On Telomeres and Telomerase in Aging
There is a contingent of researchers who see increased levels of telomerase as a viable therapy to slow aging, and shortened telomeres as a contributing cause of aging. Below find linked an open access paper written from that perspective.
It is certainly the case that genetic engineering of mice to produce additional telomerase results in a modest extension of life, though not as much as initially reported. It seems to generally boost regenerative activity, which results in similar outcomes to stem cell therapies. The primary mechanism associated with telomerase is the lengthening of telomeres, the repeated DNA sequences at the end of chromosomes that act as a counter of cell divisions - a little is lost each time a cell divides and replicates its DNA. While some researchers see shortened telomeres as a cause of aging, it seems pretty clear to me, and others, that average telomere length as presently measured is a reflection of processes of aging, not a cause. There has in the past been some discussion of other ways in which telomerase might be acting on life span, such as by affecting the pace of mitochondrial damage, for example.
In this review, we will discuss the role of telomeres in the origin of age-associated diseases and organismal longevity, as well as the potential use of telomerase as a therapeutic target to delay aging and to prevent and treat age-related diseases. Aging is a multifactorial process that results in a progressive functional decline at cellular, tissue, and organismal levels. During recent years, a number of molecular pathways have been identified as main molecular causes of aging, including telomere attrition, cellular senescence, genomic instability, stem cell exhaustion, mitochondrial dysfunction, and epigenetic alterations, among others. Interestingly, telomere attrition is considered a primary cause of aging, as it can trigger all the above-mentioned hallmarks of aging, although the degree to which it is a principal cause of aging is under active investigation. Critical telomere shortening elicits the induction of cellular senescence or the permanent inability of cells to further divide, which in turn has been proposed to be at the origin of different disease states. In addition, telomere attrition in the stem cell compartments results in the exhaustion of their tissue- and self-renewal capacity, thus also leading to age-related pathologies.A substantial number of companies are now aiming to harness the knowledge that has been generated, unveiling the molecular mechanisms of aging in order to develop a new class of drugs to prevent and treat the major age-related diseases. In this regard, telomerase overexpression studies in mice have been proof of principle that just modifying a single hallmark of aging, i.e. telomere shortening, this was sufficient to delay not one but many different age-associated pathologies in mice, including cognitive decline. Indeed, the use of telomerase activation in delaying aging-associated conditions has spurred the interest of commercial enterprises.
It is likely that the first clinical use of a telomerase reverse transcriptase (TERT)-based therapy, such as the TERT gene therapy approach developed by us, will be for the treatment of the human telomere syndromes, including aplastic anemia and pulmonary fibrosis. However, this requires the development of appropriate preclinical models and the subsequent clinical trials in humans. In this regard, we have recently generated two mouse models which recapitulate the clinical features of aplastic anemia and pulmonary fibrosis. The disease in both models is provoked by short and dysfunctional telomeres and thus these models provide a platform for further testing of TERT-based treatment strategies for the telomere syndromes.
Given that physiological aging is provoked, at least in part, by telomere shortening, a TERT gene therapy may be used not only for the prevention and treatment of telomere syndromes but also for the treatment of multiple age-related diseases. In this regard, short telomeres have been extensively associated with a higher risk for cardiovascular disease. In support of a potential use of TERT activation in the treatment of age-related diseases, we demonstrated that TERT gene therapy can efficiently rescue mouse survival and heart scarring in a preclinical mouse model for heart failure upon induction of acute myocardial infarction. Collectively, experiments in cell and animal models provide proof of concept for the feasibility of telomerase activation approaches to counteract telomere shortening and its consequences. In particular, the successful use of telomerase gene therapy in animal models of aging and short telomere-related diseases paves the way for the development of therapeutic telomerase treatments in human aging and associated disease.
@Reason
Hi Reason !
Just my opinion.
''While some researchers see shortened telomeres as a cause of aging, it seems pretty clear to me, and others, that average telomere length as presently measured is a reflection of processes of aging, not a cause''
I fully respect your opinion and understand. I too was of the opinion it was just correlative, but I changed mind or let's say I'm not so sure anymore (I'm mixed up :D. Telomere attrition (seems) is also causal to aging
not (just) correlative. It is both causative and correlative but not just correlative.
Here is something that seems show that telomeres are causal to aging :
''...we demonstrated that TERT gene therapy can efficiently rescue mouse survival and ****heart scarring*****''
Heart scarring (heart scarred tissue is full of granules of lipofuscin) reversion by heightened telomeres is a causative demonstration that heightened telomeres activate cell cycling dilution process by increasing cell cycling or in non-cycling cells, it must be capable reducing damages (done by excessive lipofuscin aggregates deposition in lysosomes (increasing junk Fenton ROS background production) by reducing ROS production (and telomerase can do that, it has a dual fuction of increasing Telomeres and Reducing ROS production; only low-enough oxidative stress states otherwise it too can leave the milieu (nucleus' chromosomal telomeres)).
Telomerase hTERT and hTERC activation just increases shortest telomeres, making telomerase therapy weak (telomerase has no point in increasing - already - long telomeres...so it concentrates on the shortest...all the while, the tallest shorten - at the same time making telomerase therapy mostly usefull as a healh-effect rather than replicative effect (sadly, it should improve replicative lifespan but its induction is not enough to - keep - the tallest telomeres from -further- reduction, because it concentrates on the shortest telomeres, so of course replicative problem continues its course/oxidative stress continues to reduce the Tallest telomeres while telomerase 'plays catch-up' on the already smallest telomeres...this gives an 'average' effect of sligtly slowing aging and improving health (I can't wait to see BioViva's Mrs Liz Parrish's results, for when ? It's been months, we should have biopsy of her telomeres right now, and not wait years to see if telomerase therapy is stronger than taking astragalus cycloastragenol, TA-65 or other TERT activators, because these have failed and all of them made slight improvement on smallest telomeres).
For somatic cells that do not have telomerase, it becomes a reduction of oxidative stress by maintenance of heightned telomeres (reduction of telomeric DNA bp rate loss per PD) and thus, maintenance of Redox homeostatis (low oxidative stress state by improved GSH:GSSG NAD+:NAPDH, SAM:SAH ratios). High telomeres dictate oxidative stress and as such, lipofuscin accrual. There is a distinct correlation - and causation - between telomere length, replicative potential, redox state and lipofuscin total (telomere end-replication problem contributes to telomere loss (if not solved by telomerase access) and lipofuscin accrual contributes to further telomere loss too). This brings about replicative lifespan end/replicative senescence where cells stop dividing; and for non-dividing cells it is also a replicative senescence (they simply reached a low enough telomere length called M1 point, around 5kb, should they escape that replicative senescence they go down further to 2kb where immortalization happens, called M2 point).
'' Critical telomere shortening elicits the induction of cellular senescence *****or the permanent inability of cells to further divide*****,
which in turn has been proposed to be at the origin of different disease states. In addition,
***telomere attrition in the stem cell***
compartments results in the exhaustion of their tissue- and self-renewal capacity, thus also leading to age-related pathologies.''
Somatic cells, cycling or not, do not have telomerase (or barely detectable levels, this is as was said a cancer inhibition protection mechanism against cancer cell telomerase highjacking/increased cancerous and transformation proliferation potential in inflammed cells/near senescent cells), stem cells,just like this article says, lose telomeres too and are victims of damages to telomeres (but not immortal gonadal testicular/ovary germ/stem cells and some immune cells (leukocyte use telomerase) who use telomerase (like cancer cells), unlike other 'somatic-like' stem cells telomerase-deficient).
In conclusion,
Telomere loss (somatic replicate-end problem of no telomerase) creates lipofuscin and vice-versa, lipofuscin creates ROS Fenton production by enlarged senescent mitochondria effete producing H2O2, which creates further/accelerates telomere-loss as a oxidative stress mechanism. It's both that are causal, but telomeres are definitely causal too - with the damage being causal too. It's not just correlation.
It's also why, Carnosine and othe AGE reducers barely make any difference on replicative lifespan. They don't stop aggregates accumulation (an unsolvable problem but solvable by peat bog bacterial enzyme degrading power or cell cycling; or perhaps cell reprogrammation (such as iPSCs) which is still dubious but reverts nearly damages supposedly), as such is mostly applicable for inducible senescence rather than replicative ones (it slow both a little, but it has more 'health (inducible)' effect, than 'maximal longevity (replicative)' effect).
Again all of this is just my 2 cents and there is much gray zones, and so I understand it seems both correlative or causative, but it points to both.
@CANanonymity
When you say Induced Pluripotent Stem Cells could be an option for clearing away AGEs, I assume you mean the restored replicative capacity would over time remove the AGEs through cell division. Am I understanding this correctly?
“I can't wait to see BioViva's Mrs Liz Parrish's results, for when ? It's been months, we should have biopsy of her telomeres right now…”
BioViva CEO Liz Parrish on Becoming Gene Therapy Test Subject:
https://www.youtube.com/watch?v=wTaX_52EIq4
@Eric
Hi Eric ! Exactly. But only in replicating mitotically active cells, not in non-dividing post-mitotic cells. Which is a big problem, AGEs accumulate mostly in post-mitotic cells and outside cells in ECM.
It's been said ECM turnover proteolytic enzymes (such as MMPs Matrix Metalloproteinases) can't degrade undegradable crosslinked collagen, AGEs (such as glucosepane mostly are in extracellular milieu ECM (extracellular matrix).
But, I am the opinion that it's not entirely true, skin of foetus are fully healed with no scarring, their ECM is rebuilt from the ground up and studies show that during that special healing (non-scarring healing of wound to exactly original state), it activates stem cells markers such as 'zinc-finger domain' which activates telomerase (an apparent powerful activator of rejuvenation that does extreme telomere rejuvenation and stem cell rejuvenation; it is apparent to Nanog, Oct, Sox and other stem cell markers that activate telomerase in immmortal gonadal sexual primordial germ-line cells). iPSCs do exactly that, they activate Nanog, Oct, Sox and we can infer zinc-finger domains that all activate telomerase and allow iPSCs to have renewed heightened telomere length.
Dilution is capable of removing all these including AGEs, the problem is cell cycle dilution is only cycling cells; organ long-lived post-mitotic cells (neurons, CNS nerve cells, cardiomyocytes and few critical other ones) don't cycle or dilute their aggregates because they are non-mitotic/non-cycling (you can be born with your neurons and, still, have them today, the same ones you had at your birth...same goes for collagen...collagen and dentine (in your teeth) is stuff that is a very long-lived protein (collagen lifespan is about 115 years, but it is degraded in turnover by ECM MMPs to allow for new collagen production/replacement).
But there is very little neuron turnover, and same goes for stem cells who are quiescent and barely replicating (except those in gonads), only when there is injury do stem cells replicate and differentiate to replace damaged tissue (this is to maintain niche levels, and a careful balance between self-replication/regeneration and self-differentiation/cell replacement to avoid stem cell depletion; quiescence is needed to maintain that balance).
I was told though (thankfully) that scientist have been capable of reprogramming neurons back to youthful state (they reprogrammed a neuron of an old person back to a young person, the reprogrammed 'old person's' neuron was (supposedly) indistinguishable from the young untouched one. That is Biorejuvenation; if it indistinguishable, it means it has the same Telomere Height (as the young one) and - also - the same amount of AGEs and aggregates (including lipofuscin). But what is even more important, is since only post-mitotic cells truly accumulate aggregates and AGEs, it means that reprogramming a neuron is a step towards proving that post-mitotic cells can - too - be reprogrammed. For we have to understand iPSCs are far more cycling than a neuron is. A neuron is a post-mitotic long-lived non-dividing/non-cycling cell. So that is extremely powerful stuff; I hope we can do it to All that post-mitotic cells (for they are the major ones responsible for intrinsic aging, since they accumulate aggregates/AGEs and don't due dilution (for the fact they don't self-replicate/self-cycle)). That way we would twarth the damage problem, simply by reprogramming 'back to original 'young' DNA code' in these precise cells. Other cycling cells could easily be reprogramm and dispose of their junk through improved cycling (after reprogramming).
How can telomere shortening cause ageing when cells with long telomeres can function just as well as a cell with a telomere that is half or even a third of its length. Its not telomere shortening that is important but the result of a single critically short telomere that induces a senescent state that can consequently contribute to ageing. Telomere shortening is an indication of the replicative capacity of cells and the likely-hood of them becoming senescent.
There is no evidence I am aware of that suggests telomere shortening negatively impacts the function of a cell prior to the induction of senescence (I would love to hear of some if anyone is aware). There has been some suggestion that telomere shortening impacts expression of genes close to telomeres-so called telomere position effect, but the evidence is poor.
DGAB You should read about telomeres and the TPE effect (wright and Shay) you will then see that as telomeres shorten gene expression changes with it (and is reversible). The evidence for the TPE effect is far from poor, I will dig out the research when I have time. Start with Wright and Shay, Rando, Fossel and Blasco for a kick off they all talk about gene expression changes with telomere loss.
@CANanonymity
Thank you, you explain things so well I understand everything you said. well done!
@Eric
No problem, your welcome.
And Thank you greatly too Eric ! : >