[ExI] reverse aging

[Damien Broderick]

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