Protein inactivation and aging
rbradbur at hardy.u.washington.edu
Fri Jun 4 15:38:58 EST 1993
In article <1umobnINN65g at news.u.washington.edu> sjohn at u.washington.edu (John Saario) writes:
>Cell division can be correlated with youth, of course, since developing
>organisms must increase cell number and are "young" by definition. Does
>this necessarily mean that if cells never stopped dividing we would never
>age or die and that this is the answer to stop the process of ageing? It
>seems a likely point to start research but I don't think that the
>restriction on the number of times a cell may divide is limiting life span
>in our society.
There are several problems with cell-division forever.
1) Eventually you would weight more than the planet.
2) You would require a huge energy input (as well as C+H+O+N...)
3) Cell replication is not perfect and errors would accumulate.
It seems clear that telomere shortening plays a key role in the aging
process primates. It probably shows up as decreased cell replication
and/or cancer from misrepair of shortened chromosomes. The real
question is it simply a side-effect of turning off telomerase at
some point in development or is it a "fail-safe" mechanism which
normally acts to "disable" cells which have divided a certain
number of times and have accumulated a number of DNA mutations
due to DNA polymerase errors. If a computer scientist were
to design a biological system for extended lifespan he might
do some of the things nature has done but he would probably
add some more reliability & redundancy, e.g.
1) Make DNA polymerase more accurate (although slower replicating)
and compensate by having more origins of replication.
2) Keep telomerase on at sufficient levels to maintain telomere length.
3) Move more of the mitochondrial genome into the nucleus where it
would be more protected from oxidative damage.
4) Have a protein recycling system which kept significantly ahead
of damage accumulation (requires increased energy input).
>I recently heard a seminar which compared the amount of certain inactivated
>metabolic enzymes with age of donor of tissue sample. As much as 60% of the
>protein appeared to be inactive by comparision of Western and activities in
>older individuals. Inactivation was postulated to be by some sort of peroxide
>modification and accumulation of inactive protein due to a decrease in amount
>of a scavenger protein. What is the current state of this research?
Clearly oxidative damage to proteins (as well as other modifications)
plays an important role in protein inactivation and decreased functioning
of organisms. This may be one of the aging factors which is offset
by calorie/protein/amino-acid restriction. The tradeoff is that by
increasing protein recycling you increase your energy consumption over
"minimal" levels which will lead to increased O2 consumption leading
eventually to higher levels of DNA damage... catch-22.
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