Skepticism of a Causative Role for Telomeres in Aging
A researcher here takes a skeptical look at telomerase studies, such as those shown to extend life in mice, most likely by boosting stem cell activity. There is a school of thought that suggests the role of telomerase in lengthening telomeres is an important mechanism in the induced longevity attained in these studies, but I think it is correct to be skeptical on this count. Erosion of average telomere length occurs over a life span, but this really does not look like a root cause of degenerative aging. Instead the average length of telomeres in immune cells, where it is commonly measured, appears to be a consequence of some combination of stem cell activity and immune health. In any given tissue, cells with long telomeres are created at some pace by stem cells, telomeres shorten with each cell division, and old cells with short telomeres destroy themselves or become senescent. Stem cell activity declines with age, and it isn't a leap to suggest that this will tend to produce shorter average telomere lengths as the supply of new cells diminishes.
Telomeres are repetitive DNA sequences at the ends of linear chromosomes and serve to maintain chromosome integrity. Additional properties have made telomeres a focus in the biology of aging: (i) telomeres shorten at each cell division due to incomplete replication of their ends; (ii) they are shortened by oxidative damage; and (iii) when telomeres reach a critical length, cells enter a senescent state and cell division ceases. This latter property has been demonstrated in now classic experiments, showing that telomere length predicts the in vitro replicative capacity of human fibroblasts and that over-expressing telomerase - the enzyme that can reverse transcribe telomeric sequence - immortalizes fibroblast cell cultures. These experiments suggest the possible causal involvement of telomeres in the aging process and this hypothesis has increased in popularity since the finding that telomere length predicts human mortality and that, in vivo, human telomeres shorten during aging.It is rarely acknowledged in telomere biology that such associations do not necessarily dictate causality. Of course in principle associations can never show causality, and experimental evidence is a starting point. Such inference is useful interpreting data in terms of biological mechanism and for policy, but can also be harmful when such causality is prematurely inferred or assumed. This can lead to reduced or misfocused research effort to uncover the mechanisms actually responsible for the associations that are reported or false inference of the associated biology. In the biology of aging it is tempting to infer causality from biomarkers of aging because aging mechanisms remain so elusive. It is therefore not surprising that causality of telomere length in aging is often inferred from associations or from the available experimental evidence.
Here I question such causal involvement of telomeres in aging. I review the telomerase knockout and overexpression studies that are often cited and hailed as providing the necessary evidence for the causal involvement of telomere biology in aging. I collated studies on the effects on longevity and conclude that, together; the results are surprisingly mixed and provide weak support. In the cases where lifespan changed as predicted in response to the manipulation of telomerase, the effect on telomere length was either outside the normal range of telomere shortening or telomere elongation was not conclusively demonstrated, thereby limiting any strong conclusions. In addition, the causality hypothesis assumes that there is a critical telomere length at which senescence is induced. This generates the prediction that variance in telomere length decreases with age. In contrast, using meta-analysis of human data, I find no such decline. Inferring the causal involvement of telomeres in aging from current knowledge is therefore speculative and could hinder scientific progress.
I suspect you are correct Reason. I find the idea that loss of stem cell mobility via mechanisms such as oxidative stress and stem cell decline far more likely. Stem cells also do loose telomere lengths as they age due to their upkeep mechanisms slowing down.
I am starting to consider telomeres as visual markers of cell "performance" rather than age per se, reason being if we remove aging markers from a cell (eg, using telomerase or as with iPS cells) we see the telomeres return to a longer length.
We do know that changes to telomeres induces different gene expression via TPE but again I am starting to see this as simply a slide into greater levels of dysfunction that spiral into eventual dormancy in the case of stem cells.
A far more interesting proposition is, what happens if we remove what causes that decline of stem cell potential in the first place? The Conboys work hints at that possibility.
@Steve
''Stem cells also do loose telomere lengths as they age due to their upkeep mechanisms slowing down.
I am starting to consider telomeres as visual markers of cell "performance" rather than age per se, reason being if we remove aging markers from a cell (eg, using telomerase or as with iPS cells) we see the telomeres return to a longer length.''
Hi Steve ! (just my 2 cent).
You nailed it, stem cell lose their telomeres too, telomeres are full of nucleotides DNA, to stem cells lose their DNA repeat content, they become dysfuncitonal and incapable of differentiation. We are composed of DNA, when we lose that DNA we have a problem (Replication End Problem), stem cells applicable too. Werner fibroblast cells that have hTERT + SV40 become litterally immortal when in fact they last barely 30 PDs, their telomeres are increased and they divided continuously. Also, they accumulate next to no lipofuscin each division, thus no damage (it is a causation). Thus, it is more than a marker of efficiency or correlative, it is a causative problem in the program. Very few cells survive on tiny telomeres, if just doesn't work, their levels of DNA repeat content is so low that all the program reads is 'activate death genes', you might think we can just stops these bad genes, I believe it's more complicated than that and that is why stem cells or regular cells when their telomeres become short, the genome is totally dysfunctional, unstable and it just doesn't work anymore, damages continue piling on and death (apoptotic or necrotic) is the next thing.
And cancer cells (at 2 kb Telomeres length) evade that death mechanism and want to survive - they mus keep the telomeres (their DNA content) at 2 kb at least, if you remove thos 2 kb of DNA from cancer cells, they accumulate too much damage and die too. It's actually ironic because cancer cells highjack Telomerase at low telomere lengths and also highjack the Redox for their advantage (they can increase glutathione content - just enough - while maintaining the high GSSG oxidized glutathione enough to promote oxidative damage and inflammation such as is the case in cancers; they ffind the sweet spot to make the whole mutagenic and damaging to the environning healthy cells (to transform them), but not for themselves (not enough to kill them) so they can invade and proliferate; overtake the body (metastasize). That is why certain therapies that block Redox in cancers are helpful, they cut the glutathione content in the tumors, thus inflammation damage continues - in the cancer cell itself, and it dies - too. Cancer patients often show reduced redox capabilities but strangely their cancer cells have maintained a certain level of redox for themselves (to overtake body). This definitely a paradox, but shows telomeres are in full control of that, that is DNA content (and DNA are segments of genes, thus the genes inflammatory or anti-inflammatory) of telomere (signals) control that.
So if they are indeed a marker of cellular "performance" in stem cells then what's the answer? Focus on the source of the damage and see if the telomeres return to normal? TGF-beta appears to inhibit telomerase which would interfere with not only keeping telomeres long but also the non telomere repair and growth pathways eg, Wnt signalling. So if we hit things like AGE (known to significantly increase TGF levels with age and reduce stem cell mobility) can we somewhat address the resulting dysfunction?
What dysfunction do you think AGEs removal will cause? AFAIK, there is no useful function of AGEs.
AGE is bad news I do not think it has any useful function and merely serves to grind stem cells to a halt
@Steve
I believe trying to focus on the damage approach as yield mixed bag results, it is so hard to stop this mega-tidal wave of (sub-sub-sub)-chain-damages and by-product residues in aging, because damage treatments, so far, do not always remove All residual or not damages or destroyed DNA junk, or touch the sensitive parts that really matter on MLSP (like say the mitochondrial membrane, the ETC complexes (Complex I-V), proteasome/lysosome/autophagosome or other special intricate 'sub'-parts that are responsible for cell energy ATP maintenance or cell control/garbage disposal systems). AGEs 'end-products' conveniently fit that description, they are end product junk-gunking DNA residues of glucose-molecule autooxidation in the whole damage process happening near the mitochondrias that makes for poor mtATP production (Complex I ROS damage mitochondria DNA (mtDNA) and electron loss/leakage in the Electron Transport Chain ETC) during OXPHOS (Oxidative Phosphorylation).
I suggest the Biorejuvenation way, (re) Programming our chromosomes, DNA and its genes. That is more powerful and a less defeating strategy than repairing the inevitable. We must erase damage and avoid it. Avoiding damage is Much Much more powerful than receiving it and trying to repair it. It's very hard to remove all these damages. Better to 'Erase them' in the code via reprogrammation.
In terms of power:
1. Reprogrammation
2. Avoid damage
3. Repair damage
@Steve and Antonio
Definitely, if AGEs are removed, it had incredible power. So much so that we would have possibility to be near immortal. How so ? Glucosepane, CML, Pentosidine, Furosine, and I'm forgetting a few others...are in direct correlation to MLSP. But not only that, AGEs are in direct correlation and CAUSATION to lipofuscin accrual. In every animal, Lipofuscin = MLSP.
That's why I wager big on SENS lipofuscin therapy with nanorobots filled with enzymes degrading lipofuscin and AGEs at the same time.
Pentosidine AGEs formation correlation to MLSP in animal skin collagen:
3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC40263
CANanonymity -
I totally agreed with your points, in particular the reprogramming. But How?! Nowadays, we even can not precisely manipulate the expression activities of two or three genes at the same time.
Of course, we can make three gene expressing simultaneously, but can not regulate their expression amounts exactly. For instead, Gene A expressed 1500 (related to actin), Gene B expressed 30 (related to actin), and Gene C expressed 500 (related to actin).
@Stan Chen
Hi Stan !
Thank your that ! You know even more than me : ), when it comes to programming, I'm like a sitting baby duck ; D (I sure hope people don't think I'm a quack quacking quacking nonsense lol). We continuously watch out what we say, things change so fast. It's a field that is so massively complex and as your comment (sadly) shows, I had hoped programming was more feasible than that; but you are putting a nail in the coffin on our hopes :D (kidding..). I know some of the genes and their results, but the extremely complicated methods (programming) still elude me, I just basically know rough RNA anti vectors to block genes KO and test on off switch effect and correlative/causative gene logic. It's as if I am asking/returning your own question to you ...How?!...can be reprogramm this. I apologize for not being more capable of helping on this (I should learn more but this program is *Insane* in complexity, we're all in this boat (sinking ? lets combine what we know and keep on rowing). I feel I may have had a 'too grand' vision about programming geneticists, and really the major gene expression studies are just that...as for induced pluripotent stem cells reprogrammation being a start, that's what I hope the future programmers will carry on; that's a start towards being capable to reprogramm - something - in us.
1. http://www.ncbi.nlm.nih.gov/pubmed/24268696
Removing the underlying damage such as AGE (Glucosophane for example) would go a long way to restoring the systemic signalling environment. You deal with the root cause of the problem and the benefits should in theory cascade down the line.
So fix AGE and reduce TGF-beta which in turn benefits stem cell mobility, telomeres, mitochondria etc...
My instinct tells me we should go as far upstream as possible to the root causes and intervene there rather than trying to reprogram a system which already knows what to do given the correct signalling environment.
@Steve H
Hey Steve,
I feel It's more than just theory, because as shown, animals accumulate lipofuscin and AGEs in their cells as they age. Diabetic animals or accelerated aging syndrome animals show the same thing but even Faster, it's not just some correlation, it really is a driver and a cause of aging.
If only we could remove them all, than immortality would be totally feasible; if DNA remains pristine and always high in telomeres; we would not die of anything. A. Islandicas (the famous 500 year old MLSP clam oyster) barely gets lipofuscin as it ages/it does not rise like it does in us; and barely gets AGEs too...plus must maintain high telomeres from little to no oxidative damage (it has a frozen Redox and gsh pool, it has powerful CS (citrate synthase activity) and strong CAT (catalase) for so long; it's antioxidant systems never fail).
AGEs = Lipofuscin = Maximum Lifespan Potential MLSP (they are all correlated and causated), if we push back the MLSP continuously than we are immortal, this is what I hope we work on, enough with the mouses, bring in them clams or oysters; will test the sh..out of them since they are our target, we don't care for 2 year old mouses...we live longer...we live shorter lives than 500 y clams though, let's study those and transfer whatever from them to us. Comparative evolutionnary anthropo/biogerontology is still a weak field and that is sad, if only we'd put so much more cash in this field; it's only by studying the longest lived animals (longer than us) that this research becomes very meaningful (studying mouses, flies and whatnot little insect...I mean it's great 'fast aging' models...but we are not those models...at least, we can study 'close 'in age' models' (not necessarily same specie, though primates are ultra-close) like primates, chimpanzees, dogs, naked mole rats, bats...still..they don't live longer lives than us again...we must put more effort on more extreme-lifespan animals (even if we can't know what happens (in our lifetime waiting after the tested long lived-animal to die even after we are dead before them!) like in a convenient short-lived model like a mouse or some fly); still certain studies that studied those animals gave us lots* of extremely important information that shows that certain pathways are the same from short to long lived animals; but that other pathways make us live much longer; it's those pathways we must capitalize on.Like you, I'm all for mouse testing (I congratulate you on your Mouse Testing Program btw) ; but I don't get the feeling if we continue testing mouse we will make extraordinary things because it does not translate well into a human. Certain incredible results in mouse can be lackluster in humans or non existant; different specie, different make up, different survival strategy, different gene effect.
Weak Translatability.
Yes exactly. We have to take certain shortcuts to get to the 'heart of the problem', sometimes quick shortcuts make for faster results and can very surprising (most quick shortcuts lead to no results but not always, it's making sure that shortcut cuts to the right end place, it if goes right to the cause and heart of the problem; it can be dramatic in effect, because it is attacking the cause straight on). Although, this is easier said than done, as Stan's comment shows. Same goes for, repairing damages; it's very hard and there is a reason (difficulty) why we still can't do better, we fail at remove these damages; it would have been done by now (but the astronomical complexity makes it near impossible). Time to find other solutions, try something else.
As said yourself, it's only combination of treatments that will end up defeating aging; doubtful reprogrammation or damage repair seperately alone will. But who knows.
@CANanonymity
No disrespect, I just mentioned the current status of reprogramming approaches. Nowadays, we can use the combinatorial compound treatments to generated iPSCs from fibroblast cells (ref http://www.sciencemag.org/content/341/6146/65 ). But, we can not precisely manipulate detail gene expressions. Particularly, we would like to reprogram the gene expression for anti-aging, but not to change the cell fates or dramatic cellular function changes. For instead, we hope the epithelial cells in our skin can be reprogramed to maintain young, but not to transdifferentiate into other cell types, such as nerve cell or muscle cells.
Actually, many scientists are working on the development of new approaches as well as strategies for anti-aging. I expect that we might have breakthrough within 15~20 years.
And what we can do now might be to set up the molecular landmarks of our tissues at current ages. These personal molecular landmarks of tissues at younger ages might be used as the reference points to stop or reverse aging.
By the way, I'm looking for partners and trying to built a team.
Hi Stan !
Thanks for the clarification ! I wish you lots of good luck on your team creation endeavors !
Florin suggested reprogramming is dead end theory because of damage accumulation source of aging problem most likely being irreversible (such as collagen crosslinks in the Extra Cellular Matrix (ECM), but that ECM turnover (balance between ECM creation/degradation) or some other way of recreating the ecm/ejecting the damage from it would mean reprogrammation does do something that we don't know to be able to rejuvenate the ecm and collagenous/fibrin/fibronectin/decorin layers and 3D scaffolds in our skin tissues). I heard that the only way that iPSCs can rejuvenate is when they are in a young ECM, the young ECM signals rejuvenation (through different special factors secreted and genes in the ECM only, it must probable alter stem cell factors like Oct, Sox, Nanog), not the old damaged one full of AGEs and lipofuscin. i have a feeling we should really concentrate on ECM, it has so much rejuvenation potential and power; as AGEs are in correlation with lipofuscin; both are to MLSP; and all of them accumulate largely
in the ECM.
Do you know of anything that can rejuvenate the ECM (not talking about iPSCs reprogrammation) through reprogrammation or other way ? Thanks in advance.
@Stan it depends what sort of team you are looking for and what you are doing? I am working with the Major Mouse Testing Project to crowdfund rapid mouse testing for basic research, any synergy there? We got three labs and researchers lined up and are exploring some SENS based stuff too.
@Stan Chen
The link in your most recent post was not functional for me. I think you may have meant this one:
http://www.sciencemag.org/content/341/6146/651
@CANanonymity,
Just like you mentioned, the iPSCs or other stem cell-based approaches might only work in the young tissues, but not the aged tissues. The aging is systemic, and the signaling might communicated between various tissues among our body. Since the younger iPSCs go into the specific region, in which the environment is aged, the cell will receipt the inter-tissues signaling , and the gene expression/epigenetic profiles of iPSCs will be modified to the aged profiles. Unless we can systemically remodel the cellular environments of various tissues as well as the inter-tissues signaling for aging, it seems impractical to stop or reverse aging. Thus, we can easily find the reporter that described inefficiency of iPSCs treatment in clinic application.
Additionally, I did not know any efficient way to precisely reprogram the cellular environments. We should work on it.
@Steve H
Sure, the work you are doing is really important.
I'm not satisfied with current experimental strategies and approaches.
First, most of lifespan studies for specific genes were whole body, and single gene transgenic.
Once the effects of this gene for aging were different in various tissues, the mice with whole body transgenic might not show the enhanced or reduced functions in aging. Hereby, several amazing transgenic studies within yeast or worm might not show positive results in mammals. Additionally, the studies about the combination multiple gene manipulation in mammals seem to impractical. Just like the Maria's project (https://mariakonovalenko.wordpress.com/2014/11/19/longevity-gene-therapy-updated-projects/), she planned to conduct the combinatorial transgenic mouse with two or three from their list. Even in the short version one, we should establish more than 100 mouse strains to investigate the effect of the combinations of two gene from 5 candidates in various tissues. It's too complicated to be conducted in any institutes, and the main reason why most of scientists tried to study the function of specific gene in specific tissues during aging.
People might be curious whether the single gene or pathway can rule the systemic aging. Unfortunately, the previous epigenetic clock and transcriptomic studies already showed that no single signaling cascades could involved in whole body for everyone.
Thereby, what I want to do is something more crazy.
First, the more information about the inter-tissues signaling during aging should be assessed by the recording the personal epigenetic/transcriptomic profiles of various tissues during aging. This idea of aging biomarkers tracking system is almost impossible to implement in academic researches due to completive stress from publications. It might be only feasible in the commercial enterprises.
Second, we should established the computable modeling of regulatory networks for cellular gene expression, which allow us to disclose the inter-tissues signaling as well as simulate in silico gene expression profiling under various parameters, such multiple genetic manipulations or combinatorial chemical compounds treatment. This is my solution to precisely reprogram the epigenetic/transcriptomic profiles of cells.
For most of people, above two ideas are too radical to give a moment's consideration.
@aaron
Thanks, that is it.