Working to Characterize the Epigenetics of Cellular Senescence
The accumulation of senescent cells is one of the causes of aging. If even 1% of the cells in a tissue become senescent, that small fraction has been shown to have very damaging effects on the function and behavior of the majority non-senescent cells. The most direct path towards addressing this problem is to selectively destroy senescent cells throughout the body every few years, and companies such as Oisin Biotechnologies and UNITY Biotechnology are working towards that goal. Many researchers are more interested in altering the behavior of senescent cells for the better, however, something that I see as an inferior path, but that fits more closely with the scientific impulse to completely map senescence as a cellular phenomenon: to produce a full understanding of the molecular biology of the processes involved. Fortunately, the sort of mapping work shown here should also make it easier to selectively target senescent cells for destruction in the years ahead.
Researchers have succeeded in identifying genes that control cellular senescence - permanently arrested cell growth. The process involved treating liver cancer cells using anticancer drugs of various concentrations, inducing apoptotic cell death and cellular senescence, and comparing gene expression levels. By developing drugs that suppress the activity of these genes, this discovery has potential applications for creating new highly-effective anticancer drugs, or use in anti-aging drugs. Living organisms experience various stresses during their lifespans. These stresses include radiation, ultraviolet rays, and chemical substances that directly damage DNA and cause cancer. Organisms are able to speedily repair DNA when it is damaged, but when the damage is severe, they manifest two different cell responses: apoptosis - a type of controlled cell death - and cellular senescence, which permanently suspends cell growth. Both these responses prevent the cell which suffered DNA damage from proliferating and becoming cancerous.
The research group had previously discovered that cell senescence was effectively induced by using low concentrations of anticancer drugs on cancerous cells. If cancerous cells are treated with a low concentration (10 μM) of the anticancer drug etoposide this induces cell senescence, and if they are treated with a high concentration of the drug (100 μM) this induces apoptosis. For this research, they treated cancerous cells under three different conditions: A) with no etoposide; B) with a low dose of etoposide (10 μM); and C) with a high dose of etoposide (100 μM). They then used DNA microarrays to identify the genes in which a rise in transcription levels could be observed. They predicted that genes which showed increased expression in response to treatment B were mainly related to cell senescence, genes expressed in response to C were mainly those involved in apoptosis, and among the genes which specifically showed increased expression in B compared to C would be genes that play an important role in implementing cell senescence.
There were 126 genes where three times as much expression was recorded under treatment B compared to A, and 25 genes that showed twice as much expression in B compared to C. These 25 genes are expected to express specifically in senescent cells since the other factors caused by DNA damage are removed, and researchers confirmed that the genes involved in causing cell senescence were among them. If we can develop a drug that targets and regulates the activity of the genes that control senescence identified in this research, by administering it together with conventional anticancer treatment we can limit the emergence of senescent cells and potentially increase the effectiveness of cancer treatment. Additionally, it has been reported that one of the causes of individual aging is the accumulation of senescent cells. This means that drugs which control cell senescence could have potentially large benefits for the development of anti-aging medication products.
Link: http://www.kobe-u.ac.jp/en/NEWS/research/2016_09_13_01.html
Hi ! Intriguing study.
I guess this is more data to show, epigenetically speaking, that
cellular senescence has an important secondary role (pathologic aging (diseases)), not a first (intrinsic, regular healthy aging - without cancer oncogenic activation) role.
'' Additionally, it has been reported that one of the causes of individual aging is the accumulation of senescent cells.
This means that drugs which control cell senescence could have potentially large benefits
for the development of anti-aging medication products.''
That is erroneous (from Donna Lowe and Steve Horvath's epigenetic research).
To think that cell senescence will have any impact on intrinsic aging, it won't; curing it will definately help
pathologies though, not healthy aging. In humans, telomeres are mostly the biggest deciders and even then,
the study shows that, even telomeres, are independent from cell aging; this means they are only a collerative marker; not
causative. Although, they do paint a bigger picture of the individual's epigenetic age.
Epigenetic
''
This point is reinforced in a separate, yet conceptually connected experiment.
Analyses of cells immortalised by telomerase showed late (p50) passage cells to have aged,
even without having been subjected to any known senescence inducers (Figure (Figure3).3).
These cells continue to proliferate in culture beyond passage 50 and do not exhibit any signs of senescence,
demonstrating that ****the process of cellular ageing continues unabated in
cells whose telomeres were maintained.***
*****This shows that removal of the inducers of senescence does not halt ageing,**** once again underlining the fact
that *********cellular ageing is a process that is distinct from senescence******.
''
''Using primary cells, telomerase-expressing cells and oncogene-expressing cells
of the same genetic background,
****we show that induction of replicative senescence (RS) and oncogene-induced senescence (OIS) are accompanied by ageing of the cell.
However, senescence induced by DNA damage is not, even though RS and OIS activate the cellular DNA damage response pathway****,
******highlighting the independence of senescence from cellular ageing******.
Consistent with this, we observed that telomerase-immortalised cells aged in culture without
having been treated with any senescence inducers or DNA-damaging agents,
re-affirming the independence of the process of ageing from telomeres and senescence.
Collectively, our results reveal that cellular ageing is distinct from cellular senescence
and independent of DNA damage response and telomere length''
''
This however, appears at first sight to be inconsistent with the fact that senescent cells
contribute to the physical manifestation of organism ageing, as demonstrated elegantly
by Baker et al., where removal of senescent cells slowed down ageing.
In the light of our observations however, it is proposed that cellular senescence
is a state that cells are forced into as a result of external pressures such as DNA damage,
ectopic oncogene expression and exhaustive proliferation of cells
to replenish those eliminated by external/environmental factors.
These senescent cells, in sufficient numbers, will undoubtedly cause the deterioration of tissues,
which is interpreted as organism ageing.
****However, at the cellular level, ageing, as measured by the epigenetic clock, is distinct from senescence.****
''
'' Clearly, DNA damage response is not coupled to epigenetic ageing and that
RS [Replicative Senescence] and OIS [Oncogene-Induced Senescence] induce cellular ageing through a mechanism that is
not part of the DNA damage response pathway.
The lack of effect on ageing by radiation-induced senescence demonstrates
that the association between senescence and epigenetic ageing is more nuanced,
in that it is an independent association, as opposed to an inextricable mechanistic one.''
and THIS :
''***The fact that maintenance of telomere length by telomerase
did not prevent cellular ageing*** defines the singular role of
telomeres as that of a means by which cells restrict their proliferation to a certain number;
which was the function originally ascribed to it.
***Cellular ageing on the other hand proceeds regardless of telomere length***.
''
''the singular role of telomeres as that of a means by which cells restrict their proliferation to a certain number;
which was the function originally ascribed to it.
''
DNA damage-induced senescence does Not induce biological cell ageing
Oncogene-signal-induced senescence Does induce biological cell ageing
Replicative senescence Does induce biological cell ageing
Telomeres = cell proliferation 'inhibitor' mechanism (against oncogene cancerous cell formation).
This means SENS's Senescence senoylitic therapy will help human health and pathology but will have no say on regular intrinsic ageing (by intrinsic cell ageing progressing, independently, of it). But it will definately help for cancer, which itself does increase cell ageing through oncogene ras-signals (people who does have cancer, thus have accelerated aging. My own mother died of cancer, and I saw the devastation it does in a few months time; and it did make 'her age' (like in progeria syndrome with 'visible' accelerated aging phenotype) her hair grayed dramatically, lost hair, her skin got dry/like old frummpy leather, very wrinkly suddenly, she lost 85 pounds by cancer, was meager, and had, now, osteoporosis/sarcopenia - all in the space of a year). Showing cancer is truly a age acceleration at the cell level, not by DNA damage, but by RAS-oncogenic cancer signals.
Epigenetic clock analyses of cellular senescence and ageing.
1. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4890984
PS:
This also means that cells' who telomeres are continuously increased and maintained, like in cancers, or the Hydra's telomerased-immortalized stem cells, - continue to age (at the cell level) - despite the telomere size - but they **do not enter replicative senescence**, since they maintain telomere size (fully methylated, capped and stable, shorten telomeres over many replications are a correlative signal for replicative senescence entry), cell replication - continues unabated and cellular senescence is post-poned as long as cell replication continue, by maintaining the telomere length; even if the cell has 'aged' epigenetically.
That may explainy why Hydra's are immortal, their cell epigenetic age must be immense, but it keeps on dividing so it doesn't matter, it keeps on building/growing tissue by cells keeping on proliferating/replicating, thus the Hydra itself stays in a eternal 'retransforming/regrowing/remorphing/replasticizing/remodelling' life state; thus immortal. What is sure is this is all very confusing...but we are getting to untangle things/nuance aging (and making sure we nuance 'cellular level' (small picture) vs 'organism level' (big picture...confusing)).
PPS: From this we can conclude, that right now, the best measure of true and accurate biological 'ageing' is thus Horvath's Epigenetic Aging measure in chromosomes. From now on, I think every thing in terms of research should be compared with epigenetic age to have any credibility in terms of what we mean by 'aging'.
Good information as always CANanonymity. Do you know of any studies which show a decrease of the rate of epigenetic aging due to some medicine or therapy? There are many studies on things which increase the rate of aging but I am only aware of the study on exercise which shows a slowing of epigenetic aging of people engaging in a high level of exercise compared to moderate or low levels of exercise.
Abstract A17: Physical activity and epigenetic age among normative aging study participants
http://mcr.aacrjournals.org/content/14/4_Supplement/A17
I would like to bring it to the readers attention that Everon Biosciences (www.everonbio.com), of which I was one of the founders and have been serving as its CEO, was founded in 2010 with the goal of discovery and development of senolytic drugs (Unity Biotechnology was founded in 2015 and Oisin Biotechnology in 2016 as far as I know). Since then we have discovered multiple senolytic compounds acting via a variety of mechanisms that selectively kill senescent cells in vitro. However, after many years of trying, we have not been able to establish a reliable assay allowing to demonstrate DIRECTLY that our senotytics eliminate senescent cells in vivo. Those senescent cells that were supposedly accumulating in the body with age! Careful examination of the mouse model genetically similar to the one used in the seminal 2011 Nature paper by Baker et al demonstrated that the p16 and beta-Gal positive cells that accumulate with age are not senescent cells at all. Rather, those cells are a special type of activated macrophages we named Senescence Associated Macrophages, or SAMs. We published these findings here: http://aging-us.com/papers/v8/n7/full/100991.html
@Alexander Polinsky: I pointed that out at the time:
https://www.fightaging.org/archives/2016/07/arguing-for-the-detrimental-effects-of-senescent-cells-to-extend-into-the-immune-system/
That work has been taken with some glee in certain quarters, as to the extent that you are correct it looks like senescent cell clearance will do double duty in both cleaning up the immune system and helping tissues.
It is the doom of those who come first and early to be buried by those who come after often as not. Yours is one of I think, four or five ventures started some years back to investigate removal of senescent cells, if we are to include the company that turned into UNITY. If nothing else you should be consoled by the fact that however your current work turns out, you will certainly find a good place in the industry that will arise in the years ahead by virtue of your experience.
Hi Santi ! Thanks for that !
I feel the same way as you about this emerging field and wonder, there is not much going in research/results for reversing or slowing epigenetic aging.
I guess in 10 years, we will definately have some kind of help to go about doing this (I am not sure about therapies but some other methods
that could slow it at the very least; as we solve this completely). Though, the more we advance in time, the more I feel like repeating the words :
''In 10 years time''...''In 20 years time''. I hate that because it shows that indeed it is more illusory and I'm fooling myself to think 'We Are There. Finally'.
Still, to epigenetics credit, it is in infancy and it rather new in the biogerontology at large (not -that- new, but new enough and has become much more
precise). New things are great, but generally they are infancy stage and there is long 'way' before they are incorporated into use for human age reversal.
But the more new things the better, the better we we'll find solutions to defeat epigenetic aging (with SENS LEV).
The biggest one and also, most obvious one, is CR (Calorie Restriction (Adequate Nutrition with Lowered Calorie Count (High Nutrient Density Per Molecule Food Consumed in Smaller Portion), but not Starvation (extreme CR by continous Fasting = energy and nutrient deprivation) or Undernutrition (Nutrient poor even if low calorie), has shown the study below).
It's truly incredible about how what happened in your mother's womb affects your entire childhood and adult life afterwards, a long repercussion effect - all happened/continuously happening in the DNA methylation CpGs locis. We often think that an even is 'forgotten' and 'repaired' as if 'nothing happened'..Turns out it's not case, each 'event' whatever it is
triggers substantials changes in methylation (our epigenetic aging, thus leaves an DNA 'imprint' long afterwards, like memory effect of what happened and it still 'felt' (you know, when like you remember a 'vivid memory' from your memories and you can 'relieve it' almost as if 'it happened today'')...it makes me think of like stars that die...it takes billions of years to 'see' a star die in space...but we see them die Today in 2016..but they in fact died a billion year ago - in the Past. It's just the 'time' it took for light
to Travel and Reach to Earth as a 'Visible Ray of Light' 'extinct signal' showing its death in color (Light Years = Millions of Earth Years), it's why we see the star's 'death light' signal so 'late' (like a long delay effect or abit like the movie 'Butterfly effect'))
Obviously CR is not a fountain of eternal youth, and it acts in exactly with example you gave, Exercise. Both CR and Exercise act on very specific
pathways (mTOR, IGF, Hormones, glucose homeostasis, etc) to slow aging a bit. And they thus slow epigenetic aging. Truthfully : Not all that much sadly,
my uncle did lots of exercice (bike marathon) and did sort of CR (or let's say ate normally), even so he died at 74 years old...of Alzheimer's.
It's so ironic and sad irony really, because exercise (and CR) both activate BDNF (Brain Derived Neutrophic Factor) in the brain, which is crucial for
Longterm Potentiation (Brain Neuronal/Axonal/Dendrite/Synapse Synthesis and Function) and he did tons of it...and still died anyway, quite young at only 74
(and perhaps, much quicker had he not done exercise...he could have died in his 60s or late 50s).
...Do your best, some exercise and some CR, that's about it. Your genetics predispositions (familial hereditary genetics and early epigenetics at birth) seem to overcome epigenetics course in late life.
Alzheimer's is a degenerative disease and mostly shows (neuron) apoptosis and dendrite loss/shortening rather than senescence as
a/beta-amyloid plaques accumulate in the brain matter from the inside.
I found another study that showed that epigenetic aging can be slowed by restoring glycine (glycine supplementation like that or as part of protein supplements like Whey powder which is glycine-rich. Whey powder is good for building muscle, although from many studies with age we lack protein (sarcopenia/muscle wastage) for muscle synthesis - yet studies shows that protein restriction lengthens lifespan (by removing methionine amino acid oxidation-prone content. My Take : Get Only the Minimal Amout of Protein Necessary - Suffisance to make sure you are not developping muscle weakness but not accelerating aging from Protein-Shakes Binging like body builders. Proteins are important but we can do with Less of them, not with None of them.)).
The reason that glycine is capable of slowing epigenetic aging, is because of the Redox. Glycine is an amino acid in proteins, it is one part (precursor block) of the tripeptide Glutathione (is composed of Cysteine, Glutamate/Glutamic acid and Glycine), it is core element of cell protection against evergoing-on oxidation phenomenon and it's also a multi-signal molecule, affecting thousands of pathways.
Of course, we you ingest glycine, you give back the needed precursors to synthethize Gluthatione and thus improve Redox (affecting aging). In fact, if you alter the redox while taking in glycine, all of its effects will be nullified (dependent on them).
Still, this too is not a silver bullet, since whey or glycine themselves won't make anyone reach 175 years old or resolve Redox failure (redox enzyme and gsh transporters becoming dysfunctional/unresponsive), but
they do post-pone aging by fueling the blocks for more glutathione production. One study showed that GSH feeding (indirectly here through glycine) allowed an 80% chance of reaching Maximum lifespan in a frog lifespan model. Demonstrating that perhaps glycine could give you up to 30% extension (so if you were supposed to die at 75, you would now reach 100+ age).
It's going to be very hard to reverse aging with epigenetic aging, only some for of epigenetics therapy may be capable (like iPSCs reprogramming) and even then.
It's better to aim with SENS.
Researchers may have discovered fountain of youth by reversing ...
1. http://newatlas.com/reversal-of-aging-human-cell-lines/37721/
Epigenetic regulation of the nuclear-coded GCAT and SHMT2 genes confer human age-associated mitochondrial respiration defects
2. http://www.nature.com/articles/srep10434
Maternal diet and aging alter the epigenetic control of a promoter
3. http://www.pnas.org/content/108/13/5449.full
Advanced aging phenotype is revealed by epigenetic modifications in liver after in utero malnutrition
4. http://onlinelibrary.wiley.com/doi/10.1111/acel.12505/full
DNA methyltransferase inhibitor, RG108 treatment in human bone marrow mesenchymal stromal cells (hBM-MSCs) caused increase in the anti-senescence genes TERT, bFGF, VEGF, and ANG, and decrease in senescence-related genes ATM, p21, and p53. The number of β-galactosidase-positive cells was significantly decreased in RG108-treated MSCs. These data suggest that impact on the epigenetics can rejuvenate tissues. Unfortunately I have not found other similar data
Source http://onlinelibrary.wiley.com/doi/10.1002/bab.1393/full
@Dmitry
Hi Dmitry ! Thanks for that too.
I would be cautious though about DNA methyltransferase inhibition since the whole purpose of DNA methyltransferase is to improve methylation in DNA. We don't wish hypermethylation of disease-promoting genes, but only
genes that are anti-inflammatory and control the inflammation response.
Conversely we don'T wish hypomethylation, because then genes that - need - to be On become Off/dysfunctional and thus, creates aging/degeneration.
Inhibiting it, here in RG108 treatment creating a form of 'senescence inhibition' thus rejuvenating MSCs is both good - And Bad. Bad because in other cells DNA methyltransferase inhibition accelerates epigenetic aging by loss of 5-methylcytosine. Good because stem cells can replace tissues and stop tissue degeneration - but stem cells - too - are bound by epigenetic aging. It's not because they have less spontaneous DNA-damage senescence that are immune from - Replicative Senescence (one day these MSCs stopp proliferating, surely with less Beta-galactosidase, they would be non-senescent, it makes sense; since in the example, TERT in increased, thus these MSCs are getting Telomerase hTERT treatemnt of elongated telomeres (elongated telomeres allow continous cell proliferation/replication/division as telomeres themselves are cell proliferation inhibitors as they shorten). I am very curious, but I am guessing this is a special effect; as replicative senescence tumore suppressor genes p21 and p53 were also lower...this is exactly what happens in cell immortalization...this is very strange (a bit like what happens with cancer cell immortalization, MSCs share much in common with cancer cells (both are 'Stem Cell' like in quality) and both use stem cell 'immortality' markers such as Nanog, Oct and Sox).
In truth :
DNA methyltransferase inhibition Accelerates the whole global demethylation process (which happens naturally with age).
5-azacytidine is a DNA methyltransferase inhibitor like RG108
and it, accelerates epigenetic aging of cells.
I think I may have found something else to consider since methylation is aging, use methyl-donor agents is a solution :
Folic acid and Folate (converted by addition of a methyl group to MethylTetraHydroFolate, MTHF), B12, the methylating agents Definately slow epigenetic aging by improving DNA methyltransferase activity. One studiy showed that Folic acid improves heart function and reduces hypertension, and is converted to Biopterin,
and Bioterin levels have been shown with health (high Biopterin means better health and methylation, thus lowered epigenetic aging).
Consider these supplements (Folic Acid/Folate, B12, B-vitamins, Biotin and Biopterin) to (lightly) slow epigenetic aging.
The in vitro lifespan of MRC-5 cells is shortened by 5-azacytidine-induced demethylation.
1. http://www.ncbi.nlm.nih.gov/pubmed/2430819
Strong effects of 5-azacytidine on the in vitro lifespan of human diploid fibroblasts.
2. http://www.ncbi.nlm.nih.gov/pubmed/2427351
Sensitization by 5-Azacytidine toward Death Receptor-Induced
Hepatic Apoptosis.
3. http://jpet.aspetjournals.org/content/328/1/107.full
PS:
I think I had some kind of 'Epiphany' Flash happen in my head. I could very wrong. I've been many times.
You know like when you sometimes correlate things you head and then all the stars, the moons and the planets Aligng Themselves - and a Eureka ! Moment happens - you just made a ''1 + 1 = 2'' moment !.
Well !...This is it...I was thinking about all of this, and now remembering that telomeres can be uncoupled from epigenetic aging of the cell - but that replicative senescence is induced when the telomeres become too low and as such the cell stops dividing/proliferating.
Acting a cell division inhibitors.
It made me think Mrs. Elizabeth Parrish, the CEO of BioViva, who did out-of-country hTERT telomerazed therapy on her own self as patient 0. And it worked - enough or so for now (we were told her cells were now back to 20 years old or so 'biologically' (epigenetically probably not, since epigenetics from the Mr.Steve Horvath/Donna Lowe study above showed that indeed it is - independent - from telomeres. I also thought about mice that received TERT (the TERT mice) and had lifespan extension. Though they were not eternal either. But other more simple beings like Hydras - Are immortal - by Telomerase in their stem cells.
What I'm getting it is that I think we may have underestimated the power of Telomerase and TERT transcript. What I mean is that we all think that if telomeres are longer then it would make no difference for aging as damage would - still - accumulate - for example Glucosepane AGEs in ECM...
Yes but what we forgot...is Telomeres, from these studies above, are Cell Cycle Inhibitors. Thus, If Telomerase - Thus - make Telomeres maintain their Height, then there is in fact no activation of 'bad genes' that promote aging and replicative senescence (when telomeres shorten too low, also called M1 (cell division arrest) and M2 crisis point (replicative senescence)), as for post-mitotic non-dividing long-lived somatic cells (like Neurons and Central Nervous System (CNS) Cells, they too are bound by epigenetics and telomeres (they lose telomeres too with age)).
If the correct genetic signature is maintained (the Youth Phenotype) than ageing per say 'is frozen', damage accrual - would not continue - and the reason for that - is not Telomerase - but the Telomeres Themselves indirectly.
Indirectly, because, since the telomeres are cell cycle 'counters/inhibitors', well if the cell stops dividing it's game over. But what about the junk and damage that accumulate in lysosomes and other extra-cellular compartments like in ECM ???...Here's the kicker :
Telomeres allow cells to continue to divide, wether epigenetically young or aged as hell...the epigenetic age to cell is no matter, what matters is the length of the telomere - acting as a cell division inhibitor.
But how does this have anything to do with damage accrual ? :
The fact the cells keep on proliferating and dividing/cycling - means that
damage will be Null(ified).
How so ? Cell cycle dilution. Cell cycling damage dilution is the ultimate mechanism to remove undegradable pigment (such as lipofuscin, ceroid, A2E, glucosepane, drusen, and what other junk).
By keeping on Cycling and Dividing - they keep on Diluting the Crap.
This is no mystery : don't ask yourself why TERT immortalized cells or cancer cells reach 300 population doublings - They Keep On Dividing/Cycling/Proliferating - And For That - As They Do It - They (Need)
Do Damage Dilution At the Same Time, as part of Normal Single Cycle.
This would thus give more power to say that Telomerase, such as BioViva, cannot revert epigenetic aging, but who cares, it can definately reverses
tissue aging and tissue degenerationg; and make Stem Cells function anew and repair tissues continuously -and not only that - slow dramatically or abrogate Lipofuscin accumulation. Because as said, cells who reach higher population doublings (higher replicative lifespan) accumulate infinitely small amounts of lipofuscin each cell cycle - they keep on cycling because of that small amount and because they dilute any there is to be (mother cell accumulates it while after replicating into new (daughter) cell is fresh empty (exchange of lipofuscin)).
I think we shall see great things in the future for TERT, even if the whole point is to block for cancers and SENS wants to remove it totally; if works it's great; but I'm realizaing now that TERT telomerase has power to Stop damages or Halt it to ultra small levels, because of said cell cycling mechanisms bound by telomeres.
AS for 'already accumulated'damage in a human, I don't think tert can do anything about it - but it will stop Subsequent damage.
PPS:
I think this is it :
There is a balance in order to achieve mortal or immortal cell, which would tie to organism mortality (i.e. human) or immortality (i.e. hydra) :
Accumulated Lipofuscin vs Cell Cycle Lipofuscin Dilution
When the proteasome and lysosomes are blocked/clogged with lipofuscin with age, the balance tips towards more lipofuscin accumulation. While, conversely, faster cell cycling dilution means less lipofuscin accumulation because it is dilute - faster - than it accumulates (make a negative balance). This is what happens in immortal cells who keep lipofuscin accumulation totally absent, unlike in mortal cells.
As for post-motic non-cycling long-lived somatic cells, they have been give very high redox capacities/antioxidative and they, by nature, accumulate less lipofuscin then highly mitotic ones (since they accrue small damage over time from high redox, lower susceptibility (robustness/genetically stronger code) and antioxidative values); simply because of the lifespan of these cycling-cells is oftenly very short (poor investment in redox values and/or high turn-over replacement like blood cells for example). The problem with them is that their telomeres shorten too and they don't do anything about their damage accumulation (as said they are non-cycling, as such non-diluting lipofuscin). Introducing TERT in them could do something incredible and this would be a strong impact, since these long-lived cells are also responsible for aging.
As for the old, cancer is increase by TERT telomerase, true, but more and more study show it's the inverse, better and longer telomeres mean a stronger immune system; which means a better thymus, intestinal and bone marrow immune cell output, thus more T-Cells, more Cytotoxic killer T-Cells, White Blood Cells, Leukocytes, Macrophages and NK-Cells, which they are powerful immune cells (producing Interferon-Gamma) that detect cancerous cells, identify them as illegit cell/pathogens and kill them outright with deadly precision (far better than many cancer therapies, the thymus is the center of the immune system; increasing its telomeres will do it much more good than bad) The risks of spontaneous cancer formation, illicit mutations, excessive 'cell proliferation' (malignancy mutation load) and progression by TERT/telomerase are outweighted by the benefits of TERT/telomerase therapy on the immune system - which itself kills cancer - and on epigenetic aging (since the study above shows that cancer accelerates epigenetic aging; thus immune destruction of cancer - by TERT improving immune function, (indirectly, TERT/telomeres are uncoupled from epigenetic age as said, Telomerase, itself, won't do anything but allow improved cell cycling and function of immune cells) will - Slow -, indirectly, hastening of epigenetic aging by removal of oncolytic cancer signals (which said earlier increase epigenetic aging) from cancerous cells elimination.
Very informative, thanks.