Concluding paragraphs from "Mitotic Misregulation and Human Ageing" Science,
31 MAR 2000
This is the article widely reported recently about errors in gene expression
as we age done right here in San Diego at the Scripps Research Institute.
Looks like they've identified about 61 genes (out of 6000 that were looked
at)that change significantly from youth to middle age to old age.
Next step: explaining WHY they change. Comments?
"We suggest that an altered expression of genes involved in cell
division occurs with age. These changes result in increased rates of somatic
mutation, leading to numerical and structural chromosome aberrations and
mutations that manifest themselves as an aging phenotype. Previous studies
have demonstrated an increase in aneuploidy with increased age (45), and
down-regulation of mitotic genes has been shown to lead to aneuploidy in
experimental models. For example, both a motorless mitotic
centromere-associated kinesin (MCAK) and antisense inhibition of MCAK lead
to chromosome lagging during antiphase (13). It has also been argued that
mutations in presenilin 1 and 2, which are associated with both the
interphase kinetochore and centrosome and account for most early onset
familial Alzheimer's disease, may result in chromosome pathologies (46).
Aneuploidy associated with chromosome 21 is involved in Down syndrome, a
disease characterized by some features of premature aging. Misregulation of
genes involved in cell division may be the result of an intrinsic lack of
fidelity that arises in the absence of selection in the postreproductive
stage. Alternatively, the growing loss of fidelity may result from the
cumulative effects of oxidative damage associated with metabolism, which are
slowed by caloric restriction (24). In fact, there may be multiple entry
points into this process. For example, Werner syndrome, which is
characterized by the premature appearance of aging in young adults (47),
shows an increased rate of chromosomal abnormalities caused by mutations in
a DNA helicase or exonuclease enzyme known as WRN.
Chromosome pathologies that begin to occur in dividing cells
relatively early in life (postreproductive stage) may then lead to
misregulation of key structural, signaling, and metabolic genes associated
with the aging phenotype, such as osteoporosis, Alzheimer's disease,
arthritis, and so forth. Misregulation of this sort is expected to increase
in each round of cell division. It may be propagated to other normal mitotic
(e.g., leukocytes, epithelial cells, glial cells, and so forth) and post
mitotic (e.g., neurons, muscles, and so forth) cells through changes in the
ECM and oxidized fatty acid derivatives that affect signaling pathways.
Aging, therefore, may occur gradually and in mosaic patterns, rather than as
a uniform phenomenon as in cancerous growth, which is clonal. Additional
studies are required before we can understand the aging process in complex
organisms, both in mitotic and postmitotic tissue, but the studies reported
here highlight important mechanisms that may contribute to aging and
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