Aubrey's "survival of the slowest" hypothesis

Aubrey de Grey ag24 at
Wed Apr 25 16:39:33 EST 2001

Iuval Clejan wrote:

> what do you think of Wallace's PNAS 98 (Feb 2001) paper about the Sod2
> (+/-) mice? I have only had time to read the abstract and conclusions,
> but it looks like he makes a case for even 1 mito having sufficiently
> defective membrane as likely to cause apoptosis before being
> phagocytized by a lysosome. Seems like an inefficient strategy. Perhaps
> it depends on the type of cell: if in a proliferating cell then maybe
> apoptosis is more efficient, while if in a non proliferating cell
> lysosomal ingestion is more efficient.

For others: The reference is Kokoszka et al, Proc Natl Acad Sci USA 98:
2278-3383.  It reports a very interesting biphasic pattern of changes
in various parameters of liver oxidative stress (i.e. the parameters
move in one direction between young and middle-aged mice and in the
other direction between middle-aged and old).

It's not clear how many mitochondria need to undergo the permeability
transition in order to tip a cell into apoptosis.  I don't know what
you're interpreting as that number being one.  However, you're quite
right in your suggestion that apoptosis is a smaller price to pay in
a tissue that can easily replace the lost cells than in one whose
regenerative capacity is little or none.  The whole idea of using the
liver to find things out about aging is extremely dodgy, because not
only is it very good at regeneration, but also it's a detoxification
organ so it's going to show changes due to aging of the rest of the
body which can be misinterpreted as intrinsic.  (Many people realise
this - the problem is that hepatocytes happen to be very easy to work
with....)  So Kokoszka et al's closing conclusion (that mitochondrial
oxidative damage causes apoptosis causes aging) may be true to the
extent that it happens in the brain or heart or muscle etc, but their
data, restricted to the liver, don't constitute particularly strong
evidence for that conclusion.

Aubrey de Grey

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