45 replies to this topic

[Phoebus]

 

In September 2015 I received two gene therapies. The first was designed to inhibit age-related muscular wasting caused by a protein called myostatin, and it was injected into my leg muscles. The average person loses a full 50% of his/her muscle mass by age 80. This age related muscle loss, known as sarcopenia, is implicated in many age-related disorders, and results in poor quality and quantity of life.

The second was designed to prevent an important aspect of cellular aging, namely telomere shortening. Telomeres are protective caps of chromosomes, which shorten as we age.  The progressive shortening of telomere leads to increase in senescent cells, increase in loss of cells, and increase in cancer risk. Shorter telomeres have also been linked with higher likelihood of having cardiovascular disease, type-2-diabetes, chronic obstructive pulmonary disease, and some forms of dementia.

My results

Before I underwent the therapy procedure, my white blood cell telomeres were measured in September, 2015 by SpectraCell’s Texas laboratory, using a blood sample. They were determined to be unusually short, meaning that I was aging much faster than others my age. According to my telomeres, I was supposed to be in my mid-sixties.

In March 2016, my telomeres were again measured by SpectraCell. I had already started at a disadvantage, which multiplied the anticipation anxiety. Thankfully, the results exceeded all my expectations. They showed that my telomeres had been extended from an initial 6.71kb to 7.33kb, meaning that my cells grew younger by about 20 years in only 6 months. The gene therapies had restored my telomeres in these cells  to my normal age. I hardly dared to hope there was room for improvement still.

In 2018 I went again for testing at SpectraCell. My telomeres further increased from 7.33kb in 2016 to 8.12kb in 2018, equivalent to another decade of cellular rejuvenation.

https://bioviva-scie...by-liz-parrish/

[Rocket]

Sooooo telomere extension equates to cellular rejuvenation?? Not mitochondrial rejuvenation, or AGE removal, ellp rejuvenation, lipofuscin removal... It comes down to simple telomere extension. I am quite positive Lizzie has aged 3 full human years since her treatment.

[Turnbuckle]

Sooooo telomere extension equates to cellular rejuvenation?? 

 

 

It's marketing for BioViva.

[Mind]

Marketing, publicity, whatever. If the test is legit, it is interesting and worth discussion. I know she has gotten some other biomarker testing done, so an additional question is, have those other markers improved.

[Phoebus]

It's marketing for BioViva.

 

sure but dont we want folks to do this exact thing? 

 

she did the experimental treatment when many experts told her it was reckless and unethical and she would get super cancer and die. And now we have this data to look at 

 

Sure its N=1, but it is something and it advances the anti aging conversation along. 

[Turnbuckle]

Marketing, publicity, whatever. If the test is legit, it is interesting and worth discussion. I know she has gotten some other biomarker testing done, so an additional question is, have those other markers improved.

 

I have no question about the legitimacy of the test, only the assertion that lengthening telomeres will reverse aging. While it may seem to do that over the short term, it will ultimately allow cells to reach unprecedented epigenetic age, and that cannot be a good thing. Epigenetic age correlates well with chronological age, but telomeric age does not. Worse, once you've lengthened your telomeres globally, there's no way to undo it. Epigenetically old cells that would have reached senescence will continue to divide.

Edited by Turnbuckle, 27 August 2018 - 03:04 PM.

[LizParrish]

Hi guys, 

 

Justin pointed me to the conversation. I have not been on this site for a long time, nice to be back.

 

Let me clarify some things. Telomere extension is not considered the only therapy that will be needed to reverse biological aging. BioViva focuses on the hallmarks of aging.  Telomere extension is one part of treating aging. I believe, one essential part. AND, When we look at the age of my t lymphocytes we measure the age in telomere length, not in any other marker. I am sure you understand that.  

 

Over time, a multitude of genes will need to be addressed to stop the biological aging process. My company, BioViva,  is set up for the long game of delivering the first artificial chromosome to treat biological aging. That means multiple genes inserted at one time that create a homeostasis in the body. We look at all potentials and track successes and failures in research. 

 

Someone wise once said -Everything that you do is a press release. So yes, we made the most of bringing light to the most dangerous disease on the planet, biological aging. 

 

I am very busy today but will try to watch this post for questions and comments for the next few hours. 

[sthira]

Someone wise once said -Everything that you do is a press release. So yes, we made the most of bringing light to the most dangerous disease on the planet, biological aging.

I am very busy today but will try to watch this post for questions and comments for the next few hours.

Thank you for your work; like you, many here believe in the do it yourself approach to attempting to reverse the aging process (since the formal science is chugging along at such a slow pace).

I'm curious about you Fiji clinic. Do you still have plans for opening potential experimental therapies to medical tourists like many here might be?

Also, what is your thinking behind the move to change Bioviva from a rejuvenation to a bioInformatics company?

[Phoebus]

I have no question about the legitimacy of the test, only the assertion that lengthening telomeres will reverse aging. While it may seem to do that over the short term, it will ultimately allow cells to reach unprecedented epigenetic age, and that cannot be a good thing. Epigenetic age correlates well with chronological age, but telomeric age does not. Worse, once you've lengthened your telomeres globally, there's no way to undo it. Epigenetically old cells that would have reached senescence will continue to divide.

 

 

this is speculation on your part. You cant possibly know this. I mean its perfectly okay to speculate, I speculate myself, but you cant state these things as absolute truths because there is simply not enough data to do so. 

[LizParrish]

Thank you, 

 

Contacts... We have learned a lot about business since we started. The agreement to go into Fiji was based on a contract where a third party would bring funding and BioViva would use our name and team to increase interest. This was a learning situation and I would never do it again. The group was supposed to incorporate BioViva Fiji, as well as many other things. We are not legally able to move forward in Fiji as an independent company because of the agreement so we were never able to fix the image of the Fiji project. Again, never again.

 

BioViva has really not changed anything, we have three patents pending and are opening research and development. We merely changed the company structure so that we are operating legally in the USA. This new structure gives us everything we need, for now, to deliver on our mission.  

[Turnbuckle]

this is speculation on your part. You cant possibly know this. I mean its perfectly okay to speculate, I speculate myself, but you cant state these things as absolute truths because there is simply not enough data to do so. 

 

 

See for yourself: This is a chart of telomere length vs age-- http://www.wired.com...omere_graph.jpg

And the left chart below shows the Horvath clock, a measure of epigenetic age vs chronological age--

https://upload.wikim...dictors.pdf.jpg

 

Telomeric age is poorly correlated, while epigenetic age is highly correlated.

 

Worse--

 

Consistent with our paradoxical association between LTL [leukocyte telomere length]-related SNPs [Single nucleotide polymorphisms] and IEAA [intrinsic epigenetic age acceleration], we find that TERT [telomerase reverse transcriptase] variants associated with a higher abundance of naive T cells (indicative of a younger adaptive immune system) are positively associated with higher values of IEAA and higher values of EEAA (indicative of an older epigenetic age, Supplementary Figs. 15 and 16, and Supplementary Data 4).

https://www.nature.c...467-017-02697-5

 

 

Edited by Turnbuckle, 28 August 2018 - 01:20 AM.

[LizParrish]

Sooooo telomere extension equates to cellular rejuvenation?? Not mitochondrial rejuvenation, or AGE removal, ellp rejuvenation, lipofuscin removal... It comes down to simple telomere extension. I am quite positive Lizzie has aged 3 full human years since her treatment.

Actually, it has been shown that telomere lengthening has a direct effect on mitochondrial function. 

 

https://www.ncbi.nlm...les/PMC3747515/

https://www.ncbi.nlm...es/PMC5399702/ 

Attached Thumbnails

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Edited by LizParrish, 28 August 2018 - 01:02 AM.

[Turnbuckle]

There are other ways of clearing out defective mitochondria. But epigenetic aging results in detuning of cells for their intended purpose. The older the epigenetic age, the worse the function. If you never let cells reach senescence, they will continue to divide and grow ever older and ever more dysfunctional. If you didn't have any stem cells to replace them, then maybe that would have some value.

[LizParrish]

It has been hypothesized to use telomerase gene therapy to target only stem cells, giving them more healthy divisions. Not possible yet. The idea is to create more genomic stability with the transduction of the gene, not to stop apoptosis. A healthy cell will go through normal apoptosis and may skip the senescent process.  I do not believe that we should hinder the body's processes in regards to a cell regulation, just make them more efficient and precise. 

[QuestforLife]

There are other ways of clearing out defective mitochondria. But epigenetic aging results in detuning of cells for their intended purpose. The older the epigenetic age, the worse the function. If you never let cells reach senescence, they will continue to divide and grow ever older and ever more dysfunctional. If you didn't have any stem cells to replace them, then maybe that would have some value.

 

Don't forget Turnbuckle, that Horvath's measure of aging is as yet just a measure, not a cause of aging. His own papers show that immortalized cell lines continue to 'age' as per his clock, but actually show no signs of aging, see:

 

https://www.ncbi.nlm...les/PMC4890984/

 

So re-extending telomeres does keep cells healthy. We just need to be careful not to fully immortalize them, as this does remove a barrier if and when a cell goes rogue due to a mutagen.

 

I believe there is more than one path to beat aging. We might find ways to renew and enlarge all stem cell pools, and use senolytics to clear out old somatic cells. Or we might find ways to rejuvenate somatic cells, whilst clearing out any cells that have gone bad.

[QuestforLife]

Also there can be little argument that at a cellular level, extending telomeres IS reversing aging.

 

https://www.ncbi.nlm...pubmed/24863242

 

At the moment the area of discussion is whether this is a good thing to do at the organism level. Various mice studies by Blasco et al. and Liz's results so far are offering tantalizing evidence it may be.

[Turnbuckle]

Don't forget Turnbuckle, that Horvath's measure of aging is as yet just a measure, not a cause of aging. His own papers show that immortalized cell lines continue to 'age' as per his clock, but actually show no signs of aging, see:

 

https://www.ncbi.nlm...les/PMC4890984/

 

So re-extending telomeres does keep cells healthy. 

 

 

If you define cellular aging by simply being alive--avoiding senescence and the resultant apoptosis--then you would be right, lengthening telomeres keeps them alive. But in an organism, cellular aging should be defined as doing the job they are assigned to do. If cellular epigenetic programing gets screwed up so cells are producing proteins in the wrong amounts--or not at all--then they aren't doing their job properly. From your link--

 

at the cellular level, ageing, as measured by the epigenetic clock, is distinct from senescence. It is an intrinsic mechanism that exists from the birth of the cell and continues. This implies that if cells are not shunted into senescence by the external pressures described above, they would still continue to age. This is consistent with the fact that mice with naturally long telomeres still age and eventually die even though their telomere lengths are far longer than the critical limit, and they age prematurely when their telomeres are forcibly shortened, due to replicative senescence. Hence senescence is a route by which cells exit prematurely from the natural course of cellular ageing.

https://www.ncbi.nlm...les/PMC4890984/

 

 

 

Apoptosis kills senescent cells, but that sacrifice keeps the organism younger that it would be if these senescent cells were rescued from senescence and continued to live. While it's true that telomere age is not directly coupled to epigenetic age, they both proceed together in stochastic fashion, so that cells with short telomeres that have become senescent will tend to be among the oldest epigenetically. Thus when you allow them to die--or actively kill them with senolytic treatments--and then replace them with stem cell derived somatic cells, you will lower the epigenetic age and improve the overall function of organs with those new cells.

 

So a long term stem-cell based-strategy for aging keeps the cellular population epigenetically young by limiting old cells (and can produce some amazing short term results as well). Telomere lengthening is a short term strategy that rescues the function of old cells producing short term benefits, but ultimately results in an epigenetically old population of cells that function poorly. 

Edited by Turnbuckle, 28 August 2018 - 10:29 AM.

[QuestforLife]

If you define cellular aging by simply being alive--avoiding senescence and the resultant apoptosis--then you would be right, lengthening telomeres keeps them alive. But in an organism, cellular aging should be defined as doing the job they are assigned to do. If cellular epigenetic programing gets screwed up so cells are producing proteins in the wrong amounts--or not at all--then they aren't doing their job properly. From your link--

 

 

 

Apoptosis kills senescent cells, but that sacrifice keeps the organism younger that it would be if these senescent cells were rescued from senescence and continued to live. While it's true that telomere age is not directly coupled to epigenetic age, they both proceed together in stochastic fashion, so that cells with short telomeres that have become senescent will tend to be among the oldest epigenetically. Thus when you allow them to die--or actively kill them with senolytic treatments--and then replace them with stem cell derived somatic cells, you will lower the epigenetic age and improve the overall function of organs with those new cells.

 

So a long term stem-cell based-strategy for aging keeps the cellular population epigenetically young by limiting old cells (and can produce some amazing short term results as well). Telomere lengthening is a short term strategy that rescues the function of old cells producing short term benefits, but ultimately results in an epigenetically old population of cells that function poorly. 

 

Yes, it may be the case that damaged cells would be better replaced than repaired - I am merely drawing attention to the fact that Horvath suggested but did not prove this. So far the methylation/demethylation he uses as a clock has not been linked to cell function. In fact gene expression seems to be reset to that of a younger cell with re-elongation of telomeres:

 

https://www.ncbi.nlm...pubmed/24863242

 

I am betting we'll eventually find youthful length telomeres contribute to chromatin stability and prevent many of the harmful epigenetic changes that occur with age (even though they don't prevent some methylation/demethylation).

 

 

  

Edited by QuestforLife, 28 August 2018 - 11:04 AM.

[Turnbuckle]

Yes, it may be the case that damaged cells would be better replaced than repaired - I am merely drawing attention to the fact that Horvath suggested but did not prove this. So far the methylation/demethylation he uses as a clock has not been linked to cell function. In fact gene expression seems to be reset to that of a younger cell with re-elongation of telomeres:

 

https://www.ncbi.nlm...pubmed/24863242

 

I am betting we'll eventually find youthful length telomeres contribute to chromatin stability and prevent many of the harmful epigenetic changes that occur with age (even though they don't prevent some methylation/demethylation).

 

As pointed out in Horvath's paper--

 

telomere length has only a modest correlation with chronological age (r = 0.5), while cellular ageing as measured by the epigenetic clock has a far higher degree of association (0.99 for solid tissues) with biological ageing. 

 

 

So what clock would you use? One that tells time accurately, or one that says you might die of old age when you're twenty?

 

As for your link above, you are misinterperting it. Yes, there are "senescence-associated expression patterns," and those can be reversed by lengthening telomeres, but that obviously cannot change the underlying epigenetic age of the cell. 

 

Only a small specific subset of genes was identified that was truly senescence-regulated and changes in gene expression were exacerbated from presenescent to senescent cells. The majority of gene expression regulation in replicative senescence was shown to occur due to telomere shortening, as exogenous telomerase activity reverted most of these changes.

 

 

The same mechanism that initiates senescence due to telomere shortening (overlapping those involved with cell cycle arrest)  appears to work in reverse when telomeres are lengthened. This involves a few genes, but there is no mechanism to change the rest of the vast epigenetic code that has steadily been corrupted by random changes during aging. You can only do that by taking the cells out and reprograming them, or by replacing them using stem cells.

Edited by Turnbuckle, 28 August 2018 - 11:47 AM.

[QuestforLife]

As pointed out in Horvath's paper--

 

 

So what clock would you use? One that tells time accurately, or one that says you might die of old age when you're twenty?

 

As for your link above, you are misinterperting it. Yes, there are "senescence-associated expression patterns," and those can be reversed by lengthening telomeres, but that obviously cannot change the underlying epigenetic age of the cell. 

 

 

The same mechanism that initiates senescence due to telomere shortening (overlapping those involved with cell cycle arrest)  appears to work in reverse when telomeres are lengthened. This involves a few genes, but there is no mechanism to change the rest of the vast epigenetic code that has steadily been corrupted by random changes during aging. You can only do that by taking the cells out and reprograming them, or by replacing them using stem cells.

 

I'm not misinterpreting it. If you look at gene expression changes from young to old cells, lengthening telomeres reverts that. This paper is one of many on the subject. This is occurs in a sliding scale from youthful expression level all the way down through middle aged and old cells and finally to fully arrested, senescent cells.

 

So in that sense the telomere is an epigenetic control mechanism.

 

It may well be that the Horvath methylation pattern age-related changes are just what happens to regions of the DNA that are not particularly well regulated, and hence are not important. Or they may be important. But that has not (yet) been shown. Correlating with age is what this clock was designed to do. Doesn't mean it's causal.

 

On accuracy the epigenetic clock Horvath uses is indeed a much better clock than measuring leukocyte telomere length. Leukocytes are continually being created and destroyed and their telomere length will vary with all sorts of things like infection and stress, hence how they can (supposedly) be improved by sleep, meditation, diet, etc. But these things are superficial. Underlying all this the telomere length of cells in important human tissues is shortening with age, and this is a cause of aging. Unfortunately we don't have an easy way to measure that right now.

[Turnbuckle]

I'm not misinterpreting it. If you look at gene expression changes from young to old cells, lengthening telomeres reverts that. This paper is one of many on the subject. This is occurs in a sliding scale from youthful expression level all the way down through middle aged and old cells and finally to fully arrested, senescent cells.

 

So in that sense the telomere is an epigenetic control mechanism.

 

 

Evidence? Because the paper you linked to does not show that. I haven't seen anything suggesting that restoring telomere length makes any change to the underlying epigenome, except for the genes directly impacting senescence.

[QuestforLife]

Here's some evidence for the regulation of gene expression by telomeres:

 

https://www.ncbi.nlm...les/PMC4233240/

 

and:

 

http://journals.plos...al.pbio.2000016

 

and a quick review article:

 

https://www.ncbi.nlm...les/PMC4233237/

 

 

[Turnbuckle]

Here's some evidence for the regulation of gene expression by telomeres:

 

https://www.ncbi.nlm...les/PMC4233240/

 

and:

 

http://journals.plos...al.pbio.2000016

 

and a quick review article:

 

https://www.ncbi.nlm...les/PMC4233237/

 

I find no evidence for your asserion in any of those papers--that extending telomere length can restore epigenetics to a more youthful level. Can you quote the actual passages that you think are relevant?

Edited by Turnbuckle, 28 August 2018 - 02:43 PM.

[QuestforLife]

I find no evidence for your asserion in any of those papers--that extending telomere length can restore epigenetics to a more youthful level. Can you quote the actual passages that you think are relevant?

 

Telomeres influence gene expression via heterochromatic spreading and via telomere looping, as per the papers. This is 'epigenetic' by definition. 

 

I did not say telomeres could reverse the changes in methylation measured by the Horvath clock. But those have yet to be shown to affect gene expression.

 

Unless you can supply references to the contrary?

[Turnbuckle]

There is some interaction between telomeres and the epigenetic code, but telomeres are not part of the code itself. Restoring telomere length may eliminate the negative effect on nearby epigenetic patterns without restoring the far larger epigenetic code to a younger age. And the changeable length of telomeres is not "epigenetic by definition" as it is not heritable. If anything that influenced gene expression was epigenetic, then the availability of nutrients would be epigenetic, but it isn't.

[QuestforLife]

There is some interaction between telomeres and the epigenetic code, but telomeres are not part of the code itself. Restoring telomere length may eliminate the negative effect on nearby epigenetic patterns without restoring the far larger epigenetic code to a younger age. And the changeable length of telomeres is not "epigenetic by definition" as it is not heritable. If anything that influenced gene expression was epigenetic, then the availability of nutrients would be epigenetic, but it isn't.

I would say availability of nutrients IS epigenetic, as it affects gene expression. As does heat, exercise, circadian rhythm, etc., etc. But maybe we are arguing semantics.

Clearly telomere length is not the only important influence on gene expression. But neither are methylation patterns. Chromatin and looping of the DNA helix is probably much more important. But no doubt there is much more to discover in this space.

[Kentavr]

Hi guys,

Justin pointed me to the conversation. I have not been on this site for a long time, nice to be back.

Let me clarify some things. Telomere extension is not considered the only therapy that will be needed to reverse biological aging. BioViva focuses on the hallmarks of aging. Telomere extension is one part of treating aging. I believe, one essential part. AND, When we look at the age of my t lymphocytes we measure the age in telomere length, not in any other marker. I am sure you understand that.

Over time, a multitude of genes will need to be addressed to stop the biological aging process. My company, BioViva, is set up for the long game of delivering the first artificial chromosome to treat biological aging. That means multiple genes inserted at one time that create a homeostasis in the body. We look at all potentials and track successes and failures in research.

Someone wise once said -Everything that you do is a press release. So yes, we made the most of bringing light to the most dangerous disease on the planet, biological aging.

I am very busy today but will try to watch this post for questions and comments for the next few hours.

You have one eye in the picture. Are you an Illuminati?

[Kentavr]

I am betting we'll eventually find youthful length telomeres contribute to chromatin stability and prevent many of the harmful epigenetic changes that occur with age (even though they don't prevent some methylation/demethylation).

But what about glucosepane?)

[QuestforLife]

But what about glucosepane?)

 

What about it?

 

No one is suggesting after short telomeres are solved (in some way) nothing else will need to be done, ever.

 

But there is some evidence that as mitotic cells age via cell division and shortening of telomeres, they not only divide more slowly but also process waste more slowly too. So youthful telomeres should reduce the rate of accumulation of AGEs.

 

https://www.ncbi.nlm...les/PMC4479064/

[marcobjj]

She does look more youthful in recent photos. It's hard to believe she's (about) 48 years old. She looked young for her age even before receiving gene therapy.