The cell kinetics of Werner's Syndrome.
The cell biology of senescence is reviewed, with
particular emphasis on models and theories derived from
work with cultured human -fibrbblas: ts. The. biochemistry-and.
cell biology of Werner's Syndrome is reviewed, and- the
relationship of this genetic disease-to the natural ageing
process is. examined... Similarities and'differenc. es between
Werner s Syndrome fibroblast cultures
'arid: those derived "
from normal individuals are given special attention.
The work presented in this thesis was undertaken to
determine whether cells derived from patients suffering
from Werner's Syndrome behaved differently in culture to
those derived from normal donors. Such a phenotype could
be used in the long term to assist current attempts to
clone the Werner'-s Syndrome gene. The cell kinetic aspects
of -the -Syndrome were studied' because an important feature
of the disease is that fibroblasts derived from Werner's
Syndrome patients are known to grow extremely poorly in
The data presented show that Werner's Syndrome
fibroblasts exhibit a severely restricted in vitro lifespan
due to a three to five fold increase in the rate at which
the cells exit irreversibly from the cell cycle and become
senescent. It is also shown that this behaviour is not due
to abnormalities in hyaluronic acid metabolism in vitro
despite the fact that elevated levels of hyaluronic acid
are diagnostic for Werner's Syndrome patients.
Finally, it is demonstrated that cultures of Werner's
Syndrome T lymphocytes do not show a reduced li fespan which
is highly suggestive that the condition is restricted to
a subset of cellular lineages. The effect of these
findings on theoretical models of cellular senescence is
discussed, as is the practical impact of this data on the
ongoing attempt to characterise the Werner's Syndrome gene.