Must an AGING PROCESS be universal?

Andrew K. Groves grovesa at starbase1.caltech.edu
Sun Apr 2 03:06:30 EST 1995

In article <Pine.SOL.3.91.950401211906.17841A-100000 at corona>, Patrick
O'Neil <patrick at corona> wrote:

>   The DNA and proteins that first made me no longer exist, as they were 
> the precise strands of DNA and extant proteins within the zygote that led 
> to me.  Those original cells and their contents have long ceased to exist 
> leaving me with many imperfect copies of that first progenitor.  I have 
> cells dying all the time, some of which are replaced, many that are not, 
> none of which are immortal.  Even stem cells cannot be said to be, in and 
> of themselves, immortal (I really hate that word...NOTHING can be 
> immortal because even matter has a finite existence).  The stem cells 
> (plural) that lead to the blood presently coursing through my veins need 
> by no means to still exist tomorrow.  They have divided into other stem 
> cell copies, some of which die...perhaps including those that carried the 
> original parental DNA.  These cells have led to differentiated cells, 
> which die even as some of the stem cells die.  What PARTICULAR cell in 
> anyone's body lives indefinitely?  Tag any stem cell, perhaps with a 
> fluorescent tag or radioactive P, C, or H and then tell us whether THAT 
> PARTICULAR cell remains for 70 or 80 years, or even a significant 
> fraction thereof.  I do not believe you would ever discover such a cell.  
> Stem cells do not have to be immortal, only constantly replicated.  The 
> progenitors to generation A stem cells need not remain to be the 
> progenitors of generation F.  The original, parental DNA from any stem 
> cell gets diluted out after only a handful of cellular generations, and 
> can even be entirely replaced by mismatch repair, excision repair, 
> recombination, and cellular death.  The strands aren't the energizer bunny.

We are dealing with a problem of definition here. Dr. Bogler and myself
are using a set of precise definitions (which I will outline below) that
are used by biologists working on the problems of cell division. You are
taking exception to Oliver's comments because you are using (and
disliking) the word "immortal" in a different way to us. I'll illustrate
what we are talking about by means of a set of simple experiments that
have been performed time and again in labs all over the world.I apologise
if this is all old news to you, but I feel we need to make clear our
definitions if we are to avoid arguing at cross-purposes.

If you take a population of embryonic rat fibroblasts (a loosely defined
mesenchymal cell population obtained by dissociating an embryonic rat
carcass) and grow them in a culture dish, you will notice that the cells
divide and rapidly fill up the area on the dish. At this point, they will
stop dividing. They are said to be QUIESCENT. If you dissociate the cells
on the dish, and replate them at a lower density, the cells will start
dividing again. You can repeat this process between four and six times (by
which time each of your founder cells will have divided probably between
20 and 30 times). At this point, the cells once more stop dividing, and
become noticeably flattened. They cannot now be induced to divide any
more. They are said now to be SENESCENT. Senescent cells do not die - they
just sit there and carry on metabolising but cannot divide any further. We
would interpret this phenomenon by saying that the cells we isolated from
the rat embryos have a finite limit to the number of divisions they can
undergo. This will tend to be roughly the same number in every experiment
you perform.

It is possible to carry out manipulations whilst these cells are still
dividing that will override their limit to cell division. This can be done
by, for example, introducing  certain oncogenes such as v-myc, or the SV40
large T antigen. The cells will now continue to divide in culture
indefinitely and will not respect their normal limited number of
divisions. We call these cells IMMORTAL, in that they can be propagated
indefinitely in culture, and the oncogenes that cause these effects
IMMORTALISING ONCOGENES. Note that this is a narrow but precise definition
of the word immortal used by biologists.

Immortal cells are not 'cancerous'. If you inject immortalised fibroblasts
into anmals, they will not form tumours. In order to become tumourigenic,
or what we refer to as TRANSFORMED, other cellular changes have to occur,
or need to be artificially introduced by, for example transforming
oncogenes, such as the activated ras oncogene.

My point here is that biologists tend to define immortal cells NOT as
cells that 'live forever', but as cells that have no intrinsic limit to
the number of divisions they can undergo. This is in stark contrast to
most normal cells, which appear to have a pre-programmed number of cell
divisions. Stem cells do not appear have a limit to the number of
divisions they can undergo. 

I hope this goes some way to clarifying what we mean.

Andy Groves
Division of Biology, 216-76
California Institute of Technology

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