talk title: Enhancing telomere maintence extends healthspan

speaker: María Blasco

event: Longevity Summit Dublin 2024

date: 2024-07-06

video: https://www.youtube.com/watch?v=Gab1xxl8Jio

LLM-generated summary: Maria Blasco elucidates telomere shortening as a primary hallmark of aging that drives chromosomal instability, stem cell exhaustion, and degenerative diseases such as pulmonary and kidney fibrosis, cancer, and exacerbated COVID-19 outcomes, supported by human telomere syndrome data, prognostic correlations, and cross-species power-law scaling of attrition rates that supersedes initial length in predicting longevity. In telomerase-deficient mice, aging accelerates across generations, while transgenic overexpression, single-dose adenoviral TERT gene therapy in middle-aged/aged animals (extending lifespan 24-30% with delayed pathologies and no oncogenic risk), and chimeric mice derived from reprogrammed iPSCs harboring ultra-long telomeres (conferring cancer resistance and metabolic benefits) demonstrate causality and therapeutic potential. Targeted AAV-TERT delivery to alveolar type 2 (AT2) cells halts/reverses short telomere-induced pulmonary fibrosis by restoring regenerative capacity, suppressing inflammation/senescence, and preventing epithelial-mesenchymal transition (EMT); analogous AT2/epithelial-basal specificity holds for kidney fibrosis, with novel POT1-mutant models recapitulating human phenotypes including multi-telomeric signals.

Introduction to Telomeres and Aging

Hello everyone. So I've been working on telomeres, I think, since 30 years ago, and I hope to convince you that telomeres are one of the things that make us age and it's an opportunity to intervene also to delay aging and also to try to cure and prevent many different diseases that have aging as an origin.

I don't have to convince this audience that aging is the cause, the origin of many diseases that kill us today. And I think since decades, a few scientists have been thinking that aging is the cause of many diseases. And really, the disease is just the consequence of aging, and that we have to understand why we age in order to be able to prevent or cure these diseases.

So, of course, aging can be partly genetic, but also can be the consequence of our life habits. In any case, if we know which are the molecular mechanisms of aging, we could, on one hand, for instance, have biomarkers to measure the rate of aging and to be able to detect diseases before they appear and intervene.

But we could do also, I think, two fantastic things that you already know. One could be to extend the time of life free of disease, to extend longevity and delay disease. And the other thing that we can do is maybe we will be able, by understanding aging, to intervene and to cure diseases, the degenerative diseases associated with aging. These two things I think we could do if we understand aging.

Hallmarks of Aging: Telomere Shortening

And a few years ago, also, as Aubrey mentioned, it was an original idea of Manuel Serrano and myself to propose to write this review on the molecular basis of aging. We call it the hallmarks of aging. It was inspired in the hallmarks of cancer by Weinberg and Hanahan.

And I will be telling you about one of these hallmarks of aging, which is telomere shortening. We, in this review, we describe this as one of the primary causes of aging, together with DNA damage, because it leads to other causes of aging. Telomere shortening can lead to other causes of aging, like chromosomal instability, stem cell exhaustion, et cetera. So it influences other causes of aging.

This review was this last year updated, also in Cell. I hope you have seen it by including other hallmarks of aging.

Telomeres, Telomerase, and Telomere Syndromes

But I will tell you about what has been my scientific life, which is to understand the role of telomeres and telomerase in cancer and aging, but I will be talking about aging.

We know that telomeres are structures that protect the chromosomes and they are very important for the viability of our cells. But telomeres actually shorten. When we are born, telomeres start shortening. And this telomere shortening has been demonstrated to be at the origin of many different diseases because there are individuals that are mutant for an enzyme called telomerase.

Telomerase is an enzyme that can elongate telomeres. It's active when we are embryos and there it elongates telomeres and with these telomeres we have to live our whole life but telomerase then is silenced and that's why telomere shortening. I'm simplifying a lot but there are people that are mutant for telomerase and they are born with very short telomeres, and they have a number of diseases that have been called telomere syndromes.

And these have been the demonstration that telomere length is rate-limiting for human longevity, and therefore we think that telomere shortening is actually causing aging.

Prognostic Value and LifeLength

And even if you don't have a mutation in telomerase, and you don't have one of these telomere syndromes, it has been shown by many groups that telomere length is predictive, or it has a prognostic value for different diseases.

And that's why I think many years ago already, in 2010, we founded a company called LifeLength. I think there are some people around from LifeLength. It's a company that started from the research of my lab to measure telomeres, and I'm still measuring telomeres as a biomarker for risk of diseases associated with aging, among them cancer and other diseases.

Mouse Models: Telomerase Deficiency Causes Aging

But my group has been mainly focusing on trying to demonstrate that telomeres matter for aging. One of our first contributions was to show that if you remove telomerase from a mouse, and this was done in part still also in collaboration with Carol Greider, where if you remove telomerase from a mouse, then this was the proof, this was the demonstration that telomeres are sufficient to cause aging. And we published a number of papers showing that.

But I think what was probably also complementary to this and also necessary was to demonstrate that if you maintain telomeres longer for longer time, so if you make a mouse with longer telomeres this was sufficient to make it live longer.

So we first made a transgenic mouse that had more telomerase and it also had more tumor suppressors and these mice were living longer. We published this in 2008 and basically what we did is to delay aging in mice or to increase the time of life of mice free of disease. You can see that the mice that have long telomeres at three years of age, they are still 50 percent, they are still alive while the control mice are basically all dead. So we were modifying longevity by making these telomerase transgenic mice.

So this is telling you that both in humans, because of the telomere syndromes that I've told you, as well as in mice, telomeres are important for longevity.

Cross-Species Analysis: Telomere Shortening Rate Predicts Longevity

But how general is this? So a few years ago in 2019, we published a paper that I think it was, for us, was very important. It was to show if there was anything related to telomeres that was important for longevity, not in mice and humans, but in many different species.

So what we did is to measure telomeres in different species of mammals and birds. We did a collaboration with the zoo of Madrid. This work has been then replicated by other groups with other species of birds and mammals. And we found whether there was any parameter related to telomeres that could explain longevity.

And we found that the initial telomere length didn't explain longevity. So mice are born with very long telomeres, but they live less than humans, that we are born with shorter telomeres. But we found that the rate of telomere shortening could be adjusted to a mathematical function, it's called a power law, and it could explain longevity. Just the rate of telomere shortening could explain longevity of many different species of birds and mammals.

And you can have, for instance, elephants and flamingos. They are very distant in evolution. A flamingo is a bird, an elephant is a mammal, but they share the same rate of telomere shortening, and they also have a similar longevity. They can live up to 70 years of age.

So in this case, this is telling you that an epigenetic factor, which is the rate of telomere shortening, is more important than genetics to explain longevity. So there is something about this rate of telomere shortening that could have been selected by evolution we think, to set different longevities.

Telomerase Gene Therapy to Delay Aging

So if telomeres are important for longevity, then we can actually think about the strategies to make telomeres longer and maybe delay aging and also treat diseases associated with aging.

And this is something that we did in 2012. We thought about using gene therapy. In particular we used adenoviruses to deliver telomerase into an adult organism. In this case we chose mice. And to see whether a single treatment with telomerase, this was an intravenous treatment with the telomerase reverse transcriptase gene, with the TERT gene, this was sufficient to delay aging in mice.

In this case, it was just this intervention. And we treated one-year-old and two-year-old mice, so middle-aged or old mice, and we found that telomerase treatment improved many different parameters that are affected with aging, and these mice had improved glucose tolerance, improved skin fitness, less cognitive decline.

Something that was important to us, it was what would happen with cancer, because cancer cells, we know that maintain telomeres, and they have telomerase mutations, and we were worried about whether single treatment with telomerase with these vectors could increase cancer risk, but in fact, cancer risk was not increased. Cancer was also delayed in these mice, because cancer is a disease associated with aging. Cancer is originated also because, in part, because short telomeres that lead to chromosomal instability, that can lead to cancer.

So cancer was also delayed, and we didn't see any negative effects of having this treatment with telomerase because, in fact, the mice lived longer. The one-year-old group lived about 24% longer, and the two-year-old group, which are very old mice, lived 30% longer. We also saw that both the median and the maximum lifespan were extended with this potential therapeutic treatment with telomerase.

So this was a way to show that increasing telomerase didn't have any apparently negative effect in mice because we follow these mice until they die.

Ultra-Long Telomeres via Cellular Reprogramming

We wanted to show in a different manner that long telomeres were not something necessarily bad. And for that, we came up with a different strategy to make mice with longer telomeres.

My group was also interested in understanding telomere elongation associated with reprogramming. Because we know that telomeres are elongated in the blastocyst, and the chromatin of telomeres is in an open conformation, and there is telomerase, and telomeres can get elongated.

We found that if you reprogram using the Yamanaka protocol, telomeres are re-elongated. So we published that in 2009 in Cell Stem Cell. But then by chance, we found that during reprogramming, telomeres are elongated, and they can be increased beyond the natural length of telomeres of a species.

So we found, for instance, that mouse telomeres could grow and grow and grow beyond the telomere length of the inner cell mass of the blastocyst. So we could generate pluripotent stem cells with what we call ultra-long telomeres.

So we immediately thought that this could be a way to generate mice with ultra-long telomeres, with very long telomeres, by using these pluripotent stem cells and generating mice.

So what we did is we took aggregate morulas. We aggregated cells with normal telomeres or ultra-long telomeres, pluripotent cells, and then we generated mice, chimeric mice. So we saw that you could generate mice which have cells which have much longer telomeres than normal.

You can see here the eye of one of these chimeras, and you can see just by eye the red dots are the telomeres, and you can see that the green areas are the ones that are derived from iPSCs with ultra-long telomeres, and you can see that the telomeres are longer just by eye. The fluorescence of the red dot is higher than in the non-green, which are the normal, the natural telomere length of this strain of mice.

So by generating these chimeras, so we generated first mice that were 31 to 70 percent chimeras, and we showed that these mice again live longer, again showing that longer telomeres make you live longer, and they don't have any bad side effect because actually these mice were cancer-protected. They had less spontaneous tumors, and even if you try to induce tumors with carcinogenic treatments, they had less tumors.

Then we went on and generated 100% chimeras, so mice that every cell of their body had much longer telomeres than normal. And you can see here by GFP, these are all the cells that have longer telomeres than normal. It's 100% chimeras, and we saw that these mice were leaner, and they also had less cancer, and they also had less metabolic aging.

So in two different ways we demonstrated that longer telomeres in a species in a mouse were not bad actually were making mice live longer.

Therapeutic Applications: Heart, Bone Marrow, and Fibrosis

So we decided to try to use our telomerase gene therapy to see whether this could be a therapeutic treatment for different diseases of aging. And we have been working on this for years, and we have shown that telomerase gene therapy in mice protects from heart infarct in mouse models of heart infarct. We published this many years ago.

And we also showed that telomerase gene therapy could have therapeutic effects for bone marrow aplasia, which is one of these telomere syndromes. People that have bone marrow aplasia because of very short telomeres.

And more recently, we have been focusing in fibrosis. And I will be telling you about pulmonary fibrosis and kidney fibrosis, which are, especially pulmonary fibrosis, one of the most prevalent diseases that we know that are associated to short telomeres.

Pulmonary Fibrosis: Role of Alveolar Type 2 Cells

So we think that short telomeres can synergize with damages to the lungs. And we have identified, I will show you in the next slide, that are the alveolar type 2 cells, the ones that matter for pulmonary fibrosis associated to short telomeres. And when you have short telomeres in these cells in the lung, this leads to fibrosis.

The current treatments are to remove fibrosis, the ones that are now approved and that have been used with patients, but they don't cure patients. So patients still die of pulmonary fibrosis and we think they are not curing patients because they are not correcting the problem, which is short telomeres.

When you have short telomeres, my group has demonstrated in many different tissues that this impedes the mobilization of stem cells to regenerate the tissue. So if alveolar type 2 cells, which are a regenerative cell type in the lung, have short telomeres, you still are going to have fibrosis. Even if you block the production of fibrosis, you have short telomeres, and this will lead into fibrosis. So you are not curing the patient.

And actually, we have identified the cell of origin. This was a collaboration with AstraZeneca in the US. What we did is to induce telomere dysfunction in every cell type of the lung. You can see here the different not every cell type but some of the major cell types. We removed one of the telomere binding proteins one of the shelterin proteins and this induces telomere dysfunction.

So we generated mice lacking or with telomere dysfunction either in the alveolar type 2 cells, in the fibroblasts, in the club cells, or in basal cells. And we saw that the relevant cell type in the lung is the alveolar type 2 cells. Only when you induce telomere dysfunction in AT2 cells, you have interstitial lung fibrosis.

So this is telling us that we have to target whatever therapy to elongate telomeres to the alveolar type 2 cells.

This is what we have done. So we have used mouse models. We have developed mouse models to show that if we target telomerase to alveolar type 2 cells, this is sufficient to stop the progression of pulmonary fibrosis in mice.

So this is already old work. So I'm not going to describe the work to you, but I will show you that we have shown that mice in which we induce pulmonary fibrosis associated to short telomeres, if we treat them with empty vector, 100% of them progress to severe fibrosis in the lung, but if we treat them with an AAV vector carrying the telomerase gene, we can clearly stop the progression of fibrosis, even reverse fibrosis.

And this is telling you that telomerase gene therapy could be a good therapy for lung fibrosis. At the molecular level, we have shown that telomerase is rescuing the inflammatory response associated to fibrosis. Even just three weeks after treatment is rescuing all the pathways associated to fibrosis. And we also have shown that it increases senescence, decreases DNA damage.

So telomerase is by elongating short telomeres sort of curing or stopping the progression of this disease in mice. So we have also isolated the AT2 cells and showed that they express telomerase and how this telomerase is rescuing pathways related to DNA damage and inflammation and fibrosis.

So what we have, I think, demonstrated, and we are convinced that if you target short telomeres in a disease like pulmonary fibrosis, you can actually have a chance to have really curation because you rescue basically everything associated to this disease.

Safety of Telomerase Therapy in Cancer Models

So one thing we wanted to see is how safe is this. And what we did is to do an experiment, a safety experiment, in which at the same time that we put telomerase, or we activate an oncogene in the lung. An oncogene, in particular, we activate KRAS. KRAS is leading to lung cancer.

So we put telomerase either before activating KRAS or at the same time that we activate KRAS in mouse models. And we wanted to see if in this scenario of a protumorigenic scenario with an oncogene active in the lung, telomerase was leading to more cancer. Because we haven't seen telomerase leading to more cancer in a regular mouse treatment. We did that in 2012. But we wanted to force the situation and have an oncogene there and see whether telomerase was changing anything in the history of these tumors.

And you can see here that putting telomerase was not increasing either in the pretreatment group or the simultaneous treatment group with the oncogene activation. We didn't see more tumors or bigger tumors or more size with more mice with tumor. So telomerase basically was not changing the tumor growth in this mice, so indicating that at least in these mouse models telomerase was being safe.

So basically this leads to the idea that maybe we can use telomerase gene therapy to treat diseases like pulmonary fibrosis, because we have shown in mouse models that telomerase is elongating short telomeres, and this is increasing survival in these mice.

Telomer Therapeutics

So we founded a company in 2021 called Telomer Therapeutics with my collaborator, Fátima Bosch. She's an expert in gene therapy. And if you are interested, you can see in the web page, this is the company that has a goal to treat fibrosis with telomerase.

Mouse Model of POT1 Mutation in Pulmonary Fibrosis

So in my lab, we're a basic research lab, and we are interested in understanding, as I said, the role of telomeres in disease. And we have been making mouse models that carry the mutations that have been found in humans, in different diseases in humans associated to telomeres.

So one of these telomere binding proteins, shelterin proteins, is called POT1, protection of telomeres 1. And it has been found mutated in pulmonary fibrosis. So there is a mutation in humans associated to pulmonary fibrosis in this protein.

So to understand the relevance of this mutation, and this is still unpublished work, we have generated mice that carry this mutation and see what happens. This is a work of Paola Martínez and Raúl Sánchez. It's not published yet.

And we are delighted to see that when a mouse carries this mutation in POT1, it has shorter telomeres like the humans. And you can see not only shorter telomeres. You can see that by FISH, which is a fluorescence technology, or by Southern blot. Telomeres are shorter in these mice.

And also, they have telomere aberrations that we discovered for the first time that we call multi-telomeric signals. When there is something wrong at the telomeres, you have several telomeric signals. Instead of having four, you will have more than one at every chromosome end.

So this is something similar to the telomerase knockout by having this mutation in POT1. Actually, these mice, we have generated generations with the telomerase knockout. I didn't tell you, but if you take a mouse without telomerase and you cross it and generate a second generation, they live less and less. There is a shorter lifespan with each generation.

And we see that this POT1 mutants also, by looking at the weight, you can see there is a weight phenotype, a size phenotype very similar to the telomerase knockout. And what is more important, the telomere shortening with increasing generation. So this is similar to a telomerase knockout. And of course, this could be also a good mouse model to understand telomere dysfunction associated to pulmonary fibrosis.

And I think it really proves the importance of telomeres at the origin of diseases like pulmonary fibrosis. And you can see also more DNA damage associated to this mutation with increasing generations. This is something very similar to the telomerase knockout. So we're very excited about this.

Kidney Fibrosis and Cell-Specific Effects

So another disease that has been described in people with shorter telomeres than normal is renal fibrosis. It's a very prevalent disease and we recently showed in 2021 that short telomeres are also at the origin of kidney fibrosis.

And to show that what we did is that we generated a mouse model, which is a telomerase deficient model that per se does not develop kidney fibrosis, but if we challenge the mice with folic acid, which is damaging to the kidney, we use a dose that doesn't do anything to the wild-type mouse, but in the context of short telomeres, this leads to kidney fibrosis.

And this shows you or demonstrates that short telomeres are at the origin of kidney fibrosis because only the mice with short telomeres develop kidney fibrosis when we challenge the kidneys with folic acid.

And you can see, you can look at the paper, but you can see how the mice that have short telomeres, when you challenge them with folic acid, are the ones that develop kidney fibrosis, which is telling you that kidney fibrosis, the short telomeres are the origin of kidney fibrosis.

We discovered something also in this paper that I think is also relevant for cancer, for the origin of cancer, because we found that short telomeres were also associated to a change in the cell identity. It's something called epithelial to mesenchymal transition. I'm sure you all know about this, EMT. This is at the origin of cancer, but it's also at the origin of fibrosis.

And we demonstrated in this paper that short telomeres could be generating this transition from epithelial to mesenchymal identity, which is at the origin of aging diseases and cancer diseases.

So, again, showing the importance of telomeres, short telomeres, in the origin of age-associated diseases, including cancer.

So I wanted to finish. I have still well this is a disease. I wanted to bring you similar to what we did with the lung we have been studying which cell type in the kidney relevant which cell type in the kidney you have to target if you want to correct your telomeres in the kidney to treat kidney fibrosis.

In the case of the kidney we saw that epithelial cells and basal cells when we induce their telomere dysfunction we get kidney fibrosis so again indicating which are the cell types that we would have to target in the kidney. This is still unpublished as well.

Telomeres and COVID-19 Severity

So I will finish with COVID-19. When COVID started I was very interested in this disease because very early on we learned that the SARS virus infects the epithelial type II cells in the lung and it generates lung fibrosis.

So to me this was reminding me that maybe short telomeres could have to do with the disease. So people with shorter telomeres in the lungs maybe were the ones that would develop a more severe disease. This was pre-vaccination of course the beginning of the pandemics.

And in order to test that, we were able to manage to take blood from patients in Spain. This was previous to the vaccines in a field hospital in Madrid. And we wanted to see whether there was a correlation between the severity of COVID and shorter telomeres in these patients. We were measuring telomere length in the blood.

And we found that there was a correlation between shorter telomeres in blood and more severe disease. As I said, this was non-vaccinated. There were no vaccines back then. And this has been also published at the same time, more or less, by a group in Belgium.

So there seems to be a correlation between short telomeres and the severity of COVID. Then later on, we published this this year, we have taken lung samples from... These were cancer patients, because it's not easy to get a lung sample, as you can imagine. Nobody wants to have a biopsy of the lung.

So these were lung cancer patients that had or didn't have COVID, right? And then we have studied fibrosis and telomere length and see whether there was a correlation between fibrosis and telomere length in the COVID patients.

To start with, you can see that COVID was generating fibrosis. So COVID patients had more fibrosis in the lung. This was normal parts of the lung, not the cancerous part of the lung in these patients. And you can see that by Masson's trichrome or, for instance, smooth muscle actin levels. And you can see that COVID patients have more fibrosis. We already knew that.

But then we saw that there was a correlation between telomere length in the lung and fibrosis. So the patients that had the longest telomeres had the less markers of fibrosis in the lung, indicating that short telomeres could be really at the origin of the disease. Of course the virus is at the origin of the disease but short telomeres could be impacting on the severity of this disease.

And this could also mean that it would be interesting to activate telomerase for all these people that has now pulmonary fibrosis as a consequence of having had the COVID disease. And this is the same you can see here in the AT2 cells, which are the cells that are infected by the virus, that there are shorter telomeres in the lungs of the patients that had COVID.

Conclusion

So basically, I will finish here. I hope I have shown you that telomeres matter for aging and there could be a way in which we can intervene in order to delay aging and to treat diseases associated with aging. Thank you very much.

Q&A

Aubrey de Grey: Thank you so much for your... Two minutes. That's great so yes so we have time for a question or two or three um microphone microphone where's the microphone my kingdom for a microphone oh here it comes here it comes.

I just want to say you know um this is the kind of wonderful talk that got Maria where she is today to be leading leading a you know the Spanish equivalent of the NCI or something like that I guess that would be a good description of CNIO, right?

Maria Blasco: Yeah. Yeah, CNIO is the Spanish National Cancer Center. So I work in the...

Aubrey de Grey: So this is also to tell you the importance for us is that telomerase is not tumorigenic, right? Several years ago, Maria and I did a kind of double act for a general lay audience somewhere in Spain, and we were very happy that we were able to convince, I think, probably like 20% of the audience to be more optimistic about the prospects for doing something about aging. So, yeah, this is what it takes. We need to have the whole community doing this. Maria was also one of the first signatories to the Dublin Declaration a year ago. Thank you. Anyway.

Q1: I don't think I'm the only person who has the simpleton's understanding of telomere length in that the understanding is that the... You know, you're born with a... I mean, the DNA initially has a long, long, whatever long is. Yeah, one of the lengths. 100, I guess it is, whatever that unit was. And then as it divides, it shrinks, shrinks, shrinks, and it becomes short. But my understanding is it's kind of like a gas tank. It's good, it's good, it's good, and then it's not good anymore. So why does shorter matter unless it's at the critical shortness?

Maria Blasco: While you have telomeres, even if they are on average short, we have shorter telomeres than mice. It doesn't matter. We live longer because our telomeres are protected, because our telomeres shorten very slowly compared to a mouse. It's when the telomeres become very short, then the chromosome end is not protected, and this leads to chromosome fusions and other aberrations, and this is related to...

We know my group and other groups have demonstrated that short telomeres in the stem cell compartments block the ability of stem cells to regenerate tissues. If you cannot regenerate tissues, then you have disease, and we think these diseases are the age-associated diseases and...

I think Walter was actually asking more about like the variance of TL. Oh okay.

So there was very interesting. There was a paper published I think a couple of weeks ago by my postdoc supervisor Carol Greider. She was also one of the discoverers of telomerase, Nobel Prize, using a technique that allows for the read, the reading of long reads in the genome. So you can actually read the telomeres, the full telomeres. She published that on Science.

I think this was an important work because she found that chromosome 17 had the shortest telomeres. And this was in a group of 140 people. So probably is when some chromosomes, the ones that have shorter telomeres, reach a short length when there is trouble, right? When there is trouble and you are starting to have chromosomal instability, impede the stem cells from regenerating.

So it's very important to understand which chromosomes, how it works, which life habits are impacting on this rate of telomere shortening. What we know, one good thing about telomerase, and this has been shown in yeast and we show it in mice telomerase would go to the short telomeres and elongate them.

So if you activate telomerase you will be rescuing the short telomeres. You don't need telomerase all the time. Actually our gene therapy these vectors are non-integrating. They will be diluted out. And you just need telomerase for a few cell divisions to rescue the short telomeres. And then you will have some extra life, right? Because you have rescued the short telomeres.

Aubrey de Grey: So who's got the microphone? Who has the microphone? Stand up. Yes. Yes, thank you.

Q2: So given that you've demonstrated that it's possible to extend mouse lifespan by lengthening telomeres, do you think it would be possible to elongate the telomeres of Ames dwarf mice, which currently hold the record for the longest mouse lifespan, and thereby create mice that live longer than five years and finally break that barrier?

Maria Blasco: That's a very interesting suggestion. We haven't done it, but it would be interesting to do it, because maybe these mice have already maximized the lifespan, and it doesn't matter to put more telomerase. Maybe not. Maybe we could increase the lifespan. That would be interesting. We haven't done the experiment. But it an interesting experiment yeah.

Aubrey de Grey: So I afraid we only have time for one more question because the staff need to clear the room set up for the gala dinner though of course the bar will be open in the meantime so you will not be short of your refreshments. Maria remembers the way the Cambridge meetings used to be in the same way. Okay, so one more question before we go.

Q3: So, actually, the KRAS thing is kind of reassuring, I'd say, but we're still much larger beings with many more cells, and besides Liz Parrish, do you know any other animal with more cells than mice that has been treated?

Maria Blasco: No, we have treated mice and followed them until the end of the lifespan, and we didn't see more cancer, we saw less cancer, and then we did an experiment with lung cancer. No, we have not put telomerase into any larger animal. Of course at the end this therapy this therapeutic product will have to go through the regulatory agencies and we will see right but no we haven't tried in a larger animal.

Aubrey de Grey: Alright thank you so much Maria thank you.

Insights

Rate of telomere shortening as longevity determinant: Initial length is irrelevant (e.g., mice vs. humans); power-law dynamics across mammals/birds reveal epigenetically tuned attrition rates as the evolved pacemaker of species lifespan, prioritizing it over genetics.
Short telomeres as causal via stem cell failure: Critically short telomeres (not average length) trigger unprotected ends, fusions/aberrations (e.g., multi-telomeric signals in POT1 mutants), blocking tissue regeneration; telomerase preferentially targets shortest telomeres (yeast/mouse data), enabling transient activation for durable rescue.
Dual role in aging/cancer: Short telomeres promote instability/EMT fueling both fibrosis and oncogenesis, but ultra-long telomeres (via reprogramming beyond blastocyst maxima) paradoxically protect against tumors/spontaneous carcinogenesis, decoupling telomere maintenance from malignancy.
Cell-type specificity trick: Disease modeling via conditional shelterin knockout pinpoints AT2 cells (lung fibrosis), epithelial/basal cells (kidney fibrosis) as origins; target TERT delivery here synergizes with damage (e.g., bleomycin/folic acid) to cure root cause, outperforming antifibrotics.
Safety in protumorigenic contexts: No acceleration of KRAS-driven lung adenocarcinoma despite concurrent/prior TERT; lifespan extension without cancer liability due to delayed instability rather than generalized proliferation.
Therapeutic vectors: Non-integrating adenovirus/AAV for dilution post-rescue; single systemic/middle-age dosing yields multi-parameter rejuvenation (glucose/skin/cognition).