Why humans grow old grungily
* 14 May 2005
* From New Scientist Print Edition.
* Jon Turney
* Jon Turney is course leader for Imperial College London's MSc in
creative non-fiction writing
MY ATTIC is a sad sight, a jumble of frayed carpet offcuts, half-empty
cans of congealed paint, broken videos, dead computers and inoperative
exercise bikes. Just the thought of dragging it all to the dump tires
me out.
Something similar is happening inside my body's cells - at least
according to a new theory about why we age. The rubbish is piling up,
and while I could clear it all out, that would take a lot of effort.
So my metabolic cleaning systems are set to "don't bother", and the
result is that harmful garbage is accumulating.
Junk plays a central role in many theories of ageing. The "free
radical" theory, for example, suggests that ageing is caused by highly
reactive oxygen species that gradually turn DNA and proteins into
toxic rubbish. But now there is a new take on junk, where it comes
from, and how it causes us to get old. By analysing unusually
long-lived variants of the tiny nematode worm Caenorhabditis elegans,
David Gems and Josh McElwee of University College London's Centre for
Research on Ageing have found that free radicals are just one part of
a much bigger story.
The story begins in 1993 when Cynthia Kenyon of the University of
California, San Francisco, discovered that some strains of C. elegans
with mutations in a gene called daf-2 lived more than twice as long as
normal. This appeared to show that ageing was controlled by genes,
contradicting the widespread view that it was largely the result of
wear and tear inflicted by free radicals. Not surprisingly the results
caused a stir. Many researchers were puzzled about how genes for
ageing could evolve through natural selection.
However, similar genes were soon found in flies and mice. There is now
good evidence that flies can live longer as a result of mutations in
these genes, and early results in mice point the same way. Most
researchers now accept that flies and nematode worms possess genes
which can exert a powerful influence on lifespan, and that similar
genes could be important for humans too. But what do all those genes
actually do? This has been the big question ever since.
A few years after Kenyon's discovery, researchers at Massachusetts
General Hospital in Boston worked out what the daf-2 gene does. They
found that it specifies a cell-surface receptor that recognises a
signalling protein called IGF-1 (insulin-like growth factor 1). Like
many such receptors, daf-2 turned out to be at the apex of a powerful
signalling cascade. When IGF-1 binds to the receptor, it transmits a
message to the inside of the cell, switching on another gene, daf-16,
which Kenyon's group found could also influence longevity. It turned
out that daf-16 codes for a "suppressor" protein that binds to genes
and turns them off. Mutations in daf-2 apparently extend life by
suppressing this suppression, keeping numerous genes active that would
otherwise be switched off.
But which genes was daf-2 affecting? Kenyon's group tried to find out
using one of the latest technologies for probing gene expression:
microarrays or "gene chips" that pack huge numbers of short DNA
sequences onto a glass slide. By taking RNA molecules - the direct
transcriptions of any gene - from living cells and seeing which DNA
sequences these bind to, microarrays can tell you which genes are
active. Kenyon's idea was to compare gene expression in normal C.
elegans with that of long-lived daf-16 mutants, and two years ago she
showed that mutations in daf-16 affect more than 300 genes.
Then she looked to see if any of these genes might be linked with
longevity. Three kinds stood out. Some directed the cell to make
antibacterial enzymes, which are vital for a worm that dines on
bacteria that can also kill it. Others coded for heat-shock proteins,
which protect cells against damage from high temperatures. A third
type shielded against free radicals.
Gems and his colleagues, however, doubted that this was the full
story. Kenyon was focusing on these genes, they suggested, because
they fitted in with established theories of ageing, particularly the
free-radical theory. What about all the others? And so they did the
same experiment, but picked out the important genes using a
statistical analysis designed to eliminate any bias toward the usual
suspects (Mechanisms of Ageing and Development, vol 126, p 381).
They identified two main groups of genes that are more active in the
long-lived worms. One group codes for proteins known as chaperonins,
which are involved in helping proteins keep their shapes under stress
and include the heat-shock genes flagged in Kenyon's study. The other,
larger set covers a variety of enzymes involved in breaking down toxic
by-products of metabolism.
Most of these enzymes were already known from mammalian liver cells,
where they neutralise drugs, toxins and carcinogens. But they also
help dispose of harmful chemicals that occur naturally inside all
cells. As Gems sees it, this second battery of enzymes comprises a
general detox and maintenance system that deals with all manner of
molecular junk.
Some of this junk is generated by free radicals, but by no means all
of it. Cells are constantly breaking down and rebuilding complicated
chemicals, and as Gems puts it, "there are an infinite number of ways
for things to go wrong". So cells need huge families of
garbage-disposal enzymes to deal with all the junk they create. But
the system carries a heavy overhead. It consumes lots of energy the
organism could use elsewhere - particularly in reproduction.
And that gives natural selection something to work on. Individuals
that damp down their garbage disposal systems and use the energy for
reproduction gain a short-term competitive advantage over those that
keep on detoxing. Of course, the price they pay is ageing more rapidly
and dying younger, but on the whole natural selection couldn't care
less what happens to an organism after it has reproduced.
The end result is that evolution has favoured cells that opt out of
the detox business and allow molecular detritus to pile up. Gems and
McElwee now believe that ageing is largely due to a breakdown in
routine waste disposal and maintenance - what they call the "green
theory" of ageing. In the end, the crud piles up and poisons your cells.
Others in the field are taking notice, but are not yet convinced. "It
pushes a lot of the right buttons," says Mark Viney of the University
of Bristol, UK. But he warns that it will be laborious to test: you
would have to deactivate each gene one by one to see what effect it
has. "There are hundreds of genes," Gems admits.
And what of the prospects for using the green theory to combat the
problem of human ageing? As it is more general than, say, free-radical
theories of damage, you'd probably have to do lots of different things
to keep the junk at bay. But the hope is that one or two of the genes
involved in this system will turn out to have big effects all by
themselves. Then, perhaps, we can learn to harness their effects, and
live longer lives. Maybe I'd even find the time to clean out my attic.
>From issue 2499 of New Scientist magazine, 14 May 2005, page 44
http://www.newscientist.com/channel/being-human/mg18624991.400
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