Telomerase gene therapy

December 9, 2012 11:59 PM

Telomerase gene therapy seems to have extended mice lifetimes and improved health and age related diseases. They applied the therapy to adult mice, not embryos, and they used a DNA modified virus to deliver the therapy. The first linked article mentions an average life extension of 24%. The original article (EMBO Molecular Medicine) is here.
posted by aleph (40 comments total)

When this happened in Red Mars it gave me chills, it was so thrilling. It's super-weird that in the real world I only feel skepticism combined with a sense of dread.
posted by cgc373 at 12:24 AM on December 10, 2012 [8 favorites]

There's an unemployed monkey in Toronto loitering around, maybe he'd volunteer for testing in exchange for some banana's and an Ultrafine Merino wool sweater.
posted by stbalbach at 12:39 AM on December 10, 2012 [3 favorites]

If anyone involved in this project is still believes in the ethos of science sub rosa, and is a Metafilter reader, consider this comment my informed consent. MeMail me.
posted by clarknova at 12:55 AM on December 10, 2012 [5 favorites]

I'd sign up in a second too, but it's probably horribly inefficient to test this on humans at this stage. You'd want extensive trials in some sort of mammal with a considerably shorter lifespan to work the kinks out first. Mice now, maybe pigs later, they're fairly similar to humans, and have a 10-15 year life span. Bonobos might be good as a final trial, they live around 40 years. Although I'd sign up myself if they got that far.
posted by Joakim Ziegler at 2:41 AM on December 10, 2012

It's super-weird that in the real world I only feel skepticism combined with a sense of dread.

this is really the only smart reaction
posted by This, of course, alludes to you at 3:18 AM on December 10, 2012 [7 favorites]

Humans die, so that it is not strictly necessary that we kill one another.
posted by effugas at 4:12 AM on December 10, 2012

I suspect we'll know the first human trials worked when, 70 years from now, a group of surprisingly old scientists comes out of retirement to hold a press conference.

I felt the same way as cgc373 when I read Red Mars, and I've been waiting for it to happen in real life ever since. That said, I'm now more excited about the possibility of it helping with age related diseases than just longevity.
posted by lucidium at 4:33 AM on December 10, 2012 [1 favorite]

This is really just a proof of concept, before anything was done anywhere near actual humans this would need to be redesigned from scratch using a more human appropriate promoter human telomerase and a viral strain with humans in the host range. As a proof of concept though it is pretty damn cool. The basic idea is to take an Adeno-Associated Virus (AAV) and cripple it by ripping out a bunch of its essential genomic guts before replacing those guts with something we want cells to express instead. This prevents the virus from replicating, which would be less controllable, and gets adult cells to express genes we want them to. What they did is replace some essential guts with mouse Telomerase reverse transcriptase (TERT), a gene that encodes for a protein with complicated interactions with both many kinds of cancer and aging. There are a few things that are especially interesting about what they accomplished:

--The mice didn’t become giant balls of cancer.
We would expect them to get a bunch more cancer as the abundance of TERT removed a key component of the Hayflick limit, which is one of the primary defenses against cancer in mammals. Indeed reactivating telomerase, which is only expressed in infancy and in some stem cells, is a really common feature of human cancers for this reason – heck one could imagine that we could prevent a lot of cancer by somehow completely deleting it from somatic cells that didn’t need it. These mice didn’t get increased rates of cancer though, which is weird and maybe indicates that it is not necessarily so important of a defense or that there is some weird aspect of oncogenesis in mice that makes in not necessarily so important only in this specific model system. Anyhow, until that is explained I wouldn’t want anyone injecting me with a virus like this.

--The mice didn’t get specific kinds of cancer, and they had improvement in measures of aging across a wide variety of tissues:
The researchers used a strain of virus that they knew would infect a whole bunch of different kinds of cells in the mice. It is thus all the more remarkable that everything didn’t all go cancer haywire in any of the different systems being affected. On top of this they saw benefits to all sorts of systems from decreases in bone loss, to improved retention of insulin resistance (an aging thing in mice), to improves scores in neuromuscular and object-recognition tests. These are really different kinds of cells all aging more slowly, which is really cool.

--They used a human appropriate type of virus:
Adeno-Associated Virus (AAV) is currently being used safely in gene therapy treatments of hemophilia and certain kinds of blindness. AAVs are a really good choice for gene therapy because they are non-integrative (don’t hide in genomes), show a poor immunogenicity (Don’t make are immune systems freak out) and are really safe in the concentrations needed to have an effect. They work in cells that are dividing or not dividing, and can gene expression going for up to several years in both mice and critters as big as us.

--This could be specifically an awesome thing for the reatment of Cri du chat
One of the components of what makes Cri du chat so horrible is probably that the part of Chromosome 5 that patients are missing also happens to contain TERT. If infants with Cri du chat are screened pre-birth and treated with something like this, maybe it would help.
posted by Blasdelb at 5:00 AM on December 10, 2012 [28 favorites]

If this gets perfected for use, yet I'm too old to be eligible for treatments, there's going to be hell to pay if I have the strength to get out of bed.
posted by Brandon Blatcher at 5:29 AM on December 10, 2012 [4 favorites]

Cool. But they will probably bump the retirement age to 102. Sure glad I was able to retire at 51.

Some of you guys are going to spend an awful lot of your life working.
posted by notreally at 6:44 AM on December 10, 2012 [1 favorite]

Also thanks for linking to the paper! Everyone has access to it right? If not just memail me with an email address I can send a PDF to and a promise not to distribute it any further - for the academic discussion that we are currently having of course.
posted by Blasdelb at 7:07 AM on December 10, 2012

Yes, I will take the engineered virus injection rather than eat way less, thank you.
posted by oneironaut at 7:13 AM on December 10, 2012 [3 favorites]

Don't get your hopes up. You won't get this for the same reason you cannot have the doctor-monitored HGH, steroid and hormone "therapies" that elite athletes and entertainers use. It is almost certain that some minor side effect will be touted as a reason to ban this except in case of therapeutic need, and that need will be authorized for the wealthy by their physicians, or the wealthy will be able to get it via medical tourism. Because there are already safe, life-enhancing medical regimens out there that you, the average person, are not permitted to enjoy.

If you are incapable of getting a doctor to manage your Dianobol cycle, prescribe post-cycle therapy, or score you GH, you're not getting this. You're the person that popular literature will encourage to accept the natural processes of aging. You're the person soul-searching articles about accepting a role as an elder in the face of flagging libido, physical aptitude and cognitive sharpness are for. They're not for *them* any more than this viral therapy will be for you.

You should at least understand that the reason you're not getting this is that improved health is now a class marker instead of a public good. While you're dreaming of posthuman innovations for everybody, those are *already happening* for people like Madonna. When she gets in line for her treatment at 65, I'm sure she'll consider, say, 25% of her earning potential over her extended career a fair price to pay.
posted by mobunited at 7:28 AM on December 10, 2012 [9 favorites]

...in other words, "Buying Time" (Haldeman, 1989) is coming true, but we get the version that doesn't include asteroid mining.
posted by aramaic at 7:39 AM on December 10, 2012 [2 favorites]

Human Growth Hormone is many things but Ponce De Leon's fountain of youth is not one of them. There have been no large scale clinical trials evaluating the efficacy of HGH in addressing aging for healthy elderly populations and there is a good reason - even if it did work, it probably wouldn't work that well - and it would almost certainly be way more dangerous than could conceivably be worth it for that purpose. Woo peddlers and bullshit artists of various flavors have been touting it for a while, but the reason big pharma hasn't jumped on the GIANT goldmine that would be a real anti-aging therapy as cheap as HGH is not because the reptilians don't want you to live long.
posted by Blasdelb at 7:41 AM on December 10, 2012 [7 favorites]

the reason big pharma hasn't jumped on the GIANT goldmine...

Can't it be both? Health (or at least possession of health insurance) is certainly becoming a class marker. And a fountain-of-youth drug is only a gold mine if your customers have money to pay for it. So, remind me again, who exactly has All Teh Moneys?

(I hope this isn't too derailey -- the science is fascinating. I think telomere therapy showed up in a Gibson novel, too: I recall that one of the [RICH] characters spent a week or two in a tank getting somewhat dissociated, cell damage repaired and telomeres lengthened, and came out a wise but slightly disoriented twenty-something.)
posted by spacewrench at 7:54 AM on December 10, 2012 [2 favorites]

I didn't claim that HGH makes you live longer, but there's really no denying that it pretty much does things people want it for -- the study you link lists them along with the hazards, and some of those hazards aren't so bad compared to dangers like falls caused by age-depleted strength, which up and kill people, or get them to the point where they go to a home, deteriorate and die. People underestimate the effects of lean muscle mass on quality of life.

And of course, rich people don't get battery tested in studies. They get it administered by physicians who monitor them for complications, just as elite athletes get monitored and treated for anabolic steroid side effects if they find their way to a doctor willing to accommodate them. Sometimes, like Michael Jackson, they get bad doctors, but not always.

Nevertheless, there are groups of people who get access to this stuff either through raw wealth or professional connections, and there's certainly a media apparatus unwilling to talk about it. Every time you see an actor getting praised for the fine shape he's in for a role as he walks around with the odd vascularity and blocky biceps of a probable Winstrol user, you are being sold the false idea that these gains are the product of virtue alone, and given the body image related discussions here, I think it has some effect.

I'm noticing the same kind of thing as drug and surgery-driven class disparities in aging grow more apparent: increased self-loathing by aging internet users who do not recognize that their failure to look like Madonna or Daniel Craig is somewhat (though not exactly) like a failure to own a bespoke suit something over a century ago.
posted by mobunited at 8:07 AM on December 10, 2012

Health, however it is defined by the ruling classes, has always been a class marker. In our current setup, it's low weight and athleticism. Affluent people have access to ranges of drugs that control hunger and increase energy, better nutrition, access to gyms and personal trainers, and if all else fails, surgeries to address those issues.

Poor people get lectures about the importance of discipline and self control.

While I think that living longer would be punishment and not reward, it would never be available to people like me. The insurance would never cover it. It will be 'experimental' and only people with the resources and cultural capital to ignore the normal rules will get it.
posted by winna at 8:15 AM on December 10, 2012 [2 favorites]

You cynical bastards are going to turn me into a greedy experimental drug hoovering capitalist, yet.
posted by bastionofsanity at 8:35 AM on December 10, 2012 [2 favorites]

These mice didn’t get increased rates of cancer though, which is weird and maybe indicates that it is not necessarily so important of a defense or that there is some weird aspect of oncogenesis in mice that makes in not necessarily so important only in this specific model system.

The idea that mouse telomerase doesn't cause cancer in mice the same way that human telomerase does in humans seems pretty reasonable to me - the old problem that our model oraganisms are not always perfect models. Do mice get cancer in the "wild"? That is to say, to control mice get cancer? Obviously in the actual wilds mice rarely live long enough to get cancer. I've never done any mouse work, so I'm not really familiar with how realistic a model they are.
posted by maryr at 8:39 AM on December 10, 2012

"I've never done any mouse work, so I'm not really familiar with how realistic a model they are."

There are a lot of advantages to working with mouse models for cancer, but they are TERRIBLE at predicting what will happen in humans. The authors inexplicably don't name the mouse strain they used (how the fuck did that get past review?) but lab strains of mice generally have so much bizarre shit already going on with these aspects of oncogenesis that, while exciting, I really wouldn't take their cancer related results too seriously for predictive value in humans.
posted by Blasdelb at 8:54 AM on December 10, 2012 [1 favorite]

When I visited Tufts for grad school there was a lab (this one, I think) studying immune response in a bunch of typical lab strains of "wild type" mice verses actual wild mice - mice that had been caught outdoors, then bred for several generations in the lab so that they were "clean". The immune responses of the lab strains, even the supposed healthy "wild type" ones, were ridiculous. Totally changed the way I view a lot of mouse work. (I didn't dare tell my friend whose PhD was in mouse immune response that her results might all be artificial.)
posted by maryr at 9:00 AM on December 10, 2012 [2 favorites]

Michael Jackson is a pretty great argument for people not getting any medical treatment they ask for. Aside from the fact that it eventually killed him, what good did plastic surgery after surgery do him? How much of his eccentric behavior was influenced by drugs? Did any of it make him any happier? Did any of it make him and healthier?

My roommate recently had elective surgery for weight loss. Without living with her, you'd notice that she ate less and that she's lost a lot of weight. So jealous, right? Well, living with her, I see that she can no longer eat many of her favorite foods because she has developed lactose intolerance, gets severe cramps when she eats plain chicken, can't eat sweets or fatty foods due to dumping syndrome, and is losing her hair. It's not an easy shortcut - she has to take a battery of vitamins the rest of her life and can no longer eat without considering the consequences in advance. It beats developing diabetes and the accompanying complications. Probably. There's no way I would recommend the surgery to a loved one if any other option was available.
posted by maryr at 9:18 AM on December 10, 2012 [2 favorites]

Blasdelb: The authors inexplicably don't name the mouse strain they used (how the fuck did that get past review?)

Is that what this is?

"All mice are of a >95% C57BL6 background."

I don't know for sure since I don't do mouse studies, but that looks like what you were referring to. It was in their materials and methods.
posted by Mitrovarr at 9:19 AM on December 10, 2012

>95%? That makes it sound like Great-Great-Great-Great-Grandpa Mouse snuck in to the C57BL6 cage.
posted by maryr at 9:24 AM on December 10, 2012

Whoops, I missed that,

Yeah, I would definitely want this at least tested in a rabbit model much less something like pigs and not just Black 6 before it got anywhere near real people.
posted by Blasdelb at 9:31 AM on December 10, 2012

This thing is going to take ages to test in humans. Both the risk and the potential benefit are strictly long-term. Testing for safety will take at least 5 years alone. Testing for efficacy will probably take at least 10. And that's assuming they get this into the FDA at all (a dangerous drug that doesn't treat a traditional medical condition? Good luck).
posted by Mitrovarr at 9:55 AM on December 10, 2012

Some of you guys are going to spend an awful lot of your life working.

Ha ha ha, like that wasn't going to be true anyway.
posted by Mars Saxman at 10:03 AM on December 10, 2012 [2 favorites]

I used to consider myself extropian/transhumanist... Now I look upon that period of, I guess, faith(?) with incredulity.

I really don't understand *why* someone would want to live a long life. Sure, I suppose a long healthy life might be a bit nicer than a long shitty life, but isn't there just a point where being alive for whatever is good enough? I suppose there's some assumption that this would coincide with the ability to be active and fully cognitive and everything else. And I admit, I didn't RTFA so maybe the article mentions that issue.

Regardless, even if *I* were healthy, I'd just be a miserable curmudgeon in an increasingly alien and hostile world which I already loathe well enough.

I suppose one could ask why I don't just off myself already. I don't particularly see the point, really. I don't necessarily want to die, but I see no reason to try to force myself alive just because I can. If I had trust that the world wasn't just a big pile of shit then maybe I'd like to see it, but I'm too cynical as it is, and I don't particularly see much hope in this shithole of a planet.

So cheers to you, longevinous mice. And cheers to your handlers, and cheers to science and the entire race of mankind. Cheers to your wars, and your deprivation. Cheers to your greed. The sun will burn up someday and you will die, and no starseed ships will carry you further. You are a lone speck of dust in a comparatively infinite universe, and the echoes you made that were so big to you, your extra 100 years of life are but a drop in an endless ocean of fire and plasma, and in the end the universe, too, will die.
posted by symbioid at 11:24 AM on December 10, 2012 [3 favorites]

Ok, then...... who wants ice cream?
posted by Senator at 12:50 PM on December 10, 2012 [3 favorites]

I really don't understand *why* someone would want to live a long life....

I think you answered your question in your own comment.

I'd just be a miserable curmudgeon in an increasingly alien and hostile world which I already loathe well enough.

Just a thought, but maybe with enough time you'd be able to find more things worth sticking around for.

For the record, if anyone else is uninterested in eternal life, feel free to yield any unused balance to myself and others who are. :)
posted by Dark Messiah at 3:43 PM on December 10, 2012

Mice already typically have way more telomerase activity than we do-- and much greater potential to develop cancer:

Vera Gorbunova, assistant professor of biology at the University of Rochester, conducted a first-of-its-kind study to discover why some animals express telomerase while others, like humans, don't. The findings are reported in today's issue of Aging Cell.

"Mice express telomerase in all their cells, which helps them heal dramatically fast," says Gorbunova. "Skin lesions heal much faster in mice, and after surgery a mouse's recovery time is far shorter than a human's. It would be nice to have that healing power, but the flip side of it is runaway cell reproduction—cancer."

Up until now, scientists assumed that mice could afford to express telomerase, and thereby benefit from its curative powers, because their natural risk of developing cancer is low—they simply die before there's much likelihood of one of their cells becoming cancerous.

"Most people don't know that if you put mice in a cage so the cat can't eat them, 90 percent of them will die of cancer," says Gorbunova. ...

Last time I saw anything which addressed the issue (a couple of years ago), the claim was that only germ cells and certain cells in the immune system ever express telomerase in humans, except for cancer cells.

And since it is expressed almost exclusively by cancer cells in humans, such expression would be likely to make the average somatic cell an excellent candidate for attack by our immune system, I'd think, so you could be looking at devastating autoimmune reactions as a side effect of telomerase therapy in humans.

I didn't claim that HGH makes you live longer...

Since HGH would have the effect of bringing the cells it affects closer to the Hayflick limit, it far more probably makes you live shorter.
posted by jamjam at 4:54 PM on December 10, 2012

There's already a telomerase activator on the market today named TA-65. It is in fact a supplement, so you can get it without a prescription. Quick facts:

- It is insanely expensive (last time I checked a 6 months supply would set you back $1200 at the low dosage. Three times as much on the high dose.
- It lengthens short telomeres.
- It repairs some old cells.
- Improves biological markers

However, there's no findings on what long term effects these translate to. Anecdotal results include modest things like better eyesight, healthier looking skin, better looking hair, more sexual drive and more energy altogether. Take into account most people that take this are older than 60.

One of the biggest concern about telomerase activators is that they might promote cancer cells to grow. In fact, T.A. Sciences, the company that markets TA-65, licensed the active ingredient from Geron corporation, which has an anti-cancer drug (not sure if it's approved or not) which works as a telomerase inhibitor, using the opposite effect to try to slow cancer growth. That's enough to give anyone chills about taking TA-65 isn't it?

The great thing about the gene therapy in the linked article is that they claim there was a 25% increase in lifespan with no cancer concerns, that's really good progress.

I can understand the arguments against increasing longevity based on world population and resource constraints but at the end of the day these arguments (although I agree with them) are useless. Humans will continue to do whatever they can to increase lifespan, these drugs are going to happen, which means we need to spend time and resources figuring out how to be sustainable while people live longer. Besides, the original purpose of these drugs are not only to extend lifespan, but to also to greatly improve the quality of life at later stages in life, and who doesn't want that?
posted by macrometa at 5:37 PM on December 10, 2012

Dark Messiah: "For the record, if anyone else is uninterested in eternal life, feel free to yield any unused balance to myself and others who are. :)"

Eponysterical?
posted by symbioid at 6:19 PM on December 10, 2012 [2 favorites]

you cannot have the doctor-monitored HGH, steroid and hormone "therapies" that elite athletes and entertainers use.

As I've learned of elsewhere it is possible for the 'lower class' to obtain some of that 'watching'.

SCOUT will not be disposable, though. The unit is a tiny hardware device that reads your vital health information on contact. You simply place it on the left temple and, in less than ten seconds, it will read your pulse transit time, heart rate, electrical heart activity, temperature, heart rate variability and blood oxygenation.

And under the DIY medical monitoring there is:
OpenEEG and the flatlined ECG project even if there is a Electrocardiography Electromiography shield for DUINOMITE, PINGUINO, MAPLE, ARDUINO like development boards and a nifty way to image your EKG in a portable format.
posted by rough ashlar at 7:00 PM on December 10, 2012

The authors inexplicably don't name the mouse strain they used (how the fuck did that get past review?)

Yeah they did, right there in the methods where it should be: "All mice are of a >95% C57BL6 background." It is a little bit weird, that sounds like a F5 or so backcross (I can't remember exactly which generation is which percentage) but they don't appear to be genetically modified, so I don't see why they're backcrossing the mice at all. Fully homozygous C57s are readily available and extremely well characterised. Even crossing up to F8 would give much higher similarity without breeding problems.

We're a long way from this being injected into humans and personally, as a biomedical scientist, there's no way in hell I'll be volunteering for trials based on this research. It does look promising for something so early stage but early stage it still is.

As for all the "people don't get HGH because of money", I work in a growth factor lab and you're all dreaming. The long term side effects are awful, there is no ethical doctor that will be handing that stuff out without a real clinical need. But hey, hating on 'big pharma' is more fun right?
posted by shelleycat at 1:05 AM on December 11, 2012 [2 favorites]

(I didn't mean to imply up there that there *are* human trials planned on this research by the way, even the researchers doing this work know that we're not there yet. Bad wording on my part.)
posted by shelleycat at 1:11 AM on December 11, 2012

shellycat--

Tell us more about the long term effects?
posted by effugas at 4:35 AM on December 11, 2012

As jamjam mentioned, the differences between mouse and human telomerase activity are big enough that trying this kind of thing in humans would be dangerous - particularly the risk of cancer, which is often what kills you in old age anyway. I wouldn't trust the mouse studies to correspond to human chances of developing cancer.

I'm not sure what animals are better models for human telomerase action, if they wanted to move this closer to human testing. Monkeys, maybe, or maybe they could manage with pigs or something.

It's easy to see results like this and get excited, but it's important to remember to think of potential dangers that are often greater than potential benefits. Interesting study though, thanks for the link!
posted by randomnity at 9:45 AM on December 11, 2012

I'm a computer programmer, and I've been hopeful for people to solve this whole immortality problem during my lifetime. A little while ago, though, I realized that this might not happen, so I started taking classes again so that I can become a mad scientist and work on this stuff. I may not get so far as to actually be helpful, but if I have to die, and I didn't even *try* to stop it, then I'm gonna be kicking myself!
posted by Galaxor Nebulon at 2:15 PM on December 11, 2012