Factor X have we finally found the fountain of Youth?

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Diogenes
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Re: Factor X have we finally found the fountain of Youth?

Postby Diogenes » Tue Jul 05, 2016 4:45 pm

DeltaV wrote:
Diogenes wrote:I think I saw that movie.

Image



Didn't seem to turn out all that well.

Huh? The underdog rebels won!




But not until after a long duration of suffering, and pretty much thanks to random chance. The possibility that a deus ex machina might rescue a future mankind from oppression is not a strategy that I would like to follow.


I perceive that much of the elite and wealthy are genuinely Malthusians at heart. All of the things they support appear to lean in that direction.
‘What all the wise men promised has not happened, and what all the damned fools said would happen has come to pass.’
— Lord Melbourne —

Diogenes
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Re: Factor X have we finally found the fountain of Youth?

Postby Diogenes » Tue Jul 05, 2016 4:49 pm

That is something I thought we would see eventually. A linear projection of the state of the art would indicate we would eventually be able to custom build molecules to meddle in any biological process that we wish.



Now of course, mankind is going to turn it into a weapon that kills specific classes of people based on their genes.


But that could just be my cynicism talking.
‘What all the wise men promised has not happened, and what all the damned fools said would happen has come to pass.’
— Lord Melbourne —

hanelyp
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Re: Factor X have we finally found the fountain of Youth?

Postby hanelyp » Tue Jul 05, 2016 5:54 pm

Effective and hopefully safe vaccines available about a week from initial outbreak, very good news.

Same tech as a selectively targeted bio-weapon, not so good.
The daylight is uncomfortably bright for eyes so long in the dark.

williatw
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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Wed Jul 06, 2016 12:37 am

hanelyp wrote:Effective and hopefully safe vaccines available about a week from initial outbreak, very good news.


Yes it sounds good...but I am wondering why they mentioned in the link relatively obscure diseases like Ebola being tested (& yes common Influenza), but no mention of say HIV or Malaria?

hanelyp wrote: Same tech as a selectively targeted bio-weapon, not so good.


Not so sure how well that would work anyway although admittedly a concern. If I was trying to kill a particular individual in a high tech kind of way some kind of swarm of insect size (or smaller) programmable or directed drones would work better. If I was trying to target an "ethnic" group like say "Muslims", too wide of a genetic net to be practical I would think, though I could be wrong. Most people while they may consider themselves to be "white", "black", "Hispanic" etc., are actually far more genetically mixed than they realize. Hard to target a germ/vaccine to be that specific; and even that isn't considering the possibility that your hypothetical "tailored" germ might not mutate (especially if its a virus) into something more generally virulent once it had greatly multiplied & infected enough people.

Diogenes
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Re: Factor X have we finally found the fountain of Youth?

Postby Diogenes » Wed Jul 06, 2016 7:22 pm

williatw wrote:
Not so sure how well that would work anyway although admittedly a concern. If I was trying to kill a particular individual in a high tech kind of way some kind of swarm of insect size (or smaller) programmable or directed drones would work better.



I agree with you about the swarmbots. I was just scaring some of my friends with this very discussion earlier today.


Soldiers cannot fight against swarmbots. Cheap, easy, and deadly. I see this coming as a very probable battlefield weapon. You can't hide from them either. They effectively neutralize any quantity of boots on the ground, in the air, or in armor.



williatw wrote:If I was trying to target an "ethnic" group like say "Muslims", too wide of a genetic net to be practical I would think, though I could be wrong. Most people while they may consider themselves to be "white", "black", "Hispanic" etc., are actually far more genetically mixed than they realize. Hard to target a germ/vaccine to be that specific; and even that isn't considering the possibility that your hypothetical "tailored" germ might not mutate (especially if its a virus) into something more generally virulent once it had greatly multiplied & infected enough people.




If you are a Malthusian, target wide, and provide an "antidote" to the people you want to keep.
‘What all the wise men promised has not happened, and what all the damned fools said would happen has come to pass.’
— Lord Melbourne —

paperburn1
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Re: Factor X have we finally found the fountain of Youth?

Postby paperburn1 » Wed Jul 06, 2016 8:46 pm

Using a combination of Y-DNA and an mtDNA indicators you could take out a family line quite easily .
I am not a nuclear physicist, but play one on the internet.

hanelyp
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Re: Factor X have we finally found the fountain of Youth?

Postby hanelyp » Wed Jul 06, 2016 11:05 pm

williatw wrote:...Most people while they may consider themselves to be "white", "black", "Hispanic" etc., are actually far more genetically mixed than they realize.

I don't expect that's a problem for a genocidal madman with delusions of genetic purity. If you carry the genetic marker for the target your blood is "dirty" and needs to be "cleaned".
...and even that isn't considering the possibility that your hypothetical "tailored" germ might not mutate...

And that's an advantage of a bio-tool consisting of packaged mRNA, it invades cells, produces the desired protein, and that's it. No chance of spread beyond the initial exposure.
The daylight is uncomfortably bright for eyes so long in the dark.

williatw
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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Tue Jan 10, 2017 4:57 pm

Image



One Man’s Quest to Hack His Own Genes


When Brian Hanley set out to test a gene therapy, he started with himself.

by Antonio Regalado January 10, 2017

Church has said he thinks the gene therapy is “underrated” as a way to conquer old age and believes in a not-so-far-off scenario where “everyone takes gene therapy” not in order to cure hemophilia, sickle-cell anemia, or some other rare disease, but to reverse the results of getting old.




I
n a dream Brian Hanley told me about, he’s riding a bus when he meets a man in dark leather clothing. Next thing he knows, he is splayed across a tilted metal bed, being electrocuted.

The dream was no doubt connected to events that took place last June at a plastic surgeon’s office in Davis, California. At Hanley’s request, a doctor had injected into his thighs copies of a gene that Hanley, a PhD microbiologist, had designed and ordered from a research supply company. Then, plunging two pointed electrodes into his leg, the doctor had passed a strong current into his body, causing his muscle cells to open and absorb the new DNA.



The effort is the second case MIT Technology Review has documented of unregulated gene therapy, a risky undertaking that is being embraced by a few daring individuals seeking to develop anti-aging treatments. The gene Hanley added to his muscle cells would make his body produce more of a potent hormone—potentially increasing his strength, stamina, and life span.




Should people be able to experiment on themselves using gene therapy without the FDA's sign-off?
Tell us what you think.
Hanley, 60, is the founder of a one-man company called Butterfly Sciences, also in Davis. After encountering little interest from investors for his ideas about using DNA injections to help strengthen AIDS patients, he determined that he should be the first to try it. “I wanted to prove it, I wanted to do it for myself, and I wanted to make progress,” says Hanley.

Most gene therapy involves high-tech, multimillion-dollar experiments carried out by large teams at top medical centers, with an eye to correcting rare illnesses like hemophilia. But Hanley showed that gene therapy can be also carried out on the cheap in the same setting as liposuction or a nose job, and might one day be easily accessed by anyone.

In an attempt to live longer, some enthusiasts of anti-aging medicine already inject growth hormone, swallow fullerenes, or gulp megavitamins, sometimes with disregard for mainstream medical thinking. Now unregulated gene therapy could be the next frontier. “I think it’s darn crazy,” says Bruce Smith, a professor at Auburn University who develops genetic treatments for dogs. “But that is human nature, and it’s colliding with technology.”

To pull off his experiment, Hanley used his scientific knowledge and part of his life savings. He put his insider know-how to work to procure supplies, order blood tests, win the sign-off of a local ethics committee, and engage a plastic surgeon who helped givehim two treatments, a small dose in 2015 and then a larger one last June.

Hanley, who drives a battered sedan humming with Hindu rave music, fits the profile of an underappreciated genius on a self-improvement quest. He’s a prolific online commenter whose opinions touch on everything from radiation to electric cars and street pickup of leaf piles. But his scientific thinking seems generally sound, and he says the meaning of his dream is straightforward too: he’d become Dr. Frankenstein’s monster. “My unconscious is really not that subtle,” says Hanley. “I had become something else, not entirely me.”

Hanley’s undertaking has caught the attention of big-league scientists. His blood is now being studied by researchers at Harvard University at the laboratory of George Church, the renowned genomics expert. Church, who provided MIT Technology Review with an introduction to Hanley, says he knows of a handful of other cases of do-it-yourself gene therapy as well. “And there are probably a lot more,” he says, although no one is quite sure, since regulators have not signed off on the experiments. “This is a completely free-form exercise.”

In 2015, we wrote about the case of Liz Parrish, an entrepreneur without a background in biology who claimed to have received a dose of gene therapy in Latin America. Parrish briefly worked for Hanley, whom she knew from anti-aging meetings. At least one additional person who underwent self-administered gene therapy is a U.S. biotech executive who did not want his experience publicly known because he is dealing with the U.S. Food and Drug Administration on other matters.

Hanley says he did not secure the approval of the FDA before carrying out his experiment either. The agency requires companies to seek an authorization called an investigational new drug application, or IND, before administering any novel drug or gene therapy to people. “They said ‘You need an IND’ and I said, ‘No, I don’t,’” recalls Hanley, who traded e-mails with officials at the federal agency. He argued that self-experiments should be exempt, in part because they don’t pose any risk to the public.

That’s not to say gene therapy is without dangers, such as immune reactions. “I spent years doing very little else other than iterating designs and thinking of all the ways something could go wrong,” he says. When I met him on Stanford University’s campus to discuss his project, Hanley zipped open his cargo pants to show me three black dots tattooed on his left thigh, marking the site of one of the injections. Had the gene therapy gone haywire, he says, his fail-safe option was to have the affected tissue surgically removed.

Growth hormone

During a day I spent with Hanley in Menlo Park, he seemed to burst with energy, several times colliding with me as we tried to walk through doors. Was it the gene therapy at work, an excitable personality, or just a show? “I think getting near Spider-Man-like transformations of people is potentially possible,” he says of gene therapy.

Most often, this approach relies on viruses to shuttle DNA into a person’s cells. Hanley opted instead for a simpler method called electroporation. In this procedure, circular rings of DNA, called plasmids, are passed into cells using an electrical current. Once inside, they don’t become a permanent part of person’s chromosomes. Instead, they float inside the nucleus. And if a gene is coded into the plasmid, it will start to manufacture proteins. The effect of plasmids is temporary, lasting weeks to a few months.

Because of its relative simplicity, the same technique is now eyed as a novel way to quickly deliver vaccines in response to emerging diseases. In August, the U.S. National Institutes of Health began dosing volunteers with a plasmid containing parts of the Zika virus.

Hanley took the technique in a different direction, poring over decade-old studies by a company called VGX Animal Health that had tried zapping plasmids into the muscles of cows, dogs with kidney disease, and baby piglets. They’d explored adding extra copies of the gene for growth-hormone-releasing hormone (GHRH)—a molecule that is normally made in the brain. One of its roles is to travel to the pituitary gland, where it acts as a regulator of growth hormone itself, telling the body to make more. It also appears to have an array of other roles, including enhancing the immune system.

“We never did try it in humans, but from everything that I saw in dogs, cats, cattle, pigs, and horses, it seems like a reasonable leap forward,” says Douglas Kern, a veterinarian who worked at VGX. “It has very profound positive effects in most species.”

Hanley says he designed a plasmid containing the human GHRH gene on his computer, with the idea of developing it as a treatment for AIDS patients. But no investors wanted to back the plan. He concluded that the way forward was to nominate himself as lab rat. Soon he located a scientific supply company that manufactured the DNA rings for him at a cost of about $10,000. He showed me two vials of the stuff he’d brought along in a thermos, each containing a few drops of water thickened by a half-milligram of DNA.

In planning his study, Hanley skipped some steps that most companies developing a drug would consider essential. In addition to proceeding without FDA approval, he never tested his plasmid in any animals. He did win clearance for the study from the Institute of Regenerative and Cellular Medicine in Santa Monica, California, a private “institutional review board,” or IRB, that furnishes ethics oversight of human experiments.

However, in the application by his company to increase “GHRH levels “to more youthful levels” in a single subject, Hanley did not indicate that he planned to be the subject himself. He says that’s not a problem, because he knows the risks so well after working on the idea for so long. “I am informed consent personified,” he says. “There is no one in the world more informed than me.”

But ethicists not involved in the study see a significant omission. “If I found out only after I approved a protocol that it was intended to be self-experimentation, I’d be seriously unhappy,” says Hank Greely, a law professor at Stanford University. “That is definitely the kind of thing an IRB should know about.” He says the issue is one of potentially impaired objectivity, as when a physician proposes to treat family members—except even more so, since Hanley is the designer of the therapy as well as its recipient, and may be financially dependent on the outcome.

“One thing you have when you’re experimenting with yourself is a very, very deep conflict of interest,” says Greely.

The video

When I asked Hanley for proof the treatment had actually occurred, he obliged by providing documentation and playing for me a video of the experiment he had stored on his laptop. In it, Hanley appears sitting in his undershorts in a doctor’s office. The scene, recorded in June, shows the surgeon from the elbows down, wearing shorts, running shoes, and white exam gloves. The two met at a gym working out, Hanley says. Off screen, a female friend of Hanley’s makes small talk as large ice packs are laid on his thighs.

“How are you feeling?” the doctor asks.

“A little nervous,” Hanley replies.

Also watching the experiment that day, via Skype, was Bobby Dhadwar, a postdoc in Church’s Harvard laboratory, which Hanley has kept abreast of his plans. “When I first heard someone is going to electroporate themselves, I thought they had to be kidding. It’s usually something we do to animals,” says Dhadwar.

The procedure, involving an electrical discharge into the body, is painful. Hanley tried it first in the summer of 2015, with no anesthetic. In a diary he keeps to track his results, he compared the feeling to torture. “Pow!” he noted. “No way is that acceptable. Have to work on that protocol.”

This time, Hanley had opted to take six milligrams of the tranquilizer Xanax and got local anesthetic in his thighs. The doctor can be seen placing a plexiglass jig built by Hanley onto the biologist’s thigh. The doctor leans in with a hypodermic needle to inject the sticky solution of GHRH plasmids into the designated spot. He also uses the jig to guide the two electrodes, stiff sharp needles the size of fork tines, into the flesh. The electrodes—one positive, one negative—create a circuit, a little like jump-starting your car.

In the video, Hanley’s thigh shudders as the current is turned on, his cells open momentarily, and the DNA rings slip inside.

“That was better than last time,” he’s heard saying.

The results

Three weeks after the treatment in June, Hanley’s diary records that he flew to Boston. By the morning of June 28 he had arrived at Church’s Harvard lab, where he spent two weeks at a vacant desk. The geneticist, who enjoys millions in NIH grants, has a large program testing 45 different gene-therapy interventions in mice to see which extend their lives the most, or even reverse aging.

Church has said he thinks the gene therapy is “underrated” as a way to conquer old age and believes in a not-so-far-off scenario where “everyone takes gene therapy” not in order to cure hemophilia, sickle-cell anemia, or some other rare disease, but to reverse the results of getting old.

That makes Hanley a person of considerable interest to the lab—he’s a sort of visitor from the near future. “We think it’s very interesting to hear about people who are self-medicating with gene therapy,” says Dhadwar. “It’s so easy to acquire these materials; it’s just one step to say ‘I am going to start treating myself.’”

Dhadwar told me the lab had received blood samples from both Hanley and Parrish and was carrying out measurements to determine whether new genes were active in their bodies. He said in Hanley’s case levels of GHRH appeared elevated, suggesting that the treatment had had an effect, although he cautioned that his results are not definitive.

With “indie” gene therapists checking in and out of his Harvard lab, I asked Church if it was becoming a sanctuary for people flouting medical convention, if not the law. One real risk is that gene therapy could become a zone of reckless and unproven treatments. “We certainly don’t encourage people to do this; in fact, we encourage them not to,” Church says. But he doesn’t see why he should give up the chance to offer scientific feedback or assistance: “I don’t think of it as offering a haven so much as a critique.”

Invictus

In many conversations and e-mails with Hanley, I frequently wondered what his deepest motive was, and whether he even knew it himself. Was it to “develop products people will love,” as he told me, as if he were the Steve Jobs of plasmids? When I described the experiment to Greely, the legal ethicist, he said it reminded him of the treacly 19th-century poem “Invictus,” by William Ernest Henley. It’s the one that ends, “I am the master of my fate: I am the captain of my soul.”

Maybe doing gene therapy on himself was Hanley’s way to take control of his business, his health, and his identity. Altering your DNA, in a very literal way, alters who you are. It also let him play in a big scientific pond alongside people doing “real science,” like those in the Church lab. “To be in that game, you need to be hooked into NIH or Google’s billions,” says Hanley. “Someone like me, I look for things that are proven and that I am convinced of, and then how do we implement it?”

So what happens next? The U.S. Food and Drug Administration could get involved, intervening with warning letters or site visits or auditing his ethics board. The plastic surgeon—whose name Hanley wished to keep confidential—could face questions from California’s medical board. Companies that supply plasmids might start taking a closer look at who is ordering DNA and what they plan to do with it. Or perhaps authorities will simply look the other way because Hanley experimented on himself.

The kind of attention Hanley is hoping for, he says, is from investors. Maybe someone will fund a larger study, or perhaps there is a wealthy person interested in paying for his treatment.

Hanley is proud of what he’s done. He created a company, secured patents, made new contacts, identified a gene therapy that has plausible benefits for people, thought in detail about the risks, and offered himself up as a pioneering volunteer. Doing gene therapy to yourself, Hanley says, “focuses the mind, it really does.”





https://www.technologyreview.com/s/6032 ... own-genes/

paperburn1
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Re: Factor X have we finally found the fountain of Youth?

Postby paperburn1 » Tue Jan 10, 2017 6:32 pm

Long life, twice a week get plasma from a 20 is year old. BOOM, healthy till you die.
I am not a nuclear physicist, but play one on the internet.

williatw
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Re: Factor X have we finally found the fountain of Youth?

Postby williatw » Fri Feb 17, 2017 3:04 am

George Church indicates reversal of aging will be a reality within ten years



In June 2016, Church indicated that first phase I aging reversal human trials could be in a year or two.

Fahy: Using your most favorable pathway for intervention, how long will it take before a human trial might be possible?

Church: I think it can happen very quickly. It may take years to get full approval, but it could take as little as a year to get approval for phase one trials. Trials of GDF11, myostatin, and others are already underway in animals, as are a large number of CRISPR trials. I think we'll be seeing the first human trials in a year or two.


While discussing creating a hybrid elephant - wooly mammoth using CRISPR genome editing, Harvard's George Church predicted that reversal of aging will be a reality within ten years.

Nextbigfuture suspects that this would likely be reversing aging in mice cells as a proof in principle. But maybe he does mean full reversal in humans.

In June 2016, Church indicated that first phase I aging reversal human trials could be in a year or two.

Fahy: Using your most favorable pathway for intervention, how long will it take before a human trial might be possible?

Church: I think it can happen very quickly. It may take years to get full approval, but it could take as little as a year to get approval for phase one trials. Trials of GDF11, myostatin, and others are already underway in animals, as are a large number of CRISPR trials. I think we'll be seeing the first human trials in a year or two.

Fahy: Can you say what those trials might be?

Church: I helped start a company called Editas that is aimed at CRISPR-based genome editing therapies in general. Some of those will be aimed at rare childhood diseases and others hopefully will be aimed at diseases of aging. We also have a company focused specifically on aging reversal that will be testing these therapies in animal and human models.



Image

A discussion with Dr George Church on reversing cell aging by restoring youthful gene expression

Fahy: If aging is driven by changes in gene expression, then the ability to control gene expression using CRISPR technology could have profound implications for the future of human aging. Why do you think aging may be at least partly driven by changes in gene expression?

Church: We know that there are cells that deteriorate with age in the human body and that we have the ability to turn those back into young cells again. This means we can effectively reset the clock to zero and keep those cells proliferating as long as we want. For example, we can take old skin cells, which have a limited lifetime, and turn them into stem cells (stem cells are cells that can turn into other kinds of cells) and then back into skin cells. This roundtrip results in the skin cells being like baby skin cells. It's as if my 60-year-old cells become 1-year-old cells. There are a variety of markers that are associated with aging, and those all get reset to the younger age.

Fahy: That's fantastic. Does this mean that reversing skin cell aging in your face would allow you to rejuvenate your entire face?

Church: If you rejuvenate at a molecular level, it doesn't necessarily mean that everything else rejuvenates. So, for example, if my face has a scar on it, it's not going to necessarily reverse that (although theoretically it's not out of the question). But we can reverse the tendency of your cells (and therefore of your whole body) to deconstruct when you reach your life expectancy.

How to Quickly Discover and Begin to Correct Currently Unknown Causes of Aging on the Gene Level

Fahy: If aging is driven by changes in gene expression and those changes in gene expression can be reversed, then we need to be able to find all of the important age-related changes in gene expression as quickly as possible. How can this be done?

Church: Gene expression results in each cell having specific RNAs and proteins, and these can be surveyed. You don't necessarily have to define every single RNA in a particular cell to understand that cell, but you can, and we have in fact developed a new method to do this that allows us to see all of the tens of thousands of RNAs in a single cell at one time, and to see the RNAs in neighboring cells as well. So now we can see how different cells relate to one another in context. This new method, called fluorescent in situ sequencing, or FISSEQ, allows us to count all the RNAs in a cell while simultaneously counting all of the RNAs in all of the cells it touches. Plus, we get the 3D coordinates for every RNA molecule in every cell.

Fahy: That's unbelievable. How can you use this method to search for changes that are related to aging?

Church: Suppose there are two different kinds of cell, and we want to know what gene expression states make them different from one another. We can first compare the two cells using FISSEQ in order to determine the differences in gene expression between them. Next, we can pick specific differences we think cause the cells to be different cell types, and change the expression of those particular genes in either or both cells using, for example, CRISPR, and see if we can change one kind of cell into the other. Even if we don't get it right the first time, we can take many guesses as to what the important RNAs are and just how much to tweak them until we do get it right.

The same principle can be applied to any pair of cells. By comparing old cells to young cells, we can find out what makes an old cell an old cell, and how to turn an old cell into a young one.

Fahy: Fantastic.

Church: One of the problems with studying development and aging is that it takes a long time. But if we know the epigenetic state of all these different cells, no matter how many years apart they are, it only takes a few days to reprogram a cell and duplicate the effects of decades of slow change in the body, or reverse those effects. So in principle we could turn a young cell into an old one or an old cell into a young one because the only difference between them is epigenetics, or gene expression.

Fahy: What other ways are there to identify powerful gene targets for intervention into human aging?

Church: There are basically four good ways to find key gene targets.

First, we can look at genes that underlie person-to-person variability in such things as low risk for viral infections, diabetes, osteoporosis, and so forth. The most extreme example here would be to compare normal people to super-centenarians, those who live to the age of 110 or older. They might have genes that are protective enough to find even with a small number of individuals, or even with a single individual.

There are hundreds of genes that have small effects, but then way out on the end of the bell curve is something like the myostatin double null mutant or human growth hormone over/under production. Genes that have gigantic effects and completely dominate the effects of small environmental and small genetic influences are the right kind of gene to look for.

The second way to find the best gene targets is to pick from discoveries made from basic studies like the GDF11 and TFAM that we talked about earlier.

A third way is to use a specialized highly genomic strategy, such as mutating thousands of genes one by one to see if any of these mutations block aging, or using the FISSEQ method we discussed earlier.

The fourth way to identify powerful gene targets is to compare closely related animals, one of which ages much more slowly than the other (like naked mole rats vs. rats).

No matter where you get your lead, you don't have to worry about having too many hypotheses. Just use CRISPR to activate or inhibit that candidate gene and look for the biomarkers of aging reversal we discussed earlier. The idea is to see whether your change has an impact or not, and whether it acts synergistically with the other things that have been shown in the past to have an impact.

Fahy: So if we saw something unusual or provocative in super-centenarians, we could create the same change in, for example, a normal human cell line and observe whether the right longevity pattern emerged.

Church: Yes.

Fahy: I've been told by James Clement, who is being funded by the Life Extension Foundation to do collaborative work with you on the genetics of super-centenarians (See sidebar: Life Extension Foundation Funding of CRISPR Research), that you might even be able to take super-centenarian gene expression patterns and put them into mice and see if the mice age more slowly.

Church: Right. Our protocol will likely be to collect leads from the four different sources and try them out first on human cells. By going straight to human cells, we won't get into the trap of spending years working on mice, which is rather expensive, only to find out that it doesn't work in humans. We can actually do a cheaper and more relevant study in human cells, confirm them in mice, then test them in larger animals, and then in humans. I think that going from human cells to mice and back to humans is likely to save us time and money. Many human cellular testing systems are getting better and better, such as "organs on a chip" or organoids, which are getting to be more and more representative of in vivo biology.

The Feasibility of Applying CRISPR Technology to the Whole Body

Fahy: To reverse human aging, CRISPR technology will ultimately have to be applied in the whole body, and not just to cells in a test tube. How feasible is it to apply CRISPR technology in the intact body?

Church: Gene therapy can be based on either ex vivo manipulations, in which cells are removed from the body, genetically modified, and then put back into the body, or on in vivo (within the body) methods, in which, for example, a modified virus might be used to carry a gene package into many different cells in the body. Each of these methods has pros and cons.

There are viral and non-viral delivery systems that could be used to deliver CRISPR constructs and that will leave the blood vessels and go into the tissues. The delivery system could contain the CRISPR plus guide RNA plus the donor DNA (See sidebar: Gene Editing with CRISPR), or it could just comprise the CRISPR, guide RNA, and protein activator, and so on. But whether it's a viral delivery or a non-viral delivery method, the total mass of gene editing devices that has to be delivered will have to be considerable. But there is no rush, you can deliver them slowly.

Fortunately, there are ways to manufacture biologicals that are dirt cheap. Things like wood and even food and fuel are all roughly in the dollar-per-kilogram range. If we could similarly make a kilogram of a viral delivery system and load it up with CRISPR, then it could become inexpensive enough to apply to the whole body.

Fahy: Yes, a kilogram would be plenty! So, the viral delivery system contains a gene for CRISPR, a separate gene for the guide RNA, etc. When it delivers these genes to the cell, the cell makes the resulting proteins and nucleic acids, and all of the components simply assemble all by themselves in the cell, is that right?

Church: Yes.

Fahy: Which is the best CRISPR delivery system?

Church: Adeno-associated viruses (AAV) are one of the favorite delivery systems right now because they can be nudged into going to tissues other than the liver (where many other delivery systems end up) more readily. This is an active field of discovery. It's moving quickly, and the CRISPR revolution just made it an even more desirable field to study.

Specific Opportunities for Reversing Human Aging TFAM: Staying Energetic Indefinitely

Fahy: There are several very exciting stories in aging intervention these days. In 2013, the Sinclair lab at Harvard came out with the revelation that the aging of mitochondria (which are the producers of usable energy within cells) is driven in significant part by reduced levels of one particular molecule in the cell nucleus: oxidized NAD (NAD+).

The team showed that they could correct mitochondrial aging just by giving old mice nicotinamide mononucleotide (NMN), which is a vitamin-like substance that can be converted into NAD+, for one week. This resulted in phenomenal overall rejuvenation, including reversal of signs of muscle atrophy, inflammation, and insulin resistance. Now your lab showed that there is a very exciting gene engineering alternative involving TFAM (Transcription Factor A, Mitochondrial). Why is TFAM important, and what have you done with it?

Church: TFAM is a key regulatory protein that is in this pathway of NMN and NAD+. It allows cells to manufacture the NMN precursor on their own, so you don't have to manufacture it outside the cell and then try to get it into the cell from outside. Ideally, you don't want to have to take NMN for the rest of your life, you want to fix the body's ability to make its own NMN and buy yourself rejuvenation for at least a few decades before you have to worry about NMN again. In order to accomplish this on a single cell level, we've used CRISPR to activate a TFAM activator, and we made it semi-permanent. (See sidebar: Gene Editing with CRISPR)

Fahy: With this technique, you were able to increase TFAM levels in the cell by 47-fold. This resulted in restored ATP levels, increased NAD+, and an increased NAD+ / NADH ratio. It also increased total mitochondrial mass and reversed several other age-related changes.

Church: Yes. We have a number of ways to measure mitochondrial function and age-related losses of those functions. When we activated TFAM, these changes returned to what you would expect of a younger cell state. And we built this anti-aging ability into the cell, so it's self-renewing and eliminates the need to take pills or injections.








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kurt9
Posts: 537
Joined: Mon Oct 15, 2007 4:14 pm
Location: Portland, Oregon, USA

Re: Factor X have we finally found the fountain of Youth?

Postby kurt9 » Fri Feb 17, 2017 3:59 am

Its becoming clearer that mitochondrial DNA damage is the root of aging. The other things such as lysosomal aggregate accumulation, accumulation of senescent cells, and the like are likely secondary effects. Church's CRISPR Cas9 may fix this problem. Another approach, MitoSENS, is to simply relocate those 13 genes into the cell nucleus and order to effect self-repair. I'm thinking that a CRISPR Cas9 related technique to repair those gene in sitsu, without relocating them into the cell nucleus, might be the best way to go. There are probably other methods I'm not aware of that can accomplish the same things.

Eventually we will be regenerating our bodies with synthetic stem cells.

What is very clear is that aging is curable and ought to be curable within the next 3-4 decades. If you think you cannot hang on this long, I would consider Plan B, which is cryo-preservation. The Alcor Foundation (http://www.alcor.org) is worth checking out.

The notion that aging is somehow immutable is pure ideology, not science.

The best part of all of this is that it will eventually be done in a home lab. Call it DIY age reversal.


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