276 replies to this topic

[QuestforLife]

Castiel, the Blasco study you post on the mice born with hyperlong telomeres is very interesting pertinent to this discussion.

 

 

https://www.nature.c...467-019-12664-x

Hyper-long telomere mice are lean and show low cholesterol and LDL levels, as well as improved glucose and insulin tolerance. Hyper-long telomere mice also have less incidence of cancer and an increased longevity. These findings demonstrate that longer telomeres than normal in a given species are not deleterious but instead, show beneficial effects.

 

These mice were born from embryos that had intentionally been cultured for longer than would be the case in the murine womb, so benefited from additional telomere lengthening in embryonic cells (before differentiation). Their telomeres still shortened with age but started from a longer length. 

 

I expect that this would also lead to the same phenomenon we are discussing - a longer time between stem cell replacements for a given somatic line. It would be interesting to see if these special mice had an epigenetic age that is older compared to control mice starting with normal length telomeres.

 

There is a human situation that is roughly analogous - the use of sartans. These were found to increase epigenetic age (I speculate through upregulated telomerase - see my thread) despite their health benefits.

 

https://www.ncbi.nlm...les/PMC6286862/

Accelerated DNA methylation age and the use of antihypertensive medication among older adults

The discrepancy of DNA methylation age (DNAmAge) with chronological age (termed as age acceleration, AA) has been identified to be associated with many aging-related health outcomes including hypertension. Since taking antihypertensive medication (AHM) could prevent aging-related diseases caused by hypertension, we hypothesized that using AHM could also reduce the AA....After the fully adjusting for potential covariates including hypertension, any AHM use showed a cross-sectional significant association with higher AA at each visit, as well as a longitudinal association with increased ΔAA between visits. Particularly, relative to participants who never took any AHM, individuals with continuous AHM use had a higher ΔAA of 0.6 year/chronological year. This finding underlines that DNAmAge and AA may not be able to capture the preventive effects of AHMs that reduce cardiovascular risks and mortality.

[Turnbuckle]

How about the fact that mice which are artificially made to have extra long telomeres from birth, which would keep cells that would otherwise go senescent dividing, live longer have less cancer and are healthier.

 

 

 

Do they really live longer? See Fig. 6e of this paper, where it appears that control mice lived substantially longer than mice with hyper-long telomeres.

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[QuestforLife]

Do they really live longer? See Fig. 6e of this paper, where it appears that control mice lived substantially longer than mice with hyper-long telomeres.

 
According to the more recent work by the same team (this time with 100% chimeric mice) that I referenced above, the answer to your question is an emphatic yes.

 

[Turnbuckle]

the answer to your question is an emphatic yes.

 

 

 

I suppose if one keeps running trials, one will show what you want it to show. It's a small difference in longevity, however, magnified by starting the plot at 50 weeks rather than zero. Is this small effect relevant for humans? Unlikely, as it is not even relevant for other strains of mice. One strain, for instance, has relatively short telomeres yet lives three times as long--

 

Additionally, we found no correlation between telomere length and longevity in closely related mouse strains. In fact, the strain with the shortest telomeres of those we studied, Pleucopus, had the longest lifespan.

https://www.ncbi.nlm...3886/#gkd651c19

 

 

 

For Pleucopus, they quote an average lifespan of 5-7 years and a telomere length of ~12 kb, whereas the control mice in the hyper-long experiment typically have a length of 40–50 kb, and presumably the hyper version were much longer.

 

A major problem with this hyper-length experiment is that the experimental mice are essentially identical, as they all came from one source of embryonic cells. So if the source of those cells happened to be a particularly healthy mouse, it would skew the results, perhaps dramatically. 

To address whether hyper-long telomeres have deleterious effects, we generated mice in which 100% of their cells are derived from hyper-long telomere ES [embryonic] cells.

https://www.nature.c...467-019-12664-x

 

 

 

Edited by Turnbuckle, 16 October 2020 - 01:41 PM.

[Castiel]

 

I suppose if one keeps running trials, one will show what you want it to show. It's a small difference in longevity, however, magnified by starting the plot at 50 weeks rather than zero. Is this small effect relevant for humans? Unlikely, as it is not even relevant for other strains of mice. One strain, for instance, has relatively short telomeres yet lives three times as long--

 

 

 

For Pleucopus, they quote an average lifespan of 5-7 years and a telomere length of ~12 kb, whereas the control mice in the hyper-long experiment typically have a length of 40–50 kb, and presumably the hyper version were much longer.

 

A major problem with this hyper-length experiment is that the experimental mice are essentially identical, as they all came from one source of embryonic cells. So if the source of those cells happened to be a particularly healthy mouse, it would skew the results, perhaps dramatically. 

 

 

We would have to see what happens with pleucopus if it is subjected to the same experiment.

 

Keep in mind that telomerase treatment caused cells to look young under the microscope and to change from producing old looking wrinkled skin to young looking skin, iirc.

 

Unless negligible senescence telomerase positive animals have some mechanism to reset epigenetic age, assuming it is true telomerase doesn't, then it would seem they would have increasing epigenetic age.

 

 

According to this

https://www.ncbi.nlm...les/PMC7093186/

 

The naked mole rat, a species that some says exhibits negligible senescence, or near negligible senescence, but some loss of fitness, appears to experience some types of age related epigenetic changes.

 

We would have to look at other negligible senescent species and see if they too experience epigenetic changes with age.

 

Also given that tocotrienols are said to activate the yamanaka factors, and Sinclair seems to have suggested activating these could rejuvenate the epigenome, it would be interesting to see if certain doses of tocotrienols reverse epigenetic age.

[QuestforLife]

I suppose if one keeps running trials, one will show what you want it to show. It's a small difference in longevity, however, magnified by starting the plot at 50 weeks rather than zero. Is this small effect relevant for humans? Unlikely, as it is not even relevant for other strains of mice. One strain, for instance, has relatively short telomeres yet lives three times as long--




For Pleucopus, they quote an average lifespan of 5-7 years and a telomere length of ~12 kb, whereas the control mice in the hyper-long experiment typically have a length of 40–50 kb, and presumably the hyper version were much longer.

A major problem with this hyper-length experiment is that the experimental mice are essentially identical, as they all came from one source of embryonic cells. So if the source of those cells happened to be a particularly healthy mouse, it would skew the results, perhaps dramatically.

I'd agree all lab mice - not just these ones - are freaks and bear little resemblance to wild mice, who have much shorter telomeres without an appreciably different lifespan (when raised in a protective environment). This would seem to discredit telomeres as a mediator of longevity. And yet...we see that the rate of telomere shortening predicts species lifespan.

https://www.pnas.org...nt/116/30/15122

Telomere shortening rate predicts species life span

...Previous studies have suggested that the telomere shortening rate rather than the initial telomere length is the critical variable that determines species life span. In particular, we have previously shown that human telomeres shorten at a rate of ∼70 bp per year, which is in line with the rate published by other authors, while mice telomeres shorten at a rate of 7,000 bp per year.

This is what Michael Fossel has long predicted. Having even longer telomeres for mice should give them only marginal benefit given their great rate of attrition. It is surprising that the previous study found as much benefit as it did.

[Turnbuckle]

And yet...we see that the rate of telomere shortening predicts species lifespan.

 

Yes, when combined with initial telomere length, though it isn't predictive for individuals as it's far too noisy. The way I see it, the length of telomeres reflects the net replacement of cells -- old cells with short telomeres being replaced by new cells with long telomeres. When the source of new cells declines, so does the average length of telomeres. So the controlling factor is the availably of stem cells.

Edited by Turnbuckle, 16 October 2020 - 04:04 PM.