pone.0031870
 
"... Using whole cerebral extracts and quantitative RT-PCR (Q-PCR), we found that Bmi1 mRNA levels decrease by ~60% in old cortices, thus suggesting reduced Bmi1 transcription (Figure 1B). Interestingly, Bmi1 expression levels were highly variable in the old age population, with some mice showing only 20% of Bmi1 levels compared to young mice (Figure 1B). To confirm our observations at the protein levels, we perform Western blot analysis of whole cortices from young and old mice, which revealed a ~40% reduction in Bmi1 levels in old mice (Figure 1C).
...
BMI1 is down-regulated in the human CNS during aging
To test if age-dependent Bmi1 down-regulation was restricted to mice, we analyzed BMI1 expression in young and old human brains by immunohistochemistry. We observed that BMI1 expression was reduced in hippocampal neurons of old brains (Figure 3A).
...
Figure 3. BMI1 is down-regulated in the aging human brain and retina.
...
Bmi1 over-expression is neuroprotective and activates antioxidant defenses
...
Figure 6. Bmi1 deficiency during aging influences neurons resistance to genotoxic stresses and mitochondrial dysfunctions.
...
Discussion
Herein, we demonstrated that the Polycomb group gene Bmi1 is down-regulated in the brain and the retina of aged mice and humans. Moreover, numerous aspects of brain aging, but not all, are recapitulated in the progeroid phenotype of Bmi1−/− mice ..."

 
and it seems that its deficiency recapitulates several of the changes that are connected to the aging process in this organ too, and also in retina.
 
It may be asked what does it cause, or what are the consequences of this. And that how it relates to the "classical" damage markers of aging, like for example the
lipofuscin:

Heterozygous knockout of the Bmi-1 gene causes an early onset of phenotypes associated with brain aging
Gu et al. 2014
http://www.ncbi.nlm....pubmed/23771506
Abstract
Previous studies reported that the polycomb group gene Bmi-1 is downregulated in the aging brain. The aim of this study was to investigate whether decreased Bmi-1 expression accelerates brain aging by analyzing the brain phenotype of adult Bmi-1 heterozygous knockout (Bmi-1(+/-)) mice. An 8-month-old Bmi-1(+/-) brains demonstrated mild oxidative stress, revealed by significant increases in hydroxy radical and nitrotyrosine, and nonsignificant increases in reactive oxygen species and malonaldehyde compared with the wild-type littermates. Bmi-1(+/-) hippocampus had high apoptotic percentage and lipofuscin deposition in pyramidal neurons associated with upregulation of cyclin-dependent kinase inhibitors p19, p27, and p53 and downregulation of anti-apoptotic protein Bcl-2. Mild activation of astrocytes was also observed in Bmi-1(+/-) hippocampus. Furthermore, Bmi-1(+/-) mice showed mild spatial memory impairment in the Morris Water Maze test. These results demonstrate that heterozygous Bmi-1 gene knockout causes an early onset of age-related brain changes, suggesting that Bmi-1 has a role in regulating brain aging.
 

...
Bmi-1 protein levels in Bmi-1+/− hippocampus were about half that in the Bmi-1+/+ control
...
Lipofuscin deposition and accumulation within the hippocampal neurons, a prominent and stable structural marker of cellular senescence (Terman and Brunk 2006; Assunção et al. 2011), was quantitatively analyzed... As expected, there were increases in volume of lipofuscin granules in the cytoplasm of CA1 pyramidal neurons of Bmi-1+/− mice, compared to Bmi-1+/+ littermates (11.94 ± 1.75 vs. 2.42 ± 0.31 μm3; P = 0.0007; Fig. 6a and b).

Figure 6 - Accumulation of lipofuscin pigment within the hippocampal neurons of Bmi-1+/− mice

 
Having established this connection with this damage marker I sought - to approach the problem from another, but connected, angle - if other protein and/or pathway dysregulations too, could be the cause of this aspect of aging.
In the initial post in this series, I've started with a study about the so-called senescence-associated secretory phenotype. This one:

...
The starting point is the second prelamin A study a couple of posts above, this:
Prelamin A accelerates vascular calcification via activation of the DNA damage response and senescence-associated secretory phenotype in vascular smooth muscle cells
Liu et al. 2013, http://www.ncbi.nlm....pubmed/23564641
...

 

And another such pathway is the NFkB, cf.:

Emerging role of NF-kB signaling in the induction of senescence-associated secretory phenotype (SASP)
Cell Signal. 2012 Apr;24(4):835-45. doi: 10.1016/j.cellsig.2011.12.006. Epub 2011 Dec 11.
http://www.ncbi.nlm....pubmed/22182507

 
Some studies pointed out that the NFkB pathway becomes deregulated during the aging process, for example:

Nfkb1/p50 and mammalian aging
Yamini, 2015
http://www.ncbi.nlm....pubmed/25704886

 
But what are the consequences? Some answers:

Age-related neural degeneration in nuclear-factor kappaB p50 knockout mice
Lu et al., 2006, Neuroscience 139 (2006) 965–978.
http://www.ncbi.nlm....pubmed/16533569
 
... In p50-/- mice, morphological examinations showed: 1) aging and degenerative changes in the cortex and hippocampus including increased lipofuscin granules in neural cytoplasm
...
Accumulations of lipofuscin granules and dark cytoplasmic bodies in neuronal cytoplasm and pericytes of capillary were apparent in the absence of p50.The lipofuscin granule accumulations are prominent in certain parts of the CNS of patients of degenerative diseases such as those with senile dementia, Alzheimer’s disease (AD), and amyotrophic lateral sclerosis (ALS) (Davis and Robertson, 1997). Lipofuscin (also called age pigment) increases with age. In fact, the time-dependent accumulation of lipofuscin in lysosomes of postmitotic cells and some stable cells is regarded as the most consistent and phylogenetically constant morphologic change of aging (Porta, 2002). The significant increase of lipofuscin in the p50-/- brain is a strong sign of accelerated aging in these animals. ...

 

to be continued ...