204 replies to this topic

[Steve H]

Florian is that proof that FSTN can reduce TGF-beta levels or that TGF-beta levels are a pro-aging factor beyond a certain level?

 

The Conboy work demonstrates the later:

 

http://www.ncbi.nlm....les/PMC4494916/

 

and is again reviewed here with a picture of signalling factors showing the interaction clearly in figure 4 (I wanted to attach the image but could not)

 

http://www.ncbi.nlm....les/PMC4637204/

 

and they demonstrate it in this older paper using FSTN

 

http://www.ncbi.nlm....les/PMC4003029/

 

These are the key papers off the top of my head but I certainly have a fair few more to support that. This picture of signalling by the Conboys explains the interactions clearly:

 

This is why I find the FSTN therapy the more interesting of the two and that it aside from FSTNs interaction with TERT which it also does.

Edited by Steve H, 20 January 2016 - 03:05 PM.

[Florian Xavier]

TGF-beta levels are a pro-aging signal beyond a certain level?

 

associated with lifespan

[Steve H]

Sorry Florian I edited as you posted. Well the Conboy paper explains:

 

"We demonstrate an elevation of TGF-β1 in the aged circulation, old muscle, and old brain and cross-tissue conservation in elevated TGF-β/pSmad2,3 signal transduction in aged skeletal muscle and neural stem cell microenvironments. An ability of circulating TGF-β1 to cross the blood brain barrier may increase with age, when BBB becomes more permeable [39], but regardless of its endocrine levels, local production of TGF-β1 by microglia and by endothelial cells increases in the hippocampus with aging. Importantly, the age-associated increase in TGF-β1 levels leads to a decline in NSC proliferation and downstream neurogenesis with age. Moreover, TGF-β may exert its pro-aging effects in brain and muscle in part by increasing inflammatory responses, as indicated by the upregulation of β2 microglobulin (B2M), a component of MHC class I molecules. Finally, youthful calibration of TGF-β1/pSmad2,3 pathway by a systemically administered inhibitor of TGF-β receptor kinase activity reduced tissue inflammation in brain and muscle, as indicated by normalized levels of B2M, and robustly rejuvenated hippocampal neurogenesis and skeletal myogenesis in the same old animal."

 

http://www.ncbi.nlm....les/PMC4494916/

 

Having spoken with Irina and Michael they believe this mechanism is likely systemic across multiple tissue types and correlates with B2M for example shown last year to be a pro-aging factor by Villeda et al. Reduction of TGF-beta levels also is shown to reduce B2M levels as shown in the Conboy paper linking TGF-beta directly with aging decline.

 

Their older paper demonstrates this same mechanism at play in muscles:

 

http://www.ncbi.nlm....pubmed/23770987

 

I do have other supporting papers that demonstrate that TGF-beta is both pro and anti aging in my research archive but I would need more time to dig them out for you. The three cited papers are however an excellent start and open access. Let me find the other papers for you in due course.

Edited by Steve H, 20 January 2016 - 03:29 PM.

[Florian Xavier]

Muscles and brain, even skin rejuvenation, differ from whole body rejuvenation. If a 70y take an anti-tgfb1, nothing will happen.

[Steve H]

Muscles and brain, even skin rejuvenation, differ from whole body rejuvenation. If a 70y take an anti-tgfb1, nothing will happen.

 

 

Florian how do you know it would do nothing? The evidence is there in the papers that inhibiting TGF-beta does rejuvenate various tissues as demonstrated in living animals. So I would disagree with your assumption it would do nothing as it clearly has and does in the living system in several cases. In the case of children with Beckers MD and severe muscle wastage FSTN improved their situation so well a trial by Milo Biotech has now been extended to treat Ducehenes MD, I am not suggesting someone in a wheelchair would be dancing and running a marathon if old and given this but its reasonable to think it might improve their situation as it has these kids and of course the various animals tested.

 

Also the point Michael Conboy was making to me is that they believe that the TGF-beta mechanism is likely universal in which case it could be used to improve whole body signalling. The review paper in talks about a combination of TGF-beta inhibiting with Alk-5, Senolytics and Oxytocin to "recalibrate the systemic Millieu". 

 

You are correct that it alone will not fix aging because aging is multi-factoral, but it would almost certainly be beneficial as inhibition of TGF-beta generally is provided it is at the right level.

 

Glucosepane is an another example of something else that needs fixing and increasing levels of that also increases TGF-beta significantly, so if we cleave AGE we can reduce systemic TGF-beta levels at the source by doing that, this in my view is a better approach than trying to calibrate and compensate for the consequence of that damage. However the Conboy work shows that this is possible.

So when I say that FSTN therapy here is the most interesting I think it will be provided the therapy was delivered properly (or even if), the vectors reached their target and there is data to demonstrate this.

I am certainly not suggesting TGF-beta is the only pro-aging factor (IL-6 is another) BUT we are making progress quickly and potential solutions to these problems are plausible in the near future. 

Edited by Steve H, 20 January 2016 - 05:29 PM.

[corb]

 

The TERT trated mice made lifespan gains against the control group. So unless AAV9-mTERT works as an appetite suppressant somehow, I think the study was controlled for CR

 

Viral infections tend to suppress appetite, yes. I thought it was common knowledge.

[marcobjj]

 

 

The TERT trated mice made lifespan gains against the control group. So unless AAV9-mTERT works as an appetite suppressant somehow, I think the study was controlled for CR

 

Viral infections tend to suppress appetite, yes. I thought it was common knowledge.

 

 

I'm not sure if you're serious but the control mice were also infected with a AAV9-eGFP (green fluorescent) virus. They were still outlived on average by the  AAV9-mTERT infected mice. So the experiment controlled for CR and infection. Unless you have reason to believe that a TERT adenovirus is a stronger appetite suppressant than AAV9-eGFP virus. and by the way, the adenoviruses are used in these sort of experiments  because they are known to produce a very mild or non existent immune reaction to begin with.

Edited by marcobjj, 20 January 2016 - 08:30 PM.

[corb]

 

 

 

The TERT trated mice made lifespan gains against the control group. So unless AAV9-mTERT works as an appetite suppressant somehow, I think the study was controlled for CR

 

Viral infections tend to suppress appetite, yes. I thought it was common knowledge.

 

 

I'm not sure if you're serious but the control mice were also infected with a AAV9-eGFP (green fluorescent) virus. They were still outlived on average by the  AAV9-mTERT infected mice. So the experiment controlled for CR and infection. Unless you have reason to believe that a TERT adenovirus is a stronger appetite suppressant than AAV9-eGFP virus. and by the way, the adenoviruses are used in these sort of experiments  because they are known to produce a very mild or non existent immune reaction to begin with.

 

 

As I mentioned there was an article on this same forum that illustrated a case where a proper control group was also present but the calorie intake was not measured, and surprise surprise the longer median life span turned out to be a result of CR. Guestimation is not science, and doubly so for biology - unless something has been measured - as in physically measured - you can't say it's been accounted for.

[resveratrol_guy]

 

A single inoculation of a TERT carrying virus extending their lifespans in 14% to 23% is impressive, as AAV viral activity (supposedly) doesn't persist over the long term. The paper mentions viral transduction efficiency of 20–50%  after one month. Multiple inoculations could yield   a much greater lifespan extension.

 

 

 

Good study done on mice using a very similar technique:

http://www.ncbi.nlm....les/PMC3494070/

It gave the mice a nice bounce in MEDIAN lifespan.

 

This is a brilliant contribution. I can't believe I missed this one, as it's been out since 2012.

 

In particular, direct your attention to Figure 3C, where you can see the causes of death in the TERTized mice.  Notice that about 60% of them died with (of?) cancer, which sounds higher than in normal human populations. Moreover, over half of these cancers were lymphomas. But as you can see here and here, the majority of human lymphoma victims are still alive 10 years after diagnosis. Personally, I would rather be fighting one of these less virulent cancers, than random cardiac arrest, or dementia, as a cause of death. So if this data implies that TERT therapy skews the odds in this direction, I think it's a good thing.

 

Right in the abstract, it is mentioned that: "Importantly, telomerase-treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. "

 

Thanks for pointing that out. In any event, it doesn't seem like the risk of death from cancer is increased by TERT therapy.

 

But in reference to what you said above, the AAVs actually don't need to stick around very long -- just long enough to accomplish the desired genetic change. Multiple therapy sessions would just increase the transduction rate, which is never going to hit 100%. But no one would do that because it runs the low-but-nonzero risk of developing an immune response to the AAV -- not to mention the massive expense for the foreseeable future. That would be bad because it might inhibit the effectiveness other future gene therapies. (We cannot just assume that CRISPR will obviate the need for AAVs any day now. Let's remember that we don't actually have AAV therapy just yet.)

 

FSTN AAV therapy sounds interesting, to be sure. As does turning off APOE4, IGF1, etc. Unfortunately, at best, we will have our choice of 2 gene therapies by the end of this year, at Elysium prices. Don't get me wrong. Much of that money will fuel the next advances, so it's a necessary burden. But this is going to take many years to get to the cost level of a common vaccine, wherein the average person could casually consider multiple sessions.

 

One thing that I find particularly troublesome about BioViva's approach (not that there's a serious alternative) is the locality of transduction, particularly in the brain. Liz Parrish makes no secret of the fact that their Alzheimer's therapy affects only the hippocampal neurons proximate to the injection site. Presumably, the therapy which she received had a fairly broad systemic impact, courtesy of the circulatory system. But CSF pulsation is so weak that the AAVs apparently don't get very far. So if it works, we end up protecting some critically important neurons from phosphotau accretion. That's great, but what about the rest of the brain? This goes back to the transduction problem. But it's hard to solve this time because you can just stick a hundred needles in a patient's head. So now you need something which will cross the BBB and dissolves throughout the brain like NGF, but not like NGF in the sense that it must create permanent genetic changes. Maybe CRISPR will solve this issue. In any event, AAVs won't. And unless you solve neurodegeneration, you're basically protecting yourself against cardiovascular failure so you can live long enough for it to become a problem. Not that systemic TERT therapy has no positive effects on the brain. It's just that, in my very limited knowledge of its effects, it won't do enough to protect neurons (via systemic health improvements) as compared to direct neuronal transduction.

Edited by resveratrol_guy, 20 January 2016 - 09:56 PM.

[resveratrol_guy]

Liz Parrish has done another hour interview with Singularity host Nikola Danaylov.

Highlights:

1. It seems objectively clear, at 4 months after therapy, that Parrish has lost visceral fat and gained muscle mass. Obviously there are more mundane explanations than myostatin inhibition.

2. She estimated that the cost of therapy, should it prove successful, would be tens of thousands of dollars 5 to 7 years down the road. (Yeah, I know. Just remember how long the FDA would take to do this.) I guess this means it will be a while before I can eat more often than every other day :(

3. Hard data is going to take 12 to 18 months to accumulate. Her company intends to look at numerous markers with the help of third parties including Harvard. This is not a matter of simple blood tests. There are numerous tissue samples and MRI studies to examine as well.

4. There are no negative effects in her report. She shows no signs of ill health.

 

5. She said that in rodent studies, TERT therapy resulted in larger brain mass. It was unclear whether it delayed brain atrophy, or actually upregulated neurogenesis.

 

6. In a few different interviews, she has mentioned shorter sleep latency and higher sleep quality, saying in one case that she felt sleepy not long after sundown. This to me is more significant than the body composition measurements because, in the absence of pharmaceutical intervention, it would be difficult to engineer deliberately in the way that working out can improve body composition predictably. (Liz says she only takes vitamins.) Moreover, it's suggestive of neurological improvement, which is consistent with #5 and would frankly be remarkable, considering that her CNS was not directly infected. Unfortunately her neurological status will be very hard to quantify.

7. She's in favor of CRISPR replacing AAVs, assuming that a patent quagmire can be avoided.

 

[niner]

7. She's in favor of CRISPR replacing AAVs, assuming that a patent quagmire can be avoided.

 

 

I don't understand this.  AAV's solve the delivery problem for you.  CRISPR is an editing technique, but how do you deliver it to the appropriate cells and get it to properly make the edit?
 

[corb]

 

7. She's in favor of CRISPR replacing AAVs, assuming that a patent quagmire can be avoided.

 

 

I don't understand this.  AAV's solve the delivery problem for you.  CRISPR is an editing technique, but how do you deliver it to the appropriate cells and get it to properly make the edit?
 

 

 

Liposomes maybe?

[Mind]

Does anyone else think it was a bad idea for them to attempt TERT therapy and myostatin inhibition at the same time? Won't it be harder to attribute health improvements with 2 therapies instead of one.

[sthira]

Does anyone else think it was a bad idea for them to attempt TERT therapy and myostatin inhibition at the same time? Won't it be harder to attribute health improvements with 2 therapies instead of one.

Maybe. It's a good question, and one I was hoping Socrates would ask her during the latest podcast. But he didn't ask and she didn't say. From what I gather they chose what they considered the best two treatments most likely to have the biggest effect. Myostatin inhibition works to help build muscle. We'll see it. But the TERT therapy seems more like a shot in the dark. Parrish repeatedly says she wants the anti-aging effects of these injections to appear visual as well as internal. She wants to look as good on the outside as her organs are functioning on the inside?

[corb]

Does anyone else think it was a bad idea for them to attempt TERT therapy and myostatin inhibition at the same time? Won't it be harder to attribute health improvements with 2 therapies instead of one.

 

Maybe they expect an additive effect so that the outcome is more easily detectable?

[Mind]

 

Does anyone else think it was a bad idea for them to attempt TERT therapy and myostatin inhibition at the same time? Won't it be harder to attribute health improvements with 2 therapies instead of one.

Maybe. It's a good question, and one I was hoping Socrates would ask her during the latest podcast. But he didn't ask and she didn't say. From what I gather they chose what they considered the best two treatments most likely to have the biggest effect. Myostatin inhibition works to help build muscle. We'll see it. But the TERT therapy seems more like a shot in the dark. Parrish repeatedly says she wants the anti-aging effects of these injections to appear visual as well as internal. She wants to look as good on the outside as her organs are functioning on the inside?

 

 

I can ask some questions during the LongeCity Now Podcast: http://www.longecity...arrish-bioviva/
 

[resveratrol_guy]

 

7. She's in favor of CRISPR replacing AAVs, assuming that a patent quagmire can be avoided.

 

I don't understand this.  AAV's solve the delivery problem for you.  CRISPR is an editing technique, but how do you deliver it to the appropriate cells and get it to properly make the edit?

 

I just assumed that CRISPR delivery was a solved problem not involving AAVs. She wasn't specific, and seems to be relying on third party experts to make the technology usable and economical so BioViva can adapt it in the future. Liposomes sound reasonable to me, but what do I know?

 

I also agree that it wasn't the greatest approach to do TERT and myostatin simultaneously, from a scientific perspective. But given the urgency of this n=1 study, it was the most practical.
 

Edited by resveratrol_guy, 26 January 2016 - 01:17 AM.

[resveratrol_guy]

Two thumbs up! While this is primarily a high calibur bioethics interview well worth watching for that reason alone, Liz drops a few scientific gems, such as murine methuselization via FGF21.

 

 

[Steve H]

Until I see any actual data I remain skeptical. 

[niner]

Liz made a point of saying that she didn't want to talk about results until the data was in because it would just be "a testimonial".  I think that's pretty good of her and BioViva.  She's a good spokesperson for life extension in general.

 

[marcobjj]

Props to Liz for stepping up, but to be honest she was probably not the best candidate for this experiment. She looked young even before this therapy took place. if her DNA is reset to a genotype of a 25 year old the results wouldn't be as dramatic as if someone like Bill Andrews took it, who'd be the ideal patient zero in my opinion.

Edited by marcobjj, 12 March 2016 - 05:38 AM.

[reason]

Fortes fortuna iuvat, as they say. I'm pleased to see that the BioViva principals have attracted the support of Deep Knowledge Life Sciences as they continue to bootstrap their very intentionally disruptive gene therapy startup:

Deep Knowledge Life Sciences and BioViva announce partnership

"BioViva aims to make gene therapy affordable to everyone. Dmitry Kaminskiy, the founding partner of Deep Knowledge Life Sciences, is enthusiastically funding gene therapy, and is himself an early adopter." said BioViva CEO Elizabeth Parrish, adding "We both want to see a world where investors actually live their legacy instead of just leaving it", alluding to a possible future trend. Parrish made headlines in 2015 when she travelled to an undisclosed location outside the US and personally underwent two of her own company's experimental gene therapies: one to protect against loss of muscle mass with age, another to battle stem cell depletion. It was a gesture intended to prove the safety of the therapies and clear the road ahead for human trials in the US. Months later, BioViva are tracking her results and she has reported no negative side-effects. "I believed the biotech industry had become over-regulated and that the prevailing model was unlikely to bring new therapies to market in our lifetime. What we needed was a company that would treat diseased patients with no other options and then develop these treatments into preventative medicines. And thus was born BioViva in 2015."

For Dmitry Kaminskiy it's not all about the portfolio. He wants to shift the entire industry up a gear, and put an end to the lack of vision he believes has mired biotechnology for decades: "Millions of human lives are affected by diseases with a genetic component. The sooner we can bring affordable gene therapies and other cell therapies to market, the more needless deaths can be avoided."

I regard the shared vision of bypassing excessive regulation in medical development to be somewhat more important than the exact nature of the therapies under development today. Rapid, effective passage to the clinic will be the legacy here, the opening of a door that will see an increasing number of developers in every important field of medicine adopting a fast path to medical tourism and clinical availability outside the US and Europe, transparency of ongoing results, and a sensible degree of safely data. The stem cell field and countless patients benefited greatly from this sort of approach over the past fifteen years, and it really should be the standard, not the exception.

What constitutes a sensible degree of safety data? That should up to companies and patients to decide upon for themselves, but it is certainly far, far less than the FDA presently insists upon. The FDA leadership are not primarily concerned with safety at all, but rather the potential political fallout that might result from approving any any therapy, ever. There is no such thing as a safe medical treatment, but the media can pounce at random on any death, and the defense put up in advance by FDA career bureaucrats is to demand as much expense and data as possible from applicants. Few people seem to care about the potential therapies that never make it through the process, or are never submitted because there is no possible profit - those losses are invisible, but they are measured in lives, not money. These perverse incentives, rife in every government agency, is why the cost of developing drugs is huge, why the process is lengthy and drawn out beyond all common sense, and why the cost has doubled in the past decade. These imposes costs are pointless and unnecessary, and a huge burden on progress. It is long past time to evade the FDA and take the road of medical tourism, transparency from companies, educated customers, and sane levels of testing and development cost.

BioViva has demonstrated prototype follistatin and telomerase gene therapies in the first human volunteer. If successful, and with a enough uptake in cells, the former should provide increased muscle mass and thus compensate partially for the sarcopenia that accompanies aging, while the latter may globally increase stem cell activity, offsetting to some limited degree the decline that occurs with age. To my eyes follistatin and similar myostatin gene therapies are about as low risk as any genetic edit can be before it has been used by thousands of people. Myostatin blockers of various sorts have been trialed in humans with positive results, and scores of animal studies for follistatin and myostatin gene therapies have taken place since the turn of the century. There are natural human and animal myostatin loss of function mutants to study as well, and most seem to do pretty well with their extra muscle tissue. Telomerase gene therapy on the other hand strikes me as being more risky. It clearly extends life and improves health in mice, but mice have very different telomere and telomerase dynamics when compared to humans. There is the strong possibility that telomerase therapies will boost cancer incidence in humans, even though they don't do that in mice. At some point it has to be tried based on the intriguing animal study results, but I wouldn't want to be first in line.

There is no reason for gene therapies to be expensive once they are out of their initial phase of development and early adoption. This is the age of CRISPR, an basis for gene therapy that makes genetic editing so cheap and easy that near every life science laboratory can now undertake this research. A gene therapy treatment to enhance capabilities or compensate somewhat for one or more of the losses of aging, such as myostatin knockout or follistatin overexpression, will trend towards becoming a mass produced infusion, the same for everyone, administered by a bored clinician, and with limited need for followup attention from a physician. All of the complexity is baked into the manufacturing process, and the cost will scale down as the production runs grow large. Unlike drugs for medical conditions, the target market here is every adult human being: the economies of scale and competition will be more like like those for present day childhood vaccinations than other types of medication, and the price will accordingly fall to the same low level.

So, I hope to see BioViva prosper in their effort to shake up clinical translation, and demonstrate that no-one really needs the FDA in order to responsibly place the next generation of therapies in the hands of patients. They have picked a set of treatments likely to attract a lot of interested parties to the clinics that will provide them, and the advent of CRISPR-based gene therapies will make expansion to other very interesting therapies quite plausible. Things should become interesting in the years ahead, I believe.

View the full article at FightAging

[Steve H]

Until there is proper data for me it is a non story. I have serious concerns from a scientific POV as two therapies were taken at the same time, how will we know which therapy is doing what? How will we know what happens is not due to synergy?

 

It would have been better to test TERT transiently and collect the data before moving into combinations especially in an n=1. 

 

The source of any positive results (if any) will be now be very hard to determine meaning the entire experiment will need repeating at further expense. Gene therapy is very expensive so for me the experimental design (assuming there was one?) is flawed. The data will be all but meaningless and the FDA will not take the results seriously. So it will not be given IND status by the FDA and never be cleared for use in the US.

 

Telocyte on the other hand who have applied for an IND with the FDA and are moving towards clinical trials in the US are a far more promising proposal, they are taking the slower path via regulatory bodies BUT this means that ultimately approved for use by the FDA it will then be available to the public and backed up by safety and efficacy data that is robust and thorough. 

 

I am all for pioneering and self testing but such experiments if they are to be given scientific respect should be properly designed.

 

 

 

 

 

 

[sthira]

I am all for pioneering and self testing but such experiments if they are to be given scientific respect should be properly designed.

Sidestepping conservative medical establishment and restrictive FDA regulations seem more important than the therapies themselves. Many in the establishment will keep repeating "until there is a properly done study..." for longer than we're willing to keep waiting. Complaining about costs, the FDA, regulations, quibbling over what therapy is best, what isn't, what's meeting scientific rigor, what's amateurism -- this is why we're stuck. Sometimes it takes people outside of the establishment who are willing risk their own safety, stake their own reputation, look like a fool, be ridiculed, called stupid, unscientific.... sometimes it takes outsiders to unstick what's stuck.

[reason]

Initial data appears to show success for the telomerase gene therapy undergone by the BioViva CEO last year. Similar gene therapies extend life in mice, most likely though increased stem cell activity and thus improved tissue maintenance. It doesn't seem to raise cancer risk in mice, but there is a concern that this may still be an issue in humans, with our quite different telomere and telomerase dynamics. Measuring the length of telomeres as presently accomplished in white blood cells is a proxy metric of dubious value for the endpoint of improved stem cell function, unfortunately, but it is the technique presently available at reasonable cost and reliability. Average telomere length in immune cells is only tenuously related to age, statistically over large populations, and does tend to change over time in both directions in individuals due to changing health and other circumstances. The alteration here is large enough and rapid enough, however, to indicate that the gene therapy worked in the sense of delivering telomerase. Finding out whether it worked in other senses, producing a more youthful tissue environment, would require a biomarker of biological age, such as the DNA methylation measures presently under development.

In September 2015, then 44 year-old CEO of BioViva USA Inc. Elizabeth Parrish received two of her own company's experimental gene therapies: one to protect against loss of muscle mass with age, another to battle stem cell depletion responsible for diverse age-related diseases and infirmities. The treatment was originally intended to demonstrate the safety of the latest generation of the therapies. But if early data is accurate, it is already the world's first successful example of telomere lengthening via gene therapy in a human individual. Gene therapy has been used to lengthen telomeres before in cultured cells and in mice, but never in a human patient. Telomeres are short segments of DNA which cap the ends of every chromosome, acting as 'buffers' against wear and tear. They shorten with every cell division, eventually getting too short to protect the chromosome, causing the cell to malfunction and the body to age.

In September 2015, telomere data taken from Parrish's white blood cells by SpectraCell's specialised clinical testing laboratory in Houston, Texas, immediately before therapies were administered, revealed that Parrish's telomeres were unusually short for her age, leaving her vulnerable to age-associated diseases earlier in life. In March 2016, the same tests were taken again by SpectraCell revealed that her telomeres had lengthened by approximately 20 years, from 6.71kb to 7.33kb. This implies that Parrish's white blood cells (leukocytes) have become biologically younger. These findings were independently verified by the Brussels-based non-profit HEALES (HEalthy Life Extension Company), and the Biogerontology Research Foundation, a UK-based charity committed to combating age-related diseases.

"Current therapeutics offer only marginal benefits for people suffering from diseases of aging. Additionally, lifestyle modification has limited impact for treating these diseases. Advances in biotechnology is the best solution, and if these results are anywhere near accurate, we've made history.". Bioviva will continue to monitor Parrish's blood for months and years to come. Meanwhile, BioViva will be testing new gene therapies and combination gene therapies to restore age related damage. It remains to be seen whether the success in leukocytes can expanded to other tissues and organs, and repeated in future patients. For now all the answers lie in the cells of Elizabeth Parrish, 'patient zero' of restorative gene therapy.

Link: http://bioviva-scien...st-human-aging/

View the full article at FightAging

[Logjam]

This is interesting, and there are some reasonable hypotheses and evidence for said hypotheses that say telomeres do effect changes in gene expression (see K Cao's paper on telomeres "collaborating" with progerin in a self-destruct sequence: http://www.ncbi.nlm....bmed/21670498).

 

But does anyone reasonable think that any cells not known for replication (like skin, hair, etc.) will just start multiplying when the telomeres get longer?  One of the things I rarely see discussed in the context of telomeres are the various tumor suppressors that abort S phase. You can't miss them.  p15, p16, etc.  Even after you extend telomeres, you're going to have to coax the cells into S phase in many cases. This would only be step 1, and only if telomeres are actually the limiting factor as a recursion limiting "hack."  If you're a programmer, it makes sense:

 

Nothing needs to replicate more than 60x.  So cap it at 60 and assume it's cancer if it goes past 60 because nothing should need that.  

 

For example, no matter how long your beta cell's telomeres are, they only replicate about 15-20x before stopping unless something signals otherwise.  Nothing does, apparently.  Brain cells behave similarly.  Getting beta cells to express hTERT does absolutely nothing in some studies:

 

http://www.ncbi.nlm....pubmed/10856888

 

The senescent phenotype was not prevented by retroviral transduction of the hTERT gene, although telomerase activity was induced.

 

A reasonable hypothesis is that there is something else that is limiting proliferation.  We evolved way more than 1 strategy to limit replication.  Otherwise we'd be gray goo and use up our proliferative capacity too early.

 

I don't get why Elizabeth thinks this works, but she's holding up better than most of us and absolutely beautiful for her age (or period), so maybe she just needs to explain it to me :>

Edited by Logjam, 22 April 2016 - 01:41 PM.

[jans]

I hope they keep Liz well now, like as she was the Holy Grail.  http://bioviva-scien...st-human-aging/

First gene therapy successful against human aging American woman gets biologically younger after gene therapies

Elizabeth Parrish, CEO of Bioviva USA Inc. has become the first human being to be successfully rejuvenated by gene therapy, after her own company’s experimental therapies reversed 20 years of normal telomere shortening.  ...

[resveratrol_guy]

Dear BioViva, where do I mail the check for my therapy?!

 

Thanks for keeping us updated, jans! If this pans out, they deserve a Nobel Prize.

 

How ironic that, despite the oft-repeated commentary that she looked too young to be of much use as a gene therapy guinea pig, it turned out that "Parrish’s telomeres were unusually short for her age, leaving her vulnerable to age-associated diseases earlier in life."

 

But then "In March 2016, the same tests were taken again by SpectraCell revealed that her telomeres had lengthened by approximately 20 years, from 6.71kb to 7.33kb."

 

The transfection was evidently successful in the sense that her telomeres have lengthened by about 9%. Obviously 20 years is much more than 9% of a human lifetime, so by implication senescence sets in well before the telomeres are fully depleted.

 

I'm impressed by the apparent fact that this can now be observed in all of her white blood cells, which seems to imply that the transfection must have made it all the way to her bone marrow. (I suspect there's a distribution here, with some cells exhibiting shorter telomeres and some longer ones, with the latter perhaps winning out over time due to superior fitness, but the former never quite disappearing due to enhanced resistance to apoptosis.) Anyway, otherwise, the telomere lengths would have reverted to baseline values after a few months of immune cell recycling. Moreover, if the virus, which has presumably died out long ago, had invaded her marrow, then I wonder if, as in the animal studies, it had also invaded her neurons. In Mind's interview, she mentioned "de novo" creation of white matter, as in, the TERTed animals not only prevented neurodegeneration, but they grew new neurons; unfortunately, she did not elaborate.

 

[Florian Xavier]

why does it feel fake ?

[Logjam]

It shouldn't.  I don't think she'd go through all this trouble to be fakey, and she seems credible.  It's probably only one piece of the puzzle, but the people on her board are top notch.  I guess you could state the obvious.  There's a conflict of interest.  But she couldn't do the study on anyone else?

 

There are some interesting counterpoints to what I said above.  This being the most convincing (to me):

 

http://www.cell.com/...1247(12)00418-4

 

Basically it says dogs with long telomeres live longer.  Dogs are way closer to humans than mice.  Poodles and labs live a long time. Good thing, too.  Labs and poodles are awesome.

Edited by Logjam, 22 April 2016 - 04:14 PM.