An Interview with María Blasco on Telomeres and Telomerase

The Life Extension Advocacy Foundation (LEAF) volunteers recently interviewed María Blasco, on the occasion of her presentation at the Ending Age-Related Diseases conference in New York earlier this month. Blasco is one of the leading researchers in the field of telomere biology, particularly the role of telomerase and the prospects for developing telomerase gene therapies to slow aging by lengthening telomeres globally throughout the body. This should have the effect of putting damaged cells back to work, resulting in better tissue maintenance and function, but quite possibly at the cost of increased cancer risk.

Telomerase gene therapy works to achieve this goal in mice, extending life and actually reducing cancer risk, possibly because of improved immune suppression of cancer overwhelming any increased generation of cancerous cells. There is some debate over whether or not the same approach will be safe in humans. Humans and mice have very different telomere dynamics, and the balance of effects may or may not be similar. It seems likely that we'll find out the direct way as human trials and clinical therapies become more widespread over the next decade.

You and your team recently showed that it is the rate of telomere shortening that predicts the lifespan of a species rather than the total length of telomeres. Does this discovery confirm the role of telomere attrition as a primary cause of aging rather than a consequence?

I think this study that means that telomeres are important in determining a species' longevity. It's not something that happens only in humans, where it's already clear that in humans, telomere length matters, because there are humans that have mutations in telomerase, and they are going to have diseases associated with telomere shortening, which means that telomere shortening rates are very limiting for humans. We didn't know whether this was general to other species or only something particular to humans. In this study, we see that telomeres seem to matter across evolution in different species, from birds to mammals. It's not the telomere length that matters but the rate of telomere shortening. So, we see that the rate of telomere shortening actually fits into a power law curve, and this predicts the longevity of a given species.

Could it mean that telomere shortening rate could be a suitable aging biomarker to test interventions against aging with?

I think so; telomere shortening rate is important in humans in order to determine if anyone is at risk of prematurely developing diseases associated with short telomeres. It's not as important to measure telomeres once, because this probably is not going to be very informative, but the rate at which telomeres shorten may be more informative of the risk of developing any disease related to short telomeres.

Telomerase has many effects that are independent of telomeres. Can you see that they matter in aging?

Well, it is interesting because we have, in the past, demonstrated that we can extend the lifespan of mice by using telomerase, but it must be wild-type telomerase; if we use catalytically dead telomerase, then we don't see this lifespan extension. So I would say that in order to see effects of telomerase in lifespan, you need it to be catalytically active telomerase, and this is the canonical pathway of telomerase, which is elongating the telomeres. At least in our hands, this is the mechanism by which telomerase can increase longevity: by extending short telomeres.

Would you say that the telomere mechanisms and the dynamics are really that different between mice and people?

I think humans and mice are not that different. What is very different is the rate at which mice experience shortening telomeres, or in other words, mice are much worse than humans at maintaining their telomeres. So, I think this makes a difference. So mice shorten their telomeres really fast, we still don't understand why compared to humans, but now we also know that different species shorten their telomeres at different rates, and I think it's very interesting to study that. We don't know why. For example, the elephant and the flamingo have the same rate of telomere shortening and they have similar longevity; why is that? Then a mouse has a much faster rate of telomere shortening and a shorter longevity. I think this is a very interesting question to solve in the future.

Link: https://www.leafscience.org/an-interview-with-dr-maria-blasco/

Comments

@Reason, these clinical trials with telomerase that you talk in your last sentence, were announced in 2017. Are there any news about that?
Thanks

Posted by: Josep at July 25th, 2019 11:59 AM

Hi there! Just a 2 cents.

''So mice shorten their telomeres really fast, we still don't understand why compared to humans, but now we also know that different species shorten their telomeres at different rates, and I think it's very interesting to study that. We don't know why.''

Mice lose telomeres really fast because of their masterplan/blueprint, which is: high-reproduction, short-lifespan, little genetic/resources for somatic tissue maintenance/repair that is needed for longevity. It's the 'live fast, die young' model for mice. Mice are about 'recouping lost numbers' in the specie, since they only live 2 years/their numbers dwindle quick/thus the body puts all the resources/translocates to sexual resources (leaving none for longevity/self-repair), reproduction is primordial to make the mouse specie survive. And, that means, fast puberty and adult entry onset; so they are capable of making offspring - Quick. In less than a few months - they are making offspring. This means, fast aging, shorter time to each phase of the aging process (childhood, teenagehood, adulthood, seniorhood, death). Reproduction falls teenagehood to adulthood. Exactly, the inverse spcie master plan, of naked mole rats (also rodents) that have late puberty, remain neotenous, have brain plasticizing until adulthood/puberty/repdroduction, reproduce much later and
live 35 years.

''For example, the elephant and the flamingo have the same rate of telomere shortening and they have similar longevity; why is that? Then a mouse has a much faster rate of telomere shortening and a shorter longevity. I think this is a very interesting question to solve in the future.''

Because telomeres shortening rate dictates longevity - number of cell cycles possible in the long run. Telomeres must remain capped, tall, methylated and 'shorten' the least possible/slowest possible. Telomeres are the chromosomes' end termini DNA - it'S crucial for chromosomal and genomic function.
Faster shortening of telomeres means that the body is experiencing oxidative stress and DNA loss, oxidized DNA is not repaired, progerin/prelamin A will accumulate/lipofuscin too and methylome is demthylating creating a wide-activation of genes that contribute to inflammation (unsilenced inflammatory genes from TNF, p53, IL6, etc. Telomere damage (DDR) signals activation and demethylation of such genes - they are activated and not silenced anymore; leading to oxidative stress and accumulation of lesions/deletions/strand breaks in nDNA/mtDNA; excess emission/rise of ROS in mitos with age (which cause cataclysmic chains of damage down the line when ROS are not quenched correctly anymore/ROS must be kept in balance for ROS-signaling but with ROS overtakes the Redox leading oxidative stress milieu - this accelerates the telomere shortening rate) and, the loss of important histones (H3K) and methylating cytosines (5metC)) which allow the genome to stay young, functional, activating anti-inflammation and fit.

Just 2 cents.

Posted by: CANanonymity at July 25th, 2019 3:45 PM

"resulting in better tissue maintenance and function, but quite possibly at the cost of increased cancer risk." - and yet this is not what happens in mouse studies, in fact, quite the opposite.

"Humans and mice have very different telomere dynamics" - no, not really. They have a faster rate of telomere shortening and hence epigenetic change via TPE-OLD.

Posted by: Steve Hill at July 25th, 2019 4:28 PM

@CANanonymity
It is not months the mice can reproduce in 20-something days after the birth. So 2 years lifespan is 24 generations. So if we take the equivalent human minimal generation to 13 years(we can take 20, but longer generations will scale even more) then by that metric humans should be able about to live 13x24 =312 on average. We are not bigger and slower longing mice, however.

Posted by: Cuberat at July 25th, 2019 7:50 PM

Hi Cuberat! Thanks for that. Just a 2 cents.

Some children had kids, I read that some children girls became pregnant at 10-11 years old, obviously these are rarer than rare and most kids have children starting around 12-13. But, some rare kids, are more fast than that, they become parents, when they are still children themselves; not even teen (13) yet. I would not be surprised that we one day see a child girl getting pregnant at 9.
Yes, you'Re right mice can have offspring this quickly in days, it demonstrates that they are truly about 'sex reproduction' in the fastest possible to curb mortality/falling pop. numbers from living a very short life. Children being capable of having children, in the earliest, is not good in the long term - animals that live the longest Retard puberty....if we hit puberty at 30...we might live 150-200 years, that's how dire the effect of reproduction is on the body (because there is a resource interchange/trade-off between sexual resources and longevity/self-repair resources; the later the puberty, the more resources you have for your longevity and the less you have for reproduction; vice versa for a short life, it's evolutionary biology for specie survival (reproduction vs longevity)). For example, quahog clams from iceland live up to 523 years in the rarer specimens but many reach 150-200 years - and all show very late puberty onset (by the age of 35, they still have immature gonads (their sexual organs are underdevelopped for a long time - showing that sex reproduction is highly costly on lifespan (because sex resources vs longevity resources, they are limited. Humans are special in the sense that we can have reproduction for a long time but we also become sexually menopaused/andropaused/sexual senescence; at that point, the body puts more resources into longevity repair because the 'sex period' is done (your purpose of reproducing is done, the body switches into 'self-preservation' mode at the cost of sexual resources (thus, leading to sexual reproduction arrest/senescence))). Humans can live long lives and be sexually healthy, that's because they push back the menopause/andropause period entry and keep a younger body; sexual reproduction is tied to health/fragility/IGF/HGH (Human Growth Hormones)/Hormonse(sexual hormones)/endrocrinal system/frailty...such as estrogen (and testosterone converted to estrogen (by aromatase)) activating estrogenic receptors, which activate telomerase; leading to protection of DNA/curbing of damage/improvement of health and fragility.

It'S interesting that if applied mice generations of offspring calculus we would reach about 312; but, as you said, that does not apply since we are humans and our specie survival/longevity/reproduction plan is different than a mouse's.

Just a 2 cents.

Posted by: CANanonymity at July 25th, 2019 10:16 PM

In the edible dormouse (Glis glis), a small hibernating rodent, in contrast to humans and other animals, telomere length significantly increases in the second half of its life. The older they get, the more they rejuvenate their cells? Since edible dormice, similar to other hibernators are long-lived and can reach a lifespan of 13 years in the wild18, the authors hypothesized that they would show high levels of investment into somatic maintenance and hence slow shortening or even stabilised levels of relative telomere length. https://doi.org/10.1038/srep36856 https://www.sciencedaily.com/releases/2016/11/161124081558.htm
According to the metabolic telomere attrition hypothesis: telomeres are finely regulated according to an individual's energetic state, with TL attrition being almost absent during torpor, when hardly any energy is needed owing to the substantially reduced metabolic rate. Telomeres can even be elongated following torpor when individuals become active again, increase their metabolic rate and have plenty of access to food resources.
See Telomere attrition: metabolic regulation and signalling function?
https://doi.org/10.1098/rsbl.2018.0885

Posted by: Dmitry Dzhagarov at July 26th, 2019 4:04 AM

Hi Dmitry! Thanks for that. Just a 2 cents.

That's a really cool study, I'm guessing this reaches what happens to the Albatros bird...albatros bird can live decades (much longer than dormice) and they Too have telomere elongation - with age.
IT's incredible (and makes sense) that torpor or 'dorming dorm-ouse' sleeping mouse will greatly reduce teloemre shortening rate because of less energy demand/slower metabolistic speed/leading to less accrual of DNA oxidative damage/which means, less telomere shortening. It reaches also what polar clams do, they do long torpor sleep in the muddy sea bed, burrowed in the mud floor, in hypoxia/anoxia. Thus, they reduce their metabolism and during 'awakening' their increase their metabolism to compensate from 'ischemia reperfusion' ROS production (massive ROS burst the minute O2 rises from hypoxia/anoxia causing ischemic injury). They only 'Activate' themselves/their bodies when needeing to flee predators, finding food sources, otherwise they are motionless/still and do torpor many times - and for days on end (they are much more 'asleep' than 'awake'). Just like hibernation.

In albatros bird, they are 'removed' from population by predation or some reason...because their telomeres lenghtened just like a dormouse's with aging - and, they still die. This means it's not really aging of telomere shortening rate...but some other problem...most likely, the same with dormouse, they may face predation which obscures results...in lab, protected from predators and with ample food/care, they could live much much longer. We may only know the half of the story...their cells may increase in telomere size...but during that last part of life, there may be Something happening just as sudden rapid telomeric 'Burst' loss....that happens (as seen in C.elegans whom have a 'ROS' burst at mid-life, so they encounter a life altering event later - in dormouse, they may experience this, at the near end - and, has Maria Blasco showed, it's the telomere shortening rate that dictates lifespan (more than the length of the telomeres), and also, the Total number of Short Telomeres dictates 'health state' - and longevity - in the long run, too. Researches must get a bigger portrait picture of telomeres - 1 Telomere means Nothing...it's the total.

Just a 2 cents.

Posted by: CANanonymity at July 26th, 2019 1:29 PM

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