Re: GLOOMY NEWS: antagonistic pleiotropy in p53

From: Robert J. Bradbury (
Date: Sun Jan 06 2002 - 11:41:25 MST

I thought I'd stamped out the improper thinking on this list
with regard to aging, but I guess there is still some meme-tweeking
to be done. ... :-)

On 5 Jan 2002, Phil Osborn wrote:

> ... discussed his findings that cancer cells were not subject to
> the Hayflick limit.

I doubt those were new findings in 1980.

> ... recall thinking, "Ah, and that's because the Hayflick limit is the
> natural brake on cancer, and why childhood cancers are so deadly."

The first conclusion is correct. The Hayflick limit, due in part,
perhaps primarily, to telomere shortening, is an an anti-cancer
program. Childhood cancers are deadly because they generally
involve really severe mutations that promote cell division.
It isn't clear whether in the cells of children the telomeres
might be longer, allowng for more replication, before one has
to perform the telomerase activation mutation(s) to continue
dividing. Many childhood cancers involve the cells of the
immune system (leukemias, etc.). I'm unaware of *any* literature
that says the telomeres of immune system cells are longer in
children than in adults. (Its not completely implausible, I'm
just unaware of any evidence.) A completely alternate explanation
could explain this -- that in children your immune system isn't
sufficiently well trained in "self"-recognition that it is
properly able to instruct cancerous cells to commit apoptosis.
Cancers in children may run amok because the opposing forces
are too naive to eliminate them.

> The reason that this kind of idea has taken so long to reach the
> forefront of research consciousness is that so many of the major
> researchers were locked into the idea that there could not be such a
> thing as genetically programmed lifespan, as most individuals never
> get very close to death from senesense anyway.

There is no such thing as a "genetically programmed lifespan".
There *is* such a thing as aging as a result of side effects
from incomplete or self-destructive programming. Antagonistic
plieotropy is self-destructive programming and it is reasonable
to consider the Hayflick limit an example of that. The program
limits cell division to limit the instantiations of cancer and
as a result may impose limits on the availability of stem cells
to perform tissue repair. It is worth noting that telomerase
is *on* in some cells in the human body and so aging may in
part be a result of a faulure to properly tune the level of
telomerase activity in various cell types.

> They pass on their genes while still young, so there's no
> evolutionary selection against aging.

This is somewhat different from antagonistic plieotropy. This
is generally called "the declining force of natural selection".
Both "antagonistic plieotropy" and "declining force of natural
selection" can result in programs that produce "aging". It has
yet to be determined the extent to which each of these operate in
various species.

I'd consider the death of salmon after swimming upstream to
mate an example of antagonistic plieotropy -- their systems
get dosed in glucocorticoids to drive them forward and in the
end this causes the failure of several organ systems. The
program is designed to allow for successful reproduction --
death is just a side effect.

> The opposing argument, as propounded by W. Donner Denkla, was that
> species require a genetic turnover in order to shift to adapt to
> changing environments. If the turnover rate is too low, the species
> becomes extinct.

I know of no evidence for this in any species. I suspect you
would have to look for environments where there are chaotic
shifts in environmental conditions. Mind you there is a related
genetic program in bacteria -- they don't change their replication
rate -- instead they change their inherent mutation rate. Some
bacteria have an "SOS response" gene set that cause their DNA
replication to get very sloppy. "Genetic turnover" doesn't do
any good unless it produces program variants more likely to survive.

| Re: an example of a population with genes for optimal replication at
| different temperatures

This looks like you are arguing for "group selection" for maintaining
an abundance of genes within a population. I've made a similar argument
on the list with regard to "novelty-seeking" or "risk-taking" behaviors
to explain migration to the United States. I also believe this situation
explains the store vs. burn calories phenotypes that produce various
body types (driven by the need to store energy reserves to survive
winters vs. being fast on your feet and a good hunter in the summer).

But ultimately rather than maintain the genes as polymorphisms within
a population it would be better to duplicate them and put them under
different regulatory control within the same individual. Then the
genetic program of the individual can be more adaptive to the environment.

> The answer I always got to this line of argument, from the LE gurus of
> the 60's & 70's was that evolution only selected via individuals

Yes, one constantly has to place an emphasis on this. There have been
some examples for "kin selection" demonstrated -- there might even
be a rare argument for "group selection" (the really smart monkey
that figures out how to sift the rice from the sand which is quickly
copied by other group members) -- but the selection pressure that
results from these is *very* weak compared to individual selection

> >>(Damien Broderick cites a recent paper indicating p53 protects
> >> against tumors in mice at the cost of speeding aging)

!##$&*#! *GO* back to the primary sources. That *isn't* what the
paper said. The paper said mice with 1 copy of a strangely mutated
p53 gene had reduced cancer and accelerated aging. Extrapolating
from this is skating on very thin ice.

> > writes in reply on Fri Jan 04 2002 - 01:27:51 MST :
> I don't think it's gloomy news. Basic population biology indicates aging
> either serves some purpose useful for the aging individual or it's really,
> really hard to fix.

(Byegones if this is misatributed).

There is no demonstration from population biology that aging itself
serves a "general" useful purpose. There is a relatively "common" belief
that to my knowledge has no scientific basis. (I.e. its urban legend).

Aging serving a useful purpose for an *individual* is "antagonistic
plieotropy" -- there does appear to be some evidence for this.

Aging is "hard" to fix in the sense that requires the evolution
of sophisticated programs and "evolution" isn't "intelligent".
It would appear however once scientists dissect out the causes
of aging that developing programs to prevent those isn't particularly
difficult. To prevent cancer one needs more error correction
and verification systems to accurately preserve the genome over
longer periods. To prevent aging due to mutations in the mitochondrial
genome one needs to complete the job nature has been doing in humans
and move the mitochondiral genes into the nucleus (away from free
radical damage) or add a program that allows the more robust DNA
repair that occurs in the nucleus to be functioning in the mitochondria
as well. Etc.

> To really fix aging, we must step outside of the box with cyborgization
> or cell line replacement (either in vivo or ex vivo via organ replacement).

No argument -- this will likely be a part of the eventual solution.

> Further, we may be able to manipulate related systems in people to
> improve quality or quantity of life in individual people.

Certainly. That is in part what extropianism is all about.


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