An Open Access Journal Special Issue on Telomerase Activity in Human Cells

If you have an interest in telomerase research, and anyone following developments in the science of aging really should pay attention to telomerase research, then you might find a recent special issue of Genes to be worth reading. It collects a dozen or so papers on the subject, adding to a growing number of reviews, calls to action, and discoveries published in the last couple of years in the field of telomere and telomerase biology. You might look at a very readable review from Maria Blasco's lab, published earlier this year, for example. The researchers there are leaders in telomerase gene therapy, and have demonstrated benefits and a slowing of aging in mice via this path. It remains to be seen how well it will translate to humans, though there are certainly people out there willing to try.

It is possible to describe cancer and aging as two sides of the same coin; the evolved systems that act to suppress cancer also suppress tissue maintenance, and the decline in stem cell activity with age that causes a slow decay of tissue function is a trade-off, balancing death by cancer against death by frailty and organ failure. Cellular replication and growth is the commonality in cancer and maintenance: one is uncontrolled growth, the other controlled growth. One of the most important mechanisms in our cellular biochemistry is the Hayflick limit, and telomeres are a part of the system that creates that limit. Telomeres are lengths of repeated DNA that cap the ends of chromosomes. Every time a cell divides some of that length is lost. When telomeres become too short, a cell halts replication and either destroys itself or becomes senescent and is soon thereafter destroyed by the immune system. Healthy tissues are in a state of balance between loss of cells to the Hayflick limit and the delivery of new cells with long telomeres, created by stem cells. How do stem cells constantly create new daughter cells with long telomeres? They use telomerase to maintain long telomeres: the primary function of telomerase is to add more of the repeating telomeric DNA sequences to the ends of chromosomes.

This ornate situation has evolved because it ensures that cancer incidence is kept low enough for it not to impede evolutionary success. The majority of cells have a limited ability to replicate, and only a small number of cells have unlimited replication rights. This greatly reduces vulnerability to cancerous mutations. Still, cancer happens, and it occurs when cells mutate in one of the few ways that can unlock telomerase or alternative lengthening of telomeres activity, or when stem cells mutate in ways that break their regulatory programs. For cancer researchers, interfering in telomere lengthening is the road to the grail of a universal cancer therapy, a single way to shut down all of the hundreds of types of cancerous tissue. On the other side of the coin, for aging, increased telomerase activity is thought to be a way to spur greater tissue maintenance in older individuals, though the processes by which this happens are many, varied, and much debated, just as the full list of mechanisms of action for stem cell therapies is a matter still under investigation. There is some thought that an increased level of telomerase activity will increase cancer risk, as damaged cells will be allowed to replicate far more often than they have evolved to replicate. Though by the same token, stem cell therapies should be similarly risky. So far the benefits look to outweigh the harms. It may be that our evolutionary point of balance has a fair amount of wiggle room.

Special Issue "Telomerase Activity in Human Cells"

The activity of the reverse transcriptase telomerase is a canonical function to maintain telomeres, the ends of linear chromosomes. Telomeres shorten in the absence of telomerase, causing senescence and ageing. In contrast to other organisms, telomerase activity is downregulated early in development in many somatic human tissues. However, some cell types, such as lymphocytes, adult stem cells, and endothelial cells retain, or can upregulate, telomerase activity. Importantly, this activity is strongly controlled by physiological conditions. In contrast, telomerase activity is continuously expressed at a high level in the majority of cancer cells, contributing to their indefinite proliferation potential. Although telomerase activity has been vigorously investigated over the last few decades, many questions still remain open regarding the mechanisms of physiological regulation in normal cells, as well as its up-regulation during tumourigenesis. The complex regulation at the levels of transcription, splicing, and posttranscriptional activation certainly contribute to that. Recently, interventions into its activation to counteract telomere shortening in healthy tissues, as well as its inhibition as tumour therapy, have been suggested and trials have been started with no final breakthrough yet. Thus, we still need to better understand the biology and regulation of telomerase activity in order to interfere with it successfully.

Telomerase Regulation from Beginning to the End

The vast body of literature regarding human telomere maintenance is a true testament to the importance of understanding telomere regulation in both normal and diseased states. In this review, our goal was simple: tell the telomerase story from the biogenesis of its parts to its maturity as a complex and function at its site of action, emphasizing new developments and how they contribute to the foundational knowledge of telomerase and telomere biology. Telomeric integrity has implications in both cancer and aging, as telomere attrition serves as a key checkpoint in the control of cell proliferation by triggering replicative senescence. There are two broadly defined mechanisms of telomere maintenance in humans: telomerase-mediated maintenance and ALT (alternative lengthening of telomeres). However, the complexity of each of these mechanisms becomes more evident with every new publication in the field of telomere biology. Approximately 80% of cancers are immortalized by constitutive activation of telomerase to maintain telomeres throughout rapid cellular proliferation. Additionally, defects in telomerase and other telomere maintenance components cause premature aging syndromes like dyskeratosis congenita (DC), due to progressive telomere shortening and subsequent proliferative blocks. As such, greater knowledge of telomerase regulation and its contribution to telomere homeostasis will contribute to our understanding of human disease and natural cellular processes alike.

The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?

Many chronic conditions in humans are associated with chronic inflammation, immune system impairment and accelerated aging. In addition, abnormalities in telomere/telomerase system of these patients have been reported in many of these disorders. Since telomerase, an enzyme directly associated with aging, is inactive in most cell types in a mature organism and active in immune system cells, one can easily hypothesize that the immune system dysfunction/accelerated aging observed in chronic conditions is connected with telomeres and telomerase biology. Indeed, a connection of this nature seems to exist since shortened telomeres, observed in aged cells, cause an inflammatory cascade whereas, at the same time, NF-κB, a master regulator of inflammation, seems to directly induce telomerase transcription as stated above. Moreover, many researchers documented correlations between lower telomerase activity and/or shorter telomeres in immune system cells and elevated cytokines in blood serum from patients with chronic disorders. One should also bear in mind that, although aging is a multifactorial and complex procedure, healthy aging and longevity are believed to be associated with longer telomeres and lower inflammation profiles among older individuals. Despite all of the above, and despite the accumulating data of a strong interconnection between telomerase regulation/activity and inflammation, the mechanistical details and the molecular pathways of this connection have not been uncovered yet.

Telomerase: The Devil Inside

Emerging evidence over the last decade supports the idea that telomere length-independent functions of telomerase are also important for its function, both in normal and tumor cells. Interestingly, current research also revealed that telomeres may sense cellular stress (such as genotoxic stress, oncogenic or aneuploidy-inducing mutations) that result from harmful mutations that lead to genome instability and induce senescence in cells with intact checkpoints. Although the mechanistic details of the 'sensing' process are yet to be revealed, this new function of telomeres, thought to be a result of accumulating replication stress at the telomeres, seems to be independent of telomere length. In this context, telomerase relieves this cellular protective mechanism by mitigating telomere replication stress and this function of telomerase apparently is separate from its telomere elongation activity. In light of the recent discoveries hinting at novel, telomere length-independent roles of telomeres and telomerase, attempts at modulating telomerase activity to improve organ function and longevity must be seriously reconsidered. In this line, interfering with telomerase activity and its extracurricular functions for cancer therapy seems to be an attractive strategy again but new concepts need to be taken into account.

Role of Telomerase in the Cardiovascular System

Aging is one major risk factor for the incidence of cardiovascular diseases and the development of atherosclerosis. One important enzyme known to be involved in aging processes is telomerase reverse transcriptase (TERT). It has been proposed for a long time that telomerase activity is absent from human somatic cells. However, there is accumulating evidence that substantial telomerase activity is present in differentiated, non-dividing somatic cells of the cardiovascular system. This is of particular importance since cardiovascular diseases (CVD) are still the leading cause of death worldwide. All of these diseases have a primary defect in the heart or in the blood vessels, and there is emerging evidence that telomerase has a protective effect against CVD. Understanding this enzymes' functions in these tissues could, in the long run, help to reveal the therapeutic potential of activating TERT in cardiovascular diseases.

Comments

Hi there,

''For cancer researchers, interfering in telomere lengthening is the road to the grail of a universal cancer therapy,
a single way to shut down all of the hundreds of types of cancerous tissue. On the other side of the coin, for aging,
increased telomerase activity is thought to be a way to spur greater tissue maintenance in older individuals, though
the processes by which this happens are many, varied, and much debated, just as the full list of mechanisms of action
for stem cell therapies is a matter still under investigation.''

Very true, I hope that OncoSENS ends up a great therapy that can solve this near-number 1 disease-killer in developped countries.
People don't die of anything anymore in developped countries because of extended life expectancy by improved hospital cares/methods
to heal people of their ills and diseases compared to long ago. Only certain diseases that did not show up (because you died younger)
now show up, later in life; like cancer; because if you don't die of natural age, you die of some disease; mostly, cancer.

I think the problem with OncoSENS telomere lenghtening blocking is that it may block telomerase activity in immune cells,
some immune cells depend on telomerase - to kill cancer cells. Because, they way I understood it, the method seemed to imply
like a system-wide blocking of telomerase activity in almost all cells. That means, certain immune cells may be affected,
which would lead to weaker/en immune system. The immune system is crucial to destroy cancers. Although, blocking
telomere lengthening would effectively render the whole 'needs to stopped by immune system' now less important.
But, it would have to be only and specifically in cancer cells, nothing else.

Although, if this is more difficult, there is also the way of transcription. Epigenetics All the way.

If they can reprogram to iPSCs from somatic cells, they can and should reprogramm cancer cells.
They even say it here :

''Although telomerase activity has been vigorously investigated over the last few decades, many questions still remain open regarding the mechanisms of physiological regulation in normal cells,
as well as its up-regulation during tumourigenesis. The complex regulation at the levels of
transcription, splicing, and posttranscriptional activation certainly contribute to that.''

Yes, exactly the complex regulation at the transcription level, if you crack it, you won't need to touch telomerase.
Studies showed that cancer formation is a - concerted steps of methylation changes that happen - way before and 'set things up' - in the pre-cancerous cell to cancerous cell stages.
For example, Histone3 H3K methylation on the chromosome is totally lost and the CpG poor areas become demethylated; while CpG rich areas get suddenly activated.
Essentially, this means there is a 'program' that activates genes that permit inflammation and thus aberant use of telomerase by these cancer cells.
This program is called the 'transcriptional drift' (from a study). I was able to determine that with age there is transcriptional drift (correlating to loss of transcription fidelity in the genome/the transcriptome at large is 'drifting' from it's 'calibrated state'/'out of tune', which means
loss of gene transcription; like for example, loss of telomere hTERT transcription (Human Telomerase *Transcriptase*) or misappropriation of hTERT in cancers (through hypermethylation of inflammation genes).
In fact, the transcriptional drift can explain intrinsic aging and damage accumulation. The methylation steps in it alter the entire course of the rate of aging and disease appearance.
And, what's more important, is that interventions who 'put back' the transcriptome to its original state (by reducing damage accumulation or altering DNA epigenetics/methylation)
reverse aging, not just slow it. The reason for that, is because transcription commands all genes, genes that promote damage production acceleration are activated with age (p53,p16 and others) through transcription infidelity/drifting,
when they are silenced, ROS and oxidative stress are minimal, thus damage rate accumulation is reduced. Not only that, transcription commands important 'immortal genes' like Oct, Sox, Nanog;
which are capable of reversing aging (not just in stem cells). The most powerful commander of gene transcription is the methyl/ethyl exchange/donation/loss in chromosomes over cytosine DNA nucleotides on the 5 position (5-methylcytosine) in CpG (Cytosine-phosphate-Guanine) areas.
Gene transcription is the true decider of the epigenetic aging program in humans, including cancer formation. By altering, hundreds of millions of genes all at the same time, it alters their longevity of the specie individual.
One study proved that with mutant yeast C.elegans (age-1(mg44)) that lived 10-fold longer (20 vs 200 days), it had dramatic gene transcription changes (like thousands of genes were disactivated/activated, and it targeted many genes pertaining to energy metabolism, oxidative stress resistance/response, immunosenescence, etc..which were causal to the extreme longevity).
What's more is that nematode was maintaining transcription fidelity and thus, was slowing transcriptional drifting seen with age (which impacts dNA methylation program patterns).
This was even demonstrated in a study that showed in brains of different ages in humans.
Humans brains from birth to a 100 years old, they showed that transcriptional drift was happening very early right from the start and at a fast rate until puberty. At puberty, there was a slight plateau and then a longer plateau from 20 to 40...then at 60 things started to drift again; by 80 to 100 the acceleration was dramatic; that last slice of aging was much faster drifting (the high morbidity period). Morbidity (from transcriptional drift) started at around 60 years old and accelerated each subsequent decade; trancriptional drift was in exact correlation to it. This exatly, also, what happened in the yeast and the mice too.
What was also intriguing was that, transcription was capable of 'extending' the lifespan of an animal - however long - you want, meaning the morbidity period was post-poned - forever long - as the transcriptonal drift was pushed back 'to later' too; which, in simple words, actually means, true eternal life, when you think about it for a second.

''On the other side of the coin, for aging, increased telomerase activity is thought to be a way to spur
greater tissue maintenance in older individuals, though the processes by which this happens are many, varied,
and much debated, just as the full list of mechanisms of action for stem cell therapies is a matter still under investigation.
There is some thought that an increased level of telomerase activity will increase cancer risk''

Exaclty, telomerase may increase cancer, but it would increase immune system fitness thus more power to kill cancer cells by thymus Cytotoxic T-Cells and white cells.
The thymus will grow anew (since it faces involution during immunosenescence and natural aging). Thus, the benefits outweigh the risks.
And you can obviate this problem altogether - not touch telomerase at all - leave it like it is, this way you keep stem cells' telomerase use to replace tissues.
Go the transcription route - do it in epigenetics - you will stop any cancer dead in its track - far better than any telomerase blocking.
Because you will make the cells commit suicide by altering their transcription and methylation patterns - no cancer cell can survive that;
it is tantamount to reprogramming ('erasin' the cancer, instead of trying to 'blocking it' with telomerase-block). Still, doing this is more complicated
and the simpler and easier way of simply blocking telomerase makes it better and faster as a 'answer' to cure cancer. If it works it works.
If it fails, use the other route and go in epigenetics reprogramming; we are there now, there is no backtracking in that field, we are so close
to reaching it - if SENS fails (I am sure it won't), epigenetics/transcriptome/DNA/methylome reprogramming is the single most powerful thing to give us eternal life - free of any cancer.

Posted by: CANanonymity at September 21st, 2016 12:22 AM

I wonder what lengthening telomeres would mean in terms of SENS, assuming complete success (no cancer etc).

It would prevent one route to cellular senescence (are there others?) and one route to cell death (pretty sure there are others.) What about other areas, like accumulated junk or crosslinks, are telomeres relevant at all?

I hear there might be a positive epigenetic effect from longer telomeres, but what would that mean in terms of SENS, still seems unlikely that it would do much by way of removing junk or crosslinks etc, but maybe it can slow down aging to some extent.

Posted by: Northus at September 21st, 2016 9:05 AM

HI Northus !

Currently, this option is not their plan and therapies, OncoSENS wants to block telomerase (from cancer cells).
The only few ways to lengthen telomeres are through telomerase, ALT, oct/sox/nanog interdependent communication
and all of this by transcription/epigenetics reprogramming (since nuclear DNA reprogrammed iPSCs have elongated 'anew'
tall telomeres back to original 'point zero' when they were 'younger' biologically. This means, telomerase, was
used in them by the reprogramming process. And, also, they show a DNA methylation 'epigenetic clock' age that
is reversed back to the start too (again demonstrating that DNA methylation and
transcription changes are the mediators behind this. Reprogramming is simply 'recoding' things so things
a back where they were originally (get the 'previous 'young' DNA code' and 'paste-it' on top of the current old DNA one).
Because DNA that is not damaged and makes aging, it through a 'epigenetic signature' (addition/removal of methyl patterns in nucleotide rich areas (that drive (inflammtory) gene activation), which poor areas drive 'gene silence' since there is no nucleotide (CpGs)) that represents itself as a visual
'phenotype'. IF you change that 'signature' you change the code back to the young epi-signature.

I think they could reconsider it, after all therapies are done and the OncoSENS is stable, perhaps then they could selectively
activate hTERT and telomerase in somatic cells (it has been shown in rodent cells and they did no form spontaneous cancerous mutations, they had replicative lifespan extension beyond their Hayflick limit by hTERT transcription in them).
BioViva telomere therapy is an early example of what telomerase did, but it's too early too tell. But, we had a few months ago, a proof in telomere size
that her telomeres were lengthning proving that she is indeed reversing/or very least slowing aging. (they say she was now 20 in terms of telomere size,
she had about 1kb length extension after therapy (1kb (a 1000 nucleotide base pairs)) is roughly 10-20 years of 'human life' Thus she is 45 years old chronologically, but now more like 30 year old biologically.

''It would prevent one route to cellular senescence (are there others?) and one route to cell death (pretty sure there are others.) What about other areas, like accumulated junk or crosslinks, are telomeres relevant at all? ''

Yes, there are others, 3 main dictint (but sharing together) ones in total : DNA-damage induced senescence; Replicative senescence and Oncogene-induced senescence.
All of these share interlapping pathways (of damage accumulation or not) but have 'transcription signals' that are behind them at the chromosome/methylation level, such as in Oncogene-induced senescence by RAS oncogene.

Me too I had much doubts about wether telomeres had anything to do with extracellular and lysosomal junk (like age pigment and crosslinks).
Apparently, yes and no is the best answer (I know that sounds ambiguous, but aging is just that) : Yes, because telomeres are cell cycle counters,
their role is to inhibit cell proliferation as evolutionary 'trade-off'. By 'shortening and uncapping' they create - senescence and death, thus
they disallow uncontrolled proliferation and cancerous mutations to form. In other words, they impede on the capacity of cancers to form - by killing
the cell - before it happens. It really is a 'quality control' 'kamikaze-controlled' form of suicide to ensure genome stability and halt illegit tumor formation (That would compromise the host and 'spread' in the organs - thus, in the 'big'
evolutionary scheme would compromise the specie's individuals' survival (they would get cancer - all of them and thus eradicate the specie and evolution would be halted).
And so, by being cell cycle inhibitors, they are also 'reducing the length of replication rounds' a normal dividing cell can do, as such it will
accumulate damage much more as it reaches its replication limit (becomes senescent)) - thanks to the shortening telomere blocking the capacity to overcome the 'proliferation arrest'.

No, because it was shown that telomeres can be uncoupled from damage and they can be more a general marker than causative.
Although, to be clear now, studies (in epigenetics) show that this a Concerted thing, meaningf for somatic cells - there is a program (epigenetic one)
that decides that this cell won't replicate any further and this happens in concert with telomere shortening.
iPSCs that are reprogrammed have a 'young DNA methylation clock' back and on top of that they have lengtened tall telomeres anew. It all happens in concert,
same thing for their damages, they are removed by the reprogrammation.
Also, one more thing, now it's clear cells or other mechanisms - can remove age pigments and certain crosslinks - it seems. For example, when telomeres
are high proliferation is high, and lipofuscin dilution per cell cycle is high too; thus they may not be able to degrade it (by exocytosis in the cytosol and for excretion outside cell),but they do find ways to remove it 'Somehow' during the reprogramming.
So if you were to ask me, can these damages be removed or at least be stalled - forever - Yes, definately, by epigentic reprogramming/transcriptome modulation, not necessarily telomere lenghtening alone though; this would need to happen in concert (and as said, the 'code' is clearly - telomeres must be lenghtened - with all of the rest 'to work' as functioning code. As seen, in iPSCs at least).

'I hear there might be a positive epigenetic effect from longer telomeres, but what would that mean in terms of SENS, still seems unlikely that it would do much by way of removing junk or crosslinks etc, but maybe it can slow down aging to some extent.''

Exactly, it may not remove the damgage that is already accumulated (or it may, that part is less clear, but more and more data, seems to show that our body does have that capacity because they will 'gradually' remove those damages through many unknown pathways yet (epigenetically speaking)).
The single fact that transcriptional drifting shows telomere loss, damage accumulation, methylation change, redox change, etc..and that reversing transcription drift changes - all - of these parameters back to how they were before (exactly like reprogramming) then it means, that
it is possible to circumvent the extra-cellular junk and other damages - it is not irreversible like once thought. We only have to 'instruct' the DNA (epigenes) and this can have dramatic changes on the whole host and it's aging process by the damage accumulation.
If transcriptional reversal - reverses aging - like true rejuvenation (like iPSCs who have Reversed Transcription Drifting Profile), then why care about the damages, they are not the end of it all (they become totally futile and do nothing anymore), we can skip them and make them stop altogether through transcription maintenance/epigenetics reprogramming.
We have to understand, animals that - live longer - have a transcriptional drifting that is delayed, and they also have a reduced damage accumulation. Thus, wether we stop the damages or we retrotranscript the DNA, the end result is the same - eternity/immortality by removing what makes 'intrinsic aging' continue its natural course until our death.

Posted by: CANanonymity at September 21st, 2016 3:43 PM

The problem with trying to reset the epigenetic markers to a youthful state in an already old person CANanonymity, is that person has already suffered decades of damage - damage that will likely be too much to clear up, even for someone with newly restored protein expression. Therefore the youthful epigenetic state will not 'stick', and likely revert to a non ideal/older state, because of the reasserting effects of unresolved oxidation, cross-linking, protein aggregations, mitochondrial mutations, etc. Resetting epigenetic state might work if you are not yet old, keeping you young, so-to-speak, but I fear that for the already old, damage clearance is the only option.

Further, clearing damage in iPSCs is certainly possible through the method you propose, but this is not an option for the majority of post mitotic somatic cells, which cannot be replaced without compromising function, i.e. neurons, so we are back with the problem of addressing multifaceted damage.

Posted by: Mark at September 22nd, 2016 7:58 AM

Hi Mark ! Thanks for the reply !

Yes, exactly, you are very right, I too had some doubts if this epigenetic clock reversal would
apply for old people. One study showed the reversal of aging (or at least cell respiration and mitochondrial respiration more precisely)
in a 97-year old donor's fibroblast cell line through glycine addition for 10 days. It showed that perhaps certain dividing
cells can indeed be reversed, but as you say long-lived post-mitotic somatic cells like neurons or CNS cells are another matter since they don't
divid. My point is not to try to replace anything, but rather reprogramm what is there already, including those somatic ones.
The truth is iPSCs cells are being made - from somatic cells. As such, somatic cells are very reprogrammable back to square 0.
I believe that these damages can be 'somehow' disappear, I know it sounds very untrue and they are 'irreversible' and 'happened' already
in an old person. The extra-cellular and the cell compartments seem to suggest, from epigenetic reprogramming, that 'epigenetic and transcriptional'
signals between ECM and the cell, can 'remodel' the ECM and the cells themselves (including somatic ones, when reprogrammed just like with iPSCs).
How can we explain that these iPSCs cells have a total rejuvenation ? Should their damages not have disappeared, my guess is yes, through
a gradual (or rapid?) cell cycling 'damage residues' dilution mechanism and a 'rebuilding' of the cell structure (including actin filament structure)
(not just repair - completely rebuild from scratch, and in the process, remove damages - totally, as if never happened).
For the ECM, that's another story (like glucosepane crosslinks and other oxidative lesions...), the ECM is capable of remodelling itself (ECM turnover),
as such with epigenetic/transcription signals from the cells in it and other 'growth factors' that reside in it, it would be capable of not only
repairing but full remodelling (rebuilding from scratch and, again, in the process remove those damages).
It may not work that way, but one thing is sure, - more damages - won't accumulate anymore with epigenetic reprogramming - so at least - it freezes
whatever damages you already have. And who cares, if you are 30, 50, or 70, as long as you 'freeze' that time and then it will be equalling almost
to the same thing as LEV of SENS, which is by 'going back in time' you reverse aging say 30 years whenever you reach 60 years old - to be back to 30 biologically,
that way at 90 chronological years you back to 30, at 120 you get back to 30, etc...infinited life. The difference with epigenetic reprogramming
is not 'getting back in time to a younger version of you' - but rather keeping that exact 'copy of You Right Now - intact - for the rest of eternity',
so if you are now at 65 yaers old, the best we could do, is post-pone death and 'keep you at 65'. Transcription drifting continues its course,
but if you reverse it, then you are back to the former 'younger' transcription. Which means, by 66 years old, you would have 66 years more or less DNA epigenetic age.
The year previous to that, you were 65, and you were indeed younger epigenetically speaking; transcriptional drift reversal would - at very least - freeze you at 65
and, not, let you continue to the 'transcriptional drift of a 66 year old'. Which means that you are doing the same thing as LEV/eternity, you are doing the 'loop di loop /rewind/forward/rewind...,
looping your previous transcription profile - you can't get back to 30 years old (because of your damage accumulated having reached 65, but you can at least stop anymore from piling and keeping that 65 year old trancriptional profile, each subsequent year after that point).
Damages are normally going to add up wether we like it or not, but transcriptional profile is causative in how much More damage is coming in,
So if you change the profile you change the damage accumulation, and so for someone older, you would litterally freeze them to that point.
That profile is linked to DNA methylation changes, that happen with natural aging (not pathological aging), cells (including somatic ones) lose
methyl content in CpG poor areas; telomeres become demethylated too and same for sub-telomeres, this means the transcriptional profile is drifting
because the methyl content is reducing (Global DNA demethylation in aging from newborn to centenarian), as such genes become 'activated' (inflammation genes mostly in CpG rich areas)
while the 'intrinsic aging' process controlled through methylation at CpG poor areas mostly is getting lower and lower. And thus, gene silencing is lost for inflammatory ones,
while gene activation conservation is lost for anti-inflammatory ones and Oxidative Stress 'Response' ones like Nrf2/ARE/EpRE/Phase-II Xenobiotics detoxifiers/BER/NHEJ DSBSSBs repair (which protect against damage accumulation, and so 'aging' continuation (tissue degeneration)).
Well, that's just my 2 cents : ) I could be very wrong, I so hope that epigenetics have indeed the capacity to stall, at least, the damages even if they don't reverse them/remove them completely; as long, as they stop from any -more- damage from piling and making age/die (freezing 'age' at a 'set frozen age DNA methylation clock point' in one's life - forever, eternal life would be possible..the younger the procedure in one's life, obviously, the better. It has to be done while you're (still) alive and if possible, young).

1. https://www.sciencedaily.com/releases/2015/05/150526085138.htm
2. http://science.sciencemag.org/content/341/6146/651

Posted by: CANanonymity at September 23rd, 2016 6:10 PM

@Mark

PS:

''Fig. 1. DNA damage at active transcription sites induces reversible transcription inhibition by the DART system. ( A ) Scheme of the DART system for inflicting genome locus-specific damage. KR generates ROS upon visible light exposure and induces localized damage at transcription either off or on sites. ( B and C ) TA-KR transfected U2OS TRE cells were irradiated with light for 10 min followed by the indicated postlight incubation time. Phosphorylated POLII detected by anti-4H8 ( B ) or YFP-POLII ( C ) is shown at the indicated time points. Quantification of the average fold increase of 4H8 foci intensity of 10 cells at TA-KR damage sites is shown, and error bars indicate the SEM of three independent experiments. Dephosphorylation of POLII but not the dissociation of POLII was observed upon damage. ( D ) The percentage of CKL-CFP positive cells (defined as CFP foci > 10/cell) in tetR-KR or TA-cherry/KR transfected U2OS TRE cells before and after damage induction is shown. n = 50, and error bars indicate the SEM of three independent experiments. ''

This shows us the DNA damage is inhibiting transcription and thus creating transcriptional drift (here through ROS production by UVs light exposure which causes oxidative stress by UVs), in the inverse, inhibiting DNA damage - or - stopping transcriptional drifting means, invariably, that DNA damage will stop. They go hand in hand, what we don't know if the DNA damage that has alraedy accumulated will really change or not. Perhaps not, since the DNA 'was' damaged (although there are DNA repair systems that may come over and repair that should there be sufficient time and no further transcriptional drift - because - transcription is important for DNA repair.) In an old person, of course, it would be far more difficult to 'slow down' or 'freeze' the drifting because of the high lifetime total damage accumulated from their longer life and closeness to death.

Here's another one demonstrating that chromosome H3K36 histones determine intrinsic lifespan and subsequent rate of damage accumulation that hinders the length/span of that life, through a transcription fidelity improvement (transcriptional drifting thus slowing) :

H3K36 methylation promotes longevity by enhancing transcriptional fidelity
3. http://www.ncbi.nlm.nih.gov/pubmed/26159996

Posted by: CANanonymity at September 23rd, 2016 6:37 PM

The Science daily article is interesting, but I am not sure that it proves that it is epigenetic changes that cause faulty respiration. Sure, it may be a cause, but not the most important one. Remember that it only takes ~1% of cells to be taken over by faulty mitochondria to cause a system wide rise in oxidation levels and large contribution to aging. They may only have selected fibroblast cells with intact mtDNA, but with other problems, which they then fixed through epigenetic adjustments.

I take your point that it may be possible to reprogram somatic cells without having to revert them to iPSCs, but I await any proof that this is possible even in lower animals with a beneficial affect (such as freezing aging as you claim)before I am convinced that this is indeed a short cut to anti aging. Would be good if you're right though!

Posted by: Mark at September 26th, 2016 9:23 AM

I also agree with CANanonymity that the way to go for real rejuvenation is reverting the epigenetic drift. The SENS approach is a bit further down the rabbit hole than current gerontology since they take care of cellular and molecular damage but as they still don't fix the root problem my guess is that they could only increase the age at which keeping someone alive gets exponentially difficult to the maximum epigenetic lifespan limit at around 120. The deal with LEV in the SENS context is that they can revert the damage in your body to that of a younger age. But the epigenetic clock is not reset and keeps counting so once the person arrives to the epigenetic maximum the damage velocity so to say exceeds that of the technological advancement.

The good thing that we can infer from the iPSCs is that if we activate the right genes we can start a cellular regeneration program that will take care of genetic and molecular damage. Then is when the SENS approach would make sense to fix the rest of the damage. Now the goal is finding the right sequence to just activate this program without dedifferentiating the cell. Does anyone know if this kind of research is happening currently at all?

Posted by: Aevitas at October 5th, 2016 1:59 AM

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