I don’t intend here to summarise the entire thread of ‘Alternative Methods to Lengthen Telomeres’, which I started almost six years ago. This is the most recent index to all those posts: https://www.longecity.org/forum/topic/102169-alternative-methods-to-extend-telomeres/page-31#entry926772, although it is almost a year old so will not capture the latest posts. But it is pretty decent as a guide to what has been discussed, particularly the section on Telomerase Activators.
This post is not going to have references, as I want it to be my opinion piece, but all the references you need will be contained in the link above, or if you really have a burning question, ask me and I’ll see what I can dig out. So take my arguments on board, but you don’t have to believe them.
Do I still believe in the telomere theory of ageing?
So after these six years, do I still think telomeres are important in human ageing?
I’ve waxed and waned in my enthusiasm for telomere extension as the primary intervention against ageing, taking time out to think about mitochondria, methylation, DNA damage, ECM, etc., but I always come back to telomeres. To date it is the only truly comprehensive theory of ageing that requires nothing else. That doesn’t mean that telomeres are solely responsible for human ageing of course, but they could be. And I am pretty confident that any intervention that does not solve the telomere problem will be a stop-gap at best.
Why are scientists not more focused on telomeres in ageing research?
When I started the thread in 2018 telomeres were already past their heyday in popularity as a theory of ageing, and we have to ask ourselves why. There are a number of reasons. Firstly, cancer. It has widely been accepted that with telomerase we might be able to stop ageing, but we’d die of cancer. It is a complex argument that I am not going to rehash here, but I will say I am not going to take the opposite view that there is zero cancer concern with long telomeres and that short telomeres are the main cause of cancer (although they are). I will merely acknowledge the possibility that extending telomeres in young people who don’t need longer telomeres, might (maybe, possibly, but not at all certainly) increase some rare cancers. I will also counter the possibility of increasing rare cancers with the certainty that old people have a huge rise in cancer (as well as all other age related diseases), and that we could prevent that by extending their telomeres. This is a key point: we don’t have to have the same priorities as evolution; we can decouple the priorities of youth (pre reproduction) from age (post reproduction).
Secondly, telomeres are too hard a problem for most scientists (and too expensive for most entrepreneurs I might add). Telomeres were discovered, there was a flurry of basic research and the start of a translational attempt to address this problem. But a solution was not forthcoming. Bill Andrews got closest with his robotic assay search for hTert RNA for small molecule telomerase activators, but his backers ran out of money in 2012 and he’s been flying on fumes ever since. So the science moved on to other, easier problems. This is not just theoretical nitpicking at overworked academics. Scientists can’t agree on whether human stem cells have active telomerase; can’t find specific antibodies for telomerase, can’t agree if a substance activates telomerase; can’t even agree if telomeres shorten with age, or even if it matters. Put on top of those difficulties the publish or perish mentality and you have a recipe for no progress. So scientists moved on to try and make their name elsewhere. It’s not like we’re trying to solve an issue of life-or death. Not like we’ve discovered a possible mechanism for ageing that we should fully explore to prove it wrong or right. Oh, it’s a bit difficult. Let’s look at methylation or the citric acid cycle instead…
Just look at the paper we’ve been discussing recently: in 2024 Ron dePinho published his search for a small molecule telomerase activator: more than a decade after Bill Andrews and he found a very weak activator. We have not moved forward in ten years! Various other unhelpful claims are made to the contrary: epitalon activates telomerase massively (it doesn’t at all: its mechanism is something else entirely), sirtuins are in charge of telomeres (it’s more the other way around, although the two are related), various poorly executed or dare I say it, fraudulent never-to-be-replicated papers claim fully lengthened telomeres from some substance, and the wheels of the great medical industrial complex roll on with promises of gene therapy for all, at a cost of $1 million per person per treatment. So what are we to do?
My thread was an attempt to find an ‘alternative’ approach to lengthening telomeres, until something changed and progress was made in terms of finding powerful ways of activating telomerase. What those alternative methods might be is open to question. It could be finding ways to reduce the shortening per cellular division, or to finding a source of telomerase positive stem cells and stimulating them, or perhaps looking at exosomes containing telomeres or telomerase, or finding synergies with the currently weak telomerase activators: increasing TERC, increasing TERT assembly into telomerase, increasing nuclear localisation, etc. In those terms the thread has not changed at all, and it is still an evolving attempt to do just that.
What am I doing?
So where are we now? We can’t do much about discovering new telomerase activators. But I do think there are things we can do. Primary among those are synergies. If we combine a telomerase activator or activators (by that I mean a substance or substances that increase hTERT from the human telomerase gene) with a substance to increase the translation of RNA into the telomerase protein, with elevated sirtuin levels (to increase nuclear localisation of telomerase) we could be onto something. This is all unmapped territory: it stands to reason that we will get improvements from optimising the whole telomerase assembly process. But we have no idea what the size of those improvements could be. Are they 1% or 100%? This is where self-experimentation can help.
This brings us to the problem of testing. As a cause of ageing telomeres are right up there. As a biomarker, they are terrible. We only have the capability to look at the telomere lengths of leukocytes in the blood. And although a conveniently replaced cell pool is useful in some ways, it is unhelpful in the sense that many things can cause this pool to have longer or shorter telomeres have nothing to do with telomerase. Things that are harmful can even give you longer telomeres (in the short run). For example causing stem cells in the bone marrow to divide more quickly. Look at all the excitement over high oxygen chambers and how it ‘increased’ telomere length. Telomere tests are also not widely available and good ones are expensive. I should also mention that any treatment that slows ageing will be quite difficult to notice. But a treatment that reverses ageing will be obvious to anyone. So bear that in mind and temper your expectations accordingly!
I will continue to cast a critical eye over telomere and telomerase research as it comes in, and look for practical interventions and protocols that we can use now to slow ageing as much as possible, until finally, we have this thing beaten.
Currently I am engaged in optimising a synergy between sirtuins and telomerase. I will post more when I have further results on this. But early signs are promising. I also keep a roving eye on publications and from time to time take a deep dive into a seemingly unrelated area of ageing.
Regarding the specific questions asked:
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How are telomeres lengthened? When cells divide you have to double the number of chromosomes so each cell gets a full suite of DNA. The ends of the chromosomes can’t be replicated with the normal polymerase (think of a builder building a wall while he is also standing on the wall, when he gets to the end he falls off, so can’t finish it), so the copied side is shorter than the original (actually, just one end of it is). This means that after X number of copies the telomere (the ‘telos’ in greek or ‘end’ of the chromosome, which is basically dummy DNA that doesn’t code for any proteins), is missing and the end of the chromosome is now recognised as broken DNA and will be fused to the nearest other bit of damaged DNA by the DNA repair machinery in the cell. This is bad; we need our DNA in the chromosomes they usually occupy otherwise the cell can become cancerous. So this activates various inflammatory and cellular arrest (senescent) signals. Mostly the cell dies now (best option), or could remain senescent (not great), or escapes control and becomes cancerous (worst outcome). The picture is a bit more complicated than I have painted above, the cell actually gradually gets more inflammatory and senescent as telomeres shorten, rather than it being a sudden all-or-nothing process, which is probably why ageing is mostly gradual (albeit with certain points where it is more noticeable).
So because the normal polymerase can’t elongate telomeres there is a specific protein to do this called Telomerase. Part of this protein can clamp onto the telomere strand (the TERC part) and part of it (the TERT part) then copies the strand of the telomere so the copy is almost as long as the original. To do this the telomere has to be unwound from its normal curled up position and this is controlled by a bunch of other telomere associated proteins called ‘shelterins’. This only happens when the DNA is being opened out and copied during cell division (this is called S-phase). So, you can only elongate telomeres during division, and unless you have enough telomerase, stimulating division will end up causing telomere loss.
In humans telomerase is only active in germline cells and deactivated in all other cells. There are various arguments about why this is: is it an intentional mechanism to ensure you are replaced by your children and the human race evolves faster? Is it an anti cancer mechanism for mammals with larger bodies? Or is the fact that telomerase remains active in mice the adaptation to deal with oxidative stress? Although very interesting, I don’t think it matters from a treatment perspective, for the reasons already given when I discussed cancer in the main part of this post.
I should mention at this point that there is one stem cell research facility that thinks there are telomerase-positive adult cells in all animals including humans. But no one else has been able to isolate them. If this does turn out to be true, then we’d need to pivot to working out how to stimulate these and working out why they are not active (or less active with age). But for now we must accept that all human cells that are normally active in the body have telomerase repressed in a very thorough manner. It is not yet understood how this is done, though it must be done epigenetically, given germline cells can turn telomerase back on.
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What is the rate-limiting step? The rate-limiting step in telomere elongation is the supply of TERT from the telomerase gene (hTERT). Without this nothing else will work. There are various studies claiming things like how telomerase is rather slow, and can be faster if you have more guanine. Or or how you can increase TERC levels to elongate telomeres. But these all need TERT. If you make TERT, the telomerase protein is made and telomeres are elongated. So, if you can activate the hTERT gene, you don’t really need to do anything else. This sounds great. But the problem is that because hTERT is so thoroughly repressed, it is very hard to turn it on all the way (think of a dimmer switch). That is why people are trying to use gene therapy, because then they just add their own unrepressed hTERT gene. With current telomerase activators we are only turning the hTERT gene on a little bit (probably pushing the dimmer switch up 1-15% depending on the activator). So, for these reasons I think it is worth optimising the other steps of the process, as already discussed.
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What molecules turn on the telomerase gene? When you hear of a molecule that elongates telomeres, you need to first ask yourself: does it really? If you are satisfied it does, you then need to discover if it activates the hTERT gene, or whether it somehow optimises the small amount of TERT that may be present using one of the other non-rate limiting steps of the process of making telomerase or elongating the telomere. For example, there is a study showing longer telomeres from using NMN (in humans and mice). Originally I was convinced this was nothing to do with telomeres or telomerase, and must have simply been an effect from reducing the loss of telomere/division, perhaps through reducing oxidative stress. But since then I have discovered that sirtuins are involved in shepherding the telomerase molecule into the nucleus. So, this may fall into the category of a molecule that helps a small amount of already present telomerase be more effective. If I were to guess, I’d speculate that metabolic controls are interlinked with telomere controls, as you can see this in cancer or embryonic stem cells when the TERT-TERC interaction becomes stronger when lactate is burned as a fuel. Coming back to the question, TAM818 and TA-65 activate hTERT, as do some other herbal products, although none are very strong (TAM818 is the strongest; it supposedly manages about 16% of what is required to stop telomere shortening). I should mention briefly what I mean when I say that ‘a small amount of telomerase is already present’. When a cell divides and the chromosomes are copied, the repression on any gene is removed. So, you will always get a little bit of telomerase produced during cell division. But it is very little, and certainly not enough to make much of a difference to telomere shortening. But it probably does slow telomere shortening a little in white blood cells, for example.
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I suspect we’ll need to use several telomerase activators together, each with a slightly different mechanism of action, to beat all the telomerase repression mechanisms. Once it is done, it will look simple, and no one will ever think about using gene therapy again. Another space to watch is exosomes. If these carry telomerase (they do), they might be a much cheaper alternative to exosomes, although more expensive and inconvenient compared to small molecules.
