From: Brian Atkins (brian@posthuman.com)
Date: Sat Dec 27 1997 - 17:38:00 MST
--
The future has arrived; it's just not evenly distributed.
-William Gibson
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HEADLINE: Cell's mortal coils hold key to ageing
Scientists are beginning to understand how cells die, reports Nigel
Hawkes
SCIENTISTS in the US have discovered an ageing mechanism in yeast
cells that may one day make it possible to slow the process of human
ageing.
They have found that the yeast cells become clogged with tiny coils of the
genetic material DNA which break off from the chromosomes and
proliferate until the cell becomes overwhelmed and dies. These "mortal
coils " - to borrow from Shakespeare - appear to be responsible for the
process of cell death, at least in this kind of cell.
"It is remarkable that this mechanism of ageing in yeast cells is so simple
at the molecular level, " Professor Leonard Guarante and Dr David
Sinclair of the Massachusetts Institute of Technology write in the journal
Cell . "It is conceivable that inhibitors of this ageing process can be found
and if so, such strategies might eventually prove useful in forestalling
ageing in yeast and, perhaps, in higher organisms. "
The search for the elixir of youth is a recurrent theme of fiction, from the
story of Faust to Oscar Wilde's The Picture of Dorian Gray . The desire
for immortality has led to countless theories of ageing, but until recently
little was actually known about how deterioration in function is related to
cellular and molecular changes. However, earlier this year the MIT team
identified a gene in Werner's Syndrome, a rare disease, whose carriers
have symptoms resembling a speeded-up ageing process. They also
showed that modifying that gene in yeast speeded ageing.
>From other yeast studies they found a series of genes that appear to
determine lifespan, and found that the products of these genes moved
into the nucleolus - a structure in the nucleus of the cell - implying that
perhaps the nucleolus was the "Achilles' heel " of cells as they get older.
They found that the nucleolus eventually breaks up, preventing yeast cells
from continuing to divide. The latest work identifies what it is that causes
the nucleolus to grow larger and ultimately to fragment. This, the
scientists say, is the accumulation of the DNA rings, which they call
"extrachromosomal ribosomal DNA circles ", or ERCs. They are created
from lengths of DNA pinched off from the chromosomes as the cell
divides. They have found that the older the cell, the more ERCs it
contains. Ultimately, they become so plentiful that they gum up the
normal processes of cell division, and the cell dies.
The ERCs act as a kind of clock, Professor Guarente suggests. "Once an
ERC is formed or inherited, the period of time until a lethal number of
ERCs has accumulated may be the clock that determines the lifespan of
the cell. "
ERCs can apparently form as a result of two processes. One is damage
to DNA, which occurs all the time, and is usually efficiently repaired. The
suggestion is that the ERCs are part of the repair process but,
paradoxically, ultimately accumulate and cause cell death. But ERCs can
also be inherited, suggesting that some cells are designed to have a
built-in clock that limits their lifespan.
The implications of the research are that it may one day be possible to
inhibit ageing in cells that are analogous to the yeast cells used in the
experiments. In mammals, these are the so-called stem cells, found in
organs such as the skin, kidney, liver and blood. The scientists say: "Next
it will be important to determine whether ERCs or other circular DNAs
accumulate in stem cells of ageing mice or humans. "
=============================================
BYLINE: By Roger Highfield, Science Editor
BODY:
THERE is more than a ring of truth in Hamlet's reference to the "mortal
coil ", according to an article to be published today. An American team
reports in the journal Cell that it has found a mechanism of ageing in
yeast cells that suggests researchers may one day be able to intervene in,
and possibly slow, the ageing process in certain human cells. The work
marks the culmination of efforts by a team at the Massachusetts Institute
of Technology in Boston that has shown that an aged yeast cell is full of
small "mortal coils " called ERCs, which consist of coils of DNA. Now
the hunt is on to find the DNA circles in aged human cells. The article,
co-written by Dr David Sinclair and Prof Leonard Guarente, reveals a
mechanism of ageing that the team says is "elegant in its simplicity ".
"There is no certainty that these will be found in humans but it is certainly
a possibility, " said Prof Guarente. During the life of a yeast cell,
whenever a particular coiled piece of DNA pinches off from one of its
chromosomes, the "extrachromosomal ribosomal DNA " or ERC
replicates until the cell becomes overwhelmed and dies. Ageing begins in
a yeast cell when the first ERC forms, although that does not seem to be
at the start of its life. "They occur early in the lifespan of a mother
cell and
then accumulate by virtue of the fact that they can replicate, once formed,
" said Prof Guarente. "When that cell divides, each circle of DNA
replicates. Every time the cell doubles the number of ERCs double. "
Prof Guarente says the ERC is like a clock in the yeast cell's mortality.
"Set the clock early and the alarm rings early, " he said. The researchers
suggest that the sheer abundance of ERCs could clog up components of
the mother cells' replication machinery, leading to an inability to replicate
the DNA necessary for life. "When a cell is old, the number of ERCs is
very high, " he said. The biologists wrote: "It is conceivable that inhibitors
of this [ageing] process can be found and if so, such strategies might
eventually prove useful in forestalling ageing in yeast and, perhaps, in
higher organisms. "
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