X-Message-Number: 25664
Date: Sat, 5 Feb 2005 12:21:18 -0800 (PST)
From: Doug Skrecky <>
Subject: the great divide between in-vitro & in-vivo aging

[This is a great deal of doubt about the applicability of the in-vitro
aging to its real life counterpart. For example, drastic telomere
shortening can limit the replication capacity of cells grown in a test
tube. A more limited shortening that occurs in-vivo is also associated
with proliferative defects. However there is some  evidence that it is
non-telomere driven P16 that is driving these defects, since telomeres
themselves are still too long to be a major aging driver.]

Exp Cell Res. 2004 Oct 15; 300(1):1-10
 From cells to ageing: a review of models and mechanisms of cellular
senescence and their impact on human ageing.
  Given the duration of ageing in humans, cell culture studies are a
promising approach to the study of human ageing. It is reasonable to
assume that human ageing has, at least partly, a cellular origin. The
question is how we can replicate in vitro the age-related changes that
occur in human cells in vivo. In this review, widely used models for
studying ageing in cell culture, such as Hayflick's, are interpreted in
the context of the human ageing process. The mechanisms behind cellular
senescence such as telomere disruption and DNA damage are reviewed and
their relation to human ageing debated. A system-level examination of
these mechanisms suggests that cell culture models are useful for
studying cancer and certain age-related pathologies. There is little
evidence, however, that cellular senescence is a significant factor in
human ageing or that the mechanisms responsible for in vitro cellular
senescence are a causative factor in human ageing in vivo. Therefore,
novel approaches for studying human ageing at a cellular level are
necessary and some suggestions are put forward.

Mol Cell. 2004 May 21;14(4):501-13
Telomere shortening triggers senescence of human cells through a pathway
involving ATM, p53, and p21(CIP1), but not p16(INK4a).
  Cellular senescence can be triggered by telomere shortening as well as
a variety of stresses and signaling imbalances. We used multiparameter
single-cell detection methods to investigate upstream signaling pathways
and ensuing cell cycle checkpoint responses in human fibroblasts.
Telomeric foci containing multiple DNA damage response factors were
assembled in a subset of senescent cells and signaled through ATM to p53,
upregulating p21 and causing G1 phase arrest. Inhibition of ATM
expression or activity resulted in cell cycle reentry, indicating that
stable arrest requires continuous signaling. ATR kinase appears to play a
minor role in normal cells but in the absence of ATM elicited a delayed
G2 phase arrest. These pathways do not affect expression of p16, which
was upregulated in a telomere- and DNA damage-independent manner in a
subset of cells. Distinct senescence programs can thus progress in
parallel, resulting in mosaic cultures as well as individual cells
responding to multiple signals.

[Telomerase exerts a mild anti-aging effect in transgenic mice, but
this is not mediated by telomeres themselves.]

Oncogene. 2005 Jan 31; [Epub ahead of print]
Antagonistic effects of telomerase on cancer and aging in K5-mTert
transgenic mice.
  Many degenerative diseases that occur with aging, as well as premature
aging syndromes, are characterized by presenting cells with critically
short telomeres. Telomerase reintroduction is envisioned as a putative
therapy for diseases characterized by telomere exhaustion. K5-mTert
transgenic mice overexpress telomerase in a wide spectrum of tissues.
These mice have a higher incidence of both induced and spontaneous
tumors, resulting in increased mortality during the first year of life.
Here, we show that in spite of this elevated tumor incidence and the
initial lower survival, K5-mTert mice show an extension of the maximum
lifespan from 1.5 to 3 months, depending on the transgenic line, which
represents up to a 10% increase in the mean lifespan compared to
wild-type littermates. This longer lifespan is coincidental with a lower
incidence of certain age-related degenerative diseases, mainly those
related to kidney function and germline integrity. Importantly, these
effects of telomerase overexpression cannot be attributed to dramatic
differences in telomere length in aged K5-Tert mice compared to wild-type
mice, as shown by quantitative telomeric FISH. These findings indicate
that telomerase overexpression extends the maximum lifespan of
mice.Oncogene advance online publication, 31 January 2005;
doi:10.1038/sj.onc.1208413.

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