Libella Gene Therapeutics to Run a Patient Paid Trial of Telomerase Gene Therapy

After Bioviva Science, Libella Gene Therapeutics is the second company to take a run at commercializing telomerase gene therapy treatments for human use. Telomerase is the enzyme responsible for lengthening telomeres, repeated DNA sequences at the ends of chromosomes, though it may have other roles. Telomeres are a part of the mechanism that limits the number of times that a somatic cell can replicate. Telomeres shorten with each cell division, and when too short they trigger programmed cell death or cellular senescence followed by destruction by the immune system. Ordinary somatic cells in humans do not express telomerase; it is only present in stem cells, which can replicate indefinitely to supply tissues with new somatic cells with long telomeres. This split between a small privileged stem cell population and the vast majority of restricted somatic cells is how higher forms of animal life keep cancer risk low enough for evolutionary success. Obviously not low enough for comfort, but evolution was never about individual happiness.

Telomerase gene therapies have been demonstrated to extend life span and reduce cancer risk in mice. The former outcome is likely largely due to increased stem cell activity, while the latter outcome is somewhat counterintuitive: if damaged cells are pushed into more activity and replication that they would not normally have undertaken, won't this raise the risk of cancerous mutations arising? It may be that improvements in immune function act to more than offset this risk - a primary task of the immune system is to destroy potentially cancerous cells before they have the chance to form a tumor. There is still some concern, in that mice have very different telomere and telomerase dynamics in comparison to humans. Will the balance of risk and improved function be the same in our species? The way we will find out is via brave volunteers trying the therapies, most likely, rather than any of the other, much slower options.

Neither Bioviva nor Libella took the standard regulatory path forward, opting for some combination of regulatory arbitrage and medical tourism to bring their therapies to patients. This sort of effort, carried out responsibly, is, I think, necessary and must spread if the present excesses of the FDA are to be reined in. The FDA sees its role as reducing risk to zero, at any and all cost, including the cost of slowing medical development to a crawl. Analyses have long shown that the cost in lives of this regulatory burden of slowed development far outweighs the benefits - but absent therapies are invisible and arouse no media outrage. Bureaucracies inevitably optimize to minimize visible problems. The only way to combat this issue effectively, given that working to change the system from within, and political advocacy to change the system from the outside, have been ongoing energetically for the past few decades, a time over which the financial burden imposed by the FDA has more than doubled, is to prove out a viable, responsible, cost-effective path to market outside the FDA system of regulation.

Libella Gene Therapeutics recently announced a patient paid trial to be held outside the US. Patient paid trials are unfairly excoriated by the research and regulatory establishment. As I have remarked upon in the past, they are an entirely legitimate approach to obtaining data. The chief objection is the lack of a control group in most such trials - but if we are only interested in large, reliable effect sizes, then the control group is the rest of the patient population, and that works just fine. In general, good therapies for aging, those that target relevant mechanisms in ways that will truly move the needle on life span, will indeed have large and reliable effects.

A second objection, more valid, is the sort of marketing that tends to accompany these trials. That is very much in evidence here, sadly. Libella should rein that in; in the long term it only harms the very necessary development of reliable, well-defined pathways for regulatory arbitrage. Telomerase gene therapies are not a cure for aging. They are a compensatory or enhancement therapy that addresses one of the downstream consequences of aging, while having little to no effect on a wide range of other important issues, such as accumulation of persistent metabolic waste in long-lived cells. No amount of telomerase will enable the body to break down harmful compounds that it cannot break down even in youth. Further, no-one has yet demonstrated that you can reverse, say, even an epigenetic clock measure by 20 years in humans using telomerase gene therapy. Even if you could, one can't say that this corresponds to 20 years of rejuvenation, given how little is known of what exactly these clocks measure. These sorts of claims are just aggravating. I understand the need for marketing, but one can carry out good marketing without having to resort to this sort of thing.

The Libella Gene Therapeutics trial will likely make waves because of the cost, at $1 million per patient. This is, however, a systemically administered gene therapy using AAV as the vector, stacked with one of the new biotechnologies that can reduce the ability of neutralizing antibodies to destroy the viral particles. If Libella is manufacturing to one of the usual Good Manufacturing Practice (GMP) standards, it is likely that the overwhelming majority of that $1 million cost is the cost of manufacture. AAV, while the most popular vector in the gene therapy development community, remains enormously expensive to manufacture. For a point of comparison, there is a systemically administered viral gene therapy for an inherited disease that is used in newborns, where it requires a 100,000 square foot facility 40 days to produce one dose. That costs more than $2 million. Everyone in the industry agrees that this situation must change and will change, that there will be disruptive advances in cost and efficiency, just as happened for monoclonal antibodies - but it hasn't happened yet.

Breakthrough Gene Therapy Clinical Trial is the World's First That Aims to Reverse 20 Years of Aging in Humans

Libella Gene Therapeutics, LLC ("Libella") announces an institutional review board (IRB)-approved pay-to-play clinical trial in Colombia (South America) using gene therapy that aims to treat and ultimately cure aging. This could lead to Libella offering the world's only treatment to cure and reverse aging by 20 years. Under Libella's pay-to-play model, trial participants will be enrolled in their country of origin after paying $1 million. Participants will travel to Colombia to sign their informed consent and to receive the Libella gene therapy under a strictly controlled hospital environment.

Bill Andrews, Ph.D., Libella's Chief Scientific Officer, has developed an AAV gene therapy that aims to lengthen telomeres. The AAV gene therapy delivery system has been demonstrated as safe with minimal adverse reactions in about 200 clinical trials. Dr. Andrews led the research at Geron Corporation over 20 years ago that initially discovered human telomerase and was part of the team that led the initial experiments related to telomerase induction and cancer.

Telomerase gene therapy in mice delays aging and increases longevity. Libella's clinical trial involves a new gene-therapy using a proprietary AAV Reverse (hTERT) Transcriptase enzyme and aims to lengthen telomeres. Libella believes that lengthening telomeres is the key to treating and possibly curing aging. On why they decided to conduct its project outside the United States, Libella's President, Dr. Jeff Mathis, said, "Traditional clinical trials in the U.S. can take years and millions, or even billions, of dollars. The research and techniques that have been proven to work are ready now. We believe we have the scientist, the technology, the physicians, and the lab partners that are necessary to get this trial done faster and at a lower cost in Colombia."

Comments

Thx Reason for your comments on this company and what they are offering.

As I stated in my comment on your last blog, I hope they enhance the longevity environment and not create a negative one. Just providing possibility of legit longevity to the general public would be very helpful to this community.

Posted by: Robert at November 22nd, 2019 1:30 PM

Why is AAV therapy so expensive?

Posted by: Antonio at November 22nd, 2019 3:15 PM

Anyone who has the ability to "pony up" US$1 million, most likely has the ability to do this independently state-side (probably invest and start-up their own company for that matter), within the legitimate U.S. research system; and not have to escape to Colombia a la Liz Parrish et al

This nonsense is a blight on the whole industry

It's amazing people like these are considered as top thought leaders

Posted by: Quinn Binnenbaum at November 22nd, 2019 3:58 PM

1) What is the difference between this and Bioviva's therapy? That didn't seem to work.

2) Why isn't Bill Andrews the first guinea pig? I mean, a one million dollar price tag requires some guarantee... and the fact that his proponent, who is pushing 70, wouldn't try it himself sounds fishy.

Posted by: Barbara T. at November 22nd, 2019 4:52 PM

@Barbara T.

Nothing is different

And Bill Andrews has always said publically that (when referring to Liz P.) he would not do it on himself...ever

It's a scam

Posted by: Quinn Binnenbaum at November 22nd, 2019 5:57 PM

@Quinn Binnenbaum: It certainly sounds like a scam. Shame it's happening because it's going to set the field back by creating a lot of distrust.

Posted by: Barbara T. at November 22nd, 2019 7:40 PM

Hey there! Just a 2 cents.

I could understand the distrust and deception this would cause; my take (I still believe) is we should not rule it out so quickly. But I am of the same opinion that 1 M $ is exhorbitant and thus, currently, is a niche 'privilege' for very wealthy people (the 1-5% or less of population, millionaires and billionaires). But it is something we had seen miles ahead; these 1st therapies would come first as expensive $$$$, for the most financiallly priviledged; then, later, the prices would (or should (hopefully, more)) come down once the ball is Rolling/more investiment towards that; and more marketing/Trust. If we know it works in a rich person, it will be the start of something (better than nothing). I agree with Reason that doing medical/theurapeutical tourism outside/off-country is good (even if it looks shady...espeically. in Colombia on top of that (not insinuating it can't work or not be good; but, sometimes, let's say, in smaller countries with less means and are poor, it's not always 100% 'well-regulated' and you're 'taking your chances' going there in alien/foreign country (whatever (non?)laws they are (lawless/'the free-for-all' Out(ted)-laws?)); it's why FDA is a double-edge sword, it'S US medical law regulation so at least, in that sense, it's good because it is trustable...but its bad sharp-side is that we can't do sh...because 'over-regulation/over-bureaucratic tape/need 0 danger - 100% tested everythin'. So the 'remotely' 'remote (risk) therapy' is shut down immediaetly (and ends up a remote thing/in another coutnry) In colombia, you are taking your chances being a guinea pig 'outside regulation' (as Reason said, it is frowned in the medical science because it's dangerous 'unregulated' 'self-experimentation'. That's how they feel about her TERT therapy)).

Yet, maybe that's what need (a bit more let's say) to 'try' because if we never try and shut down everything for fear of change/progress; we may never progress much (it is the same saying as : ''being scared in life never got you anywhere'' (being scared is important for fear keeps you alive...but being parano/hysteric/all-fearing (some will say coward)...can reduce your chances (of willing) to 'take certain/minimal (calculated) risks'..to try. Such as daring people going there 'putting it all/their life on the line' to be guinea pig/patient 0s (just like a person in the army or a police officer/firefighter putting their lives at risk for others' benefit) it is a very selfless altruistic act even if it is also an invidualistic act (for they are going there to obtain benefit from the therapy; yet..they know the danger of the therapy/as guinea pig and no one wants to be it; excep them (it takes will, noble deed, selflessness, self-carelessness, 'for the others'/for society (advancement/betterment/ prospering)), altruism, generosity, dignity and courage))). But, if it works; not only will they live longer - they will benefit everyone in the society because we Will now know that it Does work; thanks to them putting their self out there to take the therapy.

I think that if rich people as Mr. Andrews would never do it, it is combination of wariness, fear, distrust and deception; rather than just saying it's stupidity. Because yes it could be seen as idiotic to 'jump in the mouth of the lion' by having a telomerase therapy that would give you cancer...in the long run. Yet, many studies have shown repeatedly that telomerase when well-controlled and not hijacked by tumors ends up Protective and that is because it increases immunity efficiency (since some immune cells rely on telomerase and immune system is powerful cancer killer (TNF/INF/WBC/NK/T-cell..), and also, of course, stem cells that rebuild our tissues (also relying on telomerase); so it,s not all black or white, there is lots of shades of grey (and I could understand why this muddied look of things does not inspire confidence and trust in believing that Mrs. Parrish's telomerase therapy is Worth it (well, not at 1 million $...only if we knew it could give 20 years longer life at they said...but not proof yet; thus, for now, 1 million is asking too much for 'possibly' too little and why not many will dare/is too frightening going to 'Try the therapy ( (life)-risks vs rewards) in outside country with a 'it might work'; it does not it's 1 million $ lost and possible cancer in the long run (that a risk/high odds undertaking (I don't blame richer people refusing, it.s normal to be skeptic and fearing it will be loss of money and of your life altogether (yet...is there much anything else out there...not much; so maybe there has to be someone richer and bolder who doesn't care/prefers 'die trying' with that therapy then 'dying rich' (rich, yes, but still dead, one day no matter their wealth)' (I know this person will be most-rarity))).
So we need someone willing to spend (a lot) their money in their life (while they still have one).
What is money good/worth when you are 6-feet under (apart for a big family inheritance for your progeny and 'spreading that money to the society' once you're gone).

Just a 2 cents.

PS: In the mean time, there is astragalus whcih activâtes telomerase, same thing for certain herbs like ginkgo biloba (bilobalides) or panax ginseng (gingenosides) activate hTERT in cells, briefly, &yes they do so (but we all know that these herbs did not make anyone live much beyond 120 years old; yet they May have given people a huge average life boost/health boost). It's why we must not throw that telomerase therapy out yet (even if it seems shady/scam like now). Let their be people (not necessarily gullible but willing; though some will say they individualistic/capitaslistic cheap idiotic rich people seeking self-imm*rtality (which is a bit exaggerated because anyone with resources will try to obtain improvemetn for their health/life; and in doing so, they might also help many other 'less-rich' people)); Many rich people have allowed great progress (namely your great American Bill Gates engineer with micro-computer 'PC' revolution in 1970s; capitalism/money has advantages (but many more disavantages as seen when the therapy cost 1M$ becaus AAVs are ridiculous price to make; when we have this problem of unaccessibility of things due to high price it's when large-society suffers (mid/low-class), & capitalism fails (because I heard people say there is good capitalism (big new inventions/progress happening) and bad one (poor people dying no money can't afford said 'magical inventios'); money as a resources is flawed and also, double-edged). Sorry for typos.

Posted by: CANanonymity at November 22nd, 2019 9:50 PM

'Ordinary somatic cells in humans do not express telomerase; it is only present in stem cells, which can replicate indefinitely to supply tissues with new somatic cells with long telomeres. ' WRONG. Human adult stem cells certainly cannot replicate indefinitely. They have only low levels of telomerase. Hence the possibility that telomerase gene therapy may reverse aging. Let's at least do the experiment before we dismiss it so casually.

Posted by: Mark at November 23rd, 2019 6:19 AM

@Mark: Hasn't it been done already? Liz Parrish didn't come out looking a day younger, let alone 20 years. Why should this be different.

Posted by: Barbara T. at November 23rd, 2019 10:45 AM

Well I for one think Liz Parrish does look considerably younger. Her skin looks much thicker than before. Even celebrities that go to dermatologists have that telltale thinning in their forties.

Posted by: Mark at November 23rd, 2019 11:47 AM

@Mark: she looked just as good before... 20 years younger isn't a smooth(er) forehead. Plus she'd be gushing about it had she seen real changes.

Bill Andrew's "trial" is a scam. On a related note: how is whatever he finds going to have any statistical significance? With a sample of a handful, which is perhaps what he'll get with that price tag, unless he turns Kirk Douglas into Michael there's no way to justify the experiment. Frankly I hope that he doesn't get any takers.

Posted by: Barbara T. at November 23rd, 2019 12:32 PM

Firstly, 'reversing aging 20 years' is just writer's hype, the real promise is that it will lengthen leukocyte telemere length consistent with a 20 year reversal of aging. Secondly Liz Parrish looked young before her alleged self experiment, in fact being attractive seems to be her only qualification for her Title.

Posted by: JohnD at November 23rd, 2019 12:51 PM

@Quinn Binnenbaum: "These people" aren't top thought leaders. They're in the same basket as cryonicists; an albatross weighing down on the neck of legitimate researchers, siphon funding and damaging the reputation of actual, rigorously performed research that occupies the same sort of space in the public consciousness.

Posted by: Dylan Mah at November 23rd, 2019 1:59 PM

Calm down Dylan. No one has a working therapy for aging yet, and telomeres are generally acknowledged as being a primary driver of aging. So no one can make claims telomerase gene therapy is a fraud. No more than you can say Aubrey's mitomouse project is a fraud. Both are still speculative at this point. In fact the former has considerably more evidence than the latter.

Posted by: Mark at November 23rd, 2019 2:07 PM

FYI - I met Bill Andrews a half dozen years ago. I remember him saying that he jogs at 50 mile distances, ultra marathon distances. I thought him odd.

Posted by: Robert Kane Pappas at November 23rd, 2019 2:24 PM

@Mark: don't you think it odd that Bill Andrews isn't the first in line for this therapy, given that he isn't one of those scientists who claim to do things for the love of humanity but rather wants to live a long long long life himself?

Also, don't you think that had there been anything to it at all, Bioviva wouldn't have died a quick death after Liz Parrish's experiment? Telomeres shortening isn't an accepted driver of aging, and in this respect mice really aren't a good proxy for people.

This is just Libella taking an enormous gamble with someone else's money in the off-chance that something positive (even small) comes out of it, which would help Bill Andrews gain some "prestige" in the community as well as of course lots of money.

Posted by: Barbara T. at November 23rd, 2019 2:40 PM

PPS: Although looks are very subjective...sometimes someone can tell you ''Hey...you look yougner...suddenly..did you do Something???!!???'' (and then you answer : ''Wel...it must be (in) the corn flakes I ate''. Albeit, sometimes it can be : ''Hey...you look haggard, emaciated, a grey hair and a wrinkle, (Something wrong???) You are weathering'' and then you answer : ''Nope. Feeling Fine 100% Better than Ever. Or, just aging/getting older I guess (before my time? hopefully not)''. In Truth being told you are aging; really put someone down/because it's 'the Truth' oftenly from outside stranger pointing the unwanted.

Thus, one peerson may say they seem/look younger while another will tell you contrary...it's hard to know 'who's true' about it. But, I think that if there were more biological test on Mrs. Parrish we'd get more answers; especially, at the epigenetic level (we have to give her that/She made that sacrifice to be the guinea pig/she is very strong to do it on herself (And all the risks she knew it carries/it was a giant leap of faith on her end (because she believes in it to be safe/in her company); because telomeres/telomerase act/talk in concert with the epiclock; thus, we could very well have certain improvement in methylome/methylation; which would be tantamount to a 'younger signature'. She might be 45 or so; but not she has Reversed the aging process (Somewhat, probably not the entire damages/Junk that accumulated of age...but on the genomic/telomeraic level yes); because she probably still has certain levels of oxidized proteins/AGEs/ALEs/lipofuscin/glucosepane and what not; but; she may a bit younger. Though studies in mice have been conflictual (hTERT mice) so I don't wish to jump to conclusion yet; since hTERT mice made them live avout 20-30% longer lifespan; what is really age reversal not sure but it was, certainly, in some form, slowing of aging and life extension; will it be 20%/20 years in humans that's harder to say.
Because telomerase is raised even in many different normal situations (the redox raises telomerase -- you need the redox to acutally Live..so already. that makes telomerase more moot *but it depends on the activation/length of activation in which cells) for example, women have higher levels of telomerase (by nature/evolution advantage for specie survival) because they produce oestrogen hormone which upmodulate telomerase Activity (and why when women get menopause they have a drop of telomerase/Dangerous to health because not have that protection as strongly anymore (because of drop of estrogen and why estrogen therapy is protective in women entering menopause/like for men wtih andropause); humans (both women/men) have estrogenic receptors taht activate telomerase (for men, aromatase takes care of their testosterone to convert it to estrogen in their male body (it is needed because telomerase responds to estrogen receptors); and obtain hormonal telomerase activation by these same estrogenic receptors in the brain/body). Thus, there is a huge endocrine/groeth hormone element control to telomerase/telomeres (also). Already. As such, we must temper our enthusiasm about it.

Because of that; I don't jump to 'the roof' about telomerase; I'm caustiously optimistic but realistic about it (want to instead of realist pessimistic); though I Really hope teloemrase ends up giving us 20 years extra (but I am skeptic) studies in mice showed Something it; but it did not make mice live 5+ years or Something; but it Did increase their avg life ans a bit their max if I remember. It depends on your health; it your are healthy it is possible that effects may be lesser/neglible but if you are very sick you will see (should? see) improvement in health (because telomeres act immediately on the smallest telomeres to lengten them and 'restore 'overall lenghts'' among all telomeres (avg lenght). So that you do not have 'short telomeres' in the bunch of tall ones. Short telomers become uncapped/demethylated and cause chromosome havoc (SCE/fusion/fission..etC). Only 'Stabilized/capped' short telomeres are viable. It does not change the fact that they are small and 'emptying their telomeric DNA repeat content' (which is a problem/DNA loss). The big problem will be to offset sluggish immune system in old peole because telomerase increase in old mice creates mammary tumor formation (possible, in humans too, because mammary tumors hijack telomerase; much more in weak older immune system of older people).

I believe too that Mrs. Parrish looked Young before...so it is hard to tell.. but I believe that she had improvement in terms skin thickness (yes) as Mark said; skin thickness is a good correlator tobiological age (only in areas that are untouched by UVs exposure/because these areas are damages/tanned/oxidized and do not represent they intrinsic epigenetic age of the skin organ of the person); it is mesuranle by SSS (subsurface scattering; if we took photos of her with smae lighting and Under same condition; we see Something go on by looking at the shading/depth of light entering the skin dermis/Collagen (a thicker skin has more Collagen type I and looks 'glowy/pulpy/pulpous' (like baby skin) and thus yougner); we can then know that she is older/younger but the thickness of the skin layers and the formation of the skin ECM; which is mesurable 'visually, by skin light SSS in a photo program). And, the skin organ (a large organ) is overall, a good surrogate of most aging in other organs (not exactly...but a rought estiame of What's going in other organs; and can be infered thus 'the (rough) total sum' age of the organs).

https://www.pnas.org/content/99/12/8191
https://bigthink.com/surprising-science/telomere-aging
https://www.nature.com/articles/s41467-019-12664-x
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494070/
https://www.sciencealert.com/researchers-have-made-long-lived-mice-with-extended-chromosomes-inside-all-of-their-cells
https://phys.org/news/2019-10-mice-born-hyper-long-telomeres.html

Posted by: CANanonymity at November 23rd, 2019 3:05 PM

PPPS: This is what we have to be careful, never do Robust Telomerase (espeically in old people with weaker immune system/the telomerase is hijacked when Robustly activated), only mild/low-dosed. Mrs.Parrish probably is very aware of the correct dose to minimize cancer/tumor formation.

''In mouse embryonic fibroblasts, mTERT overexpression extended telomere lengths but did not prevent culture-induced replicative arrest, thus reinforcing the view that this phenomenon is not related to occult telomere shortening. ****Robust telomerase activity, however, was associated with the spontaneous development of mammary intraepithelial neoplasia and invasive mammary carcinomas in a significant proportion of aged females.*** These data indicate that enforced mTERT expression can promote the development of spontaneous cancers even in the setting of ample telomere reserve.''

Posted by: CANanonymity at November 23rd, 2019 3:35 PM

I really wonder Barbara if you've actually ever read any papers on aging, not just this blog. I'm talking about the large body of work to come out of Blasco's lab. Until you have, there's not much point me discussing telomeres with you.

As far as I'm aware, Bill Andrews is like Aubrey. He doesn't want to use anything until he's sure the risk-benefit case is strong enough. Especially if he's in good health.

Also, Libella are paying for some Alzheimer's patients to have the therapy for free, I believe. Separate to their pay to play trial. Bioviva's partners IHS are also running a trial for Alzheimer's patients, which is free too, (as well as charging others that want it but don't qualify). Michael Fossel is also trying to get a Phase I started through the FDA.

So let's stop talking about fraud.

Posted by: Mark at November 23rd, 2019 4:05 PM

Is there any evidence that shows that BioViva and IHS (via their "exclusive relationship") are NOT one and the same company?

Every single piece of pr I pull up about this company seems to link back to BioViva

No management listed

Posted by: Jim Sweeny at November 23rd, 2019 4:53 PM

@Mark: where's Bioviva's partner's trial listed? Because as far as I understand, Libella's is the first of this kind (apart from the unregulated Bioviva attempt).

Also, I am aware of Blasco's papers - they are all on mice, whose biology with regards to telemeres is very different from ours. Or if that's not the case you can perhaps explain to me why.

https://www.ncbi.nlm.nih.gov/m/pubmed/23956466/

Posted by: Barbara T. at November 23rd, 2019 6:20 PM

It's also not a question of what the treatment can achieve (and they should keep a leash on anyone claiming that they will rejuvenate people by 20 years because there are ZERO elements to make such a promise), but of getting people to pay for a safety trial. Phase III maybe, but not now.

Get funding for a disease, ace safety, and in passing do track a shitload of markers, so not just leukocyte telomere length but also methylation and phenotypical expression.

(And by the latter I don't mean looking at soneone's picture on the internet and declare their skin thicker - I am 40 and my skin looks younger just after a facial.)

THEN, if there are any signs that the therapy is doing something useful, you can start charging people.

This is a dangerous joke that may result in huge loss of confidence in the field.

Posted by: Barbara T. at November 23rd, 2019 7:04 PM

@Mark: Testing on mice is a completely different universe from testing on humans.

Posted by: Dylan Mah at November 23rd, 2019 11:23 PM

>This is a dangerous joke that may result in huge loss of confidence in the field.

They are doing what they are believing in and a bad trial would be a neck-breaking disaster for them, so at least I don't see why we should question their intentions. That's messy but nevertheless its a science in a making, the alternative would be is to crank up regulations even more and that would be a loss for the field for sure.

Posted by: Andriy at November 24th, 2019 1:33 AM

"I don't see why we should question their intentions".

Money? Or ok, if there isn't that much profit to be had after overheads have been taken care of: how will anyone disprove that they haven't reversed aging by 20 years?

Sure no one can't prove that they did, unless they have 10 guinea pigs in their 90s, because in this case after 5 years you can count those still breathing and if it's more than half you can statistically conclude that there has been some rejuvenation (Actually you need a bigger sample or a higher survival than 60% to reach statistical significance).

But you must recruit many more than a handful of 90 year olds to prove "age reversal" of 20 years, since out of 10 subjects who are returned to being biologically 70 no one should be dead 5 years later.

Point is, since they are not going to get these numbers (dozens of billionaires in their 90s who are even aware of - let alone keen on - this stuff?), it will be impossible to disprove their hypothesis.

Libella will be able to claim whatever they please - e.g. ultimately inconsequential leukocyte telomere lengthening - for decades, which means that the trial can never be a neck-breaking disaster for Bill Andrews.

On the other hand, they will have gained some useful data and kept their name in the news, which is infinitely preferable to obscurity.

There is a gigantic chasm between being strangled by regulations and asking volunters to pay a million bucks for a treatment that will absolutely not do what Libella claims it may do.

Creating super expensive snake oil will just harm people's confidence in the field. And without confidence there is no market.

Posted by: Barbara T. at November 24th, 2019 2:55 AM

I agree that the best course would be for Michael Fossel to get his telomerase trial through FDA. But we are where we are. If any of these off shore experiments can show efficacy for Alzheimer's that's a big step forward in my eyes.

I don't think mice are as different from us telomerase-wise as you seem to think Barbara. They suffer loss of telomere length with age in multiple tissues, just as humans do. In fact, telomerase deficient mice (after several generation) have startlingly similar pathologies with age as humans. So this therapy may be MORE beneficial for humans than in mice, unlike CR or metabolism modifying approaches.

In any case I don't see this kind of off shore stuff as bad. If you're old and rich, you could do this, maybe reverse aging, and contribute to science as well.

Posted by: Mark at November 24th, 2019 4:08 AM

The 2 most common objections to anti-aging efforts I hear are the only-for-the-rich and the overpopulation objection, which some people even utter in rapid succession to each other though clearly they are incompatible.

2 common reactions to expensive pay-for-play trials are that they're scams and that they are only-for-the-rich. Again, both objections can't be valid. Which objection you rush to depends on whether you believe efficacy will be achieved. Telomere science is not solid enough for me to believe in therapies based on it, but it's clearly not just science-less snake-oil, whatever specific weaknesses you can point to. Lifetime's of work and professional reputations of many people are betting on it. Solid scientific consensus just doesn't know for sure yet.

People with $1M to drop on this are clearly well into the 1%, and while some subset of these may be desperate and primed to be scammed nonetheless most in this category are also smart or have smart advisors to turn to. Do we really object to some such people paying out of their own pockets to give the world some data, however sparse, on this question?

Posted by: Karl Pfleger at November 24th, 2019 3:56 PM

@Karl Pfleger

True - it's not just "science-less snake-oil"

But it is still far from "prime time" with an unknown "therapeutic window" when it comes to human subjects

I shutter to think that we are relying on Liz Parrish and her Facebook annual "diary posts" as gold standard evidence

If there are stupid billionaires out there that are willing to take the risk on these types of initiatives, god bless them - although I tend to doubt it

Otherwise, it is a net negative for the image of the whole space

Posted by: Jim Sweeny at November 24th, 2019 4:40 PM

@Jim Sweeney

Not to mention, I'm skeptical whether the data collected would be useful? Your patient pool is either people who live a very rich lifestyle or people who are desperate for unverified treatments, and both might have a history of taking experimental medicines/supplements/treatments if they're willing to fly to Columbia for medical tourism.

Posted by: Curious Bug at November 24th, 2019 7:38 PM

U$1,000,000 buys a lot of Epithalon. Why bother with very hard to reverse AAV treatments at all if you can have cheap and safe telomerase treatments instead?
If People also need their 'Methylation Age' reduced, so that their 'Clocks' look younger, Procaine will probably do the trick.
But a fool and his money are soon parted and all that...

Posted by: Jones at November 25th, 2019 1:17 AM

No one has yet demonstrated if telomerase therapy works in humans, because no one has done it yet, simple as that, and claims otherwise should be viewed with extreme skepticism. While there is some merit in telomeres as a driver of aging via their contribution to genomic and epigenomic stability, and the regulation of gene expression directly (TPE-OLD), and no, mouse telomere dynamics are not that different to those in humans, I am deeply skeptical of this entire business.

Large scale properly regulated trials are the way to get therapies like this tested and approved, not running off to Latin America to engage in questionable antics with ridiculous marketing campaigns. The whole thing reeks of snake oil and the wider public is likely to see it this way too.

Posted by: Steve Hill at November 25th, 2019 5:40 AM

I find it interesting when you listen to these folks present, who are "all in" on telomeres and aging, like Andrews and Fossel, they all tell the similar story about some really rich people who were going to give them money at one point, and then pulled out....

Like in this recent show, where Fossel goes off on everybody and everyone who is doing "other stuff" - https://www.youtube.com/watch?v=_g6qK2g-Mm4&feature=emb_title

Frankly, as interesting as they may be scientifically, I think that telomeres are just too ubiquitous a target to mess with from any angle at this point

That's why J&J pulled out of the Geron relationship and why you see very few groups involved in the area

Posted by: Jim Sweeny at November 25th, 2019 9:39 AM

@CANanonymity
Can you write your suppliments regimen ? In detail ?

Posted by: Salman at November 25th, 2019 11:59 AM

I'm glad this is being done. If we hear nothing from the, I think we can assume it failed.

But nobody knows what's going to happen, and I sure a heck at 58 don't want to wait for the FDA to approve every little thing.

Posted by: bmack500 at November 25th, 2019 12:34 PM

@Steve Hill
"Large scale properly regulated trials are the way to get therapies like this tested and approved"

Steve, TAME took years to raise sufficient money for and Metformin is dirt cheap. If the therapy costs on the order of $1M/patient, how do you propose those that believe in this therapy achieve a large scale trial the way you want? I think there are valid objections that you could mean, but your phrasing is too fast-and-loose to be a good criticism. The criticism would have more strength if you were clearer with what feasible thing you think they should do instead of their plan that you don't like.

I'm not a believer in this therapy, but trying to put myself in their shoes it's easy to imagine they don't see many other paths open to them that aren't decades slower. It's not like they are jumping to human trials with no mouse work like the TRIIM stuff---they've got mouse work showing efficacy of the therapy, and the delivery method has plenty of human trials showing safety. Given the recent FDA comments on Ambrosia's trial, it seems understandable they might not want to bother trying to pursue a small-n self-paid trial within the US.

Posted by: Karl Pfleger at November 25th, 2019 10:13 PM

The problem is that this is an intervention that cannot be measured. Even if it gave people an extra 20 years of life, we would only find out in 20 years time.

And that's assuming that all the recruits have one foot in the grave, because given the trial's small size, it is impossible to infer anything from the mortality rate of a younger cohort. Thus, the intervention cannot be measured, and as such it's pointless with regard to what it claims it may do.

At most Libella could say that they can take your leukocyte telomeres back to their length of 20 years ago. However, aside from the fact that this may have little impact on aging, apparently such lengthening is within the margin of error of the measurement.

And of course no one would pay a million bucks for something as unexciting, which is why they must mislead people to get their experiment done. If they are in luck, amongst all the measurements they'll take there will be some interesting data for a few academic papers, which will raise the company's prestige and market value.

If this isn't a scam I don't know what is.

Posted by: Barbara T. at November 26th, 2019 1:01 AM

@Karl Pfleger: The TAME trial has hundreds of thousands of recruits, and just the cost of monitoring all those people far exceeds cost of AAV for a few dozen individuals. The first trial doesn't have to be large scale, but it must be properly designed and it must not promise an outcome that they won't even be able to say whether it was achieved or not.

Here's a compromise: raise funding for a disease, run a small trial, and then if you see encouraging changes in this group you can speed things up with a second pay-to-play trial that is safe and offers something concrete rather than just dreams to the desperate.

Posted by: Barbara T. at November 26th, 2019 1:24 AM

I think Bill Andrews has his heart in the right place, but between this and his endorsement of supplements, I unfortunately don't take his work seriously anymore.

Posted by: Quinn at November 26th, 2019 6:35 AM

Hi Salman! Thanks for asking. I used to take a ton of supplements (way more then now; trying everything under the sun) but it became a cost vs benefit problem (we can't buy the entire drugstore each month (unless rich)). Right now, it's just basic stuff like vitamins and minerals (yep!)l ditched lots of stuff, not because I wanted to (necessarily) ditched them; they were good; but costs were now too high to get it all (per month). Thus, I had to 'choose'/be picky; I found that, consistently, vitamins/minerals are hard to beat (because your body requires them for function). You might be thinking (don't I get this already from food?), true; but, extra of it is making sure you do not have 'lackings' (oftenly, sick/diseased people have lackings in vitamin/minerals - even when eating aplenty). Vitamin D/B12/folic acid has had dramatic effect on me (because these help to restore correct methylation/methyl donors (just like SAMe (SAMe:SAH (S-adenosyl methionine/homocysteine)), thus increase epigenetic methylation; at the start it was hard but now my body is adjusting (because methylation increase is a toxic event itself (since the body increases calcium to increase methylation (Which calcium itself can cause calcium overload/mito swelling). While the best mineral (for me) has been magnesium (it saved my life because it regulates vascular function (not just bone function/magnesium ions are necessary for ATP formation in mitos and for redox function). During my scary descent to death, this mineral helped me to survive when I was near dead (Atherosclerosis causes loss of magnesium in arteries and accumulation of calcium/calcified plaques (it's why I'm cautious of excess calcium intake from too much D3 (Cholacalciferol)); which messes the arterial redox and causes ROS formation/destruction/destabilizing of plaques (which can rupture and kill you/embolism). I tried Omega 3, 6, 7, 9...whatever; the whole mulla and got poor paying for supplements (when a 3rd of your money goes for that); so I decided to focus on specific primary elements 'in bulk'. I recommend most supplements, it's oftenly a question of money/if you can afford it all each month. So, all in all, I don't have 'regimen' per say (not anymore (outside of trying to eat well/exercice/I've noticed that atherosclerosis is caused/causes diabetes (my father has it) so I'm careful of carbohydrates composition/content (empty carbs have caused me ischemic events), I could end up diabetic later if I overdo the sugars/sweeth tooth); maybe when I get rich (..or not))).

Just a 2 cents.

Posted by: CANanonymity at November 26th, 2019 7:17 PM

Hi Reason, you state in this piece that telomeres are a downstream cause of aging. Do you agree with Sinclair that sirtuins and other epigenetic dysregulation is the most upstream cause of aging? Have you reviewed Amano et al. 2019 (Sinclair is a coauthor but states his sirtuins are upstream very strongly in his new book) and its discussion of what is upstream or downstream? Have you seen my latest interview with Fossel where he makes the case that telomeres are the most upstream mechanism?

Posted by: Tam Hunt at November 26th, 2019 7:52 PM

@Tam Hunt: Strongly disagree with those folk.

The most compelling argument I've seen is that stochastic DNA damage causes epigenetic dysregulation in a fairly structured way due to an unfortunate generic reaction to double strand breaks wherever they occur in the nuclear genome, and that is about as close to first cause as I think can be argued with a straight face.

Posted by: Reason at November 26th, 2019 7:54 PM

PS: I would add the same, that one of the most upstream cause of epigenetic drifting/dysregulation/epiaging is due to damages 'more upstream'...of epigenetic changes. Damages accumulating with age cause epigenetic changes, which lead to advancement of epiclock (in methylome).
These damages are telomeric nature - called TAF (Telomere-Associated Foci); TAF in other places - than telomeres - do not cause aging - like TAF - specifically, at - telomeres. In telomeres they call it γH2A.X foci, 53BP1 foci., telomeric DNA DSBs (double strand breaks).

''Telomere-specific DNA damage drives a senescent-like phenotype''.

''Combining in-silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of 'deep' cellular senescence. The essential feature of the loop is that long-term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45-MAPK14(p38MAPK)-GRB2-TGFBR2-TGFβ. These ROS in turn replenish short-lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.''

''Double-strand breaks can arise in telomeres due to replication errors when replication forks encounter single-stranded breaks. In order to ascertain whether TAF could be induced in the absence of cell division, we pre-incubated H9C2 cells with EdU for 3 h and subjected them to either X-ray irradiation (10 Gy) or 10 μM H2O2. Following a 24-h recovery period (in the presence of EdU), the mean number of TAF was significantly increased in cells, which did not incorporate EdU (Appendix Fig S4A), indicating that TAF can be induced in the absence of DNA replication. Further, we isolated adult mouse CMs, which do not proliferate in culture, and exposed them to 5 μM H2O2. We observed that the mean number of TAF was significantly increased after treatment (Appendix Fig S4B).''

''TRF1-FokI fusion protein induces telomere-specific double-strand breaks, senescence and hypertrophy in rat neonatal cardiomyocytes ''

''Aged cardiomyocytes activate senescence pathways but not a typical SASP''

Now the Deepest Upstream Element to the TAF/DSBs at telomeres - and - changes in epigenome (epiclock advancement) is due to changes in the Mitochondrias.

''Mitochondrial ROS drive TAF in mouse cardiomyocytes *in vivo*''

''Mitochondrial dysfunction is a feature of cardiomyocyte senescence and drives TAF in mouse cardiomyocytes in vivo''

''Furthermore, we found a significant increase in TAF in CMs from Polgmut/mut mice, a model of accelerated ageing due to mitochondrial dysfunction (Trifunovic et al, 2004; Fig 6G).''

''Gene Set Enrichment Analysis (GSEA) of RNA-seq data revealed that the most negatively enriched Gene ontology term in old CMs is the mitochondrial inner membrane (Fig EV4A). Consistently, in CMs from old mice we observed an overall decline in expression of most mitochondrial genes, particularly those genes involved in the electron transport chain (ETC; Fig 6A) and mitochondrial ultrastructural defects by transmission electron microscopy (Fig EV4B).
''

''Altogether, these data suggest that the majority of genomic DNA damage in CMs is reparable and that only telomeric DNA damage is irreparable and persistent. ''

''De novo TAF formation induced a senescent phenotype in CMs characterised, in addition to TAF, by increased SA-β-Gal activity and upregulation of the cyclin-dependent kinase inhibitor p21CIP (Fig 3E and F), as well as increased cellular hypertrophy (Fig 3G). Similar results were found using the H9C2 myoblasts (Fig EV2A-E).''

''****increased mitochondrial ROS driven by telomere dysfunction has been shown to induce DNA damage and activate a DDR in a positive feedback loop, making it experimentally complex to unravel which is the initiating step in the process***''

Demonstrating it is not telomere dysfunction that is the cause of increased mitochondrial ROS; but, the inverse; mitoROS create TAF/Telomere DSBs

''Genetic clearance of p16-positive cells in aged mice reduces cardiomyocyte senescence, cardiac hypertrophy and fibrosis ''

Thus, mitochondrial loss of function/increased mtROS/ETC dysfunction with age causes TAF - at telomeres - which TAF at telomeres - promotes epigenomic changes.

Stream:
Mitochondrial ROS -> TAF/telomeric DNA DSBs -> epigenome changes/epiclock advancing

Just a 2 cents.

1. Length-independent telomere damage drives post-mitotic cardiomyocyte senescence
https://www.embopress.org/doi/full/10.15252/embj.2018100492

2. Feedback between p21 and reactive oxygen production is necessary for cell senescence
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835567/

3. Oxidative stress shortens telomeres
https://www.ncbi.nlm.nih.gov/pubmed/12114022

Posted by: CANanonymity at November 26th, 2019 11:11 PM

PPS: Here is another study that helps to solidify that mitochondrias (and their mitochondrialDNA/mtDNA genes) are the most upstream of everything going on (in terms of intrinsic aging), even upstream of nucleus chromosomal control/telomeres DNA.

''In PNAS, Kopinski et al. (1) advance our understanding of this mystery by manipulating the levels of mtDNA containing either a normal (3243A) or pathogenic (3243G) mtDNA tRNALeu(UUR) mutation in a human bone osteosarcoma cybrid model. For these studies, they generated cell lines that had either 100% normal (3243A) or 100% pathogenic (3243G) mtDNA homoplasmies....Using these cell lines, they performed various measures of metabolism, including metabolic tracing and NAD+/NADH ratios, and, ****importantly, examined transcriptional and epigenetic changes in the nuclear genome****''

''Another key feature of this work is that all cell lines (homoplasmic and heteroplasmic) shared the same nuclear genome, meaning that ****any observed metabolic and epigenetic changes were *solely attributed to differences in mitochondrial genetics****''

''Overall, they find that mitochondrial-derived metabolites correlate with histone ***post***translational modifications, which differ across the different levels of heteroplasmy. Cybrids with 70 to 100% A3243G heteroplasmy have lower levels of acetyl-CoA that is associated with lower histone H4 acetylation, and additionally generate less acetyl-CoA from glucose, instead producing higher amounts of lactate, a phenotype recapitulated by inhibiting mitochondrial protein synthesis with chloramphenicol or complex I inhibition with rotenone''.

Thus, telomeres problems are really at the 'centre'/inbetween of mitochondria and epigenome; in the steps/process of aging.

Mitochondrial metabolites/mtROS/ETC dysfunction -> (nucleus) Telomere DSBs/TAF/SAHF (Senescence Associated Heterochromatin Foci) -> (nucleus) epigenetic changes/ drifting/transcription change/translation/epigenes are activated/deactivated (methylation/demethlation)/histone changes/epiclock advancing...

Just a 2 cents.

4. Mitochondrial genetics regulate nuclear gene expression through metabolites
https://www.pnas.org/content/116/32/15763

PPPS: I was wondering if epigenetic changes First would manifest as changes in the mitochondria Second - but mitochondrias have their own 'machinery' (mitochondrial DNA/mito genes) - as such, it is hard to say the epigenetic changes (1st) would cause changes in mitos (2nd); it's more the Inverse; mitos changes happen 1st & then, epigenetic changes happen 2nd.
Mitochondrial ROS damage the mitochondrias' DNA/genes...so it'S all/in the mitos.
Plus, mitos produce, as said, metabolites and ROS - these are Sources* of 'changing' the body/aging you...sources are generally 'causes' of problems; not just correlates; now you might say : ''But epigenome activates genes...that cause inflammation and downstream cause mitoROS...Thus, they came FIRST and are the Source of aging ???!??'' ...Except mitos have their own thing, just like nuclear DNA. The only reason I would say that epigenetic/programming is before telomeres or mitochondrias is because 'At the Start' of procreation when you are no more than a zygote and chromosomes and mitos are assembling...it is possible that epigenome is Already making genes activated/deactivated - this - Before - affects mitochondrias (meaing the mitos are affected After. and then produce more ROS/mtDNA dysfunction - which would cause a 'program if you will''...like a 'vicious circle'.).
Kind of like the 'Spark' that ignites the 'Aging program/process'; it may be possible that at the vey very very start; epigenome is responsible for what comes After (in the mitochondrias). And Then...it would be mitos that would Contribue - Later - 1ST to the aging process; because they would create mitochodrial ROS and hence it would create TAF/telomere DSBs...which would Change the epigenome; making an advancement of aging. So, currently, mitos are the utmost upstream element/cause of aging.

But, at the very very start; epigenome could have started it all (even 'changing' mitochondrial DNA/genes; not mitos themselves). For, now it's not telomere the real cause/largest contributor 'initiator' 'center' 'source', nor epigenome changes;
it's mitos.

Posted by: CANanonymity at November 27th, 2019 11:54 AM

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