From: Rafal Smigrodzki (rafal@smigrodzki.org)
Date: Fri May 16 2003 - 17:32:41 MDT
Aubrey de Grey wrote:
> Subject: Re: Removing lysosomal aggregates; obviating mitochondrial
> mutations
>
>
>
> Apologies for delayed reply -- been at the Foresight conference.
> Rafal Smigrodzki wrote:
>
>> ### So you are postulating a major chemical difference between fatty
>> streak in apoE null mutants and in aged animals. Would it also apply
>> to humans with hereditary hypercholesterolemia vs. aged humans?
>
> Major by the metric of degradability, yes. Not nearly so much to
> humans with hereditary hypercholesterolemia vs. aged humans, because
> the former still take several years to form plaques, as opposed to
> weeks for the apoE null mice.
### Do you have a hypothesis as to what this difference might be? What are
the postulated non-degradable molecular species?
-------------------------------
>
>> This is a legitimate hypothesis, but I'd need more data before I
>> would accept it.
>
> A key question is, are there any other comparably legitimate
> hypotheses?
### The dynamic equilibrium hypothesis.
---------------------------------------------------
>
>> ### Interestingly, there are some lucky seniors who even at age 80
>> do not have atherosclerosis. If indeed there was an inexorable
>> accumulation of indigestible material in most of us, how do they
>> escape it? Would you say they do not make such supposedly insoluble
>> plaque (hard to imagine, cholesterol oxidizes the same way in all
>> humans), or do they have superior lysosomal enzymes?
>
> Neither (well, not as the main factor anyway). Centenarians'
> arteries have lots of fatty deposits. The main difference is that
> their vascular smooth muscle is less prone to get inflamed and
> hyperplastic as a result of the presence of this nasty stuff: i.e.,
> they are better protected at the next step.
### I found the following: Homma S. Ishii T. Tsugane S. Hirose N. Different
effects of hypertension and hypercholesterolemia on the natural history of
aortic atherosclerosis by the stage of intimal lesions. [Journal Article]
Atherosclerosis. 128(1):85-95, 1997 Jan 3.
Apparently even at around age 79 you still find people with no intimal
lesions. How did they escape their accumulation?
---------------------------------
>
>> ### I went over Chinnery's articles (Am J Hum Gen, Lancet) and I
>> didn't find any clear statement that hyperproliferation must precede
>> COX negativity. Where do you think he says that it does?
>
> Right, that's part of the problem, his model ineluctably predicts that
> but he doesn't properly take it on board. The driving force that
> allows mutants to take over is an acceleration of mitochondrial
> replication when there are too few working mitochondria, with the
> mutant mitochondria playing no part -- effectively they are just
> accumulating (or fluctuating) detritus. But when they do accumulate,
> as a result of drift, the total mitochondrial number increases to
> compensate, keeping the number of wild type mitochondria optimal.
> This only breaks down when the mitochondrial number reaches "alpha"
> times the optimal wild-type. So we should see hyperproliferation
> before the cell loses COX activity.
### I don't understand. The mutants take over mainly as a result of
stochastic processes, with no clear mitochondrial proliferative response to
partial loss of function. There is a substantial functional reserve of
mitochondria, and the nucleus seems to maintain a constant mass of genomes
(at least in some experimental paradigms), so there is no mitochondrial
hyperproliferation until very late in the process, if at all. Since the
stochastic hypothesis makes no reference to the cause of hyperproliferation,
merely predicting the emergence of COX-negativity, it is compatible with
either hyperproliferation before COX negativity, after, or none at all, if
the cell simply decides not to upregulate mitos. These two processes are
most likely largely independent, over large range of heteroplasmy levels.
-----------------------------------
>
>> if indeed the mutated genome has a selective advantage, then cells
>> with more mt genomes would be at a higher risk of suffering a
>> mutation (this risk goes up as a simple function of the number of
>> genomes), and once a single mutation is present, such cell would
>> very quickly shift to 100% mutated genomes, as a result of selection.
>
> Right -- other things being equal. But they aren't equal (see below).
>
>> very large cells, like the ovum, and the syncytial muscle fiber, with
>> 100 000 mtDNA's, and very small or quiescent cells, like
>> chondrocytes, with only 1000 to 5000 mtDNA's, would differ in the
>> accumulation of mutations by an order of magnitude or more. Is it
>> indeed the case?
>
> Not really, because the rate of accumulation is also affected by many
> other things. The foremost is the mutation rate, which is probably
> very affected by the respiration rate -- so in fact, oocytes shouldn't
> get much mutant mtDNA because they are so quiescent. A second is the
> ability for cells to die and be replaced once they become
> COX-negative; this almost certainly happens, so it's not easy to do
> your comparison except across postmitotic, rather apoptotis-resistant
> cells. Muscle fibres are a bit strange because the mitochondria are
> not very mobile, but the COX-negativity does spread slowly along the
> fibre.
### In the CNS there are neurons with enormous differences in cellular mass,
from tiny interneurons to the giant alpha motor neurons. The giant ones do
have a very active metabolism. If indeed single deleterious mutations had a
significant replicative advantage, the large neurons would die much faster
than the interneurons, which is not the case.
Also, we know that the mutation level in single neurons in elderly adults is
in the range of 50 to 800 diverse aminoacid-changing mutations per million
bases (according to Simon and Beal), meaning that more than ninety percent
of genomes are mutated, and without doubt many of them are deleterious. This
leaves little place for a preferential amplification of low psi or otherwise
impaired mitos.
-------------------------
>
>> Chinnery was able to get simulation results consistent with
>> experimental observations even without stem mitochondria.
>
> Nope -- only to the superficial extent that he analysed his
> simulation. He found parameters that gave a realistic number of
> COX-negative cells in a lifetime, but he forgot to look at how many
> cells were highly heteroplasmic (had lots of wild-type and lots of
> mutant). There are far more of these than there are COX-negative
> cells -- but in real life, including in (eg) Brierley et al, a paper
> from Turnbull's group that he actually cites to the contrary!, we see
> many more totally or virtually homoplasmic mutant cells than highly
> heteroplasmic ones. Ah yes, as you note:
>
>> Chinnery's model indicates that the number of cells with 50% mutated
>> genomes will be actually pretty low, on the order of a few percent in
>> aged humans
>
> A few percent is actually a lot higher than the number of 100% mutant
> cells seen in real life in any tissue except the substantia nigra and
> one or two similarly stressed brain regions. There it's 10%; in the
> skeletal or cardiac muscle it's down around 0.1%.
>
### We see much higher levels of mutated genomes in the elderly cortex, as
noted above, very compatible with Chinnery's model.
Rafal
This archive was generated by hypermail 2.1.5 : Fri May 16 2003 - 14:45:20 MDT