Telomeres: The Longer the Better

Mice have much longer telomeres than we do, long enough that telomeres never get critically short in a mouse lifetime.Yet, when designer mice were engineered to have even longer telomeres (hyper-long by any standard, longer than we can account for the use of them), these mice lived longer and were healthier in every way than mice with normal-long telomeres.Lab mice usually die of cancer, and these with the longer telomeres were protected from cancer, along with every other ailment that was looked at.First, I ask your indulgence if I harp on the obvious: this result is not consistent with the prevailing theory of telomeres.

In most vertebrates, telomerase is rationed so that telomeres are allowed gradually to shorten over a lifetime, and this is explained by most evolutionary biologists and geroscientists as an anti-cancer program.According to theory, in each species, telomere length has been optimized by natural selection as a compromise between longer telomeres (allowing stem cells to last longer without senescing) and shorter telomeres (which provide a firewall against cancer, a drop-dead signal when unchecked cell growth might be life-threatening).In contrast, experiments have frequently shown that longer telomeres lead to a lower cancer rate.

Blascos new result is a clear case.We cant explain telomere dynamics as a cancer prevention program.(For background on what telomeres are and how they function, I refer you to my early blogs on the subject.)But beyond this, there remain many mysteries.This study highlights the truth that we dont understand the mechanisms.

How exactly are hyper-long telomeres working on a biochemical level? What can a hyper-long telomere do that an extra-long (regular mouse) telomere cant do?Known mechanisms include:Senescent cells.Much of the literature has focused on the importance not of average TL but on the shortest because a few cells run out of telomere and become senescent, and they poison the rest of the body.This is called SASP, for Senescent-Associated Secretory Phenotype.Telomerase as an enzyme.

Telomerase is best known for its ability to elongate telomeres, but there is evidence that it has other effects as well.TPE the telomoere position effect.This is the only one that fits.Long telomeres wrap back around the end of the DNA, actually masking expression of the genes closet to the end of the chromosome.

The Blasco study raises the possibility that were better off when the genes near the ends of the telomeres are silenced.In my story, genes that have legitimate uses are turned against the body in old age.But there are no pure aging genes because its hard for such genes to evolve uphill (against individual selection).Has Blasco discovered an exception? Are these genes near the end of the chromosometrue aging genes? Or is it an example of evolved pleiotropy [my blog; BioRxiv preprint].From Munos-Lorente, 2019, https://www.nature.com/articles/s41467-019-12664-x/ContextMaria Blascos Madrid telomere lab has been at the forefront of this field for more than a decade.

The new experiment is right on the bleeding edge of biotech and genetic manipulation, where the Blasco lab has staked out territory.I learned that you cant make mouse egg cells with long telomeres because the bodys process of making the egg standardizes the telomere length as it wipes clean the epigenetic markers and rewrites a starting imprint.How to get around this? Blasco grew eggs just until the third cell division (8 cells), then injected embryonic stem cells that had been grown saturated with telomerase to give them the hyper-long telomeres.Yes, this tiny embryo, just 8 cells in size, was micro-injected by hand with many stem cells, cloned to be genetically identical, so they would not fight immunologically with the cells already in the embryo.

The injected cells were marked with a gene for green fluorescent protein (GFP) so descendants of the long-telomere stem cells could be identified later.The article doesnt indicate exactly how, but the original 8 cells were induced to bow out, so that 100% of the cells in the mice that grew from these embryos had the GFP marker, and presumably, they all had the hyper-long telomeres as well.Thus, the lab made designer mice out of cells, every one of which had telomeres that (AFAWK) were longer than nature has any use for.The stated inspiration for the experiment was to determine whether the hyper-long telomeres led to any detrimental effects.

What they found was that hyper-long telomeres were beneficial in every way.The effect seems to be related to caloric restriction, since the mice are noticeably leaner and their insulin sensitivity remains high at advanced ages when mice usually become insulin resistant.Perhaps independent of these changes, the hyper-long mice had less DNA damage with age and more efficient mitochondrial metabolism.Telomeres are full of surprises, and this may signal a new telomere mechanism, probably epigenetic, that is undescribed previously.

But if it is to be described with known biochemistry, the only candidate is TPE, the telomere position effect.Long telomeres fold back on the end of the chromosome, masking some genes that are located near the end.It is already known that unmasking those genes when telomeres become short has pro-aging effects.

But the new result involves telomeres that are (presumably) longer than anything that is found in nature or in the mouse evolutionary history.It follows that the hyper-long telomeres are folding back so as to mask genes that just happen to be near (but not to near) the chromosome end.In this picture, these genes just happen to be pro-obesity, or insulin-blocking.

The effect is not evolved, but just a chance occurrence.I dont like such explanations from chance, so Id bet on a new telomere mechanism that is yet to be characterized.Related study from the Blasco LabAnother study (last summer) from the Blasco lab looked across species for relationships between telomere dynamics and species life span.This follows on the work of Seluanov and Gorbunova a few years ago.

The previous work concluded that telomere length is most closely related to the body mass but not lifespan across rodent species.The authors tried to relate this to Petos Paradox, which is the observation that large, long-lived animals ought to have much higher cancer rates than observed, assuming that cancer results from a random transformation event in a single cell.In the new work, Blasco finds the closest correlation between lifespan and the rate of telomere loss.We observed that mean telomere length at birth does not correlate with species life span since many short-lived species had very long telomeres, and longlived species had very short telomeres.In short-lived species, telomere erosion happens much more rapidly: 7,000 base pairs per year are lost in mice, compared with less than 100 in humans.In the old story [as I have reported it], telomeres shorten over a lifetime because stem cells lose a little telomere length with each cell replication.

But this huge difference in telomere attrition rates cant be accounted for in this way.Stem cells in mice dont replicate 100 times faster than in humans.So something else is going on.

Probably, there is partial expression of telomerase in a way that is programmed under control of natural selection.Telomere shortening with age has evolved in a way that contributes to aging via TPE.But (probably, by my account) telomere shortening is not the principal means of programmed aging, because the correlation between telomere length and age is too weak.

Mike Fossel continues to promote the idea that relative but not absolute telomere length is a good indicator, and indeed a driver of aging.That sounds like it accords in the abstract with the new results, but details remain elusive.The Bottom LineIts clear that telomere shortening plays a role in aging, though not a dominant role.Its clear that telomere shortening is completely under the bodys control, therefore an evolved adaptation.

Beyond this, the subject seems complicated, and there is good evidence that there are mechanisms involved beyond what we know about.At a given age, telomere length in humans does not correlate with health risks.On this basis, I have argued that various methylation clocks are far better measures of biological age, and perhaps the GrimAge clock is best.