rs1000b@yahoo.com
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 Posted: Fri Nov 14, 2008 12:28 am Post subject: Telomerase Reverse Transcriptase Delays Aging in Cancer-Resi |
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Telomerase Reverse Transcriptase Delays Aging in Cancer-Resistant
Mice.
Antonia Tomás-Loba1, 5, Ignacio Flores1, 5, Pablo J. Fernández-
Marcos2, María L. Cayuela1, 6, Antonio Maraver2, Agueda Tejera1,
Consuelo Borrás3, Ander Matheu2, Peter Klatt1, 2, Juana M. Flores4,
José Viña3, Manuel Serrano2 and Maria A. Blasco1, ,
1Telomeres and Telomerase Group, Molecular Oncology Program, Spanish
National Cancer Centre (CNIO), Madrid 28029, Spain 2Tumor Suppression
Group, Molecular Oncology Program, Spanish National Cancer Centre
(CNIO), Madrid 28029, Spain 3Department of Physiology, University of
Valencia, Valencia 46010, Spain 4Department of Animal Surgery and
Medicine, Complutense University of Madrid, Madrid 28040, Spain
Received 15 February 2008; revised 18 June 2008; accepted 15
September 2008. Published: November 13, 2008. Available online 13
November 2008.
Summary
Telomerase confers limitless proliferative potential to most human
cells through its ability to elongate telomeres, the natural ends of
chromosomes, which otherwise would undergo progressive attrition and
eventually compromise cell viability. However, the role of telomerase
in organismal aging has remained unaddressed, in part because of the
cancer-promoting activity of telomerase. To circumvent this problem,
we have constitutively expressed telomerase reverse transcriptase
(TERT), one of the components of telomerase, in mice engineered to be
cancer resistant by means of enhanced expression of the tumor
suppressors p53, p16, and p19ARF. In this context, TERT overexpression
improves the fitness of epithelial barriers, particularly the skin and
the intestine, and produces a systemic delay in aging accompanied by
extension of the median life span. These results demonstrate that
constitutive expression of Tert provides antiaging activity in the
context of a mammalian organism. |
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Thomas Carter
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| Posted: Fri Nov 14, 2008 1:51 am Post subject: Re: Telomerase Reverse Transcriptase Delays Aging in Cancer- |
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On Nov 13, 7:28 pm, "rs10...@yahoo.com" <rs10...@yahoo.com> wrote:
[quote]Telomerase Reverse Transcriptase Delays Aging in Cancer-Resistant
Mice.
Antonia Tomás-Loba1, 5, Ignacio Flores1, 5, Pablo J. Fernández-
Marcos2, María L. Cayuela1, 6, Antonio Maraver2, Agueda Tejera1,
Consuelo Borrás3, Ander Matheu2, Peter Klatt1, 2, Juana M. Flores4,
José Viña3, Manuel Serrano2 and Maria A. Blasco1, ,
1Telomeres and Telomerase Group, Molecular Oncology Program, Spanish
National Cancer Centre (CNIO), Madrid 28029, Spain 2Tumor Suppression
Group, Molecular Oncology Program, Spanish National Cancer Centre
(CNIO), Madrid 28029, Spain 3Department of Physiology, University of
Valencia, Valencia 46010, Spain 4Department of Animal Surgery and
Medicine, Complutense University of Madrid, Madrid 28040, Spain
Received 15 February 2008; revised 18 June 2008; accepted 15
September 2008. Published: November 13, 2008. Available online 13
November 2008.
Summary
Telomerase confers limitless proliferative potential to most human
cells through its ability to elongate telomeres, the natural ends of
chromosomes, which otherwise would undergo progressive attrition and
eventually compromise cell viability. However, the role of telomerase
in organismal aging has remained unaddressed, in part because of the
cancer-promoting activity of telomerase. To circumvent this problem,
we have constitutively expressed telomerase reverse transcriptase
(TERT), one of the components of telomerase, in mice engineered to be
cancer resistant by means of enhanced expression of the tumor
suppressors p53, p16, and p19ARF. In this context, TERT overexpression
improves the fitness of epithelial barriers, particularly the skin and
the intestine, and produces a systemic delay in aging accompanied by
extension of the median life span. These results demonstrate that
constitutive expression of Tert provides antiaging activity in the
context of a mammalian organism.
[/quote]
Here are some quotes from the full text. It shows mice with over
expression of tumor reduction genes and the telomerase component tert
have a 25% lower mortality, but with no extension of maximal life
span. Here are some quotes from the full text which is rather wordy.
Note that they call them TgTert.
Its in the latest copy of the journal Cell.
On the same day we see Geron has a new telomerase drug, and a murine
study showing life extension with tert over expression.
Thomas
The resulting Tert-transgenic mice with increased
tumor resistance were named Sp53/Sp16/SArf/TgTert
mice. TgTert tissues show %10-fold increase in telomerase
activity compared to wild-type tissues (Gonza´ lez-Sua´ rez et al.,
2001, 2002),
Importantly, telomapping showed that old Sp53S/Sp16/
SArf/TgTert mice had the highest average telomere length compared
with the other genotypes both in the stem cell (hair bulge)
and differentiated compartments (interfollicular epidermis) of the
skin (Figures 6C–6E and S11). Concomitant with this, old Sp53/
Sp16/SArf/TgTert mice had the lowest percentage of cells with
very short telomeres
Increased Median Life Span in Sp53/Sp16/SArf/TgTert
Mice
Given the above-described antiaging activity of telomerase, we
next addressed whether the TgTert allele had a detectable effect
on the life span of cancer-resistant Sp53 and Sp53/Sp16/SArf
mice. To this end, we obtained survival curves covering the
entire life span of Sp53/TgTert and Sp53/Sp16/SArf/TgTert
mice, compared with Sp53 and Sp53/Sp16/SArf controls; all
these mice have the same genetic background composition of
75%:25% C57BL6/DBA (see Experimental Procedures). Sp53
mice were used as a reference for normal longevity in our mouse
cohorts because they have been previously shown to have the
same longevity as wild-type mice in two independent studies
(Garcia-Cao et al., 2002; Matheu et al., 2007). Of note, we did
not observe a significant difference in the survival of Sp53
mice or Sp53/Sp16/SArf control mice, whether in a pure 100%
C57BL6 background or in a mixed 75%:25% C57BL6/DBA
background, indicating that the 25% DBA contribution does
not affect longevity in our mouse cohorts (Figure S8). Analysis
of the survival curves indicated a significant extension of median
life span of 9% and 26% by TgTert expression in the context of
cancer-resistant Sp53 and Sp53/Sp16/SArf mice, respectively
(p = 0.05; Figure 5A). To further dissociate the effects of TgTert
expression on cancer and aging, we considered separately the
life span of cancer-free mice (i.e., those mice that died without
malignant tumors; Figure S9). In this subgroup of mice, whose
life spans are determined by aging and not by cancer, the impact
of TgTert expression was even more evident, resulting in a median
life span extension of 18% and 38% in Sp53/TgTert and
Sp53/Sp16/SArf/TgTert mice, respectively, compared with the
Sp53 and Sp53/Sp16/SArf controls (Figure S9). Furthermore,
combined TgTert and Sp53/Sp16/SArf transgenes resulted in
a 40.2% extension of the median life span when compared to
single Sp53 mice (our reference for normal longevity), which
was further increased to 50% when considering cancer-free
mice (Figure S9). To estimate whether TgTert expression had
an effect on maximum longevity, we studied the group of longest-
lived mice of each genotype. First, the percentage of
mice that reached the extremely old age of 3 years is significantly
larger for Sp53/Sp16/SArf/TgTert mice than for their Sp53/Sp16/
SArf controls (42% versus 8%; Figure 5B), and this extreme old
survival is further increased when considering cancer-free mice
(up to 50%; Figure S9). Second, the mean age of the upper longevity
quartile is significantly higher in Sp53/Sp16/SArf/TgTert
mice than in their Sp53/Sp16/SArf controls (163 weeks versus
146 weeks; p < 0.01; Figure 5C). These observations indicate
that TgTert expression changes the longevity curve of mice,
significantly
extending the median life span and significantly increasing
the percentage of mice that reach extremely old
ages. In addition to its well-established telomere-maintenance
These results suggest that TgTert
expression is particularly efficient at eliminating DNA damage
associated with dysfunctional telomeres.
activation of the p16/Arf locus, which is one of the
most dramatic molecular changes associated with organismal
aging (Matheu et al., 2007; Krishnamurthy et al.,
2004; Zindy et al., 1997), was not significantly affected
by telomerase (Figure S7), thus indicating that the delayed
aging of Sp53/Sp16/SArf/TgTert mice is not due to a lower
activation of the p16/Arf locus in these mice.
Higher Serum IGF1 Levels and Decreased g-H2AX
Foci in Sp53/Sp16/SArf/TgTert Mice
tightrope test performance was significantly improved in Sp53/
Sp16/SArf/TgTert mice atR1 years of age, compared with agematched
wild-type and Sp53/Sp16/SArf controls (
Sp53/Sp16/SArf/TgTert Mice Exhibit Improved
Neuromuscular Coordination and Glucose
Tolerance Compared to Age-Matched Controls
These observations strongly implicate
telomere-maintenance as the main mechanism underlying the
antiaging activity of TERT. There are, however, nontelomeric
activities of TERT (Sarin et al., 2005; Choi et al., 2008), which
could also conceivably contribute to the antiaging phenotypes
reported here. Finally, it is worth highlighting that we have observed
an improved fitness in organs that do not express TgTert,
such as the brain or muscle (i.e., neuromuscular coordination assay),
suggesting that TgTert expression has systemic antiaging
effects. It will be of great interest to study the impact of
ubiquitous
TgTert expression on mouse fitness and longevity. |
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