[ExI] reverse aging

[The Avantguardian]

----- Original Message ----
> From: John Grigg <possiblepaths2050 at gmail.com>
> To: ExI chat list <extropy-chat at lists.extropy.org>
> Sent: Tue, November 30, 2010 5:22:24 PM
> Subject: Re: [ExI] reverse aging
> 
> Stuart, and so was this simply a first step toward rejuvenating
> normally aged mice? 

Not really although the study is not entirely without merit with regard to 
rejuvenation. There are problems with this approach. First of all, these mice 
were genetically engineered from before birth to not make any telomerase unless 
they were given hydroxytestosterone. So their telomerase gene was able to be 
switched on or off like a chemical switch. Therefore what you are really 
asking is whether reversing abnormal aging in engineered mice has any relevance 
to reversing normal aging in normal mice. The answer is some but not much. Let 
me explain.

Telomeres are the DNA at the tips of linear chromosomes. They exist specifically 
as a buffer of "extra" DNA because each time a linear chromosome replicates, it 
gets a little shorter. This is because the enzyme that copies DNA, called DNA 
polymerase, can only move in one direction and can only copy the DNA in front of 
it and not behind it. This is called "the end replication problem" and it 
suffered by all organisms except for bacteria whose circular chromosomes make 
them immune because circles do not have ends.

Now for some time a leading theory of aging has been that the gradual 
accumulation of DNA damage causes aging much like gradual accumulation of errors 
on your hard drive might lead to your operating system files becoming 
corrupt. There are several types of DNA damage that can happen and the body has 
evolved a series of defenses against said damage. One of the worst types of DNA 
damage are double-stranded breaks in the DNA. They are exceptionally bad because 
normally repair enzymes use the undamaged strand to act as a template for repair 
of the damaged strand such that each strand acts as a backup copy of the other.

When both strands are broken however, which can happen when you are exposed to 
x-rays and other ionizing radiation for example, the repair enzymes mate the 
broken ends together the best they can with random nucleotides. If the double 
stranded break happens inside of a coded gene, that gene is now either useless 
gibberish or a dangerous mutation. Because of this the cell responds to double 
stranded breaks in its DNA by shutting off the cells ability to replicate 
itself.

So what does all this have to do with telomeres and aging? Well if you are 
particularly astute, you may ask how the cell can distinguish between the ends 
of its own chromosomes and double-stranded breaks in its DNA? The answer is that 
telomeres, by virtue of their DNA sequence, bind special protein complexes that 
enable them to fold over themselves such that they bury their exposed ends 
inside a structure called the telomeric loop in a process called capping. Now 
because the telomeric loop is a literal loop of DNA, the structure cannot form 
unless the telomeres are long enough to have enough slack to allow the structure 
to form. This means that if the telomeres are too short then the telomeric loop 
cannot form and the cell is *unable* to distinguish between the ends of its own 
chromosomes and a double-stranded break in its DNA. So it reponds to both the 
same way by shutting down the cell's ability to replicate itself. This is called 
cellular senescence.

Cellular senescence is thought to contribute to aging by preventing the body 
from replacing cells when they die or wear out. But when a damaged cell manages 
to bypass cellular sensecence and tries to replicate itself despite being 
damaged, the cell will activate another program to try and commit cellular 
suicide called apoptosis. If apoptosis doesn't work, the cell is now a full 
blown turmor. So the cold hard truth about aging is that we are stuck between a 
rock and a hard place. In a certain sense, we get old in order to prevent cancer 
and if we get cancer, we don't survive long enough to get old.

So where is the silver lining to the Nature study? It is that it fully supports 
the theory that DNA damage leads to aging and that repairing that damage does 
not just halt the aging process but actually reverses it. The caveat is that you 
can't just repair the telomeres, you have to repair *all* of it, otherwise you 
get an immortal horde of rogue replicating cells known as cancer.  


> And do you think within 10-15 years we could be
> at the point where humans are being restored, despite the major
> differences between humans and mice?

Not with the way the system is currently set up. If someone figured out how to 
reverse the aging process while dodging cancer today, it would take at least 
that long just to get FDA approval.