1033 replies to this topic

[JamesPaul]

Some more information on AKG I posted on Turnbuckle's thread.

 

I was wondering about that.  The Rejuvant labels say "calcium alpha-ketoglutarate monohydrate".  I wonder if that was somehow better than the Kirkman Labs product label, which does not say "monohydrate".
 

[QuestforLife]

I was wondering about that.  The Rejuvant labels say "calcium alpha-ketoglutarate monohydrate".  I wonder if that was somehow better than the Kirkman Labs product label, which does not say "monohydrate".
 

 

That's just one calcium added to AKG, with a couple of Hydrogens dropped off. The whole point of making a AKG salt rather than the acid is that its easier on the stomach, and it's slow release. Rejuvant then take the precaution of adding Vitamin D to help deal with all the extra calcium. I don't see why this would be better than a magnesium salt, or a mixture of magnesium salt and calcium salt, especially as magnesium is something many are deficient in. 

[Andey]

In an ideal world ArginineAKG would work too, hard to come up with a reason why its different from plain AKG or Calcium salt.

 

 

[QuestforLife]

In an ideal world ArginineAKG would work too, hard to come up with a reason why its different from plain AKG or Calcium salt.

I think adding an amino acid to AKG is intended to speed it's absorption, for workout shakes, whereas adding calcium or magnesium will slow the absorption and release of the AKG.

[QuestforLife]

I've been thinking for some time about the importance of fatty acid oxidation and wanted to devote a whole post or series of posts to it.

It's only tangentially related to telomeres, but I believe it is extremely important for health and longevity.

We know AKG results in a reduction of triglycerides, LDL cholesterol, presumably because of increased demand on the Krebs cycle resulting in a requirement for beta oxidation (https://www.longevit...sults-in-humans). Other supplements like resveratrol that activate SIRT1 also increase beta oxidation. AMPK activation increases fat burning. So does carnitine, which increases import of fats into the mitochondria (https://pubmed.ncbi....h.gov/12404185/)
Alpha lipoic acid also seems to have some benefit as it's also important in the Krebs pathway and in AKG oxidation. Forskolin increases cAMP, which increases fat burning (https://www.ncbi.nlm...one.0029735.pdf) and incidentally also leads to symmetrical division at least in egg cells.

Stearic acid is a trigger fat that signals the body to burn fat (https://www.nature.c...467-018-05614-6). This might be the best way of all - eating highly saturated fat and not relying on any over stimulated supplement pathways.

It turns out that children do more beta oxidation than adults (https://nutritionj.b.../1475-2891-6-19). Elderly patients were able to increase beta oxidation by supplementing glutathione precursors (https://onlinelibrar...1111/acel.12073). Cells burning fats produce more ROS and use fused rather than fissioned mitochondria. Note this is also a signal for cells to become insulin resistant, which helps with weight loss.

I'm not posting all references here - there are many other interesting avenues for research and self experimentation (another time i'll post about using AKG, berberine and ALA). But I want to focus this post in a specific direction - stem cells.

Beta oxidation is very important in maintaining stemness. I found it easy to find supporting evidence in pluripotent stem cells (:text=Recent%20reports%20suggest%20that%20the,cells%20%5B9%2C%2032%5D.&text=Our%20study%20showed%20that%20Cpt1,for%20promoting%20the%20reprogramming%20process.' class='bbc_url' title='External link' rel='nofollow external'>https://stemcellres....amming process.)

‘Recent reports suggest that the beta-oxidation of fatty acids plays an important role in the maintenance and growth of pluripotent stem cells

Also check out this excellent paper on self renewal in intestinal stem cells (https://www.scienced...934590918301632)

Diet has a profound effect on tissue regeneration in diverse organisms, and low caloric states such as intermittent fasting have beneficial effects on organismal health and age-associated loss of tissue function. The role of adult stem and progenitor cells in responding to short-term fasting and whether such responses improve regeneration are not well studied. Here we show that a 24 hr fast augments intestinal stem cell (ISC) function in young and aged mice by inducing a fatty acid oxidation (FAO) program and that pharmacological activation of this program mimics many effects of fasting. Acute genetic disruption of Cpt1a, the rate-limiting enzyme in FAO, abrogates ISC-enhancing effects of fasting, but long-term Cpt1a deletion decreases ISC numbers and function, implicating a role for FAO in ISC maintenance. These findings highlight a role for FAO in mediating pro-regenerative effects of fasting in intestinal biology, and they may represent a viable strategy for enhancing intestinal regeneration

Neural stem cells (https://www.ncbi.nlm...les/PMC5583518/)

Quiescent NSPCs show high levels of carnitine palmitoyltransferase 1a (Cpt1a)-dependent FAO, which is downregulated in proliferating NSPCs.

and hematopoietic stem cells (https://pubmed.ncbi....h.gov/22902876/)

inhibition of mitochondrial FAO induces loss of HSC maintenance, whereas treatment with PPAR-δ agonists improved HSC maintenance.

As a result I've decided to change my diet to incorporate much more saturated fat with an emphasis on stearic acid.

It will be interesting to see if it has any effect on my epigenetic age. I have already experienced a loss of fat and gain in muscle whilst eating as many carbs as I want. There are also some potential downsides to this diet, which I will cover in a future post.

[Andey]

I recall you are following a ketogenic diet, am I wrong?

I assumed beta oxidation should be elevated to the available transport (carnitine) and demand while on ketogenic diet.

I also recall that to activated stem cells rely on anaerobic glycolysis (inhibiting Cox2 forces anaerobic metabolism and is a target for scarless healing) so there should be different optimization for when you are trying to preserve the pool vs trying to get benefit from the pool.

 

Edited by Andey, 29 July 2020 - 08:24 AM.

[QuestforLife]

I did keto the winter of 17/18, but discontinued for various reasons. I now see that the fat type consumed is more important than the elimination of carbs.

I'm not sure I agree it's as clear cut as stem cells using anaerobic energy production - many stem cells do use mitochondria for energy, both the Krebs cycle and the ETC. Fat burning definitely requires mitochondria.

I do agree that fat metabolism is likely to contribute to stem cell renewal more than their differentiation into the body.

For that part of the equation you'd want a stem cell stimulant like AFA or C60.

Edited by QuestforLife, 29 July 2020 - 12:01 PM.

[QuestforLife]

I got back the results of my June TruMe test.

 

Chronological Age: 41.6

Biological Age 41.9

Intervention: 3 1/2 months of AKG. I also did a few rounds of TB's Stem Cell protocol (with no senolytics).

This is disappointing as it means there has been no change since my March 2020 methylation age test result from Zymo (42 yo).

Possible explanations:

TruMe uses a saliva test, which is less reliable than the blood or urine results from Zymo, and might have been affected by my bad hayfever during May and June.

I also took a Vit D and K2 supplment as a precaution against all the calcium in the AKG supplement. Vit D is a telomerase activator.

In my case having reversed my telomere age by 3 years recently through epitalon (and increased my methylation age by the same amount), I might need significantly longer to reverse my methylation age.

 

Future plans: i have another TruMe test ready to go. My hayfever has relented and i've now replaced the VitD/K2 with just K2. I'll continue the AKG with occasional TB Stem Cell cycles (note I'm omitting any senolytics at this point) and report back when I done the next test (Sept or Oct).

[QuestforLife]

Small-Molecule PAPD5 Inhibitors Restore
Telomerase Activity in Patient Stem Cells

https://www.cell.com...87?showall=true

High Lights from the abstract

High-throughput screening identifies specific small-molecule PAPD5 inhibitor BCH001

BCH001 restores telomere length in iPSCs from patients with dyskeratosis congenita

Repurposed HBsAg suppressors, dihydroquinolizinones, increase TERC in stem cells

Oral PAPD5 inhibitors restore TERC and telomeres in human HSPCs in vivo

My take

I've wanted to post about this paper for a while. I don't think it's an exaggeration to say this paper may hold the answer to extending telomeres in stem cells without doing the same in somatic cells.

A couple of caveats. This work was done in human hematopoietic stem cells with a TERC mutation, such as had by patients with DC (DYSKERATOSIS CONGENITA) a disease resulting in very short telomeres and bone marrow failure, leading to early death normally via loss of red blood cells or pulmonary fibrosis. The work was done first in vitro and then on human stem cells with the mutation, implanted into mice engineered not to destroy the implanted cells.

The 'treatment' was a chemical made to adjust the balance of expression and breakdown of the TERC RNA template that is used to copy telomere strands rather than the TERT protein that does the elongation. In DC mutants the TERC template is quickly removed resulting in very fast telomere shortening. Past treatments for this have included hormone therapy and gene therapy, both have their drawbacks - hormones tend to be badly tolerated long term and gene therapy reaches a very small proportion of the target cells (to date). I've talked about these in this thread before.

One may ask why TERC and not TERT? Well, multipotent stem cells tend to have TERT already active whereas somatic cells don't. So TERC is a more targeted treatment.

You might also ask how would more TERC help people without DC as in them, most cells, including somatic cells, already have TERC present? There are some intriguing clues. Firstly, most of the mutations leading to longer or shorter telomeres in humans are associated with TERC, not TERT. Experimenting with immortalising cells in vitro via TERT has also revealed that TERT does not necessarily elongate telomeres, it just stops them getting too short to stop cell division. The concentration of TERC is the factor that decides the actual length of telomeres. If your stem cell telomeres are getting short, TERC seems a better bet than TERT, especially when you consider that it's not necessarily or just continued cell division from the stem cell compartment we want - we also want young gene expression in our cells, and short telomeres in stem cells will prevent this. The authors describe it this way: TERT is on/off switch, but TERC limits telomerase activity and decides telomere length. Stem cells can already pull the trigger. They just need a little more firepower.

The authors discover that the mechanism of action of their compound overlaps with some newly discovered, orally bioavailable hepatitis B drugs. In the mouse portion of their experiment they used one such compound called RG7834. The mice tolerated it in their water for months, and after only weeks of treatment the mutated human stem cells they carried had significantly longer telomeres. RG7834 is currently priced by the milligram, and is very expensive (for example, https://aobious.com/...0-rg7834.html).The paper does not reveal mouse doses but an earlier hepatitis B mouse trial used 4mg/kg/day with success. That's still 25mg/day for me or $170/day (admittedly it might be cheaper in bulk). Perhaps someone else on this site can find a more affordable source?

[JamesPaul]

A Chinese company,

https://www.adooq.cn/rg7834.html

says 50 mg of RG7834 is 4140 yen which is about $40 US.  Still pricey ($20US/day)

 

Their site says that they have a U.K. distributor.

https://www.bioquote.com/

I did a search on www.bioquote.com for 'RG7834'.  "No results found." 

Their Canadian distributor carries it but 50 mg is over $1000Canadian from AdooQ

What a markup!

[Turnbuckle]

A Chinese company,

https://www.adooq.cn/rg7834.html

says 50 mg of RG7834 is 4140 yen which is about $40 US.  Still pricey ($20US/day)

 

 

 

If it's yuan and not yen, then it's a whole lot more -- $594

Edited by Turnbuckle, 04 August 2020 - 04:49 PM.

[JamesPaul]

Oops, of course, sorry.  I had no idea that the same character was used for both yen and yuan.  I'd like to delete that post, but don't seem to be able to.  I can edit this one, but not my prior one.

Edited by JamesPaul, 04 August 2020 - 06:06 PM.

[QuestforLife]

Oops, of course, sorry. I had no idea that the same character was used for both yen and yuan. I'd like to delete that post, but don't seem to be able to. I can edit this one, but not my prior one.

I've never bought any compounds direct from Chinese manufacturers, but it makes sense that is where they'd be most affordable if you're willing to take a risk on purity, or test that for an added cost. It might be that RG7834 will be a very expensive patented drug if it works for hepatitis B, so we'd have no choice but to go to China. According to the paper there are numerous analogues that have the same effect on TERC (atleast in vitro) as RG7834, so there might be alternatives.

[QuestforLife]

I've posted before about how telomeres shorten at the same rate in different tissues [DOI: 10.1038/ncomms2602] Because of different rates of attrition and replacement,this suggests underlying stem cell pools are calibrated to be to the appropriate number of reserve cells.

Turnbuckle recently highlighted an interesting paper talking about a reserve for the reserve - a tiny pluripotent reserve for the adult stem cells that replace our somatic cells [https://pubmed.ncbi....h.gov/31758373/ ]In that paper the pluripotent cells (called VSELs - very small, embryonic like stem cells) were all but gone by age 40.

I was messing about with an Excel spreadsheet a few years ago, trying to model three cell pools - a somatic pool with cells dividing at a given rate and losing a set telomere length per division, a progenitor pool dividing the same way,feeding into the somatic pool, and an underlying stem cell reserve in the same way feeding into the progenitor pool. What happened is that the stem cells ran out first, then more quickly the progenitors, then very quickly the somatic cells. So maybe this is what is happening in aging.

It reminds me of another paper I wanted to highlight.

Beneficial Effects of Fermented Papaya Preparation (FPP®) Supplementation on Redox Balance and Aging in a Mouse Model

https://www.ncbi.nlm...1/#!po=0.490196

Ignore the sponsored Papaya extract which may be no worse or better than other antioxidants. The key thing is the inclusion in the telomere length data of bone marrow stem cell and ovary cells (for mice purposes a somatic tissue type). There were two treatment windows for the mice, from a human equivalent age of 13 to 41 years and (separately) from 41 to 63 years old.

See fig: https://www.ncbi.nlm...-00144-g001.jpg

In the control group by the end of the first treatment period somatic cells had declined to ~30 (arbitrary units) and bone marrow cells to ~1000 au. Note there was no measurement at the start. With papaya the relative figures were ~90 and ~5000. So it's clear bone marrow telomeres are MUCH longer ( and, we assume, less numerous).

See fig: https://www.ncbi.nlm...-00144-g005.jpg

But the paper really becomes interesting when we look at the second treatment period for which we can assume the above control group figures are a baseline. By the end of the second window somatic cells had declined from 30 to ~ 7 au (or 9 with papaya) by human equivalent age 63. In the same time bone marrow cells had declined from 1000 to ~60au (or 120 with papaya). So the somatic tissue had lost only 23 units (77%) of telomere length between (human equivalent) age of 41 and 63. Bone marrow had lost a staggering 940 units (94%) of telomere length in the equivalent time.

See fig: https://www.ncbi.nlm...-00144-g009.jpg

So it seems my old excel spreadsheet model was right. You do lose the underlying reserve pool first, and it's just a long run off to death from there.

Edited by QuestforLife, 07 August 2020 - 07:42 AM.

[JamesPaul]

Figure 2 of the paper cited by Turnbuckle showed that the number of VSELs in cardiac tissue was very low for subjects after age 40, but the number was not zero for any of the 18 subject individuals, even for the subject whose age was 76.  Could the small remaining pool be expanded?

[QuestforLife]

Figure 2 of the paper cited by Turnbuckle showed that the number of VSELs in cardiac tissue was very low for subjects after age 40, but the number was not zero for any of the 18 subject individuals, even for the subject whose age was 76. Could the small remaining pool be expanded?

That is the entire point of TB's protocol.

There may be other ways as well, for example I highlighted TERC upregulation. This thread has also spent a considerable time discussing my statin-sartan protocol, the point of which is to make cells conditionally reprogram to a more basic stem cell state.

We are starting to get evidence now of success using TB's protocol. I've not (yet) had success with it, or so far with alpha ketoglutarate. I did manage to reverse a few years from my methylation age with the statin-sartan protocol, but that was abolished with the addition of a powerful TERT activator.

[QuestforLife]

On the subject of the statin-sartan protocol, this recent paper shows the effect of short term (4 day) treatment by a ROCK inhibitor increasing mean and max lifespan in old mice, as well as in reducing biological aging as measured by DNA methylation.

 

The small molecule called CASIN, was injected into the tail, and inhibited cdc42 - a protein whose elevated presence in aging degrades hematopoetic stem cell function and (consequent) immune function, possibly though organisation of the cytoskeleton.

 

Inhibition of Cdc42 activity extends lifespan and decreases circulating inflammatory cytokines in aged female C57BL/6 mice

https://onlinelibrar...1111/acel.13208

Cdc42 is a small RhoGTPase regulating multiple functions in eukaryotic cells. The activity of Cdc42 is significantly elevated in several tissues of aged mice, while the Cdc42 gain‐of‐activity mouse model presents with a premature aging‐like phenotype and with decreased lifespan. These data suggest a causal connection between elevated activity of Cdc42, aging, and reduced lifespan. Here, we demonstrate that systemic treatment of aged (75‐week‐old) female C57BL/6 mice with a Cdc42 activity‐specific inhibitor (CASIN) for 4 consecutive days significantly extends average and maximum lifespan. Moreover, aged CASIN‐treated animals displayed a youthful level of the aging‐associated cytokines IL‐1β, IL‐1α, and INFγ in serum and a significantly younger epigenetic clock as based on DNA methylation levels in blood cells. Overall, our data show that systemic administration of CASIN to reduce Cdc42 activity in aged mice extends murine lifespan.

 

 

[JamesPaul]

"That is the entire point of TB's protocol."

 

Thanks.  I knew of Turnbuckle's stem cell renewal protocol, but didn't know if it applied only to other types of stem cells, or also these somewhat newly researched VSEL stem cells.  Or if the remaining pool was too small to be expanded to a useful size.

Edited by JamesPaul, 10 August 2020 - 03:14 PM.

[QuestforLife]

I haven’t commented on my statin skin cream for a while.

The results on aging skin were a fail. The bonus was I discovered that the cream accelerated wound healing when I tried it on some cuts and blisters on my hands.

This is in line with a ROCK inhibitor’s mechanism of action, with de-differentiated cells able to replace damaged cells in established tissue without fibrosis. It parallels the success of the statin-sartan protocol in the literature (https://pubmed.ncbi....h.gov/26214555/) in reverting pre-clinical atherosclerosis.

Perhaps a statin-sartan treatment would be useful for all kinds of repair: muscle tears (it certainly improved my weightlifting), bone breaks, maybe even brain or nervous system damage.

The ability to heal skin damage but not reverse skin to a younger phenotype suggests skin aging is not driven by a lack of replacement cells This is supported in the literature (https://pubmed.ncbi....h.gov/19826444/).

In general, I suggest that ROCK-inhibitors can repair tissues that lack flexible replacement cells, which can be considered an aspect of aging.

Edited by QuestforLife, 20 August 2020 - 10:50 AM.

[QuestforLife]

Senescence and cancer, again.

Hearing Aubrey speak on Joe Rogan, yet again I'm reminded of the prevailing view in biology that senescence must be an adaptive response to cancer. I find this to be an overly simplistic, even lazy view.

The key thing to understand is that if senescence is an adaptation to cancer then any attempt to reduce senescence must increase cancer. But if as I insist, senescence is a way of shifting cancer risk from the young to the old, then there is hope for the old by reducing senescence.

Let's look at this in more detail.

For a cancer to become malignant it must activate telomerase. To do this a large number of cells must reach senescence at once. This is guesstimated to be around 3 million cells in a human. This is how many cells must die for one to manage to turn on telomerase and become immortal. This has been adjusted by evolution for each species based on body size and other factors to maximise the chance of reproduction by trading off senescence and cancer. So far so boring.

But there is more to it than that. A young person having longer telomeres does not make them more likely to get cancer than an old person, quite the contrary. And it is also not primarily due to the benefits of longer telomeres in the immune system, though they play a part. You see an old person will have many cells approaching senescence all over the body, in many tissues and hence an increasing chance of developing an immortalised cancer cell somewhere (rather than in a specific lump). The real trade off the body has made by allowing telomeres to shorten with time is shifting cancer risk from the young reproducing individuals to the old ones. Totally acceptable from an evolution point of view. If the young were allowed even longer telomeres however, we would then start to get increasing cancer rates in the young, because the chance a rogue lump would cross the 3 million cell size boundary and develop an immortal cell would increase. Maybe the increase would be very small but this risk to the young is totally unacceptable to evolution. Far better that the old were assured of a painful death than the young would suffer even a small chance of dying before reproducing. This is why telomerase is strictly regulated in all large mammals such as humans. But it also offers hope that lengthening the telomeres of the old would decrease, not increase cancer rates. The key here is having the right length, the length of youth, it's not a case of the longer the better.

The issue then becomes only a matter of execution. Lengthening telomeres in all cells is not desirable due to the natural turnover from somatic to progenitor to stem cell that keeps epigenetic control over what a cell is and what its function is supposed to be.

[kurt9]

If senescence evolved as an adaptation to cancer, its a piss-poor adaptation at best. The chances of getting cancer rises significantly with age. Any effective adaptation should, at minimum, reduce the incidence of cancer with age such that it remains a constant.

[QuestforLife]

If senescence evolved as an adaptation to cancer, its a piss-poor adaptation at best. The chances of getting cancer rises significantly with age. Any effective adaptation should, at minimum, reduce the incidence of cancer with age such that it remains a constant.

I totally agree. And yet, it is the mainstream biologist's view.

[Andey]

If senescence evolved as an adaptation to cancer, its a piss-poor adaptation at best. The chances of getting cancer rises significantly with age. Any effective adaptation should, at minimum, reduce the incidence of cancer with age such that it remains a constant.

 

I would say biology doesnt care what happens in advanced age as its well beyond reproductive period. Our cancer defenses are either for virus protection (HMC1 complex and CD8+ cells), or from runaway division p16, p53.

I believe p16 knockouts are not viable at the embryonic stage as it would mess up development. If deactivated later in life it shows an uncontrolled division of epithelial cells, so anticancer activity is more of a byproduct.

TBH the more I read on biology the more it looks like we are 'designed' as expendables. We need to be grateful that our ancestors lived very challenging lives so we have enough robustness to our system)

[QuestforLife]

I would say biology doesnt care what happens in advanced age as its well beyond reproductive period.

This again is a mainstream biology view - that aging doesn't occur in the wild, so either it can't be selected against, or that selection for advantages early in life may have an unintended side effect of shortening life.

My view is that aging does occur in the wild as even a small amount of aging is enough to eliminate an individual in a competitive situation. And although this may be bad for the individual, it is advantageous for the species as it ensures that the only way for the species to continue is by mixing of genes through reproduction. A non-aging species might stop evolving and be vulnerable to changes in the environment.

Edited by QuestforLife, 31 August 2020 - 07:04 AM.

[RWhigham]

I would say biology doesnt care what happens in advanced age

I would say biology deliberately kills you so you don't eat your children's food.

Edited by RWhigham, 31 August 2020 - 03:32 PM.

[RWhigham]

Quest for Life, Maria Blasco says:

• A species lifespan is proportional to its rate of telomeres shortening.   Telomere shortening rate predicts species life span
• She says telomeres typically shorten to 75% (of starting length) by the end of an average lifespan and to 50% by the end of a maximum lifespan.
• Humans have 5kb to 15kb (kilo-base-pairs), with no obvious difference in lifespan.   ("Humans have relatively short telomere lengths from 5 to 15 kb" op cit)
• For humans, losing 25% by age 60 ("avg lifespan") and 50% by age 120 (max lifespan) corresponds  (5k to 15k) x 0.5 /120 yrs = 20.8 bp to 62.5 bp per year loss on average.
• If Maria is correct, the bp loss per year in humans depends on the initial length.
• Does that make any sense?

Edited by RWhigham, 31 August 2020 - 08:00 PM.

[QuestforLife]

<p>

Quest for Life, Maria Blasco says:

• A species lifespan is proportional to its rate of telomeres shortening. Telomere shortening rate predicts species life span
• She says telomeres typically shorten to 75% (of starting length) by the end of an average lifespan and to 50% by the end of a maximum lifespan.
• Humans have 5kb to 15kb (kilo-base-pairs), with no obvious difference in lifespan. ("Humans have relatively short telomere lengths from 5 to 15 kb" op cit)
• For humans, losing 25% by age 60 ("avg lifespan") and 50% by age 120 (max lifespan) corresponds (5k to 15k) x 0.5 /120 yrs = 20.8 bp to 62.5 bp per year loss on average.
• If Maria is correct, the bp loss per year in humans depends on the initial length.
• Does that make any sense?

Bear in mind the only way they have to measure telomere lengths is leukocytes, which are a dynamic pool constantly turning over with a telomere length that will vary day to day by quite a large margin.

So when you say people have between 5k and 15k base pair length with no appreciable difference in lifespan, this is not true. You may have 15k bp in some stem cells, 10k in a new leukocytes and 5k in a leukocyte near the end of its replicable lifespan.

70 base pair loss per year is a net loss; approximately 70bp is lost per division (depending on the cell type) but as cells die they are almost perfectly replaced from the stem cell pool leading to a small but appreciable loss per year. Individual differences make this hard to see in a cross sectional cohort so a longitudinal study is best.

So rate of telomere loss is not dependent on telomere length. It's largely dependent on species with some small influence from lifestyle.

Edited by QuestforLife, 31 August 2020 - 08:37 PM.

[RWhigham]

70 base pair loss per year is a net loss;

So each person has an assortment of telomere lengths starting at 5 to 15 kbp. At an average loss of 70 bp/yr there would be 120 yr x 70 bp/yr = 8.4 kbp loss at maximum lifespan. If maximum lifespan has 50% loss as Blasco says, then the average starting length would be twice as much = 16.8 kbp. Clearly too high.  Where is error?

Edited by RWhigham, 31 August 2020 - 09:10 PM.

[QuestforLife]

So each person has an assortment of telomere lengths starting at 5 to 15 kbp. At an average loss of 70 bp/yr there would be 120 yr x 70 bp/yr = 8.4 kbp loss at maximum lifespan. If maximum lifespan has 50% loss as Blasco says, then the average starting length would be twice as much = 16.8 kbp. Clearly too high. Where is error?

Probably because an average of 15k starts as an embryo and you have a lot of replications before you're even born. If you're born with only 10k base pairs you only have ~70 years at 70bp/year attrition. If you're born with the full 15k, you have ~107 years at the same attrition rate. Seems about right when you consider regenerative ability falls from young adulthood, so you probably 'save' by making your cells divide slower from age ~ 35. So a more accurate estimate would be a logarithmic slope (a decreasing negative gradient) with a gradient of -70bp/year at adulthood decreasing gradually until the line is horizontal. Probably not exactly what happens but gives you the idea. That way you'd either die of telomere loss or because your body is restricting your remaining divisions too much.

Edited by QuestforLife, 01 September 2020 - 07:14 AM.

[QuestforLife]

An interesting paper on why transplantation of iPSCs into the heart causes temporary arrhythmia. This sounds similar to what I experienced when using a combination of SubQ Oxytocin and oral ROCK inhibitors.

 

 

 

 Increased predominance of the matured ventricular subtype in embryonic stem cell-derived cardiomyocytes in vivo

https://www.nature.c...598-020-68373-9

Abstract

Accumulating evidence suggests that human pluripotent stem cell-derived cardiomyocytes can affect “heart regeneration”, replacing injured cardiac scar tissue with concomitant electrical integration. However, electrically coupled graft cardiomyocytes were found to innately induce transient post-transplant ventricular tachycardia in recent large animal model transplantation studies. We hypothesised that these phenomena were derived from alterations in the grafted cardiomyocyte characteristics. In vitro experiments showed that human embryonic stem cell-derived cardiomyocytes (hESC-CMs) contain nodal-like cardiomyocytes that spontaneously contract faster than working-type cardiomyocytes. When transplanted into athymic rat hearts, proliferative capacity was lower for nodal-like than working-type cardiomyocytes with grafted cardiomyocytes eventually comprising only relatively matured ventricular cardiomyocytes. RNA-sequencing of engrafted hESC-CMs confirmed the increased expression of matured ventricular cardiomyocyte-related genes, and simultaneous decreased expression of nodal cardiomyocyte-related genes. Temporal engraftment of electrical excitable nodal-like cardiomyocytes may thus explain the transient incidence of post-transplant ventricular tachycardia, although further large animal model studies will be required to control post-transplant arrhythmia. 

Edited by QuestforLife, 02 September 2020 - 08:21 AM.