Before you get your hopes up, keep in mind: be warned research in mice has a very poor track record for generalizing to humans.
I don't suppose there's a highly-accessible curated database of hypotheses which appear to have tested very differently between mice (or other subjects) and humans. Suddenly this strikes me as a highly valuable resource.
Now I'm wondering if there's a way to make that the start of a viable business, but of course my pondering is limited by knowledge outside my domain.
I don't suppose there's a highly-accessible curated database of hypotheses which appear to have tested very differently between mice (or other subjects) and humans.
You may find some of the reviews and meta-analyses in http://www.gwern.net/DNB%20FAQ#fn97 to be of interest!
I'm not sure about the FDA, though. IIRC, they only require all human trials to be reported, and they don't release the information. (This is why the recent Tamiflu meta-analysis was such big news: because the researchers managed to force the disgorgement of all studies' data and show poor performance of Tamiflu & systematic bias in which studies got officially published.)
There's data from clinical trials. Before doing experiments with humans a company has to make the experiments in mice (or other animals). Any clinical trial of a drug that fails can be seen as a trial where a hypothesis failed to generalize. If I remember right the FDA does release some of the relevant data.
How about providing a link to the original study instead of only linking to mainstream media coverage of it?
I hit a paywall, but found the full text here:
https://web.stanford.edu/group/twclab/cgi-bin/images/TWClab/publications/2014_villeda_natmed.pdf
An unfettered free market and access to third world countries ... thanks reality, for making Hollywood villainy be within reach!
If we look at this in the context of Aubrey de Grey's model of aging, it mostly targets damage type number 5, cell loss.
I guess the media and general public will need a lot more practice before they can break down "immortality treatments" into pieces that look like the actual research.
On the other hand, wikipedia says cell loss causes Parkinson's, so I hereby predict that within 5 years we'll have covens of Parkinson's patients roaming the streets at night, shakily sucking the blood of the innocent.
I guess the media and general public will need a lot more practice before they can break down "immortality treatments" into pieces that look like the actual research.
Mainstream media isn't in the job of informing but in the job of telling stories. As such they overhype scientific findings. Without overhyping the story wouldn't be worth a news article.
I was quite surprised when I saw this reported as news, since Heinlein wrote about it forever ago. Either something has gone wrong with the field of life extension, or this experiment ignores some major reason why it won't help anyone, or I should be paying more attention to Heinlein.
Thought experiment: let's say any and every component of the human body was transpantable (i.e. not just blood, kidney, liver).
Then if you transplanted a set of components X from a person of age 30 into a person of age 60, then the person's resulting age should logically be somewhere between 30 and 60, skewed towards 60 if X is small (one drop of blood) and skewed towards 30 if X is large (everything except the brain).
Now the question is: how do you calculate the "weight" of the set X that controls the skew? Is it something simple like number of cells or mass? Are some components preferred, such as heart cells or kidney cells?
Also, importantly, does the quality of "age" diffuse and equilibriate throughout the body, (like temperature), such that after some equilibriation period the whole body will be the same age? Or if you transplant a 30-year-old heart into a 60-year-old, will you just get a 60-year-old with a younger heart?
I would say it depends on the range of influence the transplanted organ has on the rest of the body. A new set of eyes will have little influence beside their sensory function; a new esophagus will work mostly like the old one. More central organs will have bigger effects: a new liver will improve your fat and sugar metabolism; a new pancreas will be probably life-changing. A new, stronger heart may prevent ischemia in otherwise poorly-irrigated tissues, but will do little beyond that. A blood marrow transplant will essentially give you new blood, whose consequences will depend on the donor's genetic traits. Since blood interacts with the entire body, a new set of kidneys will have huge repercussions.
Then if you transplanted a set of components X from a person of age 30 into a person of age 60, then the person's resulting age should logically be somewhere between 30 and 60, skewed towards 60 if X is small (one drop of blood) and skewed towards 30 if X is large (everything except the brain).
No, you ignore the effect of the body fighting transplants because they have different DNA. The brain also learns to control different parts of the body when it's young and when you change those parts of the body in a way that makes them react differently to neural impulses the body get's less efficient.
body fighting transplants (hey, that's close to being a contronym, how awesome is that)
Just to complete the set, there's also the inverse: the transplant fighting the host ("graft-versus-host"). Imagine how confused you'd feel as a sentient leukocyte, grafted onto a different body.
ヽ༼ຈل͜ຈ༽ﾉ Transplant hwaiting! ヽ༼ຈل͜ຈ༽ﾉ
I'm very curious about, in descending order, a) whether this protein can be synthesized, b) whether it can be efficiently extracted from nonhuman creatures, and c) whether removing it from a creature ages it, or if it can be replaced with no real loss.
a) whether this protein can be synthesized
In what way does is that a question? A protein is just a gene that get's transcribed by a ribosome. You can put that gene into least and let the yeast build the protein. The protein might kill the yeast and it might take a while to get the process streamlined but in principle every protein can by produced by yeast or some bacteria.
b) whether it can be efficiently extracted from nonhuman creatures
Who cares? It's not like we extract insulin from animals these days and we probably want the human version of the protein anyway.
c) whether removing it from a creature ages it, or if it can be replaced with no real loss.
Probably depends a lot on your definition of aging. It will take a while till the animal restores the blood levels of the protein and during that time amount of neurogenesis is going to be lower.
More interesting questions would be: d) What the half life of the protein. How often would you have to administer it to keep the levels in the blood constant?
e) Can you deliver the protein orally?
f) Are there processes that get messed up if you simply increase the levels of that protein? Does it increase cancer rates?
g) As the answer to f) is probably yes, is it worth it trade neurogenesis for a bit more cancer? Do you get enough bang for your bucks?
http://www.uniprot.org/uniprot/O95390
From the looks of it it is a secreted protein with disulfide bonds that is processed by proteases cleaving it at a particular point and other enzymes adding sugar residues at particular points. You're gonna need to make it in a eukaryote through the secretory pathway and it probably needs a suite of modifying enzymes to cleave and glycosylate it properly, but I don't know if those enzymes are widespread in the eukaryotes or animal-specific. You can always make it in animal cells but that's expensive compared to fermentation tanks. It also must make its way INTO circulation, implying injection, and I haven't been able to see how much plasma was injected and if that indicates occasional infusions or regular injections given how quickly it degrades.
EDIT: see downstream reply to ChristianKl for updated information after I followed the citations and looked at the actual papers after work. Looks like the protein is easier to make than I expected (and indeed a lot of eukaryotic proteins CAN be made in bacteria if you have the industrial-scale equipment to do the proper post-processing), but extremely expensive at this time.
You basically CANNOT give proteins other than digestive enzymes orally.
And I do indeed suspect they'll find some downside to this somewhere, likely in either cancer rates or metabolic issues.
I should go after the actual papers later today or something...
And I do indeed suspect they'll find some downside to this somewhere, likely in either cancer rates or metabolic issues.
As a researcher said the other day (I can't locate the link right now), "In the end, if heart disease doesn't get you, cancer will."
You're gonna need to make it in a eukaryote through the secretory pathway and it probably needs a suite of modifying enzymes to cleave and glycosylate it properly, but I don't know if those enzymes are widespread in the eukaryotes or animal-specific.
If the yeast doesn't produce the enzyme on it's own why not simply add the gene for it? If the enzyme messes up the yeast too much you can always switch from yeast towards some other unicellular organism. It might cost a bit to do the bioengineering but when it comes to commercial usage of the protein I don't think that's an issue.
Okay, I actually went and looked at the papers and followed a chain of citations back until I found where they are actually getting the protein.
Looks like my assessment was unnecessarily pessimistic. Those that I could find the source of their proteins who studied this protein in isolation seem to have bought a recombinant product from Peprotech, a biotech company that sells huge numbers of proteins. Their website (http://www.peprotech.com/en-US/Pages/Product/Recombinant_Human_GDF-11/120-11) seems to indicate that it is being produced in E. coli. I suspect they have altered the gene a bit to only produce the part cut by the protease that is active and may be doing some post-processing to get it folded right since they indicate that it comes as a dimer held together by disulfide bonds which have a hard time forming in bacterial cytosol. I suspect there's a bunch of industrial techniques and optimization going on in there that we in the research labs don't bother with in favor of doing things faster with more complicated or versatile small scale systems.
EDIT: and now I found this http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0085890 in which just this year someone managed to screw up the redox metabolism of bacteria such that you can more easily express proteins that form disulfide bonds in the cytosol of bacteria without the need for expensive post-processing to get the bonds right. One of a class of recent modded bacterial strains that are more amenable to expressing eukaryotic proteins at the expense of some metabolic upset. Cool stuff.
EDIT 2: Additionally, someone in my lab is in the process of trying to make large amounts of a couple of novel weird fungal proteins in order to study their activity in vitro. She can't express them in a fungus (the context in which they fold normally) since they will alter the cell division cycle of the fungi and probably kill them, so she's expressing them in bacteria. Had a very hard time getting them to both fold correctly and stay stable without degradation. Over the course of more than six months she's had to rebuild the system she is using to express it several times, and the final successful version involves expressing the protein alongside a binding partner that is required to make it not aggregate into mush immediately upon translation, fused to a tag that makes it more soluble, and using slightly nonstandard extraction chemicals to keep it from denaturing. You probably need to apply a similarly tailored approach to many novel proteins when you yank them across contexts, which you can justify more readily if you stand to make money off it.
On the other hand, I also looked at a number of recent papers studying the effects of this growth factor. All the studies used daily intraperitoneal injections (injections through the abdominal wall into the space around the intestines) for about a month, of 0.1 mg per kilogram of body weight. That might just be because it can be difficult to get lots of needles into a mouse blood vessel in a short period of time though, but it still suggests that maintaining levels needs lots of injection. Also, according to Peprotech, their cheapest cost is $3900 per milligram (at their current levels of production, which is limited and for research purposes). Of course, insulin is probably a better model of a protein product that makes it big time, though not a perfect one since that prevents rather severe issues immediately rather than slowing chronic ones.
As for stuff brought up in this post, I think that it is probably should indeed possible to muck around with yeast until you can get it to process secreted proteins how you want - just taking a lot longer.
Well, it's a growth factor. Even IGF1 and growth hormone can rejuvenate old tissue, but they don't make one age any more slowly (though they can make one more robust up to the end).
Do you think that growth factors like these can accelerate aging in the end though? Reductions in growth factor signalling are often associated with increases in longevity, especially since many growth factors increase mTOR signalling (which often results in lowered rates of protein autophagy). I'm not sure how GDF11 would impact mTOR signalling though.
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Edit: Or is it really a growth factor? https://en.wikipedia.org/wiki/GDF11 says that it's a growth differentiation factor.. And that it negatively regulates neurogenesis.. Hmm..
It will take a while till the animal restores the blood levels of the protein and during that time amount of neurogenesis is going to be lower.
But maybe when you're young, having it occasionally filtered would induce a higher set point for production.
Might be true when you're old too.
a) In a way that's economically viable.
And there's a reason I said "in descending order" - each is only a concern if the one(s) before it aren't practical.
You're right though, my list was not exhaustive.
a) In a way that's economically viable.
That depends very much on how much protein you need and how much people you can treat. It's possible to spend 100 million to genetically engineer yeast to be extremely optimized for producing a certain protein. A big pharma company can spend that much money when the drug is a block buster drug but researchers who just want the protein to run a few experiments can't.
Given how much people spend on drugs that only pretend to reverse aging or treat one small symptom of it, I'm pretty sure a pill that actually does reverse it would be of major interest to billions of people.
In general yes, if the protein works as a good drug the matter of synthesising it is a solvable engineering problem.
However we are not talking about a pill. We are talking about a daily injection. We are also not talking about completely reversing all aging but some aspects while likely suffering side effects.
Given the priors in a case like this, it's unlikely that everyone will soon take daily injections of the protein.
In experiments performed on mice, blood transfusions from young mice reversed age-related markers in older mice. The protein involved is identical in humans.
http://mic.com/articles/88851/harvard-scientists-may-have-just-unlocked-the-secret-to-staying-young-forever