Telomere Dynamics with Age are Very Different Between Mammalian Species

Telomeres are caps of repeated DNA sequences at the ends of chromosomes. They shorten with each cell division, a part of the mechanism that ensures somatic cells can only replicate a limited number of times. Telomerase acts to lengthen telomeres, and in humans telomerase is only active in stem cells. Thus our cells exist in a two-tier system, in which only tiny populations of privileged stem cells are permitted unrestricted replication, while the vast majority of somatic cells are limited. Matters are similar across all higher animals, and this state of affairs likely evolved because it keeps cancer to a low enough level, and pushed off far enough into late life, for allow for evolutionary success.

A lot of ink has been spilled on the topic of telomere length because, statistically across large populations, average telomere length and proportion of short telomeres tends to decrease with advancing age. Given that stem cell activity declines with age, this is most likely a reflection of a lower pace of creation of new somatic cells with long telomeres. The human data is complicated by the fact that telomere length is most commonly measured in immune cells from a blood sample, and is thus a very dynamic measure influenced by the day to day reactions of the immune system. In individuals, there isn't much anyone can do with measures of telomere length, given that it is so variable over time and between people of similar health and age: it is a terrible biomarker for any practical purpose.

Further, can we actually use anything that we learn about telomere dynamics in other species? It is well known that mouse telomere dynamics and telomerase expression are quite different from that of humans. This might make us suspect that positive results from telomerase gene therapies in mice, where life span is extended and health improved, without raising the risk of cancer, may not hold up in humans. There is no particular reason why increased cancer risk through putting damaged cells back to work will be balanced in the same way by improved tissue function and improved immune function, from species to species. The research and development community will find out in the years ahead by trying telomerase gene therapies in primates and then humans.

I feel that the open access paper here adds to doubts about the value that the research community can extract from a study of telomeres and telomerase in other mammalian species, though the researchers don't present it in that way. If various short and long lived mammals can have such a range of telomere dynamics, what are we supposed to make of the data resulting from animal studies of any therapeutic approach to targeting telomeres?

Telomeres and Longevity: A Cause or an Effect?

Since telomere dynamics were found to be better predictors of survival and mortality than chronological age in wild populations, many cross-sectional and longitudinal studies have been conducted on different organisms with variations in maximum life span investigating the relationship between chronologic age and telomere shortening. Yet, some studies have reported a lack of telomere shortening with age or even an increase in telomere length in organisms with exceptional longevity. Therefore, studying telomere dynamics in long-lived organisms is of particular importance since they may have developed mechanisms that actively postpone senescence and promote effective defenses against the deteriorating effects of aging processes.

The naked mole-rat (Hetercephallus glabers/NMR) and the blind mole-rat (Spalax ehrenbergi) are both considered excellent models for studying aging. They both exhibit extraordinary longevity with a maximum lifespan of approximately 30 years in NMRs (10 times longer than any other rodent of the same size) and 20 years in captivity for Spalax. They exhibit lifelong maintenance of superior anti-aging mechanisms leading to unchanged physiological functions and negligible senescence. Moreover, both of these mole-rats live in a presumably relatively stressful environment due to their subterranean lifestyle where they experience darkness, low oxygen and high carbon dioxide concentrations. Despite all these common features, NMRs and Spalax belong to different families; they are different in size and have different social lifestyles.

Whether telomere length is a "biological thermometer" that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence, and promote longevity is still an ongoing debate. In the current study, we aimed to investigate the relationship between telomere length and age in NMRs and Spalax. We tested blood telomeres in NMRs and three different tissues in Spalax and compared each one with a short-lived animal of their size.

While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.

Comments

OT: There are now 3 projects at Zooniverse somewhat related to (or useful for) aging research:

Rodent Little Brother: trying to automate the measurement of mouse behaviour (useful for neurodegeneration preclinical trials).

Etch a Cell: trying to teach machines to recognize cell nuclei shapes (nuclei with odd shapes are seen in Alzheimer's and cancer patients).

Monkey Health Explorer: basic research of rhesus macaques' immune system and behaviour (a primate species very used in medical research).

If you don't have money to donate to aging research, maybe you can contribute some time there.

Posted by: Antonio at July 11th, 2019 3:09 PM

Hi! Just a 2 cents.

I don't think we should underestimate telomeres/telomerase. The cancer concerns are very valid but if we decide to stop telomerase (like WILT was supposed to do), it could have much bigger consequences, from stem cells to somatic cells to senescent cells. I think what would happen is a form of progeria would happen (just like HGPS progeria), which would thus lead to accelerated aging. Telomeres shrink...but the speed/rate at which they shrink - is Already Abated...by telomerase. If you cut telomerase, nearly 100% sure, this will have an effect on aging speed. Thus, Faster telomere shortening rate. Telomeres shrink even so with telomerase adding telomeric DNA - but that's because No NET gain, thus only slight abating (telomerase seems to add about 400 base pairs/year, if only talking of hTERT transcript and not combined with hTR RNA TTAGGG template subunit (when they synergize, much faster lengthneing). If there is net gain, then no, the telomere will Not shrink, they will rise - despite the telomere shortening continuing its course. Net gain - negates loss. We are all experiencing net loss, and hence why telomeres shrink despite telomerase activity is detectable in certain cells and keeps on adding telomeric DNA - it's not enough to negate the loss. Testicular/primordial germ cells of male gonads show dramatic telomere elongation with age (paternal sperm telomere lengthening). Cutting telomerase may make men sterile and suffer faster andropause, and also less telomerase activity because the testosterone levels will lower (testosterone via aromatase converts into estrogen, which itself activates estrogen/estradiol receptors in human body - which they activate hTERT/telomerase. Women will also suffer of that and have faster menopause and may become sterile too. Menopause is especially hard on women - women who go through menopause sooner have faster mortality/death from heart dysfunction. Stem cells would accelerate in aging, this would mean less body repair, while immune system would be greatly compromised - telomerase is a double-edged sword for cancers high-jack it...but you need it (to keep add telomeric DNA). Immune system function is More Important than possible risk of cancer by telomerase being hijacked. Immune function (by telomerase) = stop cancer. If you lose your immune system =

Game over. Cancer will take over.

It's why messing with telomerase to stop it, is dangerous - More So than the danger of having high telomerase activity which can cause cancer (cancer hijacked)/by accelerated cell division.

There's been enough telomere studies on leukocytes telomeres to know that they are very surrogates for immune function, lifespan and all-cause mortality. If you block telomerase, the leukocytes will show it and that will be a hit on immunity...

This study here on NMR and Spalax blindmole rat is still applicable, they say that NMR did not lose much telomeres; blindmole did - it lives over a third less long (20y vs 35y). Studies that want to refute telomeres...forget that telomeres are meaninful when you view their trajectories Over Entire Lifespan.If we compare our telomeres vs NMR/blindmole rat..there would be a clear difference...we lose them even slower than them...and, hence, why would we live 120 years. I don't even need a NMR/blind mole rat...just compare a fast aging human vs a slow aging one...it's right there: a Hitchinson Gliford Progeria Syndrome Person vs Regular Person, 500 base pairs/y loss vs 50 base pairs/y loss, 15 years vs 120 years. A near-perfect correlation/10x multiplier of faster loss in HGPS.

Also, HGPS people have more defective telomerase - because their redox milieu is oxidized (when GSH is oxidized/or depleted by a GSH-depleting agent...telomerase activity drops by 60-80%), GSH is low in them and they accumulate oxidize disulfides GSSG. All this contributes to telomerase exit and never going to telomeres to do its job. This demonstrates the danger of stopping telomerase in regular people - we could end up like HGPS people having accelerated aging - maybe not as drastic but say comparable to Werner Syndrome accelerated aging (another progeria one..but milder than HGPS, these fast aging people can live 40-50 years - they never reach centenarian age because they have faster telomere shrinking (about 200-300 pd/y). Stop telomere elongation/telomerase = form of progeria.

Just a cents.

PS: Also LEV is unfeasable - Unfeasable without maintaining telomere size - impossible; teloemres will shrink and will still die. Only feasable if telomeres go back up or are frozen - Telomerase (such as iPSCs epireprogramming - REACTIVATES telomerase via OCT/SOX/NANOG/ZincFinger proteins that can lengthen telomeres via telomerase or other alternate mechanism (ALT/Ku-67). The other way is with stem cells rebuilding tissues - but nothing is certain abou that (many mice studies have been done ith stem cells, with lackluster results). Net loss = No LEV.

Posted by: CANanonymity at July 11th, 2019 9:18 PM

Speaking of research, whatever became of the SENS crowd fundraiser for mitochondrial research? Wasn't it supposed to happen this spring and I never heard anything more about it.

Posted by: Morpheus at July 11th, 2019 9:37 PM

@Morpheus: IIRC, they fixed all or almost all the genes already, but they are under publication embargo and the peer review is taking too long. They are doing some aditional experiments for confirmation in order to publish.

Posted by: Antonio at July 12th, 2019 1:00 AM

We just discussed this a few posts down! Blasco has shown its the rate of shortening that predicts both average and max lifespan. It's interesting that NMR show no telomere shortening, at least in leukocytes. Supports the tentative observation that their mortality does not go UP with age. And cancer resistant too.

Posted by: Mark at July 12th, 2019 2:37 AM

Re@ allotopic expression of mt proteins - how will they control when those proteins should be produced? For example in mt biogenesis, let's say, how will the nucleus 'know' to start sending the relevant proteins? Sure there are already some nuclear encoded mt genes, but they have evolved to be that way and have the correct epigenetic and mt cross talk in place already. I assume that having these proteins constantly ON is not a good thing. Is it possible to implant the new mt genes next to already existing mt genes, so they can benefit from the existing epigenetic regulation?

It's only when you start to consider such issues you realise that moving the gene and expressing the protein might not be all that is required.

Posted by: Mark at July 12th, 2019 6:10 AM

Once again, it is the rate of shortening that counts with telomeres, not the total length. As they shorten they influence gene expression via TPE-OLD and their ability to form loop structures. Telomere attrition and the rate of that attrition is what counts.

We will be interviewing Maria Blasco today in New York about this, so you can expect us to publish the interview in the coming weeks which may clear up this continued confusion over why telomeres are a primary hallmark of aging.

Posted by: Steve Hill at July 12th, 2019 6:58 AM

CANanonymity,

Wasn't wilt supposed to target cancer cells only? Or is it a scorched earth approach?

Posted by: bmack500 at July 12th, 2019 7:58 AM

Hi bmack500! Thanks for asking. Just a 2 cents.

I'll beh onest it's been a long time have not checked SENS stuff, but if I remember yes it was that; WILT (whole (body) interdiction lengthening of telomeres) was targeting the cancer cells - but without even wanting it it could end up itself affecting other (non-cancerous) cells that depend on it. If they found a way to selectively target cancer cells without impacting the telomerase levels in other cells (like immune cells) then I am all for it - but not so sure about that. It has to be pin-point precise to spare surrounding non-cancerous cells.

If it is a scorched earth approach (I don't think so, it was always meant for cancer cells, but their whole body approach would have to be 'whole-body selective-to-cancer cells', it is nearly certain it will cause co-lateral damage to healthy cells, it reminds me much of chemotherapy and radiation to try to destroy cancer cells - you're not just killing cancer cells; healthy cells too. Anyways, we have not heard much of this therapy, it may be possible it was abandoned when realized immunity cells actually work with telomerase. Let's hope they can make it work just in cancer cells.

Just a 2 cents.

PS: On telomeres topic, most likely, like the albatros, NMR saw no telomeric DNA loss but unlike albatros saw no increase, while albatros see increase with age, just like male sperm has telomere elongation with age. Most likely, like albatros, NMR end up 'selectively removed' (faster than their possible 'real' maximal lifespan) from population through predation or killed another way - it's why you see telomere elongation in them. In NMR no loss but no gain, thus pretty nill (there is gain but it comes to the total tally of 0 bp/y loss/gain, thus no gain no loss). IT's possible they also face some kind of 'untimely' removal in the wild, in lab they could live longer; maybe as long as humans.
I don't think there is anymore need to do research on telomeres, what there is a need is to lower telomere shortening rate (we already can do that via antioxidatives...but it needs to be More drastic than that, BJ fibroblast cells already can go down to 9 bp/y when exposed to Vit B3/NAD/Nicotinamide (but you still die anyway around same max age)...so there won't be much reducing, but if done in All Cells, then yes, we would slow aging), and help telomerase (such as what Mrs. Parrish at BioViva did to herself with her hTERT therapy). Otherwise, you have cycloastragenol/astragalus and certain terlomarase activators (like ginseng, ginger, cinnamon, etc.....all these are nice (but you still die on these spices, at max MLSP or before)...but Still No Net Gain, still Net Loss of base pairs nucleotide of TTAGGG repeats, only mild Abating/slowing shortening by gaining a lil bit - Not *Net* Gain, you still lose some each year...telomerase needs to add More (although, yes, the cancer danger by telomerase activity still lingers), and that is when there is more hTERT + hTR together, the processivity accrues multiple-folds (albeit, the cance risks rises; it would need to be in 'quick bursts'...just like what Mrs. Parrish did, just a hTERT 'once in a while' burst...gives more telomerase...and then you stop, so that is mitigates cancer highjacking risk of excessive telomerase).

The only reason that telomeres are being doubted is because of doubtful results obtained from selective sampled studies (which they themselves are doubtful too in terms of 'making a point', they don't have much point and the telomeres shrinking rate and total number of short telomerse Still dictate lifespan - in certain mammals, at least, like, us). I have noticed that the 'telomere impact/reason' is more and more important as the animal live longer - we live (among) the longest, and hence, why it applies to us. It even applies to much longer animals (like icelandic quahogs clams that live 192 to 520 years lifespan (studies showed that polar clams live for centuries/have less telomere shortening vs temperate climate clams who live short lives/'live fast'/and show accelerate telomere loss), I'm willing to bet, same thing in Greenland sharks that live 500 years). Plus, if a progeric human lives 15 years and another healthy lives 120 (HGPS/Werner vs Regular, HGPS people accrue progerin/prelamin A is mass quantity which makes chromosomal dysfunction and dissasembly - they have fast telomere loss; while regular humans accrue progerin Also, but much less so - and they have slower telomere shortening speed)...that tells you how much telomeres rate of shortening/accumulation of short telomeres seems causal to aging; and, even if, it's not exactly causal but just correlative, it's, Still correlative and applicable to maximal lifespan in humans.

Posted by: CANanonymity at July 12th, 2019 12:04 PM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.