[extropy-chat] Bene Tleilaxu and your mitochondria

[The Avantguardian]

--- Rafal Smigrodzki <rafal.smigrodzki at gmail.com>
wrote:

Here is the text (without figures) and I can
> send the pdf to
> anyone interested.
> 
> Questions and comments welcome.
> 
> Rafal 

     Sorry it took me so long to get back to you on
this but I have been swamped lately and I did want to
give it a thorough reading and digestion. First off,
congratulations for getting it published. Overall the
work was a great review on the mitochondrial/ROS
theory of aging. The review did change my mind about
some aspects of aging but not others. While I agree
with you that mitochondrial damage and failures of ETC
result in many of the problems associated with aging,
I think calling it THE mechanism and "clock" of aging
is overstatement.
     I do however believe that the role of
mitochondria in aging has been largely ignored by the
mainstream and it is definately A mechanism. That you
bring attention to this aspect of aging very
persuasively in your review is commendable. I also
understand that in our field, we are forced by the
system to so narrowly specialize. Thus if all our
research is, for example, focused on a single gene,
then we are forced, if we are to recieve funding, to
spin our gene as the most important gene in the
genome. So with these caveats in mind, here is where I
disagree with your argument.
     First of all, how do you distinguish between
pathological mitochondrial microheteroplasmy (MMH) and
normal variation due to polymorphism? It strikes me
that mitochodria and the cells that contain them
undergo overlapping and conjoined yet still distinct
selective evolutionary pressures. Since the turnover
rate of mitochondria seems to much higher than the
cells that contain them, it seems normal and natural
that some variation and competition would arise
between mitochondria in the same cell. But this
process should occur as prevalently in new borns as in
the elderly.
     To posit some magic "germline" mtDNA that the
cells try to maintain would suggest that some
mechanism of proof-reading of mt-DNA by nuclear DNA
would exist. Is there any evidence for this? Might
copies of mtDNA exist in some cryptic form in the
cellular genome perhaps functioning at the RNA level?
These are intersting questions your model raises.
        If as you say MMH is responsible for aging and
that this is the result of mistakes in mtDNA
replication, relative to some primordial germline
sequence, then it would stand to reason that the more
mitochondria an organism or cell has, the quicker it
should age. Thus elephants should age faster than mice
and atheletes (who have more mitochondria in their
myocytes) should age faster than non-athletes. Yet
neither of these corralaries is bourne out by the
facts.
     The most damaging aspect of your theory is that,
as you address in your paper, there is currently no
assay sensitive enough to detect the levels of MMH
that you say are relevant to aging. I have thought
about this too. Might I suggest that you try to use
DNA microarrays to adress this. Using Agilent
Technology's ink-jet type oligo spotters, it should be
possible to spot a custom microarray with many
hundreds of copies of overlapping 20-mer contigs that
cover the whole mitochondrial genome because it is so
small (16.5 kb). Then you just repeatedly hybridize
rho-DNA from some cells and discard it until you have
effectively "panned out" all the normal germline
mtDNA. Then all you should have left will be any
mutant mtDNA and any contamination you might have
introduced or carried over. Then you can directly
sequence what's left. Having some experimental
evidence would bolster your theory tremendously.      
     Now it generally accepted that the over-all
reason we age is the disposable soma hypothesis.
Briefly, this hypothesis suggests that the reason
organisms age is because evolutionary selective
pressures do not select for maintenance of the
organism's integrity for long beyond its breeding age.
 
     While I believe this hypothesis, my personal
study of the literature would suggest that when it
comes to animal models versus humans, some somas are
more disposable than others. While in mice, it could
be argued that ROS are the primary cause of aging,
this assertion no longer holds in humans who have
trillions more cells and live hundreds of times
longer. Of course in humans, ROS play a very important
role in aging but also in a host of other benign
cellular processes. We have far more safeguards
against this damage than mice do as well.
     For example, telomeres are irrelevant to aging in
mice but in humans they are one of these safeguards.
In human aging there are actually two forces at work
that give rise to the overall phenotype associated
with aging. These influences can be divided into two
categories, sub-phenotypes if you will. The first
phenotype is the ontological phenotype that is
associated with the Program Theories of aging. (i.e.
the theory that aging is based on some molecular clock
that ticks away your lifespan kind of like the way
they design cars these days to break down just after
the warranty expires.) For short I will coin the term
ontotype to describe this.
     The other major influence in human aging is the
pathological phenotype that I will refer to as the
pathotype. The pathotype is explainable by the so
called Error Theories of aging (i.e. ROS,
mitochondrial damage, lipofucin, etc.)
      That the field of aging is divided by these two
competing theories, when it seems to me obvious that
these two theories are not mutually exclusive and
could very well be simultaneously operating in the
phenomenon of aging is somewhat amusing.
      While I do think that mitochondrial
microheteroplamy may a role in the development of the
pathotype of aging, I disagree with your assertion
that it is the molecular clock that gives rise to the
ontotype of aging. The case that there is an ontotype
to aging is argued by the numerous gains of function
associated with aging. 
     These gains of function seem to be the result of
gene expression that deliberately ages us as a means
of mitigating the problems of shutting down the
developmental program that takes us from a single cell
to an adult organism. For example oncogenes are
silenced but still need to be called upon for wound
repair. Tumor supressor genes are upregulated,
telomeres shorten, and the majority of one's cells
undergo senescence. Even the wrinkled skin is a gain
of function. Skin cells do not stop producing elastin
and collagen but instead the cell secretes proteases
that chop it up. This is presumambly to allow for more
efficient immune surveilance of the epithelium. Indeed
most of the ontotype associated with aging seem to be
adaptations to protect against cancer. While cancer
itself might be thought of as part of the pathotype of
aging.
     Anyways I find myself having digressed from my
original intent of critiquing your article. To
summarize, I liked it and learned a lot from it (my
primary field is HIV research and I did not know that
nucleoside analog inhibitors of HIV also inhibit
mt-DNA synthesis as well). Your theory is good but has
holes best filled with actual supportive data. It is
definately a piece of the puzzle but not the solution
to the puzzle. Keep up the good work.
             

The Avantguardian 
is 
Stuart LaForge
alt email: stuart"AT"ucla.edu

"The surest sign of intelligent life in the universe is that they haven't attempted to contact us." 
-Bill Watterson

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