cron-web.org

[A1CR]

A CRONie noted:

>>>>>>>>>>>>>>>>>>>>>>>>>>>

>
http://www.eurekalert.org/pub_releases/2006-10/bsj-omb092906.php#
>
> Cawthorn (2003) first linked telomere length in red
blood cells to
> all-cause mortality.
> Cawthorn, R.M., Smith, K.R., O'Brien, E., Sivatchenko,
A. and Kerber,
R.A.
> Association between telomere length in blood and
mortality in people aged
> 60 years and older. /Lancet/, 2003; *361*: 393-395.
>
> Epel et al (2005) showed that telomere length is
dynamic, and that
> telomeres can sometimes increase in length. PMID: 16298085
>
> This latest study links the prevalence of arthritis to
telomere length
> in blood.
>
> There is suggestive evidence that simply lengthening
> telomeres may be an effective anti-aging intervention. I'm
> looking forward to more experimentation which could
> validate or refute this idea.

Telomeres shorten for a reason - the reason being to
prevent cancer.

Any therapy that lengthens telomeres had better not
lengthen them in incipient cancerous cells /too/ much,
or the organisms will suffer from accelerated
senescence and tend to die of cancer.

Note that one of the seven proposed SENS interventions is: -
http://www.sens.org/just7.htm

>>>>>>>>>>>>>>>>>>>>>>>>>>>

The role of the http://en.wikipedia.org/wiki/Telomere and
its maintenance by
http://en.wikipedia.org/wiki/Telomerase that relies heavily on
http://en.wikipedia.org/wiki/TERT for the role in
http://en.wikipedia.org/wiki/Telomerase#Cancer
http://en.wikipedia.org/wiki/Telomerase#Aging and are of
note. The below
pdf-availed paper may assist in this issue: whether
telomeres may affect
cancer and aging, or are effected by aging.

Stewart SA, Weinberg RA.
Telomeres: Cancer to Human Aging.
Annu Rev Cell Dev Biol. 2006 Jul 7; [Epub ahead of print]
Nov 2006, Vol. 22:
531-557.
PMID: 16824017

The cell phenotypes of senescence and crisis operate to
circumscribe the
proliferative potential of mammalian cells, suggesting that
both are capable
of operating in vivo to suppress the formation of tumors.
The key regulators
of these phenotypes are the telomeres, which are located at
the ends of
chromosomes and operate to protect the chromosomes from
end-to-end fusions.
Telomere erosion below a certain length can trigger crisis.
The relationship
between senescence and telomere function is more complex,
however:
Cell-physiological stresses as well as dysfunction of the
complex molecular
structures at the ends of telomeric DNA can trigger
senescence. Cells can
escape senescence by inactivating the Rb and p53 tumor
suppressor proteins
and can surmount crisis by activating a telomere maintenance
mechanism. The
resulting cell immortalization is an essential component of
the tumorigenic
phenotype of human cancer cells. Here we discuss how
telomeres are monitored
and maintained and how loss of a functional telomere
influences biological
functions as diverse as aging and carcinogenesis.

... Stress-Induced Senescence

Recently reported data have highlighted a number of
conditions that can lead
to stress-induced senescence. These include low serum or
growth factor
concentrations, exposure to high levels of DNA damage,
inappropriate
conditions of growth (including those that induce the
expression of the
p16INK4A and p21Waf1 cell cycle inhibitors), and high
oxidative stress
levels (Ramirez et al. 2001, Sherr & DePinho 2000, Wei et
al. 2001, Wright &
Shay 2002, and references in all). Exposure to these various
agents or
signals results in a phenotype that is indistinguishable
from that shown by
cells that have reached the Hayflick limit and enter
replicative senescence.

... Senescence: A Tumor Suppressor Mechanism?

... Molecular proof demonstrating that senescence blocks the
growth of
neoplastic cells in vivo recently was supplied through study
of both murine
cancer models and human cancer. ...

Crisis

Cell populations that succeed in bypassing senescence
through the
inactivation of the Rb and p53 signaling pathways continue
to divide until
their telomeres become critically short (Figure 2) and no
longer protect the
chromosome ends from the cell machinery charged with the
detection and
repair of dsDNA breaks ... which is associated with (b)
widespread cell
death. ... On occasion, however, a rare clone of cells (1 in
10^7 human
cells) can emerge from a population of cells in crisis; such
cell clones are
invariably immortal. ... resulted in the progressive loss of
telomeric
repeats during successive rounds of DNA replication and
cellular division.
Eventually telomeres became critically shortened, and as
observed in crisis,
end-to-end chromosomal fusions became evident and were
followed by
widespread cell death. ... In other words, cells that
maintain longer
telomeres require more rounds of DNA replication and
cellular division
before telomeres reach a critically short length that
results in crisis. ...

CELL SENESCENCE AND HUMAN AGING

... aging is the result of the slow accumulation of damage
that leads to
cellular and eventually tissue deterioration. The second
suggests that aging
is the result of a cellular program that is governed by a
biological clock,
such as telomere length. ... when grown in culture, normal
human cells will
undergo a limited number of divisions before entering a
state of replicative
senescence in which they remain viable but are unable to
divide further ...
contributes to the phenotypes associated with aging, such as
reduced wound
healing and weakened immune systems ... dyskeratosis
congenita ... The first
form is autosomal recessive and results from mutations in
the human TERC
gene (which encodes the RNA subunit of the telomerase
holoenzyme). The
second is an X-linked autosomal dominant form of the disease
and is the
result of a mutation in the dyskerin gene, which compromises
ribosome
biosynthesis and seems also to affect assembly of the
telomerase holoenzyme,
resulting in loss of enzyme function. ... dyskeratosis
congenita patients
reveal telomere shortening and dysfunction when compared
with telomeres in
the cells of age-matched controls. Patients ... cancer
predisposition ...
symptoms increasing in severity with each succeeding
organismic generation
... these symptoms are reminiscent of aged humans ...
Nevertheless, the fact
that aspects of human aging can be phenocopied by specific
defects in the
telomere-maintenance machinery does not prove that telomere
erosion is
normally a primary causal force that drives human aging.

TELOMERASE AND CANCER

... Despite such successes in transforming rodent cells,
similar experiments
consistently failed to transform human cells to a
tumorigenic state, calling
into question the relevance of animal models to human
carcinogenesis. ... in
human systems have suggested that four to six rate-limiting
events are
required for cancer formation ... demonstrated that a normal
human cell can
be converted to a fully tumorigenic cell with a set of
introduced, defined
genetic elements, including a clone of the hTERT gene. ...
through hTERT
expression together produced a transformed human cell
capable of colony
formation in soft agar and tumor formation in
immunocompromised host mice
... aneuploidy was not a prerequisite for the tumorigenic
cell phenotype
.... five changes suffice to transform a variety of human
cell types.
Current efforts are now focused on "humanizing" the
mutations, i.e.,
utilizing mutant alleles that are commonly found in human
tumors. ...

Telomeres and Cancer: Lessons from the Mouse ... when mated
to cancer-prone
mice, the telomerase-negative animals recapitulate some of
the phenotypes
observed in human neoplasias ... they also develop
epithelial carcinomas
that are similar to the majority of human tumors ... but the
altered tumor
spectrum suggests that tumors in these animals more closely
resemble those
found in humans. The breakage-fusion-bridge cycles occurring
in these mice
following telomere collapse presumably contribute to
generalized instability
in their cells, which in turn favors the inception of the
observed tumors.
... hTERT plays a key role in DNA repair ...
telomerase-independent telomere
maintenance (ALT) ...

... WRN and BLM are ReqQ helicases ... mutations of their
encoding genes
result in progeria and cancer predisposition (Dyer &
Sinclair 1998). ...
loss of these genes in the mouse results in premature aging
phenotypes only
when mice ... The coming years are likely to ... detailed
understanding of
... how these functions become compromised in tumorigenesis
and aging.

CONCLUDING REMARKS AND FUTURE DIRECTIONS

Is aging the price we pay for remaining cancer free during
our early life?
And are telomeres and replicative senescence at the center
of this ongoing
battle? Recent advances support the role of senescence in
tumor suppression
and the loss of telomere integrity as a driving force in the
transformation
process (Braig et al. 2005, Chen et al. 2005, Collado et al.
2005; reviewed
in Maser & DePinho 2002, Michaloglou et al. 2005). If we
have learned
anything, it is that the telomere and its associated
proteins play a
critical role in genomic integrity. Importantly,
understanding how the
telomere interacts with the DNA repair machinery in normal
as well as
pathological conditions will further our general
understanding of telomere
biology. In addition, it is now clear that cell senescence
is critical for
tumor suppression, and accumulating data suggest that the
former may also
influence many of the pathologies associated with aging. The
coming years
are sure to shed much light on telomere homeostasis and, in
turn, on the
roles of the telomere in human aging.

SUMMARY POINTS

1. Normal human somatic cells possess a limited replicative
potential that
is dictated by the proper maintenance of the telomere and by
their responses
to certain cell-physiological stresses.

2. Senescence is often triggered by cell-physiological
stresses that cells
suffer in vitro and possibly in vivo.

3. Senescence functions as an important tumor suppressor
mechanism.

4. In the event that cell lineages circumvent the
proliferative block
imposed by senescence, the telomeres of these cells will
continue to
shorten, leading to crisis, in which chromosomal fusions,
genetic
instability, and widespread cell death occur.

5. Telomere homeostasis, which is essential for the normal
function of
telomeres to protect the ends of chromosomes, is dictated by
both the
configuration of telomeric DNA and the functions of
telomere-binding
proteins.

6. DNA repair enzymes associate with telomeres and play
critical roles in
telomere maintenance in still-unclear ways.

7. The two canonical tumor suppressor pathways-involving
the Rb and p53
tumor suppressor proteins-impose senescence in the event
that telomeric DNA
is disrupted in certain ways.

8. Cells can acquire replicative immortality either through
the expression
of telomerase or through the activation of the alternative
lengthening of
telomeres (ALT) pathways.

FUTURE ISSUES

1. How is senescence activated at the molecular level, and
what pathways
govern activation of the p53 and Rb tumor suppressor
pathways, which impose
a senescent growth state?

2. What are the molecular mechanisms that enable the ALT
pathway to
maintain telomeres, and will this pathway constitute an
important escape
pathway for cells subject to antitelomerase therapies?

3. Do telomere shortening and cell senescence contribute to
human aging?

4. What is the precise relationship between DNA repair and
telomere
homeostasis?