[ExI] forward from aubrey de grey: reverse aging

[spike]

The ExI-chat server seems to be slow.  This was already forwarded by another, but nothing, so as an experiment I am forwarding the same message.  s


Forward from Aubrey de Grey

=============

Subject: Re: [ExI] reverse aging


On 12/5/2010 10:49 PM, The Avantguardian wrote:

 > http://www.sens.org/files/pdf/WILT.pdf
 >
 > My objections to it follow:

<snip>

Aubrey replies:

Hello everyone, and my apologies for the slow reply. You're only getting it now because nice KLM have allowed me to recharge my laptop in business class!

 >> 1. First what he was suggesting was similar to purposefully giving people the equivalent of  >> Dyskeratosis Congenita, a genetic birth defect where people are born without normal  >> telomerase function.

Correct. Actually rather worse than that, because DKC sufferers still have some residual telomere elongation capacity.

 >> The problem is that these people are actually *more* prone to cancer  >> and start getting them around 10 yo. You can find a complete medical description of  >> Dyskeratosis here on pubmed for free: 
http://www.ncbi.nlm.nih.gov/pubmed/20301779

That's true - but, the point is thay even in DKC sufferers, tumours still maintain their telomeres. Maybe they do it with ALT, maybe by upregulating the residual telomerase - but they still do it. It's no surprise that such people get cancers early, because we know that telomere shortening causes "crisis" and hence high genomic instability. 
What matters is what happens next: is a telomere elongation mechanism initiated, or do the cells divide into oblivion? With the genes for telomerase and ALT deleted, only the latter could happen.

 >> 2. The second reason is that once a cell violates its genetic programming and goes cancerous,  >> all the rules go out the window. If telomerase is available, it will use it to lengthen its telomeres.
 >> If telomerase is not available it will start using alternative methods to lengthen its telomeres like  >> using the homologous-recombination machinery normally reserved for DNA repair and meiosis  >> of germline cells.
 >>
 >> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892175/
 >> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649016/?tool=pubmed

Correct.

 >> And if that doesn't work, cancer cells have no qualms against just sticking chromosomes together end  >> to end with non-homologous end joining. Cancer cells will duplicate genes or entire chromosomes (polyploidy),  >> lose genes or entire chromosomes, and mix bits and pieces of different chromosomes together if need be.
 >>
 >> http://www.nature.com/onc/journal/v21/n45/pdf/1205566a.pdf

Correct too - but once large chunks of the genome are present in zero copies, the cell dies, however creative it is. Sticking chromosomes together is fatal for the cel unless the chromosome is ripped apart again (at a different place), and that's exactly how aneuploidy arises.

 >> So profound is a cancer cell's ability to mutate at fast speed that it can form structures known as ring chromosomes  >> that recapitulate the ancestral bacterium's circular telomere-independent chromosome.
 >> http://atlasgeneticsoncology.org/Deep/RingChromosID20030.html

That's true too, but the only species in which such a thing has been seen as a way to escape telomere shortening is the yeast Schizosaccharomyces pombe, which has only three chromosomes. The more chromosomes you have, the more unlikely it is that you will join one end of a chromosome to the other end of the same chromosome rather than to a different chromosome.

 >> In short, cancer cells have all the tools of evolution at their disposal at speeds normally associated single-celled organisms.

Yes again - but that's not fast enough to outrun the divide-to-death problem, unless you have a latent telomerase gene to turn on.

 >> 3. The next problem is that de Grey's strategy underestimates the importance of the immune system in cancer prevention.
 >> This process is called immunosurveillance and mice and people with defective immune systems are notoriously prone  >> to cancer.  The white blood cells that normally protect people from cancer *need* telomerase to function properly  >> because the mechanism by which they operate depends on the mass replication of the white blood cell lineages that  >> can recognize and kill tumor cells.
 >>
 >> http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1857231/
 >>
 >> Of course this mechanism of amplification of the efficacious clones is used to combat mundane infections as well.
 >> So not only would telomerase-deficiency make one prone to cancer, it would make one susceptible to death from  >> normally benign viral, bacterial, and fungal infections.

Again correct (except for the part where you say I underestimate this!). 
In fact, any cancer that gets big enough to bump up against telomere shortening in the first place has already jumped through loads of hoops in evading the immune system when it was smaller. So yes indeed, telomerase deletion can affect the immune system's ability to knock off nascent cancers, and also regular infections. But... we can deal with that problem in the same way that I've proposed for rapidly-renewing cell types in general. It may turn out to be enough just to reseed the bone marrow with haematopoietic stem cells that initially have nice long telomeres (but no telomerase genes). And if not, we can just do the same trick of extract/lengthen/reintroduce with memory T and B cells
themselves: we only need to reach a rather small proportion of such cells in order to get the desired result.

 >> 4. De Grey's solution to this problem is "reseeding" whereby engineered stem cells are periodically given to people to replace high turnover tissues such as the blood cells, skin, and gut epithelium. This work-around however brings up the next problem: The relationship between cancer and stem cells is poorly understood and these reseeded stem cells could very well *become*  cancer.
 >>
 >> http://www.ncbi.nlm.nih.gov/pubmed/20688584
 >> http://www.ncbi.nlm.nih.gov/pubmed/19684619

Not if they have no telomerase or ALT...

 >> And if the stem cells are treated to lack telomerase, like the rest of the cells of the body in WILT, they no longer qualify as stem cells since the capacity for self-renewal is one of the defining characteristics for stem cells.

So what? That's just a name.

 >> So these telomerase deficient stem cells would be the medical equivalent of GM food crops that can't make seeds, requiring one to be beholden to whatever biotech company happens to be manufacturing your crippled stem cells for you.

Yes, this has been noted. But if the only alternative is death from cancer....

 >> If we are talking about immune system stem cells, then catching a simple cold could deplete ones entire reservoir of non-self-renewing hematopietic stem cells.

Huh? I know of no evidence that HSCs divide faster when there is an infection to be tackled. In fact, I think the only cells that divide faster are the cognate naive T cells.

 >> 5. Aside from the theoretical problems with the WILT strategy, the technical challenges would be horrendous. With the current state of the art, gene knockouts are a messy and rather hit or miss affair. They involve trying the targeted gene deletion on a great many embryos, then screening for that one precious embryo or cell line in which it worked. 
While this is feasible with mice, the bioethicists would have a conniption if you tried that with human embryos. But what use is a gene knockout of an embryo going to be to an already full grown population of possible cancer victims? While gene knockouts are done routinely on human cells in a petri dish, I am not aware of any existing technique that would allow one to delete a gene from all 10^14 [~70 trillion?] cells of an adult human in vivo:

This is indeed challenging, and I never conceal that WILT is the hardest part of SENS. However, in the case of the rapidly renewing tissues that are the source of many cancers, the gene targeting can be done ex vivo and appropriate selection applied; we are getting pretty good at amplifying rare stem cells without losing their stemness.

The question is: what else is going to really really work against cancer? No one would be happier than me if we could indeed avoid the need for WILT. But I simply claim that it is irresponsible to rely on something easier working.

Cheers, Aubrey