Re: Choose how long you live

From: Robert J. Bradbury (bradbury@aeiveos.com)
Date: Wed Jul 24 2002 - 18:40:19 MDT


Joao wrote:

> Now, if stem cells play the critical role so many argue then having DNA
> damage in stem cells as a cause of aging is quite intuitive.

Agreed -- with respect to those tissues that require stem cell
support for the processes of living life. In non-dividing "static"
tissues it isn't clear how much stem cell replenishment they can
take advantage of.

> Unfortunately, as in so many other theories of aging, this reasoning
> fails to answer some key questions: How do we know that stem cells
> aren't in turn controlled by something else? (For example, brain
> signals, as Tuck Finch argues.)

No argument -- there may be a master switch that alters genetic programs
from the preservation path to the reproductive path at sexual maturity.

But those animals who live longer may have stem cells that ignore
the prime reproductive directive (and as a result continue to dedicate
resources to maintenance and repair). More likely, IMO, they have
the genetic polymorphisms that are biased towards the most genome
preserving maintenance and repair.

> Why do humans age so slower than mice?

Because all mammals evolved from creatures much smaller than mice
and at every step of evolution where one selected for greater size
(increasing survival odds) one had to also select for genetic programs
that decreased the odds of single cells becoming cancerous.

> Why do bats age so slower than mice? (Bats and mice have roughly the
> same size and the same metabolic rates.)

You can have the same metabolic rate, but have greater or lesser defenses
against the free radicals that metabolic rate produces (or even have
metabolic machinery less likely to produce free radicals).

> Lately, I've been moving toward the DNA damage theory. Yet I'm not sure as
> to how it can work. I mean, somatic mutations don't appear to be the cause
> of aging -- take Dolly as a proof.

You can't use that as an example. In any collection of cells you will
always have some that have a less critical mutational load than others
(say all of the mutations ended up in junk DNA). I posted a reference
a few months ago citing failures in human conceptions in something like
70-80% of the cases. Pointing to the surviving case is merely pointing
at a source of genomic material that was relatively undamaged. We know
from the conception and cloning odds that relatively undamaged genomes
may be the exception rather than the norm.

> One hypothesis I've been thinking is that aging alters the chromatin
> structures and thus affects gene expression -- there are some results
> from yeast that show gene silencing due to different structures of
> the chromosomes.

Agreed, but the gene silencing approach may be one to simply reduce
the metabolic rate, reducing the production of free radicals, fitting
nicely into the nematode dauer and CR paradigms.

> As for your theory Robert, if I understand it correctly, you're talking
> about a typical accumulation of somatic mutations due to NHEJ. So, how do
> you explain Dolly and all the clones?

A decade ago I thought it was "somatic mutations" due to examples
of single base mutations in tumor supressor/promoter genes found
in cancers. That was an incomplete picture. Now I'm much more
convinced that double strand breaks are the primary culprit.
Misrepair (misjoining) chromosomes with DSB and you get cancer.
Failing to repair many DSB and you get apoptosis. The alternatives
are non-homologous end joining (NHEJ) or homologus repair (HR).
With NHEJ you have exonucleases acting (Artemis, WRN, MRE11) to
produce deletions that result in frameshift mutations in 2/3 of
the cases. With HR you have the probability of repairing using
a deleterious allele 50% of the time (i.e. gene conversion, loss
of heterozygosity). Its a constant struggle -- do you use the
NHEJ pathway that gradually corrupts the genome or do you use
the HR pathway that increases your chances of getting cancer?

This ties in nicely with the free radical theory, since many of
the DSB are probably due to oxidative DNA damage. Furthermore,
as the frameshift mutations accumulate, one will have increased
production of proteins that will not fold correctly and need to
be degraded. This increases the metabolic requirements of the
cell, increasing the activity of the mitochondria, probably leading
to a downward spiral of increased ATP production, increased
free radical production, increased genomic damage, increased
demands for more energy, etc.

You can tie it back into the stem cell situation by realizing that
many stem cells sit around for a very long time doing very little.
Over that time they may accumulate DSB forcing them into apoptosis,
or mis-repaired DSB making them increasingly less viable to perform
their "assigned" functions over time.

If there happens to be a genome that selects the optimal balance
between the NHEJ and HR pathways, then the animals with that
genome will live longer.

Robert



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