time a cell divides, the protective "caps" at the tip
of chromosomes (red and green dots) erode a little bit
further. As telomeres wear down, their DNA undergoes
massive changes in the way it is packaged. These changes
likely trigger what we call "aging".
a study published in the Oct. 3, 2010, issue of Nature
Structural and Molecular Biology, a team led by
Jan Karlseder, Ph.D., at the Salk Institute for Biological
Studies reports that as cells count down to senescence
and telomeres wear down, their DNA undergoes massive
changes in the way it is packaged. These changes likely
trigger what we call "aging".
to this study we knew that telomeres get shorter and shorter
as a cell divides and that when they reach a critical
length, cells stop dividing or die," said Karlseder, an
associate professor in the Molecular and Cell Biology
Laboratory. "Something must translate the local signal
at chromosome ends into a huge signal felt throughout
the nucleus. But there was a big gap in between."
and postdoctoral fellow Roddy O'Sullivan, Ph.D., began
to close the gap by comparing levels of proteins called
histones in young cells --cells that had divided 30 times
-- ”with "late middle-aged" cells, which had divided 75
times and were on the downward slide to senescence, which
occurs at 85 divisions. Histone proteins bind linear DNA
strands and compress them into nuclear complexes, collectively
referred to as chromatin.
and O'Sullivan found that aging cells simply made less
histone protein than do young cells. "We were surprised
to find that histone levels decreased as cells aged,"
said O'Sullivan, the study's first author. "These proteins
are required throughout the genome, and therefore any
event that disrupts this production line affects the stability
of the entire genome."
team then undertook exhaustive "time-lapse" comparisons
of histones in young versus aging cells and confirmed
that marked differences in the abundance and variety of
histones were evident at every step as cells moved through
calls the "default" histone pattern displayed by young
cells "happy, healthy chromatin." By contrast, he says,
aging cells appear to undergo stress as they duplicate
their chromosomes in preparation for cell division and
have difficulty restoring a "healthy" chromatin pattern
once division is complete.
of histone patterns in cells taken from human subjects—a
9- versus a 92-year-old—dramatically mirrored histone
trends seen in cell lines. "These key experiments suggest
that what we observe in cultured cells in a laboratory
setting actually occurs and is relevant to aging in a
population," says Karlseder.
initiation of diseases associated with aging, such as
cancer, is largely attributed to DNA, or genetic, damage.
But this study suggests that aging itself is infinitely
complex: that progressive telomere shortening hastens
chromosomal aging by changing the way genes entwine with
histones, so-called "epigenetic" changes. How DNA interacts
with histones has enormous impact on whether genes are
expressed -- hence the current intense interest in the
relationship of the epigenomic landscape to disease states.
experiments in which the team cosmetically enhanced aging
cells confirmed that signals emitted by eroding telomeres
drove epigenetic changes. When aging cells were engineered
to express telomerase, the enzyme that restores and extends
stubby telomeres, those rejuvenated cells showed histone
levels reminiscent of "happy, healthy chromatin," and
a partial return to a youthful chromatin profile.
you sink your savings into schemes to elongate your telomeres,
beware. "The flip side of elongating telomeres is that
you enable cells to grow for much longer periods and can
generate what are called "immortal" cells," says Karlseder.
"That takes you one step closer to cancer cell development."
to now, the Karlseder lab has mostly focused on interactions
between telomeres and DNA repair mechanisms. This paper
now pushes them into the field of epigenetics. "We will
continue to examine epigenetic changes in cells at different
ages," says Karlseder. "We now want to determine if histone
changes follow a linear process or whether they kick in
as we age."
contributing to this work were Stuart Schreiber, Ph.D.,
of the Broad Institute of Harvard and MIT and Howard Hughes
Medical Institute and his postdoctoral fellow Stefan Kubicek,
study was funded by the National Institutes of Health,
the George E. Hewitt Foundation for Medical Research,
and the Ernst Schering Research Foundation and the European
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