Telomeric Theory - Related Research - Genes & Aging
excelife at earthlink.net
Sat Oct 3 04:04:03 EST 1998
In article <3615360a.151372458 at nntp.ix.netcom.com>, ufotruth at ix.netcom.com
>But I am wondering about something. According to what I have read
>cells in-vitro start to "age" as they divide many times before they
>even reach senescence. More specifically I have read in the book "How
>and why we age" by Leonard Hayflick that eventually, after a cell has
>divided many times, it starts to divide less quickly, looks "older",
>functions differently, and changes in other ways. In your post you
>mostly talked about age related genetic expression in cells that have
>turned senescent. But what about cells that have divided many times,
>and have grown "old" but are not yet senescent? Are age related genetic
>changes being expressed in them?
The typical Hayflick progression of cellular aging comprises a period of
rapid proliferation until cumulative population doubling level 22 to 24,
followed by a phase of slow growth and the final cessation of cell division
at 32 to 34 population doublings,(this varies somewhat depending on the type
of cell). This coincides with Dr. E.H. Blackburns' study, (Proc Natl Acad
Sci U S A 1998 May 12;95(10):5607-5610), wherein she says "Telomeric repeats
are lost rapidly (at a rate of >1 kilobase per year) from the (cells) of
young children, followed by an apparent plateau between age 4 and young
adulthood, and by gradual attrition later in life."
This is important to recognize when talking about age related genetic
expression. The most dramatic change in gene expression occurs in the first
phase of rapid growth when the cells are developing until they terminally
differentiate. While this stage is very important, especially to those
investigating the various growth factors, it is not of such great importance
The second most dramatic changes in genetic expression occurs at the time the
cell enters senescence. These have been discussed before and I won't bother
with the details here.
The changes that occur, over time, in the genes expressed or not expressed is
what your question is about. These changes have been noted in "older cells"
in most studies I was able to find. These would, for the most part, coincide
with cells in the last stages of approx 32 population doublings.
I would argue that many of theses changes noted are the result of either
senescence in cases like the slowing of population doublings or cellular loss
due to apoptosis of cells reaching senescence. Most of the research into
these observations did not control for senescence. It is likely, therefore,
that many of the results achieved were a function of the lost functioning
capacity of some of the cells due to senescence. Actual cellular mass loss
would result in similar observations of diminished functioning but this is
far less common.
A striking example of these differences can be seen in the study, (Jacobsson
G,, et.al., Mech Ageing Dev 1998 Mar 16;101(1-2):33-41, "Decreased mRNA
levels for exocytotic proteins in the pituitary of aged rats." On the one
hand "part of the decrease in the expression of mRNA in the intermediate lobe
can be explained by a decreased number of cells per unit area." Whereas "The
decline in anterior pituitary hormone secretion reported in aged rats appears
to be paralleled by a down-regulation in mRNA levels for several proteins
involved in the molecular regulation." It is likely, since the study was on
aged rats, that the observed silencing of some of the genes for these
proteins was the result of senescence in some of the cells involved, although
that was not specifically addressed in the study.
Still, studies may show different genetic expression between young and old
cells in the absence of the senescent state. (Although my brief Medline
search couldn't come up with any, that is more a lack of knowing where to
look rather than a lack of studies.) This seems to be particularly true of
some of the enzymes and hormones. The production of various hormones are up
regulated on an age dependant basis and the sudden onset of menopause suggest
there is also an age related down regulation.
If anyone in the group has references on studies of this processes,
particularly any that might have controlled for senescence, I would
appreciate the references to increase my own knowledge.
>Basically, I am curious as to whether telomere shortening causes
>changes in cells BEFORE they even reach the point of senescence. You
>see from what I have read posted by some individuals on this news
>group, and this might be totally wrong, there is no evidence that an
>accumulation of senescent cells builds up in individuals as they age.
>If this is true then the telomeric theory of aging cannot be valid if
>it only causes problems for cells that have turned senescent.
The main reasons there is a lack of evidence for senescent cellular
accumulation in the elderly is 1) it hasn't been looked for and 2) that up
until recently it was extremely difficult to distinguish between senescent
and non-senescent cells. It was in 1995 that Dimri GP, et.al. in (Proc Natl
Acad Sci U S A 1995 Sep 26;92(20):9363-7, "A biomarker that identifies
senescent human cells in culture and in aging skin in vivo.), that they found
a means of identifying senescent cells, and determined that there was
"evidence that senescent cells may exist and accumulate with age in vivo."
The arguments against the accumulation of senescent cells in the aged are
based on a lack of knowledge and research to prove this accumulation. There
is little or no evidence, to my knowledge, suggesting that they do not
accumulate with age.
>But if telomere shortening can effect cells that have not even reached
>the point of senescence, then whether or not there is an accumulation
>of senescent cells in older individuals it does not weaken the
>telomeric theory of aging because telomere loss could be causing aging
>in NON senescent cells.
Transcriptional silencing of genes, ie;blocking a gene from being expressed,
and conversely un-silencing of genes is the mechanism by which genes are
differentially expressed. This is true for different types of cells, in
individual cells and in cell lines over age. The telomeres have been shown
to be involved in some portions of these processes. It is yet to be
determined if they are a major or a bit player and the research is
>Do you know if there have been any experiments on older individuals
>tissues to see if there is an accumulation of senescent cells?
>Personally, in my opinion, it seems very possible that older
>individuals could accumulate at least some senescent cells in their
>tissues which could cause other cells in the same tissues problems.
>But, I do not personally have any verification of this possibility.
The study cited above and Dr. Effros' work on T cells in the human immune
system come immediately to mind. There is undoubtedly other research that
also shows this accumulation but most of the work dealing with senescence is
on the cellular and molecular basis. Most Universities have separate
Departments for bio-chemical research and population studies and they seldom
co-ordinate their studies. Bureaucracy at work!
Thomas Mahoney, Pres.
Lifeline Laboratories, Inc.
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