The Binarized Transcriptomic Aging Clock
Patterns of epigenetic regulation of gene expression (and thus RNA and protein levels) change constantly in response to cell state and environment. Some of those changes are characteristic responses to the damage and dysfunction of aging. Since the demonstration of the first epigenetic clocks, those that predict age based on an algorithmic combination of the status of DNA methylation at CpG sites on the genome, researchers have produced any number of new clocks based on mining epigenomic, transcriptomic, proteomic, and other databases for correlations with age. Today's open access paper is yet another example of a new transcriptomic clock.
It remains the case that in none of these clocks is there is a good, well understood connection between specific mechanisms of aging and specific components of the clock algorithm. This makes it hard to make good use of aging clocks: it isn't at all clear that any given result is meaningful. If one applies a potentially rejuvenating or age-slowing intervention, and it produces a change in the clock measurements taken before and afterward treatment, what does that change mean? Is a drop in measured age a sign that the therapy is great, or a sign that the clock is overly weighted towards the subset of mechanisms of aging that are targeted by the intervention? If the clock shows little to no change, does that mean the therapy is useless, or the clock is unhelpful for this class of intervention? And so forth.
Thus clocks and therapies will have to be calibrated against one another in order to make the clocks useful. This process is only in the earliest stages, where it is occurring at all. As matters progress, this calibration will most likely mean running the slow, costly life span studies that we'd all like to avoid by using the clocks instead. There is no free lunch here.
BiT age: A transcriptome-based aging clock near the theoretical limit of accuracy
Aging biomarkers that predict the biological age of an organism are important for identifying genetic and environmental factors that influence the aging process and for accelerating studies examining potential rejuvenating treatments. Diverse studies tried to identify biomarkers and predict the age of individuals, ranging from proteomics, transcriptomics, the microbiome, frailty index assessments to neuroimaging, and DNA methylation. Currently, the most common predictors are based on DNA methylation. The DNA methylation marks themselves might influence the transcriptional response, but aging also affects the transcriptional network by altering the histone abundance, histone modifications, and the 3D organization of chromatin. The difference in RNA molecule abundance, thereby, integrates a variety of regulation and influences resulting in a notable gene expression change during the lifespan of an organism. These changes sparked interest in the identification of transcriptomic aging biomarkers, an RNA expression signature for age classification, and the development of transcriptomic aging clocks.
While a large variety of data, techniques, and analyses have been used to identify aging biomarkers and aging clocks in humans, issues remain with regard to pronounced variability and difficulties in replicability. Indeed, a recent analysis of gene expression, plasma protein, blood metabolite, blood cytokine, microbiome, and clinical marker data showed that individual age slopes diverged among the participants over the longitudinal measurement time and subsequently that individuals have different molecular aging pattern, called ageotypes. These interindividual differences show that it is still difficult to pinpoint biomarkers for aging in humans.
Model organisms, instead, can give a more controllable view on the aging process and biomarker discovery. Caenorhabditis elegans has revolutionized the aging field and has vast advantages as a model organism. To date, no aging clock for C. elegans has been built solely on RNA-seq data and been shown to predict the biological age of diverse strains, treatments, and conditions to a high accuracy. In this study, we build such a transcriptomic aging clock that predicts the biological age of C. elegans based on high-throughput gene expression data to an unprecedented accuracy. We combine a temporal rescaling approach, to make samples of diverse lifespans comparable, with a novel binarization approach, which overcomes current limitations in the prediction of the biological age. Moreover, we show that the model accurately predicts the effects of several lifespan-affecting factors such as insulin-like signaling, a dysregulated miRNA regulation, the effect of an epigenetic mark, translational efficiency, dietary restriction, heat stress, pathogen exposure, the diet-, and dosage-dependent effects of drugs.
This combination of rescaling and binarization of gene expression data therefore allows for the first time to build an accurate aging clock that predicts the biological age regardless of the genotype or treatment. Lastly, we show how our binarized transcriptomic aging (BiT age) clock model has the potential to improve the prediction of the transcriptomic age of humans and might therefore be universally applicable to assess biological age.
Hello.
I have a comment not about this topic in specific but about aging. I follow an YouTube channel called LooksMaxx Doc. He has a video called pathing the road for immortality. He believes that we can live hundreds of years too. But not slowing it but actually doesn't aging naturally. He believes that with proper work, exercises, habits, diet, etc... we can live forever, have eternal youth without any medication, just naturally.
I don't know if that is exactly what he believes. But watching a lot of his videos and reading you blogs it's something like: you say that our body ages because of demage. Like DNA mutation, dysfunctional and senescent cells, residues like proteins outside cells and calcification, telomeres shortening, etc...
So, FOR ALL OF THAT our body has regenerative mechanics. Like hayflick limit or the immune system to clean these harmful cells and stem cells that replenish them. Telomeres regeneration, Mechanisms to eliminate residues and regenerate tissues.
So, why do we age? Because even with these regenerative mechanisms we cause damage faster than our body can regenerate. And as we get older our regenerative mechanisms gets slower and our body get damaged faster because of compensatory patterns. It's a snowball.
But what if we cut all de damage causes from the root? Causing damage slower than our regenerative mechanisms. Causing the least possible of damage and boosting our regenerative mechanisms naturally. Like, having a diet and habits that causes the minimum possible of oxidation. Having a diet and habits that boosts our immune system. Practice feats with cardio activities to stimulate autophagy and telomerase production.
Well, I don't believe 100% into that but maybe that is possible. If we regenerate faster than we cause damage we could have eternal youth.
What do you think?
Hi Just Someone! Just a 2 cents. TL, DR: too long to explain in 5 brief words.
That is a good point, regenerative processes are an important part of living longer; so are repair ones, regenerative would mean needing to have the clock lower/tick back, then you would be officially younger 'regenerated'; but, the damage and residues may not be all removed/diluted. In the reprogramming study of a progeria mouse and an old mouse...the progeria mouse lived 20% longer (it did not reach the age of a Normal/normally-speed of aging mouse (3-4 years)); while the old 'normal (but old of age)' mouse had health improvement (morbidity compression) so the mouse was 'healthier' longer/into the oldest age ;and then died precipitously. That means that epigenetic reprogramming, so far, is not able to reverse preexisting damages/residues cumulated up to this point/to the current age of the person/animal.
The progeria mouse Still died...after reprogramming it. The old 'reprogrammed/healthier' mouse too.
It means that there are limits to aging, other than the epigenetic clock. I would wager the largest other one is the mitotic clock limit; telomeres are the cell cycle counters, if they are too low; replicative senescence (hayflick limit); if telomeres are highly 'damaged' (y-H2AX foci), then they can cause 'spontaneous senescence' (different than replicative one).
Telomere damage/oxidation/accumulation of foci -> spontaneous senescence
Telomere shortening/too small size -> replicative senescence
So far we know telomerase can increase telomere size; but telomerase - itself- is a epiclock advancer.
Meaning, 'calling telomerase' to increase telomeres is a 'negative compensation'...i.e. you gain telomeres but at the cost of accelerated epigenetic clock.
Thus, it is a catch22/balance (like everything in the body). Other than telomerase, there is ALT and homologous recombination (Telomere chunking up and down/picking parts here and there and fangling it up), many of these other telomere elongation processes are 'unstable' and render telomeres unstable/prone to SCE (sister chromatid
exchange), so in essence, chromosomal cataclysm.
There may be other telomere lengthening processes that are capable of adding TTAGGG telomeric repeats - without telomerase itself.
SUch as hPOT, TERRA, TRF, Shelterin Complex (telomere enzymes/proteins that protect and cap telomeres), Ku-67 and a few others; but, overall-
besides telomerase, not many other answers as to how exactly these telomeres 'grow up in height'.
The mitotic clock, is the telomeres as a 'clock/counting counter' itself (the telomeres themselves, by the number of TTAGGG repeats; in kbs (kilo-basepairs).
Our telomeres shrinken and now, there is even a limit that if we Increase telomeres we Accelerate the Epigenetic clock. That is Catch22. 'd*mned if you do, d*mned if you don't'.
I conjecture that the acceleration would become inconsequential if We Continuously Reverse the Epigenetic Clock - While Continuously Re-Lenghtning Telomeres.
I.e. Acceleration would accelerate...but it is not a finality. It is like being 'young again' -> Fast Aging. When you are younger, you age faster because your metabolism is faster;
your clock is Behind/You are Younger..but you age Faster...because your telomeres are taller and your clock is rewinded.
0-20 years old -> Fastest Aging (lose 5-8kb in 20 years, a 'sharp drop' over short time).
20-80 years old -> Slowed Aging. (lose 3-4kb in 60 years, a 'plateauing/gliding/coasting' over long time).
Let us remember:
Tall telomeres Shrink FASTER than small telomeres (yes). This was demonstrated,
10kb telomere size (young age) -> 150kb/y rate loss
5kb telomere size (old age) -> 75kb/y rate loss
A multiple of 2, both ways. Normally we would think, if you are young you age slower...if you are older, you age faster; alas, it's dubious
and is the inverse; you age faster when you are younger.
Again..another catch22/balance that 'offsets itself'. Nature/genetic evolution has rigged us to make sure 'we die' (sadly).
Can't outwit from the looks of it.
I think we might be able to outwit it and the reason is because; by 'plugging back' both clocks we then are able to obtain true aging reversal (so long as the residues are removed...because if they are not removed they will continue to contribute to
'lesser regeneration')...in essence, it is what happened with the old and progeria mouse that were reprogrammed...they still had some 'left over/from the past' residues/damages...and they were a limit that the body could not overcome. The reprogrammed progeria mouse still died.
It's why they call the reprogramming 'partial reprogramming/partial rejuvenation'...it's not 100% epigenetic reversal of everything.
They also call it partial because the cell has not acquired a dedifferentiated 'pluripotent' state (as if back to a 'stem cell')/basically, the cell retained its 'memory/signature'...so not 100% erasure of its differentiated state/signature. The only thing that changed for the cell is that the 'cell's epi-age' dropped down back to nearly 0.
Cancer cells can replicate infinitely (are *mmortal or near-so because even cancer cells can stop dividing suddenly), they have 'frozen telomeres' (using ALT or telomerase highjack) around the
2kb size, so their telomeres don't shrink any lesser than that. Cancer cells' epigenetic clock was studied; it showed that cancer cells are 'rogue cells' completely bypassing every 'security check/cycle checkpoint' because are 'wack'...
their epigenome is clearly showing the 'pattern of 'cancer activation/inflammation' (hypermethylation of specific CpGs)). The cancer cells Continued to Age...as if, forever...the epigenetic clock continued its course...like nothing.
So a cancer cell could have 2kb telomeres -and- it could have an epigenetic age of 243 years old.
Cancer cell line was found to be over 250s years old epigenetically. So it means that epigenetic clock is just a 'counter mechanism' just like the mitotic clock (telomeres/cell cycling division/population doublings/replications). The difference, I believe, is that normal healthy cell (non-rogue/non-cancerous)...are BOUND by the replicative senescence
and telomere/telomerase hayflick problem - which there is no solution (cancer too but cancer found the solution to highjack telomerase and thus its mitotic clock can continue ticking because its telomeres never shrink to extinction/to 0). In humans, we don't even have
that luxury our telomeres (in healthy 'aged' cells) can signal replicative senescence at the 5-6kb size...so not even at 0.
It happens Before -we even reached the total telomere size/bottom. Supercentenarians women (over 110 years old) - 3kb in their immune cells; so they 'spent an extra 2-3 more'.
It means immunosenescence by replicative senescence reaching its point in immune cells - from having lived 110+ years.
These are serious limits to our cells; and until we can overcome them, being realistic, we have to temper somewhat our hopes/excitement.
In humans, what is important is the discrepancy between the biological age/epigenetic age...and the Chronological Age.
So that we stay 20 years old biologically..but we have lived for 250 years in real-time...
If our cells cannot continue dividing (due to accumulation of residues clogging proteasome and other lesser important damages (like DNA damages/oxidation/SSBs/DSBs)),
then we cannot overcome the mitotic clock problem (hayflick, by telomere attrition over time). Telomerase so far is only solution. Repairing DNA damages Does Not equal age reversal (or -if nothing happens to our clocks).
Our clocks are more ambiguous than that- they are Instrisic Limits that stand; damages or not. Plus, now it's nearly 100% sure that residues/junks or some or almost all of DNA damages need ALSO to be repaired/removed...to make a clean 'reversal'.
Because epigenetic reversal, on its own, is not able to solve the Other problems/limits.
There is confusion in the biogerontology domain where people think that damages are immediately related or causal to the 'clock advancement'. It's more nuanced.
Just a 2 cents.
@CANanonymity "telomerase - itself- is a epiclock advancer" where did you get this from? Every scientific source I've read so far claim that telomerase and telomere elongation reverses (turn back) epigenetic clock of the cell.
Hi SilverSeeker! Thank you for asking. hTERT which activates telomerase increases the intrinsic epigenetic age advancing. Even I was skeptical about it at first when I saw the study, when as you said, most other studies seemed to imply telomerase was Reversing not Increasing epigenetic age; but this large study (made with Steve Horvath himself the epigenetic age Horvath clock creator), shows that most likely telomere elongation by telomerase's processing, from hTERT activation, affects epigenetic age negatively (the intrinsic one); extrinsic is related to the 'health threshold maintenance/mitotis/cell cycling'; while intrinsic is related to the 'tabulation counting/chronological calendar tabs'. Telomerase is able to stave off extrinsic/mitotic clock; because telomeres are longer and telomeres relate to health; but, as shown, taller telomeres does not mean younger (by the epigenetic clock). It means 'mitotically younger' or extrinsically (by epigenetic age) yougner; not intrinsically. It seems there are two components (that can be classified/differentiated) to the epigenetic clock; it's extrinsic clock property and intrinsic clock property, as different thing.
The body is one paradox on top of another. Telomerase is thus I think a negative feedback/compensating element. It's meant to 'protect you' - when telomeres get too short, it protects your health and 'continued cell cycling' (by taller telomeres from it), but this protection/'addition' of telomere repeats is a negative signal; if present/asked (to reincrease telomere size), the clock interprets it as itself advancing further/faster. The telomerase/hTERT signal doing so on the clock. Animals that are *mmortal (or we suppose) or extreme long-lived such Hydras or Bristle Cone Pines have permanent activation of (cyclic) telomerase in their germ cells or meristem cells lines. When these germ cells were extricated or TERT was abolished, they became mortal. TERT itself did not/does not confer *mmortality to them, what is confers - rather - is 'indirect' eternal life or more precisely; is Allowance/Enabling of such. On its own, it does not do that. If epigenetic aging (intrinsic part) had no change; these animals would be mortal. Thus, they have 'programmatic' epigenetic clock reversal - on top - of TERT. When you allow continued health preservation/maintenance (mitotic clock) - and - you reverse calendar tabs (intrinsic epiclock) - and - you remove the residues/junks/DNA lesions/damage (cell intrinsic and extrinsic/in ECM)...now, you can see aging reversal.
Whether the study I provided is 100% accurate is up to debate; but I believe that it makes sense, telomerase/TERT protects but it has a cost when asked (a balance/catch22). It makes me think of the 'paternal/age of father sperm' paradox, where older father may make more DNA defects in the child (because he is older, and his sperm has an older epigenetic age), But...there is a but, fathers who have kids in old age 'give Long(er) telomeres' to their children (like I was born to an older father...I possibly received more defects than my older siblings who were born to him when he was younger...but, I may have obtained taller telomeres - from dad (sperm) during conception stage - as he was now older when he had me and my twin sister, who also possibly received taller telomeres like me since we are born the same day/same pregnancy when my mom had us both. The reason why taller telomeres are given by older fathers, is because older fathers 'have had the time to elongate their spem cells' telomeres' 'over time' (since time passed more/are older)...a Young man has less/immature sperm (less elongated telomeres because not enough time passed to make it happen...but, gives younger epigenetically-clock sperm; thus less chance of giving DNA defects to child than old sperm...but old sperm, in reverse, 'paradoxically' gives taller telomeres..simply because the telomeres are longer in older men sperm). I remember a few years ago I thought I had aging all figured out, I thought wrong. It's one surprise and two paradoxes (one) after another.
Just a 2 cents.
GWAS of epigenetic aging rates in blood reveals a critical role for TERT
1. https://pubmed.ncbi.nlm.nih.gov/29374233/
''Variants associated with longer leukocyte telomere length (LTL) in the ****telomerase reverse transcriptase gene (TERT) *paradoxically* confer *higher IEAA* (P < 2.7 × 10-11)****''
''****Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number*****. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for *cell replication-dependent telomere shortening*''.
Actually CANanonymity, subsequent work by Horvath has shown TERT does nothing to accelerate aging as measured by methylation clocks - it merely allows the clock to continue ticking (because the cell has not been removed by senescence). As we have not yet unpicked which elements of Horvath's clock are upstream of aging and which are downstream, I'd hold off on judgement of what elongating telomeres would do in practice. Many have been quick to jump on the bandwagon of aging being a two edged sword (with cancer), and there being multiple mechanisms to reinforce aging (i.e, telomeres and methylation), which get you no matter what you do. But the data is not in as yet. I suspect that as telomerase immortalised cell lines continue healthily in perpetuity, the continued accumulation of methylation changes in most locations is probably not harmful. In fact I'd go a step further and say there is some early evidence to show that TERT and/or TERC (the RNA template for telomerase to copy) are inactivated with age in stem cells by methylation of promoters. So they may not be opposing mechanisms after all.
Hi Mark! Thank you for that.
I tried searching for that, if you can find it again (if not no problem thank you for informing me I did not know), please tell me the link or study name where you saw this information by him on telomerase/TERT not doing anything nor acceleration on his clock's measurements. If we could ping him, I would want his opinion of this study above, why there is a discrepancy with him saying there is no change (per his clock) but there is a change with the study's calculations (using intrinsic clock...his clock does not factor that, so). Who's right? So far his clock is the most correct (but, in lesser? precision, so is the Hannum clock, GrimAge clock..and a few others...like this new Transcriptomic clock...) but what happens when they don't correlate...which one is suppose to be more accurate...should I believe His clock...or Their clock (more clocks gives 'bigger picture'...but not necessarily 'more accurate' picture, it's why sometimes 1 single clock itself using 1 or 2 factors...can be More accurate than 100 clocks measuring 100,000 factors...it becomes full of errors/'noise' despite that the more factors/the more precise it gets; just like the the more data & samples in a study the more accurate/correlative/causative in terms of power-causation/power-correlation/power-precision... it becomes). The onus on his research is to disprove there would be an extrinsic and intrinsic element to the epigenetic clock; simply saying telomerase made no change to my clock does not, necessarily, disprove the study above.
PS: Trust me even I was very skeptical when I saw this study, telomerase normally should not do that and only increase telomeres and have little to do on epigenetic clock (but they contend it does); I 100% hope he is 100% right. If his clock does not change at all after telomerase/TERT elongation of telomeres then that is very reassuring news; I just wish it to be clarified so that the study above can be removed as important to consider (not dismiss it but 'was updated' as inconsequential now that we know telomerase is inert on clock); this would mean we Can increase telomeres (with TERT) and/while not fear any epigenetic clock advancement. It's huge.
PPS: They say:
''''Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number''. I mean yes there will be an increase in DNA methylation age...but why do they say that besides just observing it, is it the TERT doing it or is it because of the number of divisions cumul/population doubling numbers so far...what could Horvath or other clocks' creators say about that. They are literally saying hTERT expression in fibroblasts 'ages them' per Their clock measurements (IEAA/EEAA)...
PPPS:
That is what I was also thinking, telomerase-*mmortalized cells, probably because of continuous methylation in them, are not affected by it in a negative way. Methylation is required for continuous epiclock ticking, thus, the clock itself would do nothing (except continue tick/keep time tabs) and they can keep on dividing forever. I had read that one cancer cell line (probably using ALT or telomerase) was somethingl like 200 years old epigenetically by epiclock. Thus, it showed that once *mmortalized cells just continue dividing forever and forever aging 'on the epigenetic clock' with no consequence; it continues unabated, as if nothing. But if methylation is lost, then the cell cannot continue to divide on...the 5-methylcytosine content emptied; studied showed that cancer cells does not lose Total methyl content in their epigenome; because normal/mortal cells do (a 1980s study by Mazin had shown that mouse lost 90+% of their epigenome methyl content in their life; same for humans; the difference is mouse lost it 100x times faster and hence live 2-3 years instead of 122). 'Global DNA demethylation/hypomethylation' with time passing, is a very real thing and cancer cell lines do not have that (keep methyl content and 'hypermethylate' CpGs that are cancer-related genes/inflammatory genes) and hence can be divideng forever - so long as they keep the telomeres tall enough too to avoid replicative senescence signal in very short telomeres.
"Epigenetic ageing is distinct from senescence-mediated ageing and is not prevented by telomerase expression" by Sylwia Kabacik, Steve Horvath, Howard Cohen, Kenneth Raj https://pubmed.ncbi.nlm.nih.gov/30332397/ this one?
Re Thank you very much SilverSeeker, yes, I think that is the very study.
''***Although hTERT did not induce any perceptible change to the rate of epigenetic ageing***, hTERT-expressing cells, which bypassed senescence, continued to age epigenetically.''
I'll try to see if I can figure out/reaching authors to clarify why they see acceleration while in this study, hTERT/telomerase does not change rate of epigenetic aging - they say 'perceptible'...maybe it was imperceptible to them; does not mean it is not there or necessarily inactive; just imperceptible (so low...that is imperceptible/under detection level/no change). Of course, they could also be right, and indeed, hTERT does nothing on the epiclock; for now I will believe them but the contradictory study I had pointed is still a - ??
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224244/ NCBI has full text online.
Interesting question how much telomeres got extended (if at all) in this study. Immortalising cell (and preventing replicative senescence) requires that it's telomeres stop shrinking only. Bill Andrews achieved this with TAM-818 (with only 16% of hTERT expression compared to HeLa) for skin cells some time ago - they got immortalized in a dish (i.e. Hayflick limit removed). The previous going hypothesis was that significantly *extending* telomeres had an impact on genomic expression (aka epigenetic pattern). I read that telomerase has effect on rejuvenating mitochondria (exported from the nuclei), the direct effect of telomere length (not telomerase itself) on epigenetic expression was guess for further study. Disproving that telomerase itself don't affect epigenetic clock doesn't disprove that longer telomeres will, but seeing how it goes it becomes unlikely. We are left with demethylation agents, like TAM-818, CaAKG, ISRIB, and the likes. Or 'atomic option' like Yamanaka factors...
Re In the Table 1 (hTERT wt/wild type) they show:
''Catalytic activity - YES; Extension of Life-span - YES; ***Telomere Synthesis - YES***; *mmortalization - YES'';
albeit, you are right that it does not say anywhere that the telomeres were Actually lenghtened - from this synthesis. I mean, the telomeres could be synthesized...still, the telomeres would have shrunk, just slower, but they would still be smaller over time passing - synthesis or not. Telomere Synthesis should elongate the telomeres, but it is 'telomere Net loss vs telomere Net gain'; meaning If the telomeres are lost 75 basepairs (bp) per year...and there were 25 bps/year that were 'synthesized' and 'elongated' onto these telomeres; the telomeres would Still lose 50 bps/year...instead of 75 (because that 25 'Added' on that initial rate..would nullify/slow down the rate from 75 to 50 bp/y loss (75 - 25 = 50). It would not be enough to overcome the 75, and thus, telomeres would still shrink, albeit slower, at 50 bp/y.
But from their study, hTERT does create/add-on telomeric DNA repeat on the telomeres (as they say 'Telomere synthesis'); now is taht enough to 'counter the rate loss' that is not known from this study because they did no point the telomere lengths after hTERT.
The more interesting bit is ''*mmortlization - YES''; it means that these cancerous cells are able to maintain infinite replication potential (and overcome Hayflick/replicative senescence limit), but, mostly likely too (since they say ''Telomere Synthesis - YES'' and, only, this one has ''*mmortalization - YES'' Too; so it means that telomere synthesis is mandatory/unconditional to their *mmortalization; it means that cancer cells 'maintain 'enough' telomere length to replicate forever. Thus, they Do increase telomere size; I had read that cancer cells 'stuck/froze' telomere length in the very low telomere size at 2 kbps (2000 basepairs/2 kilo basepairs of TTAGGG telomeric DNA repeats) so that it did not go any lower than that and was 'viable' to divide forever and overcome replicative Hayflick. Of course, not for non-rogue/non-cancerous healthy cells.
In the study they say that it's regrettable that telomerase does not stop epigenetic aging/does Nothing on it and so epigenetic aging continues its course, telomerase or not.
Albeit, you raise a good point, that it might not be telomerase taht does Something..but the Telomeres themselves - (after being lenghtened and Increased with Net Gain thus are higher size than before after telomerase extended them) - Would have an effect on the epiclock's ticking rate. I learned taht Tall Telomeres have a Faster rate of attrition/shortening than Small/Short telomeres. I always thought it was the inverse, but alas, it is exactly the case; tall telomeres, it seems, promote faster replication and this translates has accelerated telomere shortening; while short telomeres, promote sluggish/incomplete replication/'cell replication errors'/cell replication arrest'...in essence it promotes cell division to stop. Thus, the Height of a telomere itself, drives the speed of the telomere itself to shrink faster or slower; if it would be taller, then the telomere would shrink faster; while if it would be short, it shrinker Slower.
10 Kbps tall- telomere size (young age) -> 150 bps/year loss (double rate/speed of attrition)
5 Kbps Short- telomere size (old age) -> 75 bps/year loss (Half rate/speed of attrition)
It means, I believe, that telomeres are rigged to 'lose the same amount same/equal' (as negative compensatory mechanism, the body/cells are trying 'to mitigate loss' doing that, short telomeres would be selected for protection and 'shrink slower'; while tall telomeres would be unselected - because are tall -no need for lenghtening; they would be selected for 'acceleration' of aging/allowing the aging to continue unabated, and thus bring a 'balance' between both Tall or Short telomere's rates of attrition)
whether tall or short...
because a tall telomere is taller - but shortens twice faster;
while a Shorter telomere (half in size) - shortens twice *Slower.
I'm not saying this is exactly the correct speed/rate of attrition, I am just saying that the telomere lengthening 'offsets itself/negates itself' by accelerating in Speed As The Telomere Becomes Taller.
In effect : No Loss No Gain/perfect balance. And thus, telomeres Will shrink down because you can't Add Enough to Compensate for the Accelerated Loss As They Get Taller (remember, taller teloemrs shrink faster. anyways, that is what I learned, it could be wrong; but I think so far that info seems true and makes sense; the body/cells 'want you to age'...and so if long telomeres did not accelerate in attrition rate...then you would not really age 'on the mitotic clock/telomeres'...you could keep tall telomeres forever - thus, not age; though, on the epigenetic clock...you would still age...not on the mitotic/telomere shrinking mechanism; well, not enough, to be consequential on your aging (because, your teloemres are so long and kept that way...continuoulsy). In studies they showed that it was not the telomere lenght that mattered; but rather the Attrition Rate/The Speed at which their shorten. Mice have much longer telomeres than us...and they die in 3 years or so....that is because they lose 5000 basepairs/year...while humans lose 50 basepairs/year...They have 50,000 base pairs (while we have 15,000 or so at birth); losing an immense 'chunk' of base pairs -> causes replicative senescence rapidly.
But they say in study:
''Epigenetic ageing is distinct from senescence-mediated ageing'' .....and is not prevented by telomerase expression''.
Thus, I believe that what is happening is that mice and other ultra-long telomers animals are experiencing 'loss of health/mitotic capability'; a mouse could live 120 years like us, just look at a Naked Mole Rat, they live 35 years...while a mouse live 3 years.
''We cross-sectionally tested **telomere length** in different tissues of two long-lived (naked mole-rat and Spalax) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. ''
1. https://www.mdpi.com/1422-0067/20/13/3233
This is starting to look an awful like the Albatros that has telomere Lengthening -As it ages, and dies around 30 years old. Though, it is surmised, that predation is the reason/individuals are removed from the pool 'suddenly' due to predation, and not so much its telomeres.
They say NMRs do not have telomere shortening...yet NMRs die at 35 or so. Spalax one does show telomere shortening.
Clams like Iceland quahogs (that live for 500 years) have telomeres lengthening/preservation for over - 200 years..and then in the space of 10 years or less, their telomeres shrinken real fast and they die at that point.
It means, telomeres are enables/allowers, but in certain species it seems they are not the be all end all; and that is where the epigenetic aging/transcriptomic aging/splicing aging clocks take over. I mean, the fact is, epigenome suffers global dna demethylation with age; thus it Becomes a limit - itself; if your genome is emptied of its methyl content, or the chromosomes have total loss of protective histones; then it can't continue (replicative senescence or not).
2. https://pubmed.ncbi.nlm.nih.gov/32126024/
They say:
''We also profiled skin samples with the same age range, finding a striking correlation between their predicted age versus their actual age (R=0.93), but which was lower when compared to the liver, ***suggesting that skin *ages* slower than the liver in NMRs.***''
That is the key word, Ages. Thus, Naked Mole Rats, might not lose telomere size...they Still Age, per the epigenetic clock. Suggesting, that epigenetic clock as final say or in this specie it is was one the final ones to have say; not the telomeres as they saw now change of their telomeres. Albeit, the problem wit hstudies like that , is often they do not measure 'over time'...they just measure some 'random point in time' and say 'you see no change'...they need to Measure All the Time/Over Time...all the life -of the animal so we can see a clear 'degradation' 'over time'./i.e. a downhill slope as 'graphic'. Thankfully some studies do make sure to measure Young animals, Mid-Aged animals and Old animals to get the full picture.
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There are at least four (we know these so far) mechanism to elongate telomeres:
1. normal telomerase expressed extension at 100-150 base pairs per division (normal shrinkage per division is around 50, but under stress it can rise to 75-100 or more)
2. germ cell division and early embryonic development where epigenetic clock is reset (mostly, as some epigenetic changes may be passed onto offspring) and telomeres restored to starting point of 30000(?)-50000(?) base pairs (where during antenatal development it shrinks to ~15000)
3. telomere exchange between two typed of white blood cells (in chunks up to 3000 pairs) which makes any measurement of telomere length from blood so puzzling and contradictory to measurement in other tissues; as you see some species can even lengthen it during lifetime there, not shrink
4. ALT as in some cancers without telomerase (how many distinct ALT paths exist and how much - if at all - are related to (2) and (3) ??)
Is there any word a year later as to when this rate of aging test will be commercially available? I've taken the Index test by Elysium Health, but would also like to take this one.