12 replies to this topic

[Phoebus]

This is the study done on 500k citizens from the Uk biobank. 

 

 

 

Polygenic basis and biomedical consequences of telomere length variation

 

doi: https://doi.org/10.1....03.23.21253516

This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

 

Abstract

 

 

Telomeres, the end fragments of chromosomes, play key roles in cellular proliferation and senescence1. Here we characterize the genetic architecture of naturally-occurring variation in leucocyte telomere length (LTL) and identify causal links between LTL and biomedical phenotypes in 472,174 well-characterized participants in UK Biobank2. We identified 197 independent sentinel variants associated with LTL at 138 genomic loci (108 novel). Genetically-determined differences in LTL were associated with multiple biological traits, ranging from height to bone marrow function, as well as several diseases spanning neoplastic, vascular, and inflammatory pathologies. Finally, we estimated that at age 40 years, people with >1-SD shorter compared to ≥1-SD longer LTL than the population mean had 2.5 years lower life expectancy. Overall, we furnish novel insights into the genetic regulation of LTL, reveal LTL’s wide-ranging influences on physiological traits, diseases, and longevity, and provide a powerful resource available to the global research community.

 

 

 

Article on this study 

 

 

 

UK Biobank, the large-scale biomedical database and research resource, has today made available to approved researchers the data from a study into telomere length.

The study, conducted by Dr Veryan Codd, Dr Chris Nelson and Professor Sir Nilesh Samani and their team at the University of Leicester, working with Professor John Danesh at the University of Cambridge  measured telomere length in almost all 500,000 UK Biobank participants to deduce why some older adults succumb to chronic disease while others do not. Telomeres are tiny pieces of DNA found on the end of each chromosome, which play a central role in cell death and are thought to be a good biomarker of biological ageing.

Professor  Samani and his colleagues believe that measurement of telomere length in all UK Biobank participants will help the understanding of the causes of ageing and age-associated diseases. This has the potential to support the prevention and treatment of diseases of the heart, brain, bone and cancer.

"This study is a prime example of UK Biobank’s unique role as a research resource for the scientific community and highlights the important contributions to improving human health that our researchers can provide. I want to thank Professor Samani and his colleagues for their extensive work."

Professor Sir Rory Collins, Principal Investigator of UK Biobank

 

"It has been a truly heroic effort over more than 4 years to generate these measurements. I would like to thank my team for their fantastic achievement. We hope that this resource will be of enormous value to the scientific community to advance understanding of the determinants and biomedical consequences of inter-individual variation in telomere length."

Professor Samani, Professor of Cardiology, University of Leicester

These data will be available to all approved researchers, through the UK Biobank database, from today.

The study was funded by the Medical Research Council (MRC), British Heart Foundation (BHF) and the Biotechnology and Biological Sciences Research Council (BBSRC).

https://www.ukbioban...-to-researchers

Edited by Phoebus, 22 April 2021 - 02:56 PM.

[QuestforLife]

Great find. Will read with interest.

[Turnbuckle]

Finally, we estimated that at age 40 years, people with >1-SD shorter compared to ≥1-SD longer LTL than the population mean had 2.5 years lower life expectancy.

 

 

2.5 years isn't much to base a life extension protocol on. And it can't be concluded that intervention to make telomeres longer will confer another couple of years of life expectancy, as the reason for the shorter telomeres has to be examined. For instance, average telomere length will decline if old cells are replaced at a lower rate, and lengthening telomeres with telomerase will only further lower the replacement rate.

Edited by Turnbuckle, 07 May 2021 - 09:34 AM.

[QuestforLife]

2.5 years isn't much to base a life extension protocol on. And it can't be concluded that intervention to make telomeres longer will confer another couple of years of life expectancy, as the reason for the shorter telomeres has to be examined. For instance, average telomere length will decline if old cells are replaced at a lower rate, and lengthening telomeres with telomerase will only further lower the replacement rate.

 

There aren't many interventions in humans known to increase life by 2.5 years.

 

By your argument increasing replacement rate will move telomere length from stem cells to tissue cells and then slow down the rate of replacement again.

[Turnbuckle]

There aren't many interventions in humans known to increase life by 2.5 years.

 

By your argument increasing replacement rate will move telomere length from stem cells to tissue cells and then slow down the rate of replacement again.

 

When senescent somatic cells with short telomeres are replaced with new somatic cells derived from stem cells (where telomerase is naturally expressed), the average telomere length goes up, but those somatic cells with short telomeres that have not yet become senescent are not affected by this replacement. They are next in line to become senescent and replaced. Applying telomerase globally will stop those next in line from ever getting there.

 

The body is highly dynamic. One percent of all cells are replaced every day, amounting to some 50 billion cells. This huge turnover requires, among other things, a source of new cells (stem cells and transit amplifying cells), and a clock (telomeres) to tell old cells when to check out (apoptosis).

 

Aging occurs because the source of new cells dries up. Tissue is lost and not replaced, and the loss of tissue results in a loss of function. Preventing the source of new cells from drying up will maintain youth. Doing things from the other end by preventing old cells from dying may slow the loss of tissue, but the cells themselves are losing function due to epigenetic aging. So fiddling with the telomere clock, as suggested by this study, won't extend lifespan much, and it certainly won't restore youth.

Edited by Turnbuckle, 07 May 2021 - 11:48 AM.

[QuestforLife]

When senescent somatic cells with short telomeres are replaced with new somatic cells derived from stem cells (where telomerase is naturally expressed), the average telomere length goes up, but those somatic cells with short telomeres that have not yet become senescent are not affected by this replacement. They are next in line to become senescent and replaced. Applying telomerase globally will stop those next in line from ever getting there.

 

The body is highly dynamic. One percent of all cells are replaced every day, amounting to some 50 billion cells. This huge turnover requires, among other things, a source of new cells (stem cells and transit amplifying cells), and a clock (telomeres) to tell old cells when to check out (apoptosis).

 

Aging occurs because the source of new cells dries up. Tissue is lost and not replaced, and the loss of tissue results in a loss of function. Preventing the source of new cells from drying up will maintain youth. Doing things from the other end by preventing old cells from dying may slow the loss of tissue, but the cells themselves are losing function due to epigenetic aging. So fiddling with the telomere clock, as suggested by this study, won't extend lifespan much, and it certainly won't restore youth.

 

I don't think we can be certain yet about what will or won't restore youth.

 

Telomerase can certainly rescue near senescent cells with short telomeres, probably giving them a few more divisions. But it won't extend their life indefinitely. For that you'd have to immortalise them, and there is no current in vivo treatment that can do that.

 

As senescent cells don't seem to accumulate any more methylation (at least according to Horvath) lengthening their telomeres to allow continued division might be interpreted as a the cells 'getting older' if they suffered further methylation. But the practical significance of this is unknown. Even if a cell line was immortalised, would it stop being a skin cell, or a liver cell?

 

Africans have longer telomeres than Caucasians, and an older age as measured through methylation (on average). But it is difficult to make the claim they are older (or younger). The balance point of replacement is just slightly adjusted.

 

Animals that don't suffer from aging (like lobsters or turtles) have active telomerase in every cell. But they still have cellular replacement. There is still a stem cell system of multilineage cells that can respond to injury, etc.

 

Most likely human tissues are deprived of replacement cells with age because the stem cells that are most likely to differentiate all die because of telomere shortening. The stem cells that are less likely to differentiate maintain their telomeres so they persist (but are unhelpful to the body). Your idea of forcing them to come out of stasis has merit, but likely you are rejuvenating the tissue by depleting stem cells.

 

My idea is that we increase telomerase to the point where stem cells have just enough to self renew indefinitely whilst still differentiating as required. Because of the general effects of telomerase, this might also alter the balance point of replacement of somatic cells, or it might be possible to activate telomerase exclusively (or mostly) in stem cells, in which case we avoid that altogether.

[Turnbuckle]

I don’t think we can be certain yet about what will or won’t restore youth.

 

I believe I have with my endogenous stem cell treatment. Certainly my 22 year epigenetic age reversal looks and feels at least that much.

 

Telomerase can certainly rescue near senescent cells with short telomeres, probably giving them a few more divisions. But it won’t extend their life indefinitely. For that you’d have to immortalise them, and there is no current in vivo treatment that can do that.

 

Yet another strike against the telomerase approach.

 

Even if a cell line was immortalised, would it stop being a skin cell, or a liver cell?

 

Different epigenetic codes are the entire difference between liver cells and skin cells. Scramble the code and cells have no particular identity. And the older it gets, the more scrambling occurs.

 

Animals that don’t suffer from aging (like lobsters or turtles) have active telomerase in every cell. But they still have cellular replacement. There is still a stem cell system of multilineage cells that can respond to injury, etc.

 

Lobsters and turtles do age. The American lobster has an average lifespan of around a hundred years, but considering its low metabolic rate, not particularly impressive compared to humans. Epigenetic aging should still occur, though perhaps slower with lower metabolic rates and temperature. However, I’m unaware of any epigenetic studies as yet.

 

Most likely human tissues are deprived of replacement cells with age because the stem cells that are most likely to differentiate all die because of telomere shortening. 

My idea is that we increase telomerase to the point where stem cells have just enough to self renew indefinitely whilst still differentiating as required. Because of the general effects of telomerase, this might also alter the balance point of replacement of somatic cells, or it might be possible to activate telomerase exclusively (or mostly) in stem cells, in which case we avoid that altogether.

 

Embryonic stem cells are immortal, including VSELs that are present in the adult, yet even VSELs decline with age. (See this paper and the figure below.) Stimulating proliferation is therefore necessary. An occasional telomerase supplement while stimulating proliferation should be sufficient to keep adult stem cells going. It has to be very judicious, however, so as not to do more harm than good. I believe 1-2 treatments per year in conjunction with proliferation may hit that sweet spot. This is not just hypothetical. I’ve tried taking telomerase supplements with every stem cell treatment, and found it produced a rapid increase in epigenetic age.

 

 

 

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[QuestforLife]

Turnbuckle

You have this theory about VSELS and this protocol with a tonne of supplements, some of which, or all together, reduce epigenetic age and you think that proves your theory.

Totally separately to you, and before I might add, I used AKG on its own and reduced my epigenetic (so-called) age from 42 to 35. I don't claim it does this by lengthening telomeres (although there is some evidence for telomere benefit). Likely AKG is just counteracting the additional de Novo methylation that occur with age.

As to your assertion aging is cells getting epigenetically scrambled, they've done actual experiments on mortal and immortalised cells (like you think VSELs are). And the epigenetic changes are very different. Mortal cells have methylation changes associated with senescence, as you'd expect. But immortal cells have random changes, which undergo selection pressure for those cells which are best able to self renew. This matches papers where we see stem cells get gradually more selfish and more likely to self renew, and less likely to differentiate (the ones that do differentiate are dead). So its not scrambling, it's self preservation. This doesn't suggest that epigenetic age reversal would work through more self-renewal, but less. If anything maybe your protocol is causing differentiation.

I don't pretend to know exactly what is going on. But telomeres are playing an important part; probably their shortening in stem cells is encouraging stem cells in this unhelpful direction.

Finally, Lobsters. They die because they grow so big they can't shed their shells. But as far as anyone knows they don't age. I've not seen any methylation studies to prove this. I just go on real biomarkers like fertility.

[Turnbuckle]

Totally separately to you, and before I might add, I used AKG on its own and reduced my epigenetic (so-called) age from 42 to 35. I don't claim it does this by lengthening telomeres (although there is some evidence for telomere benefit). Likely AKG is just counteracting the additional de Novo methylation that occur with age.

 

Lobsters. They die because they grow so big they can't shed their shells. But as far as anyone knows they don't age. 

 

 

 

 

It's likely that AKG reduces spurious methylation of dividing stem cells, but doesn't increase the numbers of SCs or change the length of telomeres. In 2019 you reported that your epigenetic age went from 40 to 38 from using statins, so this AKG result is -3 years from the statin treatment, right? Or was there something in-between?

 

As for lobsters, I believe that the not-aging part is a myth. The Smithsonian ran a story on where it came from. Epigenetic testing will ultimately settle the question.

Edited by Turnbuckle, 07 May 2021 - 05:51 PM.

[QuestforLife]

Thanks I'll read the article about the lobsters.

I haven't done the statin-sartan protocol since that result. And I subsequently lost those earlier gains when i used epitalon.

AKG was all I took so the later -6.6 year delta was all due to it.

It's likely that AKG reduces spurious methylation of dividing stem cells, but doesn't increase the numbers of SCs or change the length of telomeres. In 2019 you reported that your epigenetic age went from 40 to 38 from using statins, so this AKG result is -3 years from the statin treatment, right? Or was there something in-between?

As for lobsters, I believe that the not-aging part is a myth. The Smithsonian ran a story on where it came from. Epigenetic testing will ultimately settle the question.

Edited by QuestforLife, 08 May 2021 - 06:56 AM.

[QuestforLife]

That lobster article is unconvincing. Lobsters can't keep shedding bigger and bigger shells, so they keep them longer and eventually this causes them problems.

If it wasn't for that they'd just keep getting bigger, stronger and more fertile.

You'd have a hard time (geddit?) arguing increased methylation age due to failing stem cell numbers is the reason lobsters die.

It a different matter in humans when we can actually see reduced stem cell numbers (you and I just disagree on the exact cause).

[Turnbuckle]

That lobster article is unconvincing. Lobsters can't keep shedding bigger and bigger shells, so they keep them longer and eventually this causes them problems.

If it wasn't for that they'd just keep getting bigger, stronger and more fertile.

You'd have a hard time (geddit?) arguing increased methylation age due to failing stem cell numbers is the reason lobsters die.

It a different matter in humans when we can actually see reduced stem cell numbers (you and I just disagree on the exact cause).

 

 

I wonder if lobsters, great white sharks and a few reptiles might be using a different approach to avoid epigenetic aging, a relic from the distant past when big was always better. Because as long as you keep growing and blocking cells from going senescent, epigenetically old cells don't matter as much. By keeping them in the minority, you limit their negative effects. Thus you keep growing until you're too big to attack, but ultimately you grow yourself to death. The growth plan of dinosaurs, while mammals from that era had to come up with a plan that limited growth. For them, getting large just made them a more attractive meal. Thus they dialed back on telomerase and growth hormones, going for cellular replacement rather than dilution.

 

Birds descended from dinosaurs, and the bones of early birds showed growth rings just as dinosaur bones do, but as they evolved, these rings disappeared. Some claim this reflects a change from cold-blooded to warm-blooded metabolism, but it also suggests a switch from adding on to remodeling.

Edited by Turnbuckle, 08 May 2021 - 10:22 AM.

[QuestforLife]

I wonder if lobsters, great white sharks and a few reptiles might be using a different approach to avoid epigenetic aging, a relic from the distant past when big was always better. Because as long as you keep growing and blocking cells from going senescent, epigenetically old cells don't matter as much. By keeping them in the minority, you limit their negative effects. Thus you keep growing until you're too big to attack, but ultimately you grow yourself to death. The growth plan of dinosaurs, while mammals from that era had to come up with a plan that limited growth. For them, getting large just made them a more attractive meal. Thus they dialed back on telomerase and growth hormones, going for cellular replacement rather than dilution.

Birds descended from dinosaurs, and the bones of early birds showed growth rings just as dinosaur bones do, but as they evolved, these rings disappeared. Some claim this reflects a change from cold-blooded to warm-blooded metabolism, but it also suggests a switch from adding on to remodeling.

Constantly growing species are definitely understudied.

Do all their cells continuously divide? Does this mean errant methylation never gets a chance to occur because cells don't stay past their sell by date? Or does it mean methylation is acquired constantly and stochastically in these long-lived cell lines?

My guess would be you'd get epigenetic age acceleration during early growth phase, same as humans, then it will stop at maturity, and then gradually restart as the growth rate slows and cells stay around for longer.

Horvath has done bats, maybe he'll do the senescence-free species next.

Edited by QuestforLife, 08 May 2021 - 01:27 PM.