FightAging!
7-28-19

https://www.fightaging.org/archives/...nd-telomerase/

The Life Extension Advocacy Foundation (LEAF) volunteers recently interviewed Marķa 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.